H Hematology

Anya McLaren, Ines Meojak and Rosanne St. Bernard, chapter editors
Doreen Ezeife and Nigel Tan, associate editors
Steven Wong, EBM editor
Dr. Janey Hsiao, staff editor

Basics of Hematology .................... 2 Disorders of Secondary Hemostasis ....... 29

Complete Blood Count Hemophilia A (Factor VIII Deficiency)
Blood Film Interpretation Hemophilia B (Factor IX Deficiency)
Bone Marrow Aspiration and Biopsy Factor XI Deficiency
Liver Disease
Common Presenting Problems ............. 5 Vitamin K Deficiency
Anemia Disseminated Intravascular Coagulation (DIC)
Polycythemia
Thrombocytopenia Venous Thrombosis .................... 31
Thrombocytosis Approach to Treatment of Venous Thrombosis
Pancytopenia Hypercoagulable Disorders............... 33
Neutrophilia
Neutropenia Hematologic Malignancies and
Lymphocytosis Related Disorders ...................... 34
Lymphocytopenia
Eosinophilia Myeloid Malignancies ................... 35
Agranulocytosis Acute Myeloid Leukemia (AML)
Leukemoid Reactions Myelodysplastic Syndromes (MDS)

Approach to Lymphadenopathy ........... 10 Myeloproliferative Neoplasms ............ 37

Polycythemia Rubra Vera (PRV)
Approach to Splenomegaly . . . . . . . . . . . . . . 11 Chronic Myeloid Leukemia (CML)
Idiopathic Myelofibrosis (IMF)
Microcytic Anemia ...................... 12 Essential Thrombocythemia (ET)
Iron Metabolism
Iron Deficiency Anemia Lymphoid Malignancies ................. 41
Anemia of Chronic Disease Acute Lymphoblastic Leukemia (ALL)
Lead Poisoning
Sideroblastic Anemia Lymphomas •••••••••••••••.••••••.•••• 42
Thalassemia Hodgkin's Lymphoma
Non-Hodgkin's Lymphoma (NHL)
Normocytic Anemia ..................... 16
Aplastic Anemia Malignant Clonal Proliferations of
Mature B Cells ......................... 46
Hemolytic Anemia (HA). . . . . . . . . . . . . . . . . . 17 Chronic Lymphocytic Leukemia (CLL)
Thalassemia Multiple Myeloma (MM)
Beta-Thalassemia Minor (Thalassemia Trait) Monoclonal Gammopathy of Unknown
Beta-Thalassemia Major Significance (MGUS)
Alpha -Thalassemia Waldenstrom's Macroglobulinemia
Sickle Cell Disease
Autoimmune Hemolytic Anemia (AIHA) Complications of Hematologic Malignancies.. 49
Microangiopathic Hemolytic Anemia (MAHA) Hyperviscosity Syndrome
Hereditary Spherocytosis Tumour Lysis Syndrome
Hereditary Elliptocytosis
Blood Products and Transfusions .......... 50
G6PD Deficiency
Blood Products
Macrocytic Anemia ..................... 22 Red Blood Cells
Vitamin B12 Deficiency Platelets
Folate Deficiency Coagulation Factors
Acute Blood Transfusion Reactions
Hemostasis ............................ 24 Delayed Blood Transfusion Reactions
Three Phases of Hemostasis
Common Medications .................. 54
Disorders of Primary Hemostasis .......... 26 Antiplatelet Therapy
Immune Thrombocytopenic Purpura (ITP) Anticoagulant Therapy
Heparin-Induced Thrombocytopenia (Hin Chemotherapeutic Agents
Thrombotic Thrombocytopenic Purpura (TTP)
and Hemolytic Uremic Syndrome (HUS) Landmark Hematology Trials ............. 57
Von Willebrand's Disease (vWD)
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Toronto Notes 2011 Hematology H

H2 HematolO!JY Basics ofHematolO!JY 1'oroDio 2011

Basics of Hematology

\•,
E..,cllracyla- Cllrriaa oxygen fram
ID pariphnl1iauas
Rn.-.,..- inrnabn arylhrucylll
llallnlpbii-1JW!uhx:ylll in!BP in
innlt8 maW! cell i1 acute
inllammllliun
Wlvolved in I'IIIP-ID
p1111111i1111 [11pacillly halmirlhs) IRI
llllqic l'lllp-
IBIIIpllil- QIWIUiocy!B many invalvlld
il alargy and p1111silic infactian
Lyn....,..- in18P cell il adlpliva
inmunily
MIIIICYIII- involved in imate
inmunily; cen dilfnntiBIB iniD
Ill' dlnlritic cell

Pldlld - mlliltor Ill priiTllll'f

hamDStasis
PIUIII-Iiquid CDIIIponant of bklod
CGntliq W111r. progill, COIII\IIItion
far;Un and
Erythrocylll B11cphil E011inop/lil NBUinJphil Lymphoeybl MonocyiB
111111-!QMent ta pil11111 milua
clot1ing flclanl end tbinogan L__ GIWiulocyiB __j L J
L--1--l.aJkocylll _ __JI

Figure 1. Ha1118blpoiaia

• over 1011 blood cells are produced dally

• sl.te8 ofbematopolesl8 in adults: pelvis, sternum, vertebral bodies
• lifespan of mature blood cells
• erythrocytes (120 days); neutrophils (-1 day); platelets (10 days); lymphocytes (varies-
memory cells persist for ytma)
• role oflymphoid OJB8115
• spleen: part of reticuloendothelial system: removes aged RBCs, removes antibody-coated
bacteria/cells, site ofantibody production
• thymus: site afT-cell maturation, involutes with age
• lymph nodes: sl.te8 of B and T cell activation (adaptive immune respoDlle)

Complete Blood Count

1 _______________,
Tabla1. Ca111ma1 T...s Faund a1 CBC
... _._ Namal Vllual•
C..lcll U. rl RDW Had blaCid callIllC) r:oull: The oorrk of RBCs per volume of bload 4.2-4.9x 10'/nJmS
To lhBIIIiologills Ill
mic:rucy!Gsis:
llellotllallil IIIII Almllll af axygan-CMYing protein in the bklod 13tHBOW).(13-181VdL} (mala)
Fe dllliciel'll:'f- incnued ROW (12·161V'dL) (female)
(..isuc:y!DIIii) l'lmllage of B giva! \dune of wlu* blood 45%-62% (lillie)
ThaiiiiBmil minor- normal ROW by pacbd RBC&
11- carpuctlar...... (IICV} Maaall'lllllll1f: li size of RBCII

. 11- carpuctlar IIICIQ Almllll of axygan-CIIJYing 11:1 insidll RBCs 27-321¢1j

..... 1 II- carpuctlar COIWib-li Ill in&illl RBCs 32W&%
._---------------,
Abllolubl Nautrgplil CGunt (ANC) = RIC dfllrllullln wiiB (RDWJ Maaall'lllllll1f: li Vllilnce il RBC aiza 11.!Rr15.11%
WBC cDII'II x (VMNs + 'lllllnds)
Willa MDCIII caiiWBC) I:IUt n. IIID afWBCs perw!UIIII of blood 4.3-10.8x
e-n. orr--+ Me <D.s x1oa,.t = WIC dlllndll Includes nadnlphia, 801irq:bla, btaophls,
FmRILE NBITROPENIA
lymlk'YtJs and mcnac:ytBs
n. oonilw of piB!alll$ per Vlime of blood
Maaall'lllllll1f: li pllltlllat size
IITIIlBiure RBCs 1lllt canlllin oo ru:leus but have Normally malre..., 1'1af ID1lll
rasiUIRNA RBC cal.llt
'IbroDlo Nota 2011 Hematology H3

Appraac:h for Interpreting CBC

1. consider values in the conU:xt of individual's ba.seline
• up to 5% of population without disease may have valua outside "normal" range
• an individual may displ.o.y a subatantial change from their baseline without viol.o.ting
•normat" reference range
2. 1.8 one cell line atfected or are several?
• If all lines are low: consider pancytopenia (see Pancytopenia, H7)
• if RBCs and platelets are low: consider microangiopathic hemolytic anemia (MAHA)
(see H21)
• if single cell line affected: see corresponding section in Common Presenting Problems, HS

Blood Film Interpretation

----------------------------
RED BLOOD CELLS

Size
• microcytic (MCV<80), normocytic (MCV=80-100), macrocytic (MCV>100)
• anisocytosis: RBCs with increased varlabiJity in size (increased RDW)
• lron defi.dency anemia, thalassemia major, myelo1ibrosls

Colour
• hypochromic: increase in size of central pallor (normal =less than 1/3 ofRBC dlameter)
• lron deftdency anemia, anemia of chronic disease, hemolytic anemias, siderobhstic anemia
• polychromasia: increased reticulocytes (pinkish-blue cells)
• increased RBC production by the marrow

Shape (see Table 2 and Figure 2)

• polldlocytosl8: Increased proportion ofRBCs of abnormal shape
• lron deftdency anemia, myelotibrosl8

Tillie Z. Comman Erylhracyta Sill..-

Tllriap cal NuclllllllldiiBC

Dilcaqta BictiiCIIIII! disc NonnaiRBC
SJD!rical RBC (ctJ.eto lela of 111111111r'n) Hsnditary spharac'jiD&is, inmma hiiiiDiytic
anemia
Dvll-ahlpad, aklngated RBCil HI!II!Citary eliptll:ytDsis, megalolllastic
• BliptDc:yta&: 1ha RBC lq .US is :?:2x the length anemia, myelofibrosis. m.deliciell:y, t.IJS Heinz bDiias Spur eel
of thnhllt oil
• O'o'lllcytes: 1118 RBC ICIIll axis is <ZX tha langth
of lhnhcrt axis
Scalllllcylll ctls) fnlgmented eels (ctJ.e to1nlunatic disruption of Mil:loqiopathi: hemltjtic anenia Schistocybl Siclda cal
menmne) 1lP, DIC, pre«<lmpaia. HEllf, maligl'lllll

llidd. cell RBC (ct.uJ to polynwimtian of

HTN), vascltlis, glcmarulonepllitis, praslhatic
hlllt:VIM
Sidda call disonlats: HbSC. HbSS
0
Nonnal RBC
0.
Hypochromic
hemoghmin S) microcytic

(1lrgal cal) "B..'• mad film Liver fiMIIa. SC,Ihllllsemia. Fe

Dla1qta 11-NniP Sir9& painllld and, looks lib a tariap
AcutHqtl IIIU' cell
Emilacylll (lalrr CIIQ
lkiiMIIIKIIImltial
daficiancy, a&pllril
MYI*Ifbusis, 1hii1Mssmia m&A
magalablastic anemia
Diltmted RBC with iri!!P..tv disbhded thorn-lib Seven! liver dislml! (spll" eel anemia),
prajecliDns (dua ID 1b11111111l mantnnllipidl) BtiMtimnll'llllia.
RBC with 1U11810US RIQUialty spaced. Slllll tpiny Uremia. HUS.Iuns. bypass. Tlrll8! cell Bwr ell
prajecliDns post-tnnfusion. sknga lltif1r;t
Aggragatas of RBC 11511111Alg tlacb of cains mast common causa; due to
Due to increa5ed plasma concenlllltion of hV! physiological incmse in fibrinogen
moleclilr weight pmlaina lnfiiiiiiii!Dry conditions: ctJ.a to HOWIIII.Jolly
ilmJIIOQiobulns badia
Plasma cal dyscnsias: ella to manoclanal
ag. 11111tiple myaltllll,
macmgob!6Jemia
Smga wr.:t

Figure z. MorphiJiotv
H4 Hematology Rasia of Hematology Toronto Notes 2011

Teble 3. RBC Inclusions lsaa Figura Z)

Inclusions Definition Associltld Cenlilions
Nudaus Present in erythroblasts (imlllture RBCs) Hyperplastic erythropoiesis (seen in hypoxia, hemolytic
anemia), extramedullary hematopoiesis (in BM
infiltration)
Heinz llodies Denatured and pracipillltad hemoglobin G6Pil deficiency (post-exposure to oxidant),
thalassemia, unstable hemoglobins
Howell-Jolly llodies Small nuclear remnant resembling a pyknotic Post-splenectomy, hyposplenism (sickle cell disease),
nucleus neonates. megaloblastic 111emia
Basophilic slipping Daep blue grenulations indicating ribosome Thalassemia, heavy metal (Pb, ln, Ag, Hg) poisoning,
aggregation megaloblastic anemia. hereditary (pyrirridine
5'nucleo1idase deficiency)
Erythrocytes with Fe containing granules in the Hereditary, idiopathic, drugs, hypothyroidism (see
cytoplasm Sideroblastic Anemia, H15)

WHITE BLOOD CELLS

• lymphocytes: comprise 30-40% of white cells
• Reed-Sternberg cell: giant, multinucleated B-lymphocyte
• seen in Hodgkin's lymphoma, other lymphoproliferative disorders, reactive nodes
• smudge cells: lymphocytes damaged during preparation of the blood smear indicating cell
fragility
• seen in Chronic Lymphocytic Leukemia (CLL) and other lymphoproliferative disorders
• neutrophil&
• normally only mature neutrophil& (with 2-4lobed nucleus) and band neutrophils
(immediate precursor with horseshoe-shaped nucleus) are found in circulation
• hypersegmented neutrophil: >Slobes suggests megaloblastic process (B12 or folate
deficiency)
• left shift: increase in granulocyte precursors (bands, metamyelocytes, myelocytes,
promyelocytes, blasts) in circulation
• seen in acute infections, pregnancy, hypoxia, shock, CML
• blasts
• immature, undifferentiated cells; associated with acute leukemia, MDS, severe infection
• Auer rods: clumps of granular material that form long needles in the cytoplasm of
myeloblasts
• pathognomonic for Acute Myeloid Leukemia (AML)

PLATELETS
• small purple anuclear cell fragments

Bone Marrow Aspiration and Biopsy

• sites: posterior iliac crest. sternum, anterior iliac crest
• possible analyses
• aspiration: histology, flow cytometry, cytogenetics, molecular studies, microbiology
(C&S,AFB)
• biopsy: for histology

Indications
• unexplained CBC abnormalities
• diagnosis and evaluation of plasma cell disorders and leukemias
• diagnosis and staging of lymphoma or solid tumours
• evaluate iron metabolism and stores
• evaluate suspected deposition and storage disease (e.g. amyloidosis, Gaucher's disease)
• evaluate fever of undetermined origin, suspected mycobacterial, fungal or parasitic infections,
or granulomatous disease
• unexplained splenomegaly
• confirm normal bone marrow in potential allogenic hematopoietic cell donor

Contraindication•
• absolute: hemophilia. severe DIC
• thrombocytopenia not a contraindication - may need platelet transfusion prior to procedure
Toronto Notes 2011 Common Presenting Problems Hematology HS

Common Presenting Problems

Anemia
Definition
• a decrease in red blood cell (RBC) mass that can be detected by hemoglobin (Hb) concentration,
hematocrit (Hct), and RBC count
• adult males: Hb <135 giL, (13.5 gldL) or Hct <41%
• adult femalc:s: Hb <120 giL, (12 gldL) or Hct <36%

I Low Hemoglobin I
•
Low MCV (<801
.
I Normal MCV (ID-111111 I
.
High MCV (>1001
•
•
•
Iron deficiency
Thalassemia
Anemia of chronic
. .. Megalablade:
• B,. Daficiancy
• Folate Deficiency
• Sideroblastic anemia I High fllliculacybl I Low fllliculocyte • Drugs that impair DNA
• Lead Poisoning Increased diiS!ruction (mics >2-3%1
I Dac111asad production (llllics <2'1.1 synthesis (methotrexate,
sulfa. chemol
I I Nan-magalabladc:

+
H111alylia BINding
+ +

+
Nan-pancytaptmia
• Liver Disease
• Alcoholism
• Reticulocytosis {saa
lnh•ihld • Gl • Aplastic anemia • Anemia of chronic disease High reticulocyte, on lift)
• Hemoglobinopathy (sickle call diseut1, • GU •MDS • Renal/liver disease • Hypothyroidilm
1hlll111semia.unstabla Hbl • Othar • Myalofibrosis • Mvelodvsplasia
• Membrane (spherocyticI • Leukemia
• Metabolic {HMP shunt. glycolytic pathway) •lB
Al:quired • Amyloidosis, sarcoidosis
• Immune (Coombs positive, drug-relatBd, • Drugs (e.q. chamotharapy)
cold agqlulinill
• Infection (malarial
• Microangiopathic hemolytic anemias
{DIC, Tif, HUS, HELLP)
• Oxidlltive/drug-fl!llllild

Figura 3. Approach to Anamia

Clinical Features
• history
• symptoms of anemia: fatigue, malaise, weakness, d}'llpnea, decreased exercise tolerance,
...... ,•}-----------------,
,
palpitations, headache, dizziness, tinnitus, syncope lltlliculocytea
• acute vs. chronic, bleeding. systemic illness, diet, alcohol, family history • Reticulocytes 11111 immature
• rule out pancytopenia (recurrent infection, mucosal bleeding/easy bruisability) erythrocytes and 1111 markers of
erythrocyte productian
• physical signs • Normally they 8hould increase when
• HEENT: pallor in mucous membranes and conjunctiva at Hb <90 giL (<9 gldL), ocular there is a decrease in RBC
bruits at Hb <55 giL (<5.5 g/dL) • With blood loss, raticulocytai should
• cardiac: tachycardia, orthostatic hypotension, systolic flow murmur, wide pulse pressure, increase 2·3x initiallv and then 5·7x
over the n8XI: week
signsofCHF • A normalmiculocytl count in allllllia
• dermatologic: pallor in palmar skin creases at Hb <75 giL (<7.5 gldL),jaundice (if due to shauld be interpreted as a sign of
hemolysis) decreased productian

Investigations
• rule out dilutional anemia (low Hb due to increased effective circulating volume)
• CBC with differential (note MCV, RDW)
• reticulocyte count
• bloodfilm
• rule out gastrointestinal disease in iron deficiency anemia
• additional laboratory investigations as indicated (see Microcytic Anemia, Hl2, Normocytic
Anemia, Hl6, Hemolytic Anemia, H 17 and Macrocytic Anemia, H22)

Polycythemia
Definition
• an increase in the number of RBCs: Hb > 185 giL or Hct >52% (males); Hb > 165 or Hct >47%
(females and African males)
H6 Hematology Common Presenting Problems Toronto Notes 2011

Etiology
• relative/spurious erythrocytosis (decreased plasma volume): diuretics, severe dehydration,
bums, "stress" (Gaisbtick's syndrome)
• absolute erythrocytosis
• primary (low or normal erythropoietin)
• polycythemia rubra vera (PRV) (see PRV, H38)
• secondary (elevated erythropoietin)
• poor tissue oxygenation/hypoxia
• pulmonary disease: COPD, sleep apnea, pulmonary hypertension
• cardiovascular disease: R -+ L shunt (Eisenmenger syndrome)
• RBC defects (Hb with increased 0 2 affinity, methemoglobinemia)
• carbon monoxide poisoning (heavy smoking)
• high altitude
• inappropriate production of erythropoietin
• renal cell carcinoma, cerebellar hemangioblastoma, hepatocellular carcinoma, uterine
leiomyomas, ovarian tumour
• other: polycystic kidney disease, post-kidney transplant, hydronephrosis, androgens

Clinical Features
• secondary to high red cell mass and hyperviscosity
• headache, dizziness, tinnitus, visual disturbances
• symptoms of angina, CHF
• thrombosis (venous or arterial) or bleeding (abnormal platelet function)
• physical findings
• hepatomegaly, plethora (ruddy complexion) of face (70%) and/or palms

Investigations
• RBC mass: normal suggests relative erythrocytosis (confirms increased red cell production,
rules out decreased plasma volume)
• serum erythropoietin (Epo): increased Epo suggests autonomous production or hypoxia and
rules out PRV
• search for tumour as source ofEpo as indicated (e.g. abdominal U/S, CT head)
• arterial p02 : decreased p02 suggests hypoxic etiology
• sleep studies if history suggestive of sleep apnea
• carboxyhemoglobin (hemoglobin-carbon monoxide complex) level, hemoglobin 0 2 affinity

Treatments
• if secondary: treat underlying cause
• 0 2 for hypoxemia, CPAP for sleep apnea, surgery for EPO-secretingtumours
• phlebotomy

..... ,,

Thrombocytopenia
Definition
Must rule out fictitious • platelet count <150 xl09/L
thromiiKJIOpenia - pllllelet clumpif'IIJ
{IICDndary to EDTA antibodinl
I 'lllrombocytDpania I

I
•
lllc111111141d
I
•
S.q1estrlltion
I
•
I ne-ed
I
•
Hamodlutian
I
• •
Productian Destruclian

Spl•no""Pir • Massive
• Liver diseases 1nnlfusion

•
Nutritional •
Marrowda11111g1
• Malign111cy
• Myelofibrosis

Immune
. •
Noll-immune
• Cardiopulmonary
bypass

• B,,lfolate Def • Alpert's • Aplastic anemia •ITl' • DIC

• Fanconrs • Chemo, radiation • Vind [HIIJI • TTl'
• Drug-induced • Systemic [SLEI • HUS
• Malignancy • Alloimmune • Pra-echunpsia
• Myelodysplasia • HIT • HELLP
• D111g Induced • APLAS

Figura 4. Approach to Thrombocytupania APLAS = AntbldySyndrame

AdlptldfnrnCacls fssantialaafMedn
Toronto Notes 2011 Common Presenting Problems Hematology H7

Clinical Features
• history: bleeding gums, epistaxis, bleeding post-surgical procedures, metromenorrhagia
• physical exam: bruising, petechiae, ecchymoses, non-palpable purpura
• hemarthrosis and deep muscle hematomas are rarely initial signs in patients with primary
hemostatic disorders
• see Disorders ofPrimary Hemostasis, H26, for complications of thrombocytopenia
Investigations
• CBC and differential
• bloodfilm
• decreased production: possible other cell line abnormalities, blasts, hypersegmented PMNs,
leukoerythroblastic changes
• increased destruction: large platelets, schistocyte& (seen in MAHA)
• work-up for nutritional deficiencies: vit B1:2, RBC folate
• LFTs

Thrombocytosis
Definition
• platelet count >500x109/L
• reactive thrombocytosis: acute phase reactant (e.g. surgery, inflammation, infection, trauma,
bleeding, iron deficiency, neoplasms)
• autonomous thrombocytosis: due to myeloproliferative or myelodysplastic disorders [e.g. CML,
primary myelofibrosis, polycythemia rubra vera (PRV), myelodysplastic syndrome (MDS)]
Clinical Features
• history: trauma, surgery, splenectomy, infection, inflammation, bleeding, iron deficiency, prior
diagnosis of chronic hematologic disorder, constitutional symptoms indicating malignancy
• autonomous thrombocytosis more likely to cause vasomotor symptoms (headache, visual
disturbances, lightheadedness, atypical chest pain, acral dysesthesia, erythromelalgia, livedo
reticularis, aquagenic pruritus)
• clotting risk, bleeding risk (rare)
• physical exam: splenomegaly can be seen in myeloproliferative disorders
Investigations
• CBC, peripheral blood smear, serum ferritin concentration
• non-specific markers of infection or inflammation (e.g. CRP, ESR, plasma fibrinogen, ferritin)
• if reactive process has been ruled out, bone marrow biopsy may be required to determine cause
of autonomous thrombocytosis

Pancytopenia
----------------------------------------------
Definition
• a decrease in all hematopoietic cell lines
Clinical Features
• anemia - fatigue
• leukopenia - recurrent infections
• thrombocytopenia - mucosal bleeding and ecchymoses
Investigations
• CBC and differential, blood film
• investigate secondary causes: HIV test, serum B12, RBC folate, ANA
• often requires bone marrow biopsy to determine cause

Pllncytope11ia I
•
lllypoeallel•r BM I I •
Callel•rBM
I
+ +
• Acquirad aplastic anemia
• lnharibld aplastic anamia
1°8M dil1ut1
• Myulodylplasia
2." tD 1,.U.mic
• SLE
di-•
• Some myelodysplasia syndromes • PNH • Hyparsplenism
• Acuta myalogenous laukemia • Myuloftrosi1 • Vii B,Jiohde deficiency
• Ovarwhalming infactions (a.g. bactaria/vil'll) • Lymphoma • Alcoholism
• Toxic depnililiion of BM • TB
•AnoraxianaMJsa • Sarcoidosis
• HIV

Figure 5. Approach to Pancytopenia PNH = l'lroxylmll Noctumallllmogbbinuria

H8 Hematology
L.t'llblft
Rufun 1iJ 1111 irx:r88111 in grmuloc:ybl
precursors in 1he peripheral smear
(myelocytes, ml!lllmyeloc:ytn,
promyelocytn, blasts!. If pruant,
implies increaaed miii'Ow production
of grellllocytes (a.g. inflammation.
infection, G·CSF ldministnrtion, CMLI.
Tha pmerx:a of predominantly blasts
in 1118 paripharal11111111r without caUa
lmwHn mann nautrophil and blast
suggests clonal cell disorder [MDS,
ICUb lauksmiasl.
Common Presenting Problems Toronto Notes 2011
Neutrophilia
Definition
• absolute neutrophil count (ANC) >7.7 x 109/L
Etiology
• primary neutrophilia
• hereditary neutrophilia (autosomal dominant)
• chronic idiopathic neutrophilia in otherwise healthy patients
• chronic myelogenous leukemia {CML)
• other myeloproliferative disorders (PRY, ET, myelofibrosis)
• leukocyte adhesion deficiency
• secondary neutrophilia
• smoking - most oommon cause of mild neutrophilia
• infection -leukocytosis with left shift± toxic granulation, Doble bodies (intra-cytoplasmic
structures composed of agglutinated ribosomes)
• inflammation - e.g. RA, IBD, chronic hepatitis, MI, PE, burns
• malignancy- hematologic (ie. marrow invasion by tumour) and nonhematologic (especially
large cell lung cancer)
• stress/exercise/epinephrine- movement of neutrophils from marginated pool into
circulating pool
• medications- glucocorticoids, beta-agonists (e.g. epinephrine), lithium
Clinical Features
• look for signs and symptoms offever, inflammation, malignancy to determine appropriate
further investigations
• examine oral cavity; teeth, peri-rectal area, genitals and skin fur signs of infection
Investigations
• CDC differential: mature neutrophils or bands >20% oftotal WBC suggests infection/inflammation
• blood film: Doble bodies, toxic granulation, cytoplasmic vacuoles in infection
• review other blood counts
Neutropenia
Definition
• mild: ANC 1.0-1.5 X 109/L
• moderate: ANC 0.5-1.0 x 109/L (risk of infection starts to increase)
• severe: ANC <0.5 x 109/L
Etiology
• decreased production
• hematological diseases - idiopathic, aplastic anemia, myelofibrosis, BM infiltration
• infection - TB, typhoid, EBV, malaria, viral hepatitis, HIV
• drug-induced- alkylating agents, antimetabolites, anticonvulsants, antipsychotics, anti-
inflammatory agents, anti-thyroid drugs
• toxic- high dose radiation, chemicals (e.g. benzene, DDT)
• nutritional deficiency - B1z, folate
• idiopathic - constitutional neutropenia, benign cyclic neutropenia
• peripheral destruction
• antineutrophil antibodies
• spleen or lung trapping
• autoimmune disorders - RA, SLE
• Wegener's granulomatosis
• drugs- haptens (e.g. a-methyldopa)
• excessive margination (transient neutropenia)
• idiopathic (most common)
• overwhelming bacterial infection
• hemodialysis
• racial variation (e.g. people of African descent commonly have mild neutropenia)
Toronto Notes 2011 Common Presenting Problems Hematology H9

Clinical Features
• fever, chills (only if infection)
• infection by endogenous bacteria (e.g. S. aureus, gram negatives from GI and GU tract) = N..... = Filgmtilll
• painful ulceration on skin, anus, mouth and throat following colonization by opportunistic GM-CSF = Leutint• = S.rgnm.-tim
organisms
• avoid digital rectal exam
..
Investigations FICIIIn • lllllllly IIIII llfladal
JmilllmMid2007; 147:4011-11
• depends on degree of neutropenia and symptoms . . .a: Ta riVilw IIIIIIIICII al caklny-
• ranges from observation with frequent CBCs to bone marrow aspiration and biopsy DIJ!aq flctDr (CSF) an mallalty, metians,
a fibril in Pl1iarD
Treatment cbemcllhellpy or slem-ce111llnl!illrt {SCI).
S1udy Slllcliln: 1481111dornilld CCIIIIIGI1rilll
• regular dental care - chronic gingivitis and recurrent stomatitis major sources of morbidity lllllfllcllllf CSFs ID lillm plaba
• febrile neutropenia (see Infectious Diseases, ID44) or no 111111py- illcludlld.l'niJihyllctic CSfs
• in severe immune-mediated neutropenia, G-CSF may increase neutrophil counts CGaCUI!IIIdvl'tithor lftlrinililtion af
• if no response to G-CSF, then immunosuppression (e.g. steroids, cyclosporine, methotrexate) cbernclttlempy.
bulls: Thn 1111111 no dlflllncll in d-CIII•
mamMy ormdian-rellled delllll CSF
a plabo gnqll. C..nlll mpllcabo 111 no
Lymphocytosis thenlvf. CSfs reduced nectian Tilt (rrailn nde
38J'J.vs. 43.1\; llhllllia 0.851. mil:ralliqicdy
docullllllfld irflc1ianl (MH 23.5'4 VI. 28.6\; 1111
Definition IIIia a fllria neutropenia !Mit 25.3\ vs.
• absolute lymphocyte count >4 x 109/L 4.U\;ratalllioo.7n
CancbiPI: Prapt¥1ctic CSh dec:lvla
Etiology inllclianallldiJiiiOd•alllbriil.._..il
in plliantl cllamaltalpy or SCT, but
• infection hunoalllctonmDfllllily.
• viral infections (majority)
• TB, pertussis, brucellosis, toxoplasmosis
• physiologic response to stress (e.g. trauma, status epilepticus)
• hypersensitivity (e.g. drugs, serum sickness)
• autoimmune (e.g. rheumatoid arthritis)
• neoplasm (e.g. ALL, CU., lymphoma)

Investigations/Treatment
• peripheral smear
• smudge cells --+ do flow cytometry to rule out clonal process
• atypical lymphocytes --+ suggestive of viral infection (EBV or others)
• treat underlying cause

Lymphocytopenia
Definition
• absolute lymphocyte count <1.5 x 109/L

Etiology
• idiopathic CD4+ lymphocytopenia
• chemotherapeutic agents
• radiation
• mY/AIDS, hepatitis B, hepatitis C, autoimmune disease (e.g. SLE)
• malignancy

Clinical Features
• opportunistic infections (see Infectious Diseases)

Treatment
• treat underlying cause
• treat opportunistic infections aggressively and consider antimicrobial prophylaxis
(see Infectious Diseases, 1049)
HlO Hematology Common Presenting Problema/Approach to Lymphadenopathy Toronto Notes 2011

Eosinophilia
..... ,,
• absolute eosinophil count >0.5 x 109/L
Baaphilialllll/or Eosinophilia • most common causes are parasitic (usually helminth) infections and allergic reactions
Can be an indicator of Chronic Myeloid • less common causes:
L.aukamia or lith• myeloprolifllrativll • polyarteritis nodosa
diseau, auocilrtld with pruritis due to
sxc11111ive himmi1111 production.
• cholesterol emboli
• CML
• Hodgkin's disease
• adrenal insufficiency
• hypereosinophilic syndrome
• 6 months of eosinophilia with no other detectable causes
• can involve heart, bone marrow, CNS

Agranulocytosis
• severe depletion of granulocytes (neutrophils, eosinophils, basophils) from the blood and
granulocyte precursors from bone marrow
• associated with drug use in 70% of cases: e.g. clozapine, thionamides (antithyroid drugs),
sulfasalazine and ticlopidine
• pathogenesis
• immune-mediated destruction of circulating granulocytes by drug-induced antibodies or
direct toxic effects upon marrow granulocytic precursors
• abrupt onset of fever, chills and weakness, oropharyngeal ulcers
• high fatality without vigorous treatment

Investigations/Treatment
• discontinue offending drug
• pan-culture and screen for infection if patient is febrile (blood cultures .x2, urine culture and
chest x-ray as minimum, initiate broad-spectrum antibiotics)
• consider bone marrow aspirate and biopsy if cause unclear
• consider G-CSF (growth factor that stimulates neutrophil production)

Leukemoid Reactions
• blood findings resembling those seen in certain types of leukemia which reflect the response of
healthy BM to cytokines released due to infection or trauma
• leukocytosis >50 x 109/L, marked left shift (myelocytes, metamyelocytes, bands in peripheral
blood smear)
• important to rule out CML
• differential diagnosis:
• myeloid leukemia: pneumonia, other acute bacterial infections, intoxications, burns,
malignant disease, severe hemorrhage or hemolysis
• lymphoid leukemia: pertussis, TB, infectious mononucleosis
• monocytic leukemia: TB

Approach to Lymphadenopathy
Clinical Features
• history
• constitutional/B-symptoms - weight loss, anorexia, fever, night sweats
• seen in TB,lymphoma, other malignancies
• symptoms of infection or malignancy
• exposures- cats (cat scratch- Bartonella henselae), ticks (Lyme disease- Borrelia
burgdorfen), high risk behaviors (HIV)
• joint pain/swelling, rashes
• pruritis (seen in Hodgkin's disease)
• medications (can cause serum sickness-+ lymphadenopathy)
• physical exam
• basic assessment: occipital, preauricular, submandibular, cervical, supra/infra-clavicular,
axillary, epitrochlear, inguinal, popliteal nodes
• characteristics oflymph nodes (Table 4)
• look for signs of infection in regions which lymph nodes drain
Toronto Notes 2011 Approach to Lymphadenopathy/Approach to Splenomegaly Hematology H11

• determine iflymphadenopathy is localized or generalized ... ,

• localized: typically reactive or neoplastic
• cervical (bacterial/mycobacterial infections, ENT malignancies, metastatic cancer) D111111Thlt C.n C.••
• supraclavicular
-right (mediastinal, bronchogenic, esophageal cancer) AUopurinol
- left (gastric, gall bladder, pancreas, renal, testicular/ovarian cancer) AlllnoiDI
Captopril
• axillary (cat scratch fever, breast cancer, metastatic cancer) Carbamazepine
• epitrochlear (infections, sarcoidosis) Cephalosporils
•lower/inguinal (STDs, skin, cervix, vulva/penis, rectum/anus cancer) Gold
• generalized: see Table 5 Hychlazina
PenicHiin
• thorough examination required to assess for systemic disease Phenytoin
• investigations Primidone
• CBC and differential, blood film Pyrimuthamine
• ± PPD, HIV RNA, RPR/VDRL, monospot/EBV serology, ANA, imaging as indicated Quinidine
Sulfonamides
• iflocalized and no symptoms suggestive of malignancy, can observe 3-4 weeks (if no
resolution -+ biopsy)
• if generalized: lab workup; if negative -+ biopsy
• if signs suggestive of malignancy, biopsy immediately
• cxcisional biopsy is preferred as it preserves node architecture (essential for diagnosing
lymphoma)
• in difficult to access areas (retroperitoneal, mediastinallhilar) multiple core biopsies may be
more practical/feasible
• FNA - helpful for diagnosing recurrence of solid tumour malignancy

Table 4. lntlammatory vs. Neoplastic Lymph Nodes

Feature lnllam11llllry Nodes Neapllstic:
ConsistEncy Rubbery Fim'b!Wll
Moblily Mobile Matted/Immobile
Tenderness Tender Non-tender
Size <2cm >2cm
• clusificlticms 1re nDIIIIdlte; lympho1111 111d CU nodes Clll1 hleiMibery llld 1re fretpintly moble,11011-tnler

Table 5. Differential Diagnosis of Generalized Lymphadenoplthy

Naaplutic
Bacterial (TB, Lyme, brucellosis, Collagen disease (RA, dermatomyositis, Lyrl1lhocytic leubmias
cat-scratch disease! lymphoma Slf, vasculitis, Sjogren)
Viral (EBV, CMV, HIV) Drug hypersensitivity Metastatic cancer
Parasitic (toxoplasmosis! Sarcoidosis, amyloidosis Histiocytosis X
Fungal (histoplasmosis) Serum sickness

Approach to Splenomegaly
Table &. Differential DiagnDsil of Splenomegaly
lnc:r.ud D111111nd for Spl•ic Functioa Canglltiva lnfiltratin
Hematological lnlectious lnllammltllry Cinhclil
SphartJcytosis CMV Fllhy syndrome Splenic Vllin thrombosis Benign m&tilplasia
Hemoglobinopathies Bacterial endccs'ditis S1ilrs disease Portal vein obstruction Amyloidosis
Hemolysis 1B SLE CHF (riltrt heart failure) Lysosomal storage diseases
SI)(Jiestration crisis HIV/AIDS Sarcoidosis (Gaucher"s, Niemann-Pick)
Nutritionalanemias EBV storage diseases
Elliptocytosis Malaria Mllgnant
Histoplasmosis Leulamia (CML)
Leislmaniasis Lymphoma
Hcdgkin"s disease
Myaloprclifsndiw disorden
Metastatic umour

• history
• constitutional symptoms
• signs or symptoms of infection or malignancy
• history of liver disease, hemolytic anemia or high-risk exposures
H12 H.ematoJ.osr .Approach to Splmomeply/Microcytic Anemia 1'oroDio 2011

a ... Exm 111r ..MIIIr
.
J4AM 1113; 271): 221t-21
lha IIJalminltion for ...,om.-, is
mas! usllful to Ml illhe
amung pdii!Q mwhom llun ia a
clinicalllllpicion af It 1111111: I Mi.
l'lralssian is mDI'I snitive but less
'P8Cilic 111an pllpalion BJ a daanolltie
talltfor lplanamagaly- idllllly, u-
11s15 should ba dDna tDQalhw.
• physical exam
• percussion (Castell's sign, Traube's space) and palpation
• signs ofchronic liver disease
• associated lymphadenopathy or hepatomegaly
• jaundice. petechiae
• signs ofCHP
• investigations
• CBC and differential, blood film
• as indicated: liver enzymesnlver function testa, reticulocyte count, Manospot, haptoglobin,
LDH. infectious and autoimmune workups
• imaging
• ultrasound of abdomen/liver to rule out cirrhosis and portal vein thrombosis
• echo fur cardiac function
• CT to rule out lymphoma

Microcytic Anemia
Tlllla 7.1ron lndicaaaad Bload Rl11 in Micracytic Anamia (MCV<BG)
Lib Tillis
flnitia S.U11 hn 'IIIC RDW

c.u-., llicruqtic ......

1-1>15) • llypaclmni:, micnx:ytic
• Norrmcytictmicrocytic
OOLS
1bal118111llia • lklal poptjltian
0 Basophilic stipplilg
Anemia of chronic
Iron dllficien.:y
N N/1' o lfo/paclnnic, micnltylic
lad poisoning
Sideroblutic ...... • Basophilic slipping
• Paikilocytosil

Iron Metabolism
Iron Intake (Dietary)
o •average" North American adult diet =10-20 mg iron (Fe) daily
• absorption is 5-1096 (0.5-2 mgtday); enhanced by citric acid, ascorbic acid (vitamin C) and
reduced by polyphenols (e.g. in tea), phytate (e.g. in bran), dietary calcium, and soy protein
• malea have positive Fe balance; up to 20% of.tnen9t.ruatlng females have negative Fe balance

LEBEND
r;:2 Ferritin G Hamosidam
\b:!lTIIIIIII'wrril

RBC pracui'SDIS

....,...
c

I Iran HGIIaalt.lia
il bona1'1'181111W :i
0

Figure 1. Iron Metabollm

Iron Absorption and Transport

• dietary iron is absorbed in the duodenum (impaired by IBD, celiac disease. etc.)
• in c1rculation, the majority of non-heme iron is bound to transferrin which tra.n8fers iron from
enterocytes and storage pool sites (macrophages and hepatDcytes) to RBC precursors in the
bone marrow
Toronto Notes 2011 Microcytic Anemia Hematology H13

Iron Storage
• ferritin
• ferric iron complexed to a protein called apoferritin (hepatocytes are main ferritin storage site)
• minute quantities are present in plasma in equilibrium with intracellular ferritin
• also an acute phase reactant - can be spuriously elevated despite low Fe stores
• hemosiderin
• aggregates or crystals of ferritin with the apoferritin partially removed
• macrophage-monocyte system is main source of hemosiderin storage

Iron Indices (see Table 7 and Figure 7)

• bone marrow aspirate: gold standard test for iron stores
• serum ferritin: single most important blood test fur iron stores
• decreased in iron deficiency anemia
• elevated in
• infection, inflammation, malignancy
• liver disease, hyperthyroidism and iron overload
• serum iron: measure of all non-heme iron present in blood
• varies significantly daily
• virtually all serum iron is bound to transferrin, only a trace is free or complexed in ferritin
• total iron binding capactty (TffiC): total amount of transferrin present in blood
• normally, one third of Tmc is saturated with iron
• high specificity fur decreased iron, low sensitivity
• saturation
• serum Fe divided by TIBC, expressed as a proportion or a percentage
• low in iron deficiency anemia
• soluble transferrin receptor (sTIR)
• reflects the availability of iron at the tissue level
• the transferrin receptor is expressed on the surface of erythroblasts and is responsible fur
iron uptake - some is cleaved off and is present in circulation as sTIR
• in iron defictent states, more transferrin receptor is expressed on erythroblasts,leading to an
increase in sTIR
• low in reduced erythropoiesis and iron overload
• useful in determining iron defictency in the setting of chronic inflammatory disorders
(see Iron Deficiency Anemia, below)

Iron Deficiency Anemia

• most common cause of anemia in North America

Etiology
• increased demand
• increased physiological need fur iron in the body (e.g. pregnancy)
• decreased supply: dietary defictencies (rarely the only etiology)
• cow's milk (infant diet)
• "tea and toast" diet (elderly)
• absorption imbalances
• post-gastrectomy
• malabsorption (IBD of duodenum, celiac disease, autoimmune atrophic gastritis)
• increased losses
• hemorrhage
• obvious causes - menorrhagia in young women
• occult - peptic ulcer disease, GI cancer
• intravascular hemolysis
• paroxysmal nocturnal hemoglobinuria (PNH)
• cardiac valve RBC fragmentation

Clinical Features
• iron defictency may cause fatigue before clinical anemia develops
• symptoms of anemia: fatigue, weakness, irritability, exerdse intolerance, syncope, dyspnea,
headache, palpitations, postural dizziness, tinnitus, feeling cold. confusion/loss of concentration
• brittle hair, nail changes [brittle, koilonychia (spoon-shaped)]
• dysphagia (e.g. esophageal web, Plummer-Vmson ring)
• pallor - conjunctiva, palmar creases
• glossitis
• angular stomatitis (inflammation and fissuring at the corners ofthe mouth)
• pica (appetite fur non-food substances, e.g. ice, paint, dirt)
Hl4 Hematology Microcytic Anemia Toronto Notes 2011

Investigations
Table B. The Utility of Ferritin in • iron indices, including soluble transferrin receptor (Figure 7)
the Diagnosis of Iron Deficiency • low ferritin ( <45 IJg!L) is diagnostic of iron deficiency (Table 8)
Anemia
• ferritin is an acute phase protein and is elevated in the setting of inflammatory conditions
Fenitin Likelihood ratio for and liver disease; serum ferritin <100 IJg!L in these settings is suggestive of iron deficiency,
(fiG/IJ i'an deficiency anemia necessitating further workup (Figure 7)
>100 0.13 • peripheral blood film
• hypochromic microcytosis: RBCs are under-hemoglobinized due to lack of iron
45-100 0.46
• pencil forms, anisocytosis
111-45 3.12 • target cells (thin)
41.47 • bone marrow (gold standard but not commonly done)
1 iron stain (Prussian blue) shows decreased iron in macrophages and in erythroid precursors
Sourca: Am J Mtd 1990; 88:211&-8
(sideroblasts)
1 intermediate and late erythroblasts show micronormoblastic maturation

..... '..}-----------------,
, Treatment
• treat underlying cause
Iron deficiency anemia is a common • supplementation
pm1ntation of clronic '--r Gl • oral (tablets, syrup)
bleeds (right-sided cDiorecml cancer, • ferrous sulphate 325 mg tid, ferrous gluconate 300 mg tid, or ferrous fumarate 300 mg tid
angiodYJPialill. atc.l.
• supplement until anemia corrects, then continue for 3+ months until serum ferritin
In miles and in post-menopiUsal returns to normal
WOIIIIII,a Gl work-up is always
warranted. • oral iron should be taken with citrus juice to enhance absorption
• IV (Venofer•) can be used if patient cannot tolerate or absorb oral iron
• monitoring response
• reticulocyte count will begin to increase after one week
• Hb normalizes by 10 giL per week
• iron supplementation required for 4-6 months to replenish stores

Patient willl microcytic anemia

+ ...
•i
Fanitin s45 Fanitin 46--99 Fanitin :!1DD IJG!ml

Assass other iron indices

- - - 1' TIBC, serum Fe

+ Arrt Dlhlr result:
...
TIBC, 1' serum F1 - - - -
..--- satumion Order iTIR 1' satumion ---
I

14------1' sTIR
+ ...

Iran dllficiancy •n•i• NO iran dllficiancy 1n•il

Figura '1. Approach to lntarprllling Iron Indices

Adlptldfnrn Killip 2007; 75:671-8

Anemia of Chronic Disease

Etiology
• infection, malignancy, inflammatory and rheumatologic disease, chronic renal and liver disease,
endocrine disorders (e.g. diabetes mellitus, hypothyroidism, hypogonadism, hypopituitarism)

Pathophysiology
• an anemia of underproduction, due to impaired iron utilization
• trapping of iron in macrophages -+ reduced plasma iron levels making iron relatively
unavailable for new hemoglobin synthesis

..... '...-----------------·
, • erythropoietin levels are normal or slightly elevated, but marrow is unable to respond with
increased erythropoiesis
• mild hemolytic component is often present
lnln-ddciency n•i1 c•manly
• RBC survival is modestly decreased
ca--.. with anmda al c...anlc
UIIH. S1111181ted by:
• Serum furrilin < 100 IIG"1- in letting of Investigations
• diagnosis of exclusion
• BBYB!ion of IIOiuble tramfenin • associated with elevation in acute phase reactants (ESR, CRP, fibrinogen)
recaptor
• Absence of stainable iron on bone • "classicD serum iron indices (see Table 7)
marrow aspiraliOI\Ibiopry • serum iron and Tmc low, % saturation normal
• Response to a therapeutic bill of oral • serum ferritin is normal or increased
irun • anemia of chronic disease often co-exists with iron deficiency (see sidebar)
Toronto Notes 2011 Microcytic Anemia Hematology HIS

• peripheral blood
• mild: usually normocytic and normochromic
• moderate: may be microcytic and normochromic
• severe: may be microcytic and hypochromic
• absolute reticulocyte count is frequently low, reflecting overall decrease in RBC production
• bone marrow
• normal or increased iron stores
• decreased or absent staining for iron in erythroid precursors

Treatment
• anemia resolves if underlying disease is treated
• only treat patients who can benefit from a higher hemoglobin
• erythropoietin may normalize the hemoglobin value

Lead Poisoning
•
•
L: Lead Lines on gingivae and epiphyses oflong bones on x-ray
E: Encephalopathy and Erythrocyte basophilic stippling
.... ,,

• A: Abdominal colic and microcytic Anemia (sideroblastic) Consider lead poisoning in any child
• D: Drops (wrist and foot drop) who lives in a house before 1977.
• treatment: dimercaprol and EDTA are first line agents

Sideroblastic Anemia
• uncommon compared to iron deficiency anemia or anemia of chronic disease

Sideroblasts
• erythrocytes with iron-containing (basophilic) granules in the cytoplasm
• "normal": granules are small, randomly spread in the cytoplasm
• found in healthy individuals
• "ring": iron deposits in mitochondria, forming a ring around the nucleus
• abnormal, large granules
• the hallmark of sideroblastic anemia

Etiology
• due to defects in heme biosynthesis in erythroid precursors
• hereditary (rare): X-linked; median survivallO years
• idiopathic (acquired)
• a.k.a. refractory anemia with ringed sideroblasts - a subtype of MDS (see Myewdysplastic
Syndrome, H36)
• may be a preleukemic phenomenon (10% transform to AML)
• reversible
• drugs (isoniazid, chloramphenicol), alcohol, lead, copper deficiency, zinc toxicity,
hypothyroidism

Clinical Features
• anemia symptoms (see Iron Dejidency Anemia, H13)
• hepatosplenomegaly, Fe overload syndrome

Investigations
• serum iron indices
• increased serum Fe, normal TIBC, increased ferritin, increased sTfR
• blood film/bone marrow biopsy
• ringed sideroblasts (diagnostic hallmark)
• RBCs are hypochromic; can be micro-, norma-, or macrocytic
• anisocytosis, poikylocytosis, basophilic stippling

Treatment
• depends on etiology
• X-linked: high dose pyridoxine (vitamin B6) in some cases
• acquired: Epa and G-CSF
• reversible: remove precipitating cause
• supportive transfusions for severe anemia

Thalassemia
• see Hemolytic Anemia- Thalassemia, H18
Hl6 Hematology NOl'Dlocytic Anemia Toronto Notes 2011

Normocytic Anemia

C.uHI of Normocytic Anemia Aplastic Anemia

ABCD
Acute blood loss Definition
Bone marrow failure • destruction of hematopoietic cells of the bone marrow leading to pancytopenia and hypocellular
Chronic disaua bone marrow
Dllllllction (h1111olysis)
Epidemiology
• occurs at any age
• slightly more common in males

Etiology
• congenital
• Fanconi's anemia
• Shwachman-Diamond syndrome (bone marrow failure and pancreatic insufficiency)
• acquired
• idiopathic
• often T-cell mediated (112 to 2/3 of cases)
• drugs
• dose-related (e.g. chemotherapeutic agents)
• idiosyncratic (e.g. chloramphenicol, phenylbutazone)
• toxins
• benzene and other organic solvents
• DDT and insecticides
• ionizing radiation
• post-viral infection (parvovirus Bl9, EBV, HDV, HEV, HHV6, HIV)
• autoimmune (e.g. SLE)- rare
• paroxysmal nocturnal hemoglobinuria (PNH) - associated with aplastic anemia, but not a
cause

Clinical Features
• can present acutely or insidiously
• symptoms of anemia, thrombocytopenia
• absence of splenomegaly and lymphadenopathy

Investigations
• exclude other causes of pancytopenia (Figure 3)
• CBC
• anemia or neutropenia or thrombocytopenia (any combination) ±pancytopenia
• decreased reticulocytes (<1% of the total RBC count)
• bloodfilm
• decreased number of normal RBCs
• bone marrow
• aplasia or hypoplasia of marrow cells with fat replacement
• decreased cellularity

Treatment
• remove offending agents
• supportive care (red cell and platelet transfusions, antibiotics)
• immunosuppression
• anti-thymocyte globulin- 50-60% of patients respond
• cyclosporine
• allogenic bone marrow transplant
Toronto Notes 2011 Hemolytic Anemia (HA) Hematology H17

Hemolytic Anemia (HA)

Classification
• hereditary
• abnormal membrane (spherocytosis, elliptocytosis)
• abnormal enzymes (pyruvate kinase defictency, G6PD defictency)
• abnormal hemoglobin synthesis (thalassemias, hemoglobinopathies)
• acquired
• immune
• hemolytic transfusion reaction, autoimmune HA (AIHA), drugs (e.g. penicillin), cold
agglutinins
• non-immune
• microangiopathic HA (MAHA): thrombus in blood vessel causes RBCs to be sheared
- associated with DIC, HUS/TTP, pre-eclampsia!HELLP, vasculitides, malignant
hypertension
• other causes: PNH, hypersplenism, march hemoglobinuria (exertional hemolysis),
infection (e.g. malaria), mechanical heart valves
• also classified as intravascular or extravascular:
• intravascular: G6PD deficiency, TTP, DIC and PNH
• extravascular: AIHA and hereditary spherocytosis

Clinical Features Specific to HA

• jaundice
• darkurine
• cholelithiasis (pigment stones)
• potential for an aplastic crisis (ie. BM suppression in overwhelming infection)
• iron overload with extravascular hemolysis
• iron deficiency with intravascular hemolysis

Investigations
• screening tests
• increased reticulocyte count
• decreased haptoglobin
• increased unconjugated bilirubin
• increased urobilinogen
• increased LDH
• tests specific for intravascular hemolysis
• schistocytes on blood film
• free hemoglobin in serum
• methemalbuminemia (heme + albumin)
• hemoglobinuria (immediate)
• hemosiderinuria (delayed)
• tests specific for extravascular hemolysis
• direct Coombs' test (direct antiglobulin test)
..... '.. '

• detects IgG or complement on the surface ofRBC

Hama
• add anti- IgG or anti-complement antibodies to patient RBCs; test is positive if RBCs
agglutinate
• indications
- hemolytic disease of newborn
l Hama oxwanue

l
Bli•nlin
- autoimmune hemolytic anemia (AIHA)
- hemolytic transfusion reaction Biiwrdin rudul:lllli8
• indirect Coombs' test (indirect antiglobulin test)
Blirubin
• detects antibodies in serum that can recognize antigens on RBCs
• mix patient serum with donor RBCs and then Coombs' serum (anti-human Ig
antibodies); test is positive if RBCs agglutinate
• indications
- cross-matching of redpient serum with donor's RBC
- atypical blood group
- blood group antibodies in pregnant women
-AIHA
Hl8 Hematology
n.lnSEAmill
11-Thal-+ prevalent in
SEA
a-Thai -+ prevalent in South Ealt Alia
(SEAl. (a = Asi1, Afrieal
..._, , • defect in single allele of beta gene (heterozygous)
Micrvcytallia in B8ta Thlllllllmor
Microcytosis is much mora profound
and the anemia is much milder 1han 1hBI
of iron dricii!IC'f.
Hemolytic Anemia (HA) Toronto Notes 2011
Thalassemia
Definition
• defects in production of the alpha or beta chains of hemoglobin
• resulting imbalance in globin chains leads to hemolysis in the spleen or BM
• clinical manifestations and treatment depends on specific: gene and number of alleles affected
• common features:
• increasing severity with increasing number of alleles involved
• hypochromic microcytic anemia
• basophilic stippling, abnormally shaped RBCs on blood film
Pathophysiology
• defect may be in any ofthe Hb genes
• normally 4a genes in total; 2 on each copy of chromosome 16
• normally 2jJ genes in total; 1 on each copy of chromosome 11
• fetal hemoglobin, HbF ( switches to adult forms HbA ( and HbA 2 ( at
3-6 months of life
• HbA constitutes 97% of adult hemoglobin
• HbA 2 constitutes 3% of adult hemoglobin
Beta-Thalassemia Minor (Thalassemia Trait)
Definition
• common in people of Mediterranean and Asian descent
Clinical Features
• palpable spleen (rare)
Investigations
• Hb 90-140 giL or 9-14 gldL, MCV<70, normal Fe
• peripheral blood film - microcytosis basophilic stippling
• Hb electrophoresis
• specific: HbA2 increased to 2.5-5% (normall.S-3.5%)
• non-specific: 50% have slight increased in HbF
Treabnent
• no treatment required
• genetic counselling for patient and family
Beta-Thalassemia Major
------------------------------
Definition
• defect in both alleles of beta gene (homozygous, autosomal recessive)
Pathophysiology
• ineffective chain synthesis leading to ineffective erythropoiesis, hemolysis of RBCs and increase
inHbF
Clinical Features
• initial presentation at age 6-12 months when HbA normally replaces HbF
• severe anemia, jaundice
• stunted growth and development (hypogonadal dwarf)
• gross hepatosplenomegaly {due to extramedullary hematopoiesis)
• radiologic changes (due to expanded marrow cavity)
• slrull x-ray has uhair-on-endn appearance
• pathologic fractures common
• evidence of increased Hb catabolism (e.g. pigmented gallstones)
• death can result from
• untreated anemia (should transfuse)
• infection (should identify and treat early)
• iron overload: late complication secondary to repeated transfusions and ineffective
erythropoiesis
Toronto Notes 2011 Hemolytic Anemia (HA) Hematology HHI

Investigations
• Hb 40-60 giL (4-6 gldL)
• Hb electrophoresis
• HbA: 0-10% (normal >95%)
• HbF: 90-100%

Treatment
• lifelong regular transfusions+ Fe chelation to prevent iron overload (e.g. deferoxamine)
• folic acid supplementation
• allogenic bone marrow transplantation

Alpha-Thalassemia
Definition
• defect(s) in alpha genes
• similar geographic distribution as beta-thalassemia but higher frequency among Asians and
Africans

Clinical Features
• 1 defective a gene: clini.cally silent; normal Hb, normal MCV
• 2 defective a genes: decreased Mev; normal Hb
• 3 defective a genes: HbH (jW) disease; presents in adults, decreased MCV, decreased Hb,
splenomegaly
• 4 defective a genes: Hb Barts (y4) disease (hydrops fetalis); not compatible with life

Investigations
• peripheral blood £1m - screen for HbH inclusion bodies with special stain
• Hb electrophoresis not diagnostic for a-thalassemia
• DNA analysis using a gene probes

Treatment
• depends on degree of anemia:
• 1 or 2 defective a genes: no treatment required
• HbH disease: similar to major

Sickle Cell Disease

• see Pediatrics. P49 r
'!'
Bioodflowl
alows ...
,v PO.
Definition
• sickling disorders arise due to a mutant chain, most commonly caused by a Glu -+ Val

substitution at position 6 resulting in HbS rather than HbA Distor18d RBC D HB S
sickle cells ,. e l

lL
• increased incidence ofHbS allele with African or Mediterranean heritage (thought to be -t-H•
protective against malaria) HbS -r-eo,
• sickle cell disease occurs when an individual has two HbS genes (homozygous, HbSS) or one polymers
HbS gene + another mutant gene (compound heterozygote} - most commonly Impaction
and HbSC disease
Infarction
Figura 8. Pathophysiology of
Pathophysiology (Figure 8) Sickling
• at low pO:z, deoxy HbS polymerizes leading to rigid crystal-like rods that distort membranes -+
'sickles'
..... ,.. ,

• the p02 level at which sickling occurs is related to the percentage ofHbS present
• heterozygotes (HbAS); sickling occurs at a p02 of 40 mmHg Functional aspl1nism- incneud
IUiiceplibility to infaction by
• homozygotes (HbSS); sickling occurs at a pO:z of 80 mmHg
encapsulated orvanisms
• sickling aggravated by acidemia, increased CO:z, increased 2,3-DPG, increased temperature and • s. pntMJtJIOIIiae
osmolality • N. meningitidis
• sickle cells are fragile and hemolyze; they also obstruct small vessels • H. influenziH
• Salmonella (ostaomyelitis)
Clinical Features
• HbAS (sickle cell trait): patient will be asymptomatic except during extreme hypoxia or infection
..... ,_._, ______________


• HbSS
• chronic hemolytic anemia
• jaundice in the first year of life
AeN Ch_. Syn·-
Aiflell30'll. of patii!Tis with siclda c1U
disease lllld may be life 1hrea1Ening.
• retarded growth and development ± skeletal changes Presentation includes dyspnea, chest
• splenomegaly in childhood; splenic atrophy in adulthood pain, fever, tacl'lypnea. leukocytosis, lllld
pLJm111111ry on CXR. Caused by
vaso-occlusion, infection, or pulmoiiiiiY
fat embolus from infarcted marrow.
H20 Hematology Hemolytic Anemia (HA) Toronto Notes 2011

..... ,

• HbSS often presents with crisis:
1. aplastic crises
Organa Afflctlld lly Vuo-Dcclulivll • toxins and infections (especially parvovirus Bl9) transiently suppress bone marrow
CrUi• 2. splenic sequestration crises
Organ Problem
• usually in children; significant pooling of blood in spleen resulting in acute Hb drop and
shock
Bl'lin Seizures, stroke • uncommon in adults due to functional asplenia from repeated infarction
Eye HemonhaQe, blindneu 3. vase-occlusive crises (infarction)
Livar lnfarl:ll, RUQ synd111111e • may affect various organs causing pain (especially in back, chest, abdomen and
extremities), fever, and leukocytosis (e.g. acute chest syndrome)
Chnt long-Uim
pum01111ry hypertenion • precipitated by infections, dehydration, rapid change in temperature, pregnancy, menses
and alcohol
GaD bladder Stones
4. chest crises (see sidebar, Hl9)
Heart Hyperdynamic flow • HbSC (most common compound heterozygote)
murmurs
• 1:833live births in African-Americans, common in West Africa
Spleen Enlaroed (child I; atrophic • milder anemia than HbSS
(adLitj
• similar complications as HbSS although typically milder and less frequent (exception is
Kidnrt Hamii!Uria; loss of oolll proliferative sickle retinopathy)
concentrating ability
• spleen not always atrophic in adults
lni8Stines Aculll abdomen
Placenta Stillbirths Investigations
• sickle cell prep (detects sickling ofRBCs under the microscope in response to 0 2 lowering
Penis Priapism
agent): determines the presence of a HbS allele
Digits
• Hb electrophoresis distinguishes HbAS, HbSS. HbSC and other variants
Femoral Avaaculu
haad Tabla 9. Investigations for Siclde Call Disease
Bone lnfan:lion, infection HbAS HbSS
Ankle Leg ulcers
CBC Normal Increased reticulocytes, decreased Hb, decreased Hct
Periphelll blood Normat possibly afew target cells Sickled cells
Hb electrophoresis HbA fraction of 0.65 (65%) No HbA, HbS and HbF (proportions change with age)
_E..._.......__.IbiNIH HbS fraction of 0.35 (35%)

. .... Treatment
llr*a1u• '-1111 hllmlll "M*s wid!
Sicldl Clll DinMI • genetic counselling
"""ill8m Atid 2008; Mly 5 • HbAS - no treatment required
Objldn: To..,.._ 1111 liiiiDn
• HbSC - treatment as per HbSS, but is dictated by symptom severity
Cllthe efticq llld 1Dxiciy gf
wf1111 used in ed•witlllictllcel
• HbSS - see Peiliatrics. P50
1. folic acid to prevent folate deficiency
S1udr S*alilll: lllndCIIimd 1rilll. oblaMtianll 2.hydroxyurea to enhance production ofHbF
Sldies, 11111:1111 ,.,arts MbiliJg elliclcy llld • mechanism of action: stops repression of Hb-garnma chains and/or initiates
1Dxiciy rl in llillll will! sictll eel
diseue, lllldiDxicityS!dies in
differentiation of stem cells in which this gene is active
Gthel in E!Qilh • presence of HbF in the SS cells decreased polymerization and precipitation of HbS
were inc:Uied. • NB: hydroxyurea is cytotoxic and may cause bone marrow suppression
a.ulll: In 1lla si"QIIImdomilldtrill, 1lla 3. treatment of vase-occlusive crisis
hlniiQiobin IMI- 119* •oxygen
18Cipienl$111an pllcebo recip-. $ 21"11'
(dillnncl, 6!Vll.•-fmllwnoglolil • hydration (reduces viscosity)
(llbsoki11 tlle!nce. The medi;m runber • antimicrobials
al peililll criSIS wasoMiowertllln in the • correct acidosis
plcello IIIII. The 12 allseMtiDnll stlldies 1hlt
emded ..... rupol18d in-. il flllll • analgesics/narcotics
hemJglolin rl4% 111m lAd • Rllltive 11Cllcti111 • magnesium (inhibits potassium and water efilux from RBCs thereby preventing
il crilii lltBI by 68%11184'- Holiilllldmiuilns dehydration)
diCined by 18% Ill aa 1hl widance qgam • indication for exchange transfusion: acute chest syndrome, stroke, bone marrow necrosis,

Lmillll nidance indicllll11111 hydraxyur. priapism, CNS crisis
trellbnent il siclde eel ilsene is 4. prevention of crises
not IIIIOCillld witllllukamL Similar!,, limited • establish diagnosis
evidelu awes1s 11111 hydraxyurea llllleg WceiS • avoid conditions that promote sickling (hypoxia, acidosis, dehydration, fever)
.. not IIIOCQd in si:lde eel
disease, lllld evidence is illllll&ient11 esti111111 • vaccination in childhood (pneumococcus, meningococcus, Hib)
111arilklorstin ....,.,IMhOUll U.. • prophylactic penicillin (age 3 months-5 years)
be lllribiDd to in adler • good hygiene, nutrition and social support
conditianl. 5. screen for complications
Clllllbloes: liydrmr,<u111 his dlmonsttlted
elficlcy in lfUbl Mil sictle t:el dise111. The • regular bloodwork (CBC, reticulocytes, iron indices, BUN, LFTs, creatinine)
paucity rllong.tam lkllill imts COIICIUiions • urinalysis annually
lliloltblxicily. • transcranial doppler annually untill6 years old
• retinal examinations annually from 8 years old
• echocardiography every two years from 10 years old (screen for pulmonary
hypertension)
Toronto Notes 2011 Hemolytic Anemia (HA) Hematology H21

Autoimmune Hemolytic Anemia (AIHA)

Tabla , D. Classification of AIHA
Alllibody Allotp
Agglulinlllion Tempel'llunl
Direct Coanm' Test
(direct IIJti.globuli• tat)
Etiulagy
Blood Film
Mln1111mant
W.nn Cold
lgG lgM
37"C 4-37"C
Positive for lgG Positive for complement
Idiopathic Idiopathic
Secondary to lyrrflhoproliferative disorder Secondll'f 1o infection
(e.g. CU. Hodgkin's) {e.g. mycoplasma pneumonia, EBV)
Secondary 1D IIU!oirnnune dis811&B Secondll'{1o lymphoprolifllllltiw disorder
(e.g.SI.f) {e.g. macroglobulinemia, CLl)
Drug induced:
Type 1- haptEn-mediated e.g. penicillin
Type II - irnnunKo""lex mediabld e.g. quinine
Type Ill- "true" anti-RBC Ab e.g. methyldopa
Spharocytas Agglutination
Treat underlying cause Treat underlying cause
Corticosteroids Wann patient
Immunosuppression lmm1110suppmsion
Splenectumy Plasmapheresis

Microangiopathic Hemolytic Anemia (MAHA)

Definition
• hemolytic anemia due to intravascular fragmentation of RBCs

Etiology
• thrombotic thrombocytopenic purpura (TTP)Ihemolytic uremic syndrome (HUS) (see Table 17}
• DIC
• eclampsia, HELLP syndrome
• malignant hypertension
• vasculitis
• malfunctioning heart valves
• metastatic carcinoma

Investigations
• blood film: evidence of hemolysis, schistocytes Fe portion
• hemolytic work-up oflgG
• urine: hemosiderinuria, hemoglobinuria

Hereditary Spherocytosis
• most common type of hereditary hemolytic anemia Figura 9. Spharocyta
• abnormality in RBC membrane proteins (e.g. spectrin)
• spleen makes defective RBCs more spherocytotic (and more fragile) by membrane removal;
also acts as site of RBC destruction
• autosomal dominant with variable penetrance
• investigations: blood film shows spherocytes, increased osmotic fragility, molecular analysis for
spectrin gene
• treatment: splenectomy (pre-surgical vaccination against pneumococcus, meningococcus and
Hib); avoid in early childhood

Hereditary Elliptocytosis
• abnormality in spectrin interaction with other membrane proteins
• autosomal dominant
• 25-75% elliptocytes
• hemolysis is usually mild
• treatment: immunizations; splenectomy fur severe hemolysis

Figura 10. Schistocyte

H22 Hematology Hemolytic AnemiaJMauocytic Anemia Toronto Notes 2011

G6PD Deficiency
Definition
• deficiency in glucose-6-phosphate dehydrogenase (G6PD) leads to a sensitivity of RBC to
oxidative stress due to a lack of reduced glutathione (GSH) (Figure 11)

Pathophysiology
• X-linked recessive, prevalent in individuals of African, Asian and Mediterranean descent

Clinical Features
• frequently presents as episodic hemolysis precipitated by:
• oxidative stress
• drugs (e.g. sulfonamide, antimalarials, nitrofurantoin)
• infection
• food (fava beans)
• in neonates: can present as prolonged. pathologic neonatal jaundice

Figure 11. G&PD Deficiency Investigations

• neonatal screening
• G6PDassay
• should not be done in acute crisis when reticulocyte count is high (reticulocytes have high
G6PD levels)
• bloodfilm
• Heinz bodies (granules in RBCs due to oxidized Hb); passage through spleen results in the
generation of bite cells
• features of intravascular hemolysis (e.g. RBC fragments)

Treatment
• transfusion in severe cases
• stop offending drugs and avoid triggers

Macrocytic Anemia
• MCV>lOO
• see Figure 3, Approach to Anemia, HS

Table 11. Comparison BatwHn Megeloblllltic end Nom-Megaloblastic Macrocytic Anemia

Magaloblllltic Nan-Magalablntic:
Morphology Large, oval, ll!CIIIIIllld RBC pr&Cunor Large round RBC
Hypi!ISI!{Imented neutrophils Normal neutrophils
Pathophpialagy Failure of DNA synthesis resulting in Reflects mermrane abnormality with abnormal
asynchronous maturation of RBC nucleus and cholesterol metabolism
cytoplasm

Vitamin 812 Deficiency

8 12 (cobalamin)
• binds to intrinsic factor (IF) secreted by gastric parietal cells
• absorbed in terminal ileum
• total body stores sufficient for 3-4 years

Etiology
• diet
• strict vegan (rare, more likely to present in infants and toddlers)
• gastric
• mucosal atrophy secondary to chronic gastritis
• pernicious anemia (see below)
• post-gastrectomy
• intestinal absorption
• malabsorption (e.g. Crohn's, celiac sprue, pancreatic disease)
• stagnant bowel (e.g. blind loop. stricture)
• fish tapeworm
• resection of ileum
• rare genetic causes (e.g. transcobalamin II deficiency)
Toronto Notes 2011 Macrocytic Anemia Hematology H23

Pathophysiology of Pernicious Anemia ... ,

• auto-antibodies produced against gastric parietal cells leading to achlorhydria and lack of •t-----------------,
intrinsic factor secretion Charactllriltice of Megalollllllic
• intrinsic factor is required to stabilize B 12 as it passes through the bowel M-oc:ylic Anlmi•
• decreased intrinsic factor leads to decreased ileal absorption ofB 12 1. Pancytoplllill
• may be associated with other autoimmune disorders (polyglandular endocrine insufficiency) 2. HypmegmeniBd neutrophil&
3. Megaloblastic bone marrow
• female: male = 1.6: 1; often >60 years old

Clinical Features
• neurological
• cerebral (common, reversible with B12 therapy)
..... ,
•}-----------------.
• confusion, delirium, dementia
Scbim111 Test
• cranial nerves (rare)
• optic atrophy l'llrt1
• Tracer dose (1 IICI) of radiolabeled 8 12-
• cord (irrevezsible damage) given PO
• subacute combined degeneration • Flushing dose (1 mg) of 1.11liibeled B12
- posterior columns - decreased vibration sense, proprioception and 2-point IM 1 hr IIIIBr to Mtum& lillu& binder$
discrimination of Bu thus allowing radioactive B12
- pyramidal tracts - spastic weakness, hyperactive reflexes to be excreted in urine
• 24 hour urine radiolllbllad Bu
• peripheral neuropathy (variable reversibility) measured
• usually symmetrical, affecting lower limbs more than upper limbs • Nonnal > 5% excr.lion (a nonnal
excretion will only be seen if the low
812 was due to distaty daficiancy)
Investigations
• CBC, reticulocyte count l'llrt2
• Sarna II pllrt 1. but radiolllbelad 812
• anemia often severe ± neutropenia ± thrombocytopenia given with oral intrinsic factor
• MCV>llOfL • Should ba dona only if first sllga
• low reticulocyte count relative to the degree of anemia (<2%) shows reduced excretion
• serum B12 and RBC folate • Nonnalllllt I1IIUit (> 5'1!. axcration) =
pernicious -mia
• caution: low serum B 12 leads to low RBC folate because of failure of folate polyglutamate • Abnonnalllllt result ( <5% axcration)
synthesis in the absence ofB12 = iniBstilal causes (malabsorption)
• bloodfilm
• oval macrocytes, hypersegmented neutrophils
• bone marrow OniV....Bu-lnlrlllulcA'WU..
• hypercellularity llt!fwVblill,lllllil:ilncy
• nuclear-cytoplasmic asynchrony in RBC precursors (less mature nuclei than expected from CDrJnns lllflbll8 S)lt lliN 2005; {l}:C!Dl4655
lllldy: Sys!lmltic nMew. 2HCTs met inct.ni111
the development of the cytoplasm) llilaril; flllll 108 pltients with follow.!Jp from
• bilirubin and LDH 90 cllys fD 411111111hs.
• elevated unconjugated bilirubin and LDH due to breakdown of cells in BM IIIIIVIIIiln: 011111Udy Mklltad IIDJ IIQ ol
• Schilling test (see sidebar) to distinguish pernicious anemia from other causes 1111111111 compnd!D 11DJ IIQ N 811 1111hl11n
(see G17) dosing sciNAe. n. ather CIII1JII8d 2Im IIQ
dati 0111 8,2 to IIDJ pgiM 8,2 Cllllals
dosing ldla!Ut. Nauologiclllrld illmllllogical
Treatment and pairawara IIVILIIBd.
• vitamin B12 1000 IM monthly for life or 1000-1200 11g PO daily if intestinal absorption intact lilllllll: natlllllmpllda
Bath studies"'IIJ!!ed
o less frequent, higher doses may be as effective (e.g. 1000 11g 1M q3 months)
in lwnlfDIDgicllud naLrOiogicll
o watch for hypokalemia and rebound thrombocytosis when treating severe megaloblastic anemia entJ.poinls in balh Olll111d IM groups. No
i!J!iliclnt dilflllncai\U absaMMI balwaan
UIUUPI in iiiMr IIUdy.
Folate Deficiency t.lcUilnl: 1191dosa Dill vitamin B,! 1110).
21DJ iJG) is IIPMrtto IM 'lbnil 812 1111111
11ma ar lass flllrJant •11:'-lula. This cilia
• uncommon in developed countries due to extensive dietary supplementation isSM181ylini1ldbySIIIIIIIIII1JiaiMIIIIIhclrt
• folate stores are depleted in 3-6 months periodl.lnNiici8llt oonan o1 pllim
Mh malbuption IXIIIditiorll were incbled to
g-.liiiiU..IIIIIJIIs fD lballfllill prinlly Clll
Etiology pojdllian. LIIQ11 studies bued in the prirnll'( tu
• diet (folate is present in leafy green vegetables, fortified cereals) pojdllian 111 raquirad.
• traditionally most common cause (less frequent with universal supplementation in foods)
• seen mainly in infants, elderly, alcoholics
• intestinal
• malabsorption
• drugs/chemicals
• alcohol
• anticonvulsants
• antifolates (methotrexate)
• birth control pill
• increased demand
• pregnancy
• prematurity
• hemolysis
• hemodialysis
• psoriasis, exfoliative dermatitis
H24 Hematology Macrocytic Anemia/Hemostasis Toronto Notes 2011

..._, , Investigations
9.-------------------,
Never give folate alone to an individual
with megaloblastic anemia because
it will mask B12 deficiency and
neurological degeneration will continue.
Clinical Features
• mild jaundice due to hemolysis of RBCs secondary to ineffective hemoglobin synthesis
• glossitis and angular stomatitis
• melanin pigmentation (rare)
• purpura secondary to thrombocytopenia (rare)
• unlike B12 deficiency, folate deficiency has no neurologic manifestations
• similar to B12 deficiency (CBC, reticulocytes, film, RBC folate, serum B12 )
• if decreased RBC folate, rule out B12 deficiency as cause
Management
• folic acid 15 mg PO OD x 3 months; then 5 mg PO OD maintenance if cause not reversible

Hemostasis
..._, ,
9}-------------------,
Normal hemostasis occurs as a result of Three Phases of Hemostasis
the balance between procoagulant and
anticoagulant factors. 1. Primary Hemostasis
• goal is rapid cesstion of bleeding
..._, , • vessel injury results in collagen/subendothelial matrix exposure and release of
vasoconstrictors
9}-------------------,
• blood flow is impeded and platelets come into contact with damaged vessel wall (Figure 12a)
3 Phases of Hemostasis • adhesion: platelets adhere to subendothelium via vWF
1. Primary hemostasis • activation: platelets are activated resulting in change of shape and release of ADP and
• Vascular response and platelet plug thromboxane A2
formation via vWF
• aggregation: these factors further recruit and aggregate more platelets resulting in formation
2. Secondary hemostasis oflocalized hemostatic plug
• Fibrin clot fonnation
3. Resolution 2. Secondary Hemostasis
• Fibrinolysis
• platelet plug is reinforced by production of fibrin dot in secondary hemostasis (Figure 12b)
• extrinsic pathway
• initiation of coagulation in vivo
• intrinsic pathway
"''
Tests of Secondary Hemostasis
• amplification once coagulation has started
PT/INR: Tennis is played outside
(Extrinsic Pathway) 3. Fibrin Stabilization and Fibrinolysis (resolution)
• conversion from soluble to insoluble dot
PIT: Table Tennis is played inside
(Intrinsic Pathway) • once healing initiated, dot dissolution (anticoagulant pathway)

IEXTRINSIC PATHWAY [[INTRINSIC PATHWAY I

HMWK

•
Tissue Damage

Tissue Factor (TF) (AT)

i i
'' ''
Lumen of vuJ.vlla IX IXa ·----------e-• l::

blood vessel
Ca"
.. PL
r-&---· :
X : xa •--------e-:

+
1
PL

r
Protem C II> APC----&----'
Exposed collagen fibres in subendothelium

-L
HMWK- High Molecular II . lla •---&
Weight Kininogen (Prothrombtn) (Thrombtn)
PK - Prekallikrein
von Willebrand factor (vWF) t:! Unactivated
Activated GPifbAifa
Fibrinogen
PL - Phospholipid
APC - Activated Protein C
tPA
SK
- Tissue Plasminogen
Activator
- Streptokinase
Plasminogen tPA/SKJUK II> Plasmin
. .

i
Ftbnnogen
. .
Ftbnn
Xllla._l!LXIII
UK - Urokinase
FOPs - Fibrin(ogen) FOPs
IS> _ Products Crosslinked Fibrin Clot
-Activated
© Diana Kryski 2007

Figure 12a. Platelet Activation Cascade Figure 12b. Coagulation Cascade

Toronto Notes 2011 Hem.ost:aais Hematology H25

Tabla 1Z. Commonly Used Tests of Hemostasis

Type of Test Relei'IIICIIIIngl l'lrpDH Assaciltld
Hemllltllis DiiQnoses
PlatElet count 150-450 x 1Q9JL To «JJ&ntitate platelet number Low in ITP. HUS/TTP. DIC
Bleeding time N <8 mins Pllllelet function and vessel wall High in severe thi'DIIilocytopenia,
function vWD, platelet dysfunction
ZZ-35 sec Measures intrinsic pathway (factors High in hernophilias A111d B
VIII, IX, XI, XII) 111d common pathway
Used to monitor heparin 1harapy
PT 11-Z4sec Measures extrinsic pathway (factor VII High in factor VII cleficiency
in particular) and common pathwlly
INR 0.9-1.2 Permits detannination of axtrinsic
pathway status independent of
labDI'IIIIIry perfonning measurement
Used to monitor warfarin therapy
Mixing studies Differen'liate inhibitors of ciDIIing CIDIIing faclolis) deficiency if test
from a deficiency in clotting becomes nonnlll
lnhibitm of clotting factor1sl if
Mix patient's plasma with nonnal test stil abnormal
plasma in 1:1 ratio and repelll
lllmonnal test
Fibrinolysis EuglobLJin lysis N >9 min Looks for accelerated fibrinolysis May be accelerated in DIC
time Low in hareditary deficiancy of
fibrinogen
Dlh• Fibrinogen
Fibrinogen degradation products (FOPs). D-dimers
Specific factor assays
Tests of pllysiological inhibitors (antithi'DIIilin, proteinS, protein C, hereditary resistance to APCJ
Tasbi of pathologic inhibitors {e.g. lupus inlicoagulant)

Tabla 13. Signs and Symptoms of Disardars of Hamastasis

Primuy (PIItalll] Sacandary (CDII!Iulatian)
Surface Cuts Excessive, prolonged bleeding NonnaVslightly prolonged bleeding
Onut Afllr Injury lrrmediate Delayed
SitB of Bleeding Superficial i.e. mucosal {nasal, gingival, Deep i.e. joints, muscles, Gl tract, GU bllct
Gl bllct, utaine), skin Excessive post-traumatic
Lesions Petechiae, ecchymoses Hemarthroses, hemlllomas

Tabla 14. Lab Valuas in Disorders of Hemostasis

PT m Plltalat Count RBC Calllt
Hemophilia NB N .,. N N
vWD N .,. N N
DIC .,. .,. NI..V
Liver Falure .,. N/'1' ""NI..V N
ITP N N N
m N N "" .J,
""
H26 Hematology Disorders of Primary Hemoatasis Toronto Notes 2011

Disorders of Primary Hemostasis

..... ,'
Definition
D111111 "-18tH wltb • inability to form an adequate platelet plug due to:
Thrombocytopenia • disorders of blood vessels
JMP.SMl( H8pn NSAID1 • disorders of platelets
• abnormal function
Ylncomyi:il Digmdn Acellminophen
• abnormal numbers {thrombocytopenia)
Ailampin AniJdnle Elllillol • disorders of vWF
Bbllltutol i).Jinidine HrWQonin
Classification

I 1• Hamaltalis Di1ard.. I
•
IPLATILETS I I •I
vWD •
IvASCULAR I
... ... ... ...
ILow plmlet caunt:
• Thrombocytopenia (.ee H6)
j INonnal plmlet count:
• Platelet dysfunction
J Hereditlry
• Osler-Weber.flendu
Acquired
• Purpura simpll!X
• Connective tissue (eiS'f bruising)
disorder$ • Senila purpura
I
•
• [)ysprotainamiu

+
o.c-•d lncr..Nd Seq.-tration
+
Ha111ditary Acquired
+ • HSP
• Scurvy
• Cushing's syndrome
prodlll:tion destructian • Splenomegaly • Barnard Soulier • Drugs [ASA. • lnfaclians, drugs
• ApiiiSiic • ITP syndrome (GPib EtOH, NSAI!ls)
anemia • TTP/HUS deficiancvl • Uramiai'CRF
• HIT • Glanzmans • Myeloprolifemive
syndrome [GP disorders
llb,lllla dllficiancvl

Figure 13. Approach to Disorders of Primary Hemostasis CRF Chnlnic Rnl fliDnl

.... ,•t----------------.
' Immune Thrombocytopenic Purpura (ITP)
------
fur
TbramllacyiDpenia Table 15. Immune Thrombocytopenic Purpura
1. Direct effect of HIV on marrow FlltUNI Ac:lltiiiTP ChraniciTP
2.1rnmunaofllediltad platalat dastruction Peak Age years 2G-40years
3. Some antiretrovirals reduce platelet Sex Prediection None F>M(3:1)
production
History of Recant Infection Common Rare
Onsst of Bleed Abrupt Insidious
Duration Usually weaks Months to years
Sponlllneous Remissions 80% or more Uncommon

ACUTE (CHILD-TYPE) ITP

• see Pediatrics. P51

CHRONIC (ADULT-TYPE) ITP

• most common cause of isolated thrombocytopenia
• diagnosis of exclusion {ie. isolated thrombocytopenia with no clinkal.l.y apparent cause)

Pathophysiology
• anti-platelet antibodies bind to platelet surface -+ increased splenic destruction and clearance

Investigations
• CBC: thrombocytopenia
• bleeding time: increased
• PT and aPTT: normal
• peripheral blood film: decreased platelets, giant platelets
• bone marrow: increased number of megakaryocytes
• critical test to rule out other causes ofthrombocytopenia for age >60 years
(e.g. myelodysplasia)
Toronto Notes 2011 Disorders of Primary Hemostasis Hematology H27

Treatment I'IPtl:mCII . .
A. Emergency Treatment (active bleeding or in need of emergency surgery) Di.... rl .................,..
•methylprednisolone 1 g/d fur 3 days, then prednisone 1.5 mglkg/day illwllti:IIS...
•IVIG 1 glkg/d X 2 days J 1lilllmb lllemol2006; 4:7§9·65.
•tranexamic acid 1 g IV q6h SIUr.l'rospectiveml
ICOIIIPIJiicltiln il two cinicalslttings (H11milmn
•vaccination (pneumococcus, meningococcus, HIB) Generll HasJml HGH: 1nd G!thwlld il 61111'1111\'.
•fur life-threatening bleeding, platelet transfusions are appropriate (max. 1 pool q4-6h) GW).
•emergency splenectomy may be considered l'apUtial: 33& prienb wilh IUII)eCIBd HIT.
...........: Rilt51rltfic:alionMIII4Tsdinicll
•management of intracranial bleeding: IV steroids, IVIG, platelets, emergency splenectomy, ICOII compuld Ntiiiii'Diagy lor HIT mlilady.
and then craniotomy; maintain Plt >100 for at least 7 days post ICH ._.: 1./6411.6\1 in HGti lnd (ll'IIJ] in r1N
B. Non-Urgent Treabnent (platelet count <20-30 x 109/L and no bleeding OR significant bleeding wilh low IICOIII18111d PQiiM 011 HIT serology.
symptoms with platelet count <50 x 109) &128[28.6\1 ill HGti 111111 lln39 (7.9%) il GW-Mtll
illl111111111t sansllllld poli1M far HIT. .-&
• platelet transfusion does not work [100\1 in HGH lnd 9142 121.4\1 in GWwilh high
• avoid IVIG for patients with no active bleeding ICOIII mal poliiv8 fur HIT.
• prednisone 1-2 mg/kglday, taper once response is seen (Plt >50 x 109) by 50% every 14 days c.:luin: Alow llfdeSt cflicllsae CUI help
• all patients should be vaccinated (pneumococcus, meningococcus, lflB) 1D IIIII aut HIT in plliara Mill thramboc:ytDpenil.
• if steroids fail, or patient relapses on taper, or requires >10 mg prednisone daily to maintain
Pit >20 x 109 AND has a persistent severe thrombocytopenia (<20 x 109/L or 20 x 109
to 50 x 109 with bleeding), splenectomy may be considered ,.,
C. Post-splenectomy Refractory ITP
AIIIIIICI of 4rs 111111111 HIT ...Uklly:
• dexamethasone 40 mg x 4 days, every 28 days fur 6 cycles Thrombocytopenia
• tranexamic acid 1 g IV tid ifPlt <10 x 109 , active bleeding Timing of platalst count faU
Thrombosis or Olllar
Prognosis other causes for ThrombocyiDpeniB

'.'
• fluctuating course
• overall relatively benign, mortality 1-2%
• major concern is cerebral hemorrhage at Plt <5 x 109/L, although very rare ....
LMWH is also Ulociated with HIT
but 1he risk is len than unfnlctioiiBied
Heparin-Induced Thrombocytopenia (HIT) heparin.
------
Table 16. HIT·IIIHeperin-induced Thrombocytopenia, Type II)
Pltllophysiolagy mmune mediated ...,, '
Ab recognizes a complex of heparin and platelet factor 4 (PF4) leading to platelet activation via
pllllelet Fe receptor and activation of coagullllion system
...----------------.
HIT Type I (Hepui-nc.....
Diagnosis 50% reduction in platelets while on heparin within 5-15 days of initilllion thromllocytopenil]
• llir8ct heparin medillted plllbJiet
Onset of Decreaed Pllleleb 5-15 days exposed to heparin, HIT can develop in hours) (non-immLl111)
Rilk of Thrumbolil -30% {25% of events are art!rial) • Platelets > 100 X 10111.
• Self-limillld (no 1hrombotic ri&k)
Clinil:ll Features BIB&ding compliclllions uncommon • May continue with heparin therapy
Venous throrrtosis: DVT. PE, limb gangll!lle, cerebral sinus 1hrombosis • On.ut 24-72 hoUr$
Arterial thrombosis: stroke, acute limb ischemia, organ inflrt:t (mesentery, kidney)
Heparill-induced skin necrosis (w!LMWH)
Acuta platalst activation syndromes: eculll inllammlllory reactions (e.g. f&var/chills, flushing, etc.)
Transient global amnesia {rare)
Specific Tall1 14(: serotDnin release assay (uses donor pllllelets with 14(: serol!min and heparin with patient's
plasma)
EUSA for HIT-Ig (more sensitive, less specific !han serotonin assay)
Flaw cytom&try
Mln11111mant Clinical suspicion of HIT should prompt discontinuation of heparin (specific tests taka several days)
Because 11190% crOIRHllectivity, LMWH should not be substituted
agents include: Lepirudil (recorrtinant hirudin. avoid in renal disease), Argatraban
{effective thrombin inhibitor, monitored with aPTT, use with caution in liver disease), Danapnid
H28 Hematology Disorders of Primary Hemoatasis Toronto Notes 2011

Thrombotic Thrombocytopenic Purpura (TTP)

and Hemolytic Uremic Syndrome (HUS) ---------

Table1'l. TTP and HUS

T1P HUS

..... ,
..----------------.
Plthopbysialagy of TTP
Epidemiology
Etiology
Predomimlltly aU
Deficiency of mellllloproteinase that breaks
down ulba-lir'ge VHF muttimn
• Congenital (genetic absence of ADAMTS-13)
Predominandy children
Shiga toxin (f. coli serotype 0157:H7)

• VWF secreted by endothelial cells in a

-v lara- polymlr rapidly ciiiMd by
the ADAMTS-13 protEase
• Conganital TIP ill deficiant in
ADAMTS-13
• Antibodies against ADAMTS-13 a111
pnsllllt in acquired TTP
Clnicll faaturas
• Acquired (drugs, malignancy, transpllllt.
HIV-essociated, idiopathic)
1. Thrombocytopenia 1. Severe thrombocytopenia: purpura,
2. Microangiopathic hemolytic anemia (MAHA) epislaxis, hematuria. hemoptysis. Gl bleed
3. Neurological headache, 2. hemolytic anemia (MAHA)
confusion, focal dalacls, saizunls 3. failure: abnormal urinalysis,
4. Renal failure oliguria, acule renal failure

,, ,
.
5. Fever
lrmlltigdana (both TIP, HUS) CBC and blood film: dea-eased platelets and schistocyll!s
PT, aPTT, fibrinogen: normal
Dil'fllrtntill Di._.ullit of TIP: Mirls15 of hemolysis: incraa&ed unconjugated bilirubin. incraased LDH, decraased haptoglobin
S.pail
DIC Negative Coombs' test
HEUP Creatinine, urea, to follow renal function
Antiphosptlolipid Ab syndrome Stool C+S (HUS)
EVIIIIS ll'fndrome (autoimmune hemolytic
anllllia + ITPI Manqem11t (both TIP, HUS) Plasmapheresis ± steroids
Platelet transfusion is conlraindicated (increased microvascular thrombosis)
Plasma infusion is not immedialaly available
TIP mortality -90% if untreated

Von Willebrand Disease (vWD)

Pathophysiology
• heterogeneous group of defects
.... ,...----------------.
, • usually autosomal dommant (type 3 is autosomal recessive)
• qualitative or quantitative abnormality of vWF
• vWF needed for platelet adhesion and acts as carrier for Factor VIII; abnormality of vWF
Consider vWD in 1111 women with can affect both primary and secondary hemostasis
m-nllagil. • vWF exists as a series of multimers ranging in size
• largest multimers are most active in mediation of platelet adhesion
• both large and small multimers complex with Factor VIII
• usually mild in severity

Classification
• type 1: mild quantitative defect (decreased amount of vWF) - 75% of cases
• type 2: qualitative defect (dysfunctional vWF)- 20-25% of cases
• type 3: severe total quantitative defect (no vWF produced) - rare

Clinical Features
• mild
• asymptomatic
• mucosal and cutaneous bleeding, easy bruising, epistaxis, menorrhagia
• moderate to severe
• as above but more severe, occasionally soft-tissue hematomas, petechiae (rare), GI bleeding,
hemarthroses

Investigations
• increased bleeding time and PTT
• decreased Factor VIII (5-50%)
• platelet count nonnal or rarely decreased
• decreased ristocetin cofactor activity (normally causes vWF to bind platelets tightly)
• decreased von Willebrand antigen (in types 1 and 3)
• blood group (as antigen quantification reference range differs dependent on blood group)
• analysis of vWF multimers to detect variants
Toronto Notes 2011 Disorders of Primary Hemostasis/Disorders of Secondary Hemostasis Hematology H29

Treatment
• desmopressin (DDAVP•) is treatment of choice for type I vWD
• causes release ofvWF and Factor VIII from endothelial cells
• variable efficacy depending on disease type
• need good response before using with further bleeding
• not to be used in type Im (will cause worsened thrombocytopenia)
• tranexamic acid (Cyklokapron•, antifibrinolytic) to stabilize clot formation
• high-purity Factor VIII concentrate containing vWF (Hemate p•) in select cases and type
• fresh frozen plasma (FFP) is not useful
• conjugated estrogens (increase vWF levels)

Prognosis
• may fluctuate, often improves during pregnancy and with age

Disorders of Secondary Hemostasis

Definition
• inability to form an adequate fibrin clot
• disorders of clotting factors or co-factors
• disorders of proteins associated with fibrinolysis
• characterized by delayed bleeding, deep muscular bleeding, spontaneous joint bleeding

Tabla 1B. Classification of Secondary Hamostlsis Disorders

Hnlitary Acquired
Factor VIII: Hemophilia A. vWD Liver disease
Factor IX: Hemophilia B(Chrislmas Disease) DIC
Factor XI Villmin Kdeficiency
Other factor deficiencies are rare Ac(Jlired inhibitors

Hemophilia A (Factor VIII Deficiency) - - - - - -

Pathophysiology
• X-linked recessive, 1/5,000 males C'
• mild (>5% of normal factor level), moderate (1-5%), severe (<1 %} H•mophiliiiA
Fivll H•
Clinical Features Hemarthroses
• see Table 13 - Signs and Symptoms ofDisorders ofHemostasis, H25 Hem&tl!mas
HIIIIIBIIIch&zill
Hernallril
Investigations Head hemonhage
• prolonged aPTT, normallNR (PT)
• decreased Factor Vlll (<40% of normal)
• vWF usually normal or increased
Treatment
• desmopressin (DDAVP•) in mild Hemophilia A
• recombinant Factor VIII concentrate for
• prophylaxis
• minor but not trivial bleeding (e.g. hemarthroses)
• major potentially life-threatening bleeding (e.g. multiple trauma)
• anti-fibrinolytic agents (e.g. tranexamic acid)

Hemophilia B (Factor IX Deficiency) Figura 14. Clotting Factors

------- Involved in PT and PTT
• a.k.a. Christmas disease
• X-linked recessive, 1/30,000 males
• clinical and laboratory features identical to Hemophilia A (except decreased Factor IX)
• treatment: recombinant Factor IX concentrate, anti-fibrinolytic agents

Factor XI Deficiency
• a.k.a. Rosenthal syndrome
• autosomal recessive; more common in Ashkenazi Jews
• usually mild, often diagnosed in adulthood
• Factor XI level does not correlate with bleeding risk
• treatment: fresh frozen plasma, Factor XI concentrate
H30 Hematology Disorders of Secondary Hemostasis Toronto Notes 2011

... '"
lnnstiplillns in Unr Di•ne
Factor V, VII, VIII. Expect decreiiSed V
and VII because they have the shortest
half-life_ Factor VIII wiUbe nonnal or
incralllld because it is produced in tha
endo111elium.
Liver Disease
• pathophysiology
• deficient synthesis of all factors except VIII
• aberrant synthesis of fibrinogen
• deficient clearance of hemostatic 'debris' and fibrinolytic activators
• accelerated destruction due to dysfibrinogenemias: increased fibrinolysis, DIC
• miscellaneous: inhibition of secondary hemostasis by FDPs
• investigations
• peripheral blood film: target cells
• primary hemostasis affected
• thrombocytopenia 2° to hypersplenism, folate deficiency. alcohol intoxication, DIC
• platelet dysfunction (e.g. alcohol abuse)
• secondary hemostasis affected
• elevated INR (P'I), aPTT and thrombin time
• treatment: supportive, fresh frozen plasma, platelets, treat liver disease

Vitamin K Deficiency
Etiology
'"
...
• drugs
• oral anticoagulants inhibit Factors II, VII, IX, X, protein C and S
• antibiotics eradicating gut flora, which provide 50% of vitamin K supply
Vitamin K Depndant f1ct11111
1972 Canada vs. Soviet • poor diet (especially in alcoholics)
X. IX. VII, II protein Cand S • biliary obstruction
• chronic liver disease (decreased stores)
• malabsorption (e.g. celiac disease)
• hemorrhagic disease of newborn, see Pediatrics, P73

... '"
..
Investigations
• INR (PT) is elevated out of proportion to elevation ofthe aPTT
PT should improve within 24 hours • decreased Factors II, VII, IX and X (vitamin K-dependent)
ofvilllmin K lldministnrtion !onut is
in 6-12 hrs). If not. sean:h fur other
causes. Treatment
• hold anticoagulant
• vitamin K 1 mg PO for INR between 4.5 and 10 and not bleeding (excludes hemorrhagic disease
of the newborn)
• if bleeding, give vitamin K 10 rng IV/PO
• if life-threatening bleeding, give fresh frozen plasma (FFP)
• note: excessive vitamin K will delay therapeutic warfarin anticoagulation once re-started

Disseminated Intravascular Coagulation (DIC)

...__,"
• Definition
flctor Levels in Acquired • uncontrolled release of plasmin and thrombin leading to uncontrolled intravascular coagulation
C:O.IPJhlpdlin and depletion of platelets, coagulation factors and fibrinogen
FICIIr lillrllilla Vblil DIC • risk oflife-threatening hemorrhage
IIIII
v .j.. N .j.. Etiology
'II .j.. .j.. .j.. • occurs as a complication of many other conditions
VII N/1' N .j.. • widespread endothelial damage ± extensive inflammatory cytokine release
• adifttlon of procoagu]ant adivity
• antiphospholipid antibody syndrome
• intravascular hemolysis (incompatible blood, malaria)

... '"
• tissue injury (obstetric complications, trauma, burns, crush injuries)
• malignancy (solid tumours, hematologic malignancies especially acute promyelocytic
leukemia- AML-M3)
DIC is a spectrum which may induda
thrombosis or bleedilg or boltt • snake venom
• fat embolism
• heat stroke
• endothelial injury
• infections/sepsis
• vasculitis
• metastatic disease (adenocarcinoma)
• aortic aneurysm
• giant hemangioma
• reticuloendothelial injury
• liver disease
• splenectomy
Toronto Notes 2011 Disorders of Secondary HemostasWVenoiB Thrombosis Hematology H31

• l'Ucular stasis
• hypotension
• hypovolemia
• pulmonary embolus
• other
• acute hypoxia/acidosis
• extracorporeal circulation
Clinical Features
• signa of m.icrovucular thrombosis
• neurological: multifocal infarcts, delirium, coma, seizures
.... ,.. ,

• skin: focal ischemia, superficial gangrene
lmparlainl EliDIDgiel of DIC
• renal: oliguria, azotemia, cortical necrosis • Traum•
• pulmonary: ARDS • Shock
• GI: acute ulceration • Infection
• RBC: microangiopathic hemolysis • Malignancy
• signa of hemorrhagic diathesis • Obstetric complications
• bleeding from any site in the body 2° to decreased platelets and clotting factors
• neurologic: intracranial bleeding
• skin: petechiae, ecchymosis, oozing from puncture sites
• renal: hematuria
• mucosal: gingival oozing, epistaxis, massive bleeding
Investigations
• primary hemostasis: decreased platelets
.... ,_._, ______________

• secondary hemostasis: prolonged INR (PT), aPTT, TT, decreased fibrinogen and other factors
• fibrinolysis: increased FOPs or D-dimers, short euglobin lysis time (ie. accelerated fibrinolysis) Ltvals of c1111 still Ill normal in
• extent of fibrin deposition: urine output, urea, RBC fragmentation DIC H it is 1111 acuiB phHa reaelant.
Sarill fibrinogen ltvels shoWi Ill
meuured to see if there is a trending
Treatment along with an incl'lau in
• recognize early D-dimer.
• treat underlying disorder
• individualized critical care support
• in hemorrhage: replacement of hemostatic elements with platelet transfusion, FFP, cryoprecipitate
• in thrombotic phase: LMWH (controversial)

Table 19. Screening Test Abnormalities in Coaguloplthies

lncrGIJIId INR o-, lncreaiiGd PIT Only Botil ..creaiiGd
Factor VII deficiency Hemophilia A and B Prothrombin deficiency
Vrtanin Kdeficiency vWD Fibrinogen deficiency
Warfarin Heparin Factor V and X deficiency
Liver disease Antiphospholipid Ab Severe liver disease
Factor VII inhibitors Factor inhibitors Factor V and X. prothrorrilin, and fibrinogen inhibitors
FXliF XII daliciency Excessive illlticoaiJIIiltion

Venous Thrombosis
Definition
• thrombus fonnation and subsequent inflammatory response in a superficial or deep vein
• thrombi propagate in the direction of blood flow (commonly originating in calf veins)
• more common in lower extremity than upper extremity
• incidence -1% if age >60
• most important sequelae are pulmonary embolism (-50% chance with proximal DVT) and
chronic venous insufficiency
Etiology (Virchow's Triad)
• endothelial damage .... ,,

• leads to decreased inhibition of coagulation and local fibrinolysis
• venous stasis
• immobilization (post-MI, CHF, stroke, post-op) inhibits clearance and dilution of • Endothalill damiiQII
ooagulation factors • Stasis
• Hypen:oagulability
• hypercoagulability
• inherited (see Hypercoagulable Disorders, H33)
• acquired
• age (risk increases with age)
• surgery (especially orthopaedic, thoracic, GI and GU)
• trauma (especially fractures of spine, pelvis, femur, or tibia, spinal cord injury)
• neoplasms (especially lung, pancreas, colon, rectum, kidney and prostate)
H32 Hematology
..... '.. ,
Folic acid 5 mg PO dl.ily wiD problct
agaillll incr1111aad homacy&biinelevela.
...... WularillBIPJ
Amlllfllmu.ll2003; 138(11:714-9
l'llilnll:201 ,.tiarDwitbaciDWIIOUI
.......-: 5ntwarflrin inilildionnOITIOIJIIII
V1111l110
Mlir...._:frrne1DtlrenrfeuticNI.
1111*1: PlliantJ il the 10 q 11101111 rMCIIad I
1berlpdc IMIU days faller ttu b in lhe
5 mg graup willl no dllam:a illl'ljor blladll
IIIIYMn 1llltwoP411 (p<O.DD1].
Ca:llliln: lnitildion «.tann
lllll'lpywitb •
10 narnogr1111alows lalllr EliMmlricia
1berlpdc bleedilgrist.
D-....
NEJM 2m3; 349(13):1227-35
- llllllarrizedtrillwitl1 &WIIIk
follow-lip.
l'llilnll: 59& pllierts with suspected leg 1M.
ltlltDid u mt. iklly or mhM D'IT
were lll1danimd 1D receive or not l).dimer
1BIIilg in lddilian 1D &lmllfd lilpili: . . .
set !Ubylbe irvesligas.
.....: Pllienl$ il11111}6nar lrQd graup
undlrwlnt ln.w ubllllllllfl1111111111111 in 1111
coi'UOI graup [0.7118atsl* palientuwws1.34
18atsperpdn, • prevent further clot extension
negative leslllld no ulbasculd performed
wm1111r clricllt dlllllld 1D hM 1DVT.
Ca:llliln: flsli1g is usefW in
lllr&:ullrttillilw·riskpllierrls.
........ ' .weilhlllirplriiQIUI
c:..n.ilt. lllll'rlllrdln ., 111111111111
'Maullhi............ ir ........
c.-
NEJM 2003; 348:146·53
SlUr. RCT Clll11pllilg 1111111icacyo1LMNH
(drrbplrir) witb an Dllllllli-CIIIPniiQ!nl
(Cawnlrin] ir piMidilg IUMiit thrombolsii ir
pllierts • cancer.
........ PllierQ witb- who '-IIICU18,
.,.......,. pl'lllliniiiM, PE. or bath-
1111domly IIAipd 1otwo1JDU111.
aiJAWH (dribplril200 IUI«g SC ODJ
far days and 1 cOIII1lria derimive for six
daillpllir IIane far sit mantlrs 1200 Rfta 1li1111111.
foii!JNed by I daily diJII (i lfllllllimlilltr
150 ILVK; far 51111n!rs].
..... D.ringlbe P.rnontlr •dr period.
l1 al336 pllilrts in 1111 dllllpmin PIP hid
oomrtwnausltrunOiumboilmr. H_. in
1111 53
{lrmnl ndio. 0.48; P=O.DOZ] hill rec:IIRIIIt
VliiliUS ltrarranbollm. 1111 pmhlbirt af
111C1mi1111mrrrmoerrlldisrn • 6monllrs WIS 17ll
ir 1111 Oi'IHOOCOIQUiri prp CDII'!III'Id 1o ll'li
ir lire drillepnl GIDUP· There WIS no siGnificant
ditlnrce hltwrilri the dllbiplrin and 11111
lll1licoiGuUI Gf1141 i11ll11111 ci lllljor
{li'hnd 4'- nllfi8CiivlliV]onnyblalding (1.ftiMd
111'1i, IISIIIC1MM. AI& rrrcnhl, the rnortBily 1111
- 311'1i in lire dllleperin group lilid 41, illlre
group.
c:..:IIUE In patieuls witb CliiCel' lilid acute
WIIOUI ltrarranboism, dllt8puiiWIS mDII
efleclive1lrllll an 0111 mlicolaulllll in decreasinG
11111 risk oiiiiCIIIIIIIII!nnillolmbollm Mhaut
irC!IIIing the rilt rl bllldira.
Venous Thrombosis Toronto Notes 2011
• blood dyscrasias (myeloproliferative disorders, esp. PRV, ET), PNH, hyperviscosity
(multiple myeloma, polycythemia, leukemia, sickle cell)
• prolonged immobilization (CHF, stroke, MI,leg injury)
• hormone related (pregnancy, OCP, HRT, SERMs)
• antiphospholipid antibody syndrome (APLAS)
• hyperhomocysteinemia
• heart failure (risk ofDVT greatest with right heart failure and peripheral edema)
• idiopathic (10-20% are later found to have cancer)
Clinical Features
• absence of physical findings does not rule out disease
• unilateral leg edema, erythema, warmth and tenderness
• palpable cord (thrombosed vein)
• phlegmasia cerulea dolens and phlegmasia alba dolens with massive thrombosis
• Homan's sign (pain with foot dorsiflexion) is unreliable
Differential Diagnosis
• muscle strain or tear, lymphangitis or lymph obstruction, venous valvular insufficiency,
ruptured popliteal cysts, cellulitis, arterial occlusive disease
Investigations
• D-dimer test only useful to rule out DVT if negative and low clinical suspicion of disease
• doppler ultrasound is most useful diagnostic test for DVT
• sensitivity and specificity for proximal DVT -95%
• sensitivity for calf DVT -70%
• other non-invasive tests include MRI and impedence plethysmography
• venography is the gold standard, but is expensive, invasive and higher risk
Approach to Treatment of Venous Thrombosis
Purpose
• prevent acute pulmonary embolism (occurs in -50% of untreated patients)
• reduce the risk of recurrent thrombosis
• treatment of massive ileofemoral thrombosis with acute lower limb ischemia and/or venous
gangrene (phlegmasia cerulea dolens)
• limit development of late complications, e.g. postphlebitic syndrome, chronic venous
insufficiency and chronic thromboembolic pulmonary HTN
Initial Treatment
• unfractionated heparin (UFH)
• requires bolus (7500-10,000 ill), followed by continuous IV infusion (1000-1500 IU/h)
• weight-based heparin nomograms help to achieve proper dosing
• advantages: rapidly reversible by protamine
• disadvantages: must monitor aPTT with adjustment of dose to reach therapeutic level
(-2x normal value); monitor platelet counts for development of HIT
• low molecular weight heparin (LMWH}
• administered SC, at least as effective as UFH
• advantages: predictable dose response and fixed dosing schedule; lab monitoring not
required; lower risk of HIT; safe and effective outpatient therapy
• disadvantages: only partially reversible by protamine
• renally cleared - may need to adjust dose in patients with renal dysfunction
• alternatives to LMWH and UFH
• heparinoids (patients with HIT}, direct thrombin inhibitors (hirudin, lepirudin, argatroban),
Factor Xa inhibitors (fondaparinux)
• thrombolytic drugs (e.g. streptokinase, tPA) reserved for limb/life-threatening thrombosis,
recent symptoms, low bleeding risk
Long-tenn Treatment
• warfarin
• standard treatment; should be initiated with heparin overlap - dual therapy for at least 5 days
• discontinue heparin after INR >2.0 for two consecutive days
• warfarin should be dosed to maintain INR at 2-3 except in select cases
• monitor INR twice weekly for 1-2 weeks, then weekly until INR stable, then every 2-4 weeks
• recent evidence suggests therapeutic INR can be reached quicker with warfarin initiation
protocol that starts with 10 mg dose (see sidebar)
• LMWH more effective than warfarin at preventing recurrence of venous thrombosis in
cancer patients (see sidebar)
• duration of anticoagulant treatment (with warfarin unless otherwise noted):
• first episode DVT with transient risk factor: 3 months
• first episode DVT with ongoing risk factor (e.g. cancer, antiphospholipid antibody) or
>1 risk factor: consider indefinite therapy
Toronto Notes 2011 Venoua ThrombosWHypercoagulable Disorders Hematology H33

• first episode DVT with no identifiable risk factor (idiopathic) or single inherited risk factor ........ , ........... VIulill
(e.g. Factor V Leiden): 6-12 months or indefinite therapy (controversial) Anllgalillsil .....
• recurrent DVT (2 or more episodes): indefinite therapy nn.........
• IVC filters C«<rMe Dfllllu ri Sl'$ffllll!i:/1Miws 2006;
• useful in those with contraindications to anticoagulant therapy, recurrent thromboembolism Issue 1
llldr: M11Hn1Jw1is a1 aRCTs (2994 pililnlsl
despite adequate anticoagulation, chronic recurrent embolism with pulmonary HTN, or cmpllilq dllenld Mtians rllreltmiR Mil
those who require emergent surgery without time to initiate anticoagulation Wllnil KIIIDplisll in
• special considerations waoos dnurrlloembolsm !Viti.
I'MI ._.: pn.rOu.ndwilb willnin K
• pregnancy: treat with LMWH during pregnancy, then warfarin for 4-6 weeks post-partum lllllgani111 Ia! a ]Riangld plriod, thllllll:tian in
(minimum total anticoagulation time of3-6 months) risk riiiMIIliVTE
• surgery: avoid elective surgery in the first month after a venous or arterial thromboembolic rl1he period rltinuinctthl indauvent lOR D. IB,
event C1 0.1"2SJ.In adiltioli, oll5eMd
IXC. . rl VTE I'ICIIIIIIIC. fDIDNillll c.atian rl
• preoperatively: IV heparin may be used up to 6 hours pre-operatively pralanged vitamin II. 111111goJis11bmpy 11111.24,
• perioperatively: surgery safe when INR <1.5; warfarin should be discontinued for at least Cl 0.11·1.681-llowMf, pltiemswho receivad
4 days pre-operatively to allow INR to fall pralanged treltment hid I persislm iiiCIIille il
• postoperately: IV heparin or LMWH can be used for anticoagulation (start 12 hours after tllai' rilkaf mljor blaadillll campbtiana(Oft 2.61,

major surgery until therapeutic INR reached after restarting warfarin) Candlliln: l'lokllgad 1MimelltMh vDri1
• for patients at high risk for thromboembolism (VTE < 12 weeks, recurrent VTE, lupus K leeds ID I cnstlnt reduclion in
anticoagulant, atrial fibrillation with prior stroke, mechanical heart valve), intravenous 1be IS
heparin or LMWH (bridging) should be given before and after the procedure while the is I:I!OIIIId.lbmpy lllioold be clilcadiruld
• the risk af hlllll !rum lrlljur blllding 1\\tich
INR is below 2.0 nlr1lliiiCOIIIIJnlovarlil-.jisriQ1'8118rconcem
1llln 1be lbsoUtt risk af rec:nutVTE (wflicll
Prophylaxis dacl1181-timal. No spiCili: 18C0111rrwldllion
• consider for those with a moderate to high risk of thrombosis without contraindications Wllnwdl opinll duration Dfhltmlnl.

.
• non-pharmacological measures include: early ambulation, elastic compression stockings
(TEDs), intermittent pneumatic compression (IPC)
• UFH 5000 IU SC bid for moderate risk .... ' !

• UFH 5000 IU SC tid or enoxaparin 40 mg SC OD for high risk
lnililtion of Warfllm Tlterapy
llequi1111 !Mrlllp with Heparin
Contraindications and Adverse Reactions of Anticoagulant Therapy Therapy for 4-S D.ys
• see Anticoagulant Therapy, H55 • 10 mg loading da&e of warhuin
causes a precipitous decline in Protein
Clevels in 1st 36 hours resulting in a
Treatment of Pulmonary Embolism (PE) transient hypen:aagulllbla sbllll.
• see Re!!l?irology. Rl9 • Wllrfarin decreases Factor VII levels
in 1st 48 hts 4 INR is prolonged
(most sensitive to Factor VII levels},
Hypercoagulable Disorders however fuU llnlillrarixrtic effect is
not achiewd until Factor IX, X. and D
arv &Ufficienlly rvduced altar
approx. 4 daysl.
Hypercoagulability Workup- Venous Thrombosis
• workup for malignancy or hypercoagulable state indicated for idiopathic VTE in presence ofthe
following features: age <50, recurrent VTE, family history ofVTE, unusual site ofDVT (portal,
hepatic, mesenteric vascular beds), heparin-resistant disease (AT deficiency), warfarin-induced
.... ',

skin necrosis or neonatal purpura fulminans (Protein C or S deficiency) Low rilt aur1ical ,.tilllbl:
<40 'fR, no risk factllrs for VIE,
• workup: anesthetic IGA} <30 mins, minor
• initial alBCiiva, abdominal or thoracic surgery.
• CBC, blood smear, coagulation studies, liver/renal function, urinalysis, fasting M....rabl rlakaarP:.I plrlienta:
homocysteine >40 'fR, > 1 risk factor for VTE, GA
• malignancy work up (see sidebar, H34) >30minti.
• APLA: ACA {anticardiolipin antibodies) and LA {lupus anticoagulant) High rill! aurgica1 ,-111111:
• APCR (activated Protein C resistance) >40 'fR, surgery for malignancy or
• DNA: FVL {Factor V Lei.den), PT (prothrombin G20210A}, MTHFR loweriiXIrvmity orthopedic surgary
luling >3D mir11, inhibitora d&ficiency
(5,10-methylenetetrahydrofolate reductase) or other risk lector.
• after the acute event
High rill! 1111dlcal ,.tt.nta: hallrt
• antithrombin (not on heparin) felure, severe respiratory disease,
• FVIII (increased levels predict recurrence) ischemic rtroke and lower limb
• post-treatment pn.lysis, confined ta bad and have
• Protein C, S (not on warfarin) > 1 additional risk lector (a.g. active
cancer; previous VTE, sepsis, acul8
neurologic disease, lBO).
CAUSES OF HYPERCOAGULABILITY LEADING TO VENOUS THROMBOEMBOLISM

Activated Protein C Resistance (Factor V Leiden)

• most common cause ofhereditarythrombophilia
• 5% of general population are heterozygotes
• point mutation in the Factor V gene (R506Q) results in resistance to inactivation of Factor Va by
activated Protein C

Prothrombin (PT) G20210A

• G to A transposition at nucleotide position 20210 of the prothrombin gene promoter region
results in increased levels of prothrombin, thus increased thrombin generation
H34 Hematology Hypercoagulable Disordera/Hematologic Malignancies and Related Diaorders Toronto Notes 2011

Hyperhomocysteinemia
It' • both a genetic and acquired abnonnality
Comman eau- of ltypercoagullbility • increased homocysteine levels are found in vitamin B12> B 6 and folate deficiencies, chronic renal
CALMSHAPE
failure, hypothyroidism, malignancy, methotrexate, phenytoin, theophylline
Protein Cdaficiency • folate 5 rnglday can decrease plasma homocysteine by 50% (effect on thrombosis risk unclear)
Antiphospholipid Ab • also increases risk of arterial thrombosis
Ftlctor v Lliun
MaliiJIIIIIICY
s
Protein dllfici•ncv
Protein C and Protein S Deficiency
lncreued Homocysteine • Protein C inactivates Factor Va and VIlla using Protein S as a cofactor
Antithrombin daficiency • Protein C deficiency
Pro1hrumbin G2021 OA • homozygous: neonatal purpura fulminans
lncreued Factor VIII (Eight)
• heterozygous:

.. ,
• type I: decreased Protein C levels
.... • type II: decreased Protein C activity
• acquired: liver disease, sepsis, DIC, warfarin
Although lupus anti-coagulant prolongs • 1/3 of patients with warfarin necrosis have underlying Protein C deficiency
PTT. its mein clinical feature is • Protein S deficiency
1twombosi11.
• type 1: decreased free and total Protein S levels

.... ,
...-----------------.
• type II: decreased Protein S activity
• type III: decreased free Protein S levels
• acquired: liver disease, DIC, pregnancy, nephrotic syndrome, inflammatory conditions, warfarin
Protein C, ProteinS, and ATill aru
decrell5ed during acute thrombosis - Antithrombin Deficiency
therefore to test fur dllficiency, mull be • antithrombin slowly inactivates thrombin in the absence of heparin, rapidly inactivates
tested outsiu of thit time period.
thrombin in the presence ofheparin

.. ,
• autosomal dominant inheritance or urinary losses in nephrotic syndrome
.... • type 1: decreased AT levels; type II: decreased AT activity

• diagnosis must be made outside window of acute thrombosis and anticoagulation treatment
c.- fl BG111 VenD. and art.illl (acute thrombosis, heparin, systemic disease all decrease antithrombin levels)
Thromlllllis includll:
• deficiency may result in resistance to unfractionated heparin (LMWH must be used)
• Anliphospholipid antibodies
• Hypamomocysteinamill
• Mveloprolifanltiva disorders Elevated Factor VIII Levels
• Heparin induced thrombocytopenia • an independent marker of increased thrombotic risk
• genetic basis for increased levels poorly understood
....
.. ,
Disorders of Fibrinolysis
• include congenital plasminogen deficiency, tissue plasminogen activator deficiency
MlliiDincy i1 a C1111mon Acquired
C:.uu of Hyp-qulability.
Wo.... indud•: Antiphospholipid Antibody Syndrome (APLAS)
• Complm hiiiDry and physical • definition: clinical and laboratory criteria
• Routine bloodwork
• Urinalytis
• clinical: thrombosis, spontaneous abortions, fetal loss, premature birth before 34 wks
• CXR • laboratory: anticardiolipin or lupus anticoagulant antibodies
• Mlmmognlm and Pap in flmaln • mechanism: not well understood, interact with platelet membrane phospholipid and increased
• PSA in males adhesion and aggregation; also can interfere with action of protein C and S
• ColonO&Copy
• Close foUow-up

.... '...-----------------.
, Hematologic Malignancies and Related
Typic:.. Aae of l'relentalilln of
Disorders
l.eulatmllls
All- Chilchn
CML - 40.60 yrs
AMI., CLL- 60+ years
I Hematologic M•lign1ncie. ..d RelatBd Di•order. I

.... '.., I •
lymphoid
I I •
Myeloid Disorders

Leulatmill- malignant cells arise + + + ...

in bone m11110w and may spilled
elsewhere (including lymph nodet and I Acute I I Chronic I I Acute I I Chronic I
lymphoid tissue)
Lymphom•- malignant cells ariu in
lymph nod81 and lymphoid tisSU&IIIIId
may spraad elsewhere (including bone
I

ALL I •
M..i....nt Clonal
Proliferrion of B Cells
•
l.rmphama
• Hodgkin's
I

AML I •
Mywluprolifaratiw
Neoplams
l •
Myalodpplalllic
Syndromes
l
maiTilw) •CLL • Non-Hodgkin's • PRV
BUT: thiiiDCition wheru thll malignant • Plasma cell dyscrasiBS •ET
cells are found does not deline the • myeloma • CML
type of hematDiogic malignancy- •MGUS • Idiopathic
classified based on the ctlaracteristics • Waldanllrom's myelofibrosis
of the call (histology, histochemistry, macroglobulinemia
immunophlnotyping. cytogenaticl,
molecular changes]
Figure 15. Overview of Hematologic Malignancies and Related Disorders
Toronto Notes 2011 Myeloid Malignancies Hematology H35

Myeloid Malignancies
Acute Myeloid Leukemia (AML)
Definition .... ,,

• rapidly progressive malignancy characterized by failure of myeloid cells to differentiate beyond
blast stage
Myeloblast
Epidemiology
• incidence increases with age; median age of onset is 65 years old
• accounts for 10-15% of childhood leukemias
+
Promyalocyta

Risk Factors +
M'f8locyltl

+
• myelodysplastic syndromes (MDS), benzene, radiation, alkylating agents for previous
malignancy
Metamyelocyte
Pathophysiology
• etiology subdivided into: +
Blind
• primary - de novo
• secondary- hematologic malignancies (e.g. myeloproliferative disorders and :MDS) or
previous chemotherapeutic agents (e.g. alkylating agents)
+
NIUI!ophil

• uncontrolled growth of blasts in marrow leads to: * AML Cllfl inwlva any myeloid
• suppression ofnormal hematopoietic cells
• appearance of blasts in peripheral blood
• accumulation of blasts in other sites
• metabolic consequences of a large tumour mass

Clinical Features
• anemia .... ,,

• thrombocytopenia (associated with DIC in promyelocytic leukemia)
• neutropenia (even with normal WBC): leads to infections, fever AciD Leuklmil
• accumulation of blast cells in marrow Dtlinilion- {WHO) Prvsence oi20Y.
blast cells or gnllder i1 bone IIIIUIOW at
• skeletal pain, bony tenderness (especially sternum)
pmantrion.
• organ infiltration
• gingival hypertrophy- may present to dentist first Cllalliclllon - divided into myeloid
(AML) and lymphoid (All.), depending
• splenomegaly- early satiety, LUQ fullness on vm.th1r blutl1r11 rnyllobluts or
• hepatomegaly lymphDblam, respectively.
• lymphadenopathy (not marked)
• skin -leukemia cutis
• gonads
• eyes -Roth spots, cotton wool spots, vision changes (uncommon)
• leukostasis!hyperleukosis syndrome (medical emergency)
• large numbers of blasts interfere with circulation and lead to hypoxia and hemorrhage- can
cause diffuse pulmonary infiltrates, CNS bleeding. respiratory distress, altered mental status
• metabolic effects; aggravated by treatment (rare)
• increased uric acid -+ nephropathy, gout

•
• release of phosphate -+ decreased Ca, decreased Mg
• release of procoagulants -+ DIC
decreased or normal K before treatment. increased K after treatment
.... ,•

Fl'lllllh-Amllrlcu·Brililb (FAB)
Investigations Clauifitlldi-
• bloodwork
Sulltype Freq Common Name
• CBC - anemia, thrombocytopenia, variable WBC
• INR, aPTT, FDP, fibrinogen (in case ofDIC) MO <5'11i Mininlllly
dillerentillled
• increased LDH, increased uric acid, increased P04 (released by leukemic blasts), decreased Ca
• baseline RFTs, LFTs Ml 21l'J(, Myalobllstic
• peripheral blood film- circulating blasts with Auer rods (azurophilic granules) without maturation
• bone marrow aspirate M2 25% Myeloblastic

• blast count: AML >20% {normal is <5%) maturation

• histologic classification {French-American-British {FAB)-+ MO-M7)- based on stage at M3 lll'J(, Prornyelocytic
which cell differentiation stops (see sidebar) (APML)
• cytogenetics, immunophenotyping M4 21l'J(, MyaiDITIDnocytiC
• CXR to r/o pneumonia, ECG, MUGA scan prior to chemotherapy {cardiotoxic) M5 21l'J(, Monoc:ytic
M6 5'lfo Erythroleuksmic
M7 <5'11i Magakaryoblastic
H36 Hematology
..... ,
C•o: survival that parallels age·
mlltched po(J\Ution
Complltl RemiiCion: 1umoll' load
billow lhmhold of delactabla di1181sa
(n0111111l periphlnl blood film. nonnel
bona marrow with < 5% b!U, nDI1IIII
clinical state)
..... ,,
WHO MDS Clusllieation
1. Relncto!y anemia (RAJ
2. Relncto!y anemia with ringed
sidi!Oblasts (RARS)
3. Relncto!y cytopenia with
multilinoage dysplasia (RCMD)
4. Relncto!y cytopenia with
multilinoage dysplasia and ringed
sideroblasts (RCMD·RS)
5. Relncto!y anemia with excess blosts
1 and n
6. 5q· IJYildrome (MD with dal(5q))
7. Myelodysplasia unclassified (seen in
Clllll of rnegalurfoc:ylll dylplaaia
with fibrosis and olhars)
.. ,
.....
Investigations
Myalodysplllllic Syn*omoo:
inllfectiw matundion
Naapllla1111:
overproduction of mature cells
Myeloid Malignancies Toronto Notes 2011
Treatment
• mainstay of treatment is chemotherapy (rapidly fatal without treatment)
• all AML subtypes treated similarlyexcept promyelocytic variant with t( 15:17) translocation -
all-trans-retinoic acid (ATRA) added to induce differentiation
• treatment strategy
1. Induction- chemotherapy to induce complete «remission· of AML (see sidebar)
• several possible regimens [e.g. cytarabine with anthracycline (daunorubicin)]
• patients with poor response to initial induction therapy - poorer prognosis
2. Consolidation - to prevent recurrence
• intensive consolidation chemotherapy
• stem cell transplantation - autologous or allogeneic (younger patients with better
performance status)
• consider acceleration with hematopoietic growth factors (e.g. G-CSF) if increased
incidence of severe infection
• supportive care
• screening for infection via regular C&S of urine, stool, sputum, oropharynx, catheter sites,
perianal area
• fever - C&S of all orifices, CXR, start antibiotics
• platelet and RBC transfusions (irradiated to prevent transfusion-related GVHD) ± Epo
• prevention and treatment of metabolic abnormalities
• allopurinol for prevention of hyperuricemia
Prognosis
• achievement of first remission
• 70-80% if 60 years old, 50% if >60 years old
• median survival12-24 months
• 5 year survival40%
• survival may be improved by bone marrow transplant (BMT) - 50-60% cure rate
• adverse prognostic factors: age >60, poor performance score before treatment, AML secondary
to chemotherapy or MDS/chronic myeloproliferative disorder, WBC >20 OOO/cm3, increased
LDH, unfavourable cytogenetics (e.g. monosomy or deletion of chromosomes 5 or 7)
Myelodysplastic Syndromes (MDS)
Definition
• heterogeneous group of malignant stem cell disorders characterized by dysplastic and ineffective
blood cell production resulting in peripheral cytopenias
• syndromes defined according to French-American-British (FAB) or World Health Organization
(WHO) classifications
Pathophysiology
• disordered maturation - ineffective hematopoiesis despite presence of adequate numbers of
progenitor cells in bone marrow (usually hypercellular)
• intramedullary apoptosis - programmed cell death within bone marrow
• both processes lead to reduced mature cells in periphery
• 30-40% develop AML
Risk Factors
• elderly, post-chemotherapy, benzene or radiation exposure
• occurs in 49-89/100,000 in patients >60 years old
Clinical Features
• insidious onset
• fatigue, weakness, pallor, infections, bruising, epistaxis
• rarely: weight loss, fever, hepatosplenomegaly
• infections and bleeding out of proportion with peripheral blood counts
• diagnosed by
• anemia ± thrombocytopenia ± neutropenia
• bone marrow hypercellularity with tri-lineage dysplastic changes (dysmyelopoiesis,
dyserythropoiesis, dysthrombopoiesis)
• CBC and peripheral blood film
• RBC: usually macrocytic with oval shaped red cells (macro-ovalocytes), decreased
reticulocyte count
• WBC: decreased granulocytes and abnormal morphology (e.g. bilobed or unsegmented
nuclei = Pelger abnormality)
• platelets: thrombocytopenia. abnormalities of size and cytoplasm (e.g. giant hypogranular
platelets)
Toronto Notes 2011 Myeloid Malignancies/Myeloproliferative Neoplasnu (MPNs) Hematology H37

• bone marrow aspirate and biopsy with cytogenetic analysis required for definitive diagnosis
• bone marrow- normocellularlhypercellular (but 10% hypocellular), often with
U.."Eplril ..
wilhC.•
...._.il,....
micromegakaryocytes; 10% have marrow fibrosis lfllod21D1;111:2S41
• may see ring sideroblasts in varying proportion Clncal practice Lfdm by Amlrican
• cytogenetics - partial or total loss of chromosomes 5, 7, Y, or trisomy 8 Soc:ielies rl HIIIIIIDiogy 11M! Clni:ll Daq
120071
1111 iidAIW:
Prognosis 111rD1B Ill llg8lll
• the MDS International Prognostic Scoring System (IPSS) uses 3 factors to estimate mean {ESA) Min hmiQiohin {1111 ii118U or hllow
survival: 100 IJ\.110 Iilli >Mill
IIIIICillld llllf11iiiD dlcrml tfwJWid far
• the percentage of bone marrow blasts, the karyotype and the number of cytopenias 1nmslusillns.
• based on the calculated score, a patient's MDS is categorized as "intermediate 1 Zl SIIINM #1 lorplliara>MIIII!Jw.rill
"intermediate or "highu with a mean survival of 0.4, 3.5, 1.2 and 5.7 years respectively
31 FolkwlthlpackiQtilwtfordoeeinilillioniiMI
II1Jdillcltion.
Treatment 4lllilcontille ESAa wllen patillt 1101 responding
• low risk of transfonnation to acute leukemia (IPSS low and intermediate 1) 1D trallliWi blyund 61D 8wallb.
• supportive care: RBC and platelet transfusion, antibiotics, antifungals 51 MoniiDr inm IIDniiiiMIIuppMIInt iron il1llal
• erythropoietin SC weekly may be effective in reducing transfusion requirements lor W.·IIIIIIIIIJIIilllllwhln
61 Use fSAs caiDius¥ v.itll ciEmatlmv;' or
• hematopoietic growth factors (G-CSF, GM-CSF} may decrease risk of infection in pdllllJ with .. eiMIId risk for tfmlmo.
• high risk oftransfonnation to acute leukemia (IPSS intermediate 2 and high) embole complicllions.
• supportive care 11151. llllould nat Ill Llllll for plliln1l Mil CIIICII'
• stem cell transplantation wlla m nat IUMng •
ilcraues lllrombonlalic rilb end lowers
• AML-type chemotherapy .m.III1L
• epigenetic therapy: DNA methyltransferase inhibitors (e.g. 5-Azacytidine), histone
deacetylase inhibitors
• angiogenesis inhibitors
• arsenic trioxide
• farnesyl transferase inhibitors

Myeloproliferative Neoplasms (M PNs)

Definition
• clonal myeloid stem cell abnonnalities leading to overproduction of one or more cell lines _._______________
.....

(leading to abnormalities in erythrocytes, platelets and other cells of myeloid lineage)
Buophilill ill um:ommon in Dlhar
Epidemiology medical conditions.
• mainly middle-aged and older patients (peak 60-80 years)

Prognosis
• may develop marrow fibrosis with time
• all disorders may progress to AML

Tabla 20. Chronic Myalaproliferll'liva Disorders

PV CML IMF ET
Het N
WBC ""'""' N
Pit
""' ""' ""' 1'1'1'
Marraw llll'lllil
""'± ± +++ ±
Splenomeply + +++ +++ +
+ + ++
G.atic Alsocidion JAK2 mut (95%) Bcr-Abl rnrt. (90+%) JAIQ mut (-511%) JAKZ mut (-511%]
PV polyc:ythelria VIII CML clmic myelailleukemia IMF idiaplllicrnyelJfibrusis ET essentiallllartocythemia
H38 Hematology Myeloproliferative Neoplaama (MPNa) Toronto Notes 2011

..... '.. ,

Polycythemia Rubra Vera (PRY)
--------------------
Erylhr'Drulalgia is 1 pathognomonic
microvascular thrombotic camplicalion
Definition
in PRV and ET. • stem cell disorder characterized by elevated RBC mass (erythrocytosis) accompanied by
increased white cell and platelet production

Clinical Features
• those secondary to high red cell mass and hyperviscosity (see Polycythemia, HS)
• bleeding complications: epistaxis, gingival bleeding, ecchymoses and GI bleeding
• due to platelet abnonnalities
• thrombotic complications: DVT, PE, thrombophlebitis, increased incidence of stroke, MI
• due to increased blood viscosity, increased platelet number and/or activity
• erythromelalgia (burning pain in hands and feet)
• associated with platelets >400 x 109 /L
• pathognomonic microvascular thrombotic complication in PRY and ET
• pruritus, especially after wann bath or shower (40%)
• due to cutaneous mast cell degranulation and histamine release
• epigastric distress, PUD
• due to increased histamine from tissue basophils, alterations in gastric mucosal blood flow
due to increased blood viscosity
• gout (hyperuricemia}
• due to increased cell turnover
• characteristic physical findings
• plethora (ruddy complexion) offace (70%), palms
• splenomegaly (70%), hepatomegaly (40%)

Investigations
• see Polycythemia, HS
• must rule out secondary polycythemia
• diagnosis (WHO) involves two required (*)A criteria+ 1 other A or 2 B criteria
• A Criteria (Major)
• elevated red cell mass* (>25% above mean predicted value)

..
• no cause of2° erythrocytosis* (ie. arterial P02 >92%)
• palpable splenomegaly
• clonal genetic abnormality other than bcr-abl fusion gene
....,......
Ellicuy . . Wllyula.....Aipnlln

Nf.N 2004; 350:114-24

llldy: llaubll·binil paba-cantrallld.
lllldamiled trial
I'MiicipaiD: 5181)1tientsMh
v.rith .., c:lelr indication for or cormildicllilm tD
llfililtt.nvf.
....,....: I'UrD111Ceived elberlaw-dase
llfilil 100 plaalba !n=ZS51
and -loiDIWd for up ID5lllll.
of IQ norhbll
Ml lllrillll strallll, ardlllll fnrn CltdicMsctmr
CIIIIIS 1nd 1he IJIIUitiw 1lle al (IQ 1he pmiaus
3 pUs pOOTuBy arrmoim llllllllljar WIIIDUI
11nria!is.
.....: l'rilrwy out-(lllnd llt-1W.Iclld
v.rith pllcllllo (RR 0.41; • allopurinol- as needed
P=O.Oilnd RR 0.4; P=0.03, 1'811)ectivalrt. There
Will Ill dillnras in IMIII ar ClfdicMsctmr
marlllily lnd mljor bleeding episodes.
c.llllan: LM-do!l npirin can lllflly Pf-.1
111ariatic aamplcatians in pllieiO witli
pDtfcyttlllll'il V8l'l.
• endogenous erythroid colony formation in vitro
• B Criteria (Minor)
• thrombocytosis (>400 x 109/L)
+leukocytosis (>12 x 109/L)
• bone marrow biopsy revealing panmyelosis with erythroid and megakaryocytic
proliferation
• low serum EPO level
• JAK2 mutation identified in most cases
Treatment
• phlebotomy to keep hematocrit <45%
• hydroxyurea (age >65, prior thrombosis or symptoms), 32P (age >80 or lifespan <10 years)
• low-dose aspirin (for erythromelalgia and/or antithrombotic prophylaxis)
• antihistamines - as needed
Prognosis
• 10-20 year survival with treatment
• complicated by thrombosis, hemorrhage, leukemic transformation (AML)

Chronic Myeloid Leukemia (CML)

Definition
• myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line
without the loss of their capacity to differentiate

Epidemiology
• generally presents in fourth or fifth decade of life

..... ',

Pathophysiology
• Philadelphia chromosome (Ph)
Detection af the bcr.;tbl fusion gene is 1 • translocation between chromosomes 9 and 22
dillgnastic tall for CML (prasant in OVIIr
90'llo af patients!.
• the c-abl proto-oncogene is translocated from chromosome 9 to "breakpoint cluster region"
(bcr) of chromosome 22 to produce bcr-abl fusion gene, an active tyrosine kinase
Toronto Notes 2011 Myeloproliferative Neoplasms (MPNa) Hematology H39

Clinical Features
• 3 cUnical phases
• chronic phase- disease process easily controlled (85% diagnosed here)
• few blasts (<5%) in peripheral film
• slightly elevated eosinophils and basophils
• no significant symptoms
• accelerated phase - impaired neutrophil differentiation, difficult to control
• circulating blasts (10-19%) with increasing peripheral basophils (pruritis)
• CBC: thrombocytopenia <100, WBC count unresponsive to therapy
• cytogenetic evidence of clonal evolution
• worsening constitutional symptoms and splenomegaly (extramedullary hematopoiesis)
• blast crisis - more aggressive course, blasts fail to differentiate
• blasts (>20%) in peripheral blood or bone marrow
• evolution to acute leukemia (113 ALL, 2/3 AML)
• large foci of blasts in bone marrow, extramedullary blast proliferation
• clinical presentation
• 20-50% of patients are asymptomatic when diagnosed (incidental lab finding)
• nonspecific symptoms
• fatigue, weight loss, malaise, excessive sweating, fever
• secondary to splenic involvement
• early satiety, LUQ pain/fullness, shoulder tip pain (referred)
• splenomegaly (most common physical finding)
• anemia
• bleeding - secondary to platelet dysfunction
• pruritus, PUD - secondary to increased blood histamine
• leukostasis, priapism, encephalopathy (rare) -secondary to very elevated WBC (rare}
Investigations
• high increase in WBC, decreased/normal RBC, increased/decreased platelets, increased basophils
• peripheral blood film
• leukoerythroblastic picture (immature red cells and granulocytes present, e.g. myelocytes
and normoblasts)
• presence of different mid-stage progenitor cells differentiates it from AML IIIMCo.,..twiii ........ IIIIILGw-
.._ Cylriill far Nlllllr lllfllllll Cllrn.
• bone marrow ..... Cln*llpllld IAibnil.
• myeloid hyperplasia with left shift, increased megakaryocytes, mild fibrosis NE./M2U03; 341:994-1004
• molecular and cytogenetic studies of bone marrow or peripheral blood for Philadelphia S1udy: llandried. !l"llllic:enla lrill
chromosome l'llillls: 11II& plliiii1I!Wh IIIWiy lilgnDIId
• abdominal imaging for spleen size (used in Sakal prognostic scoring system) dnnic-phue duonic rnylbd leullail (Cr.t..l.
nlinib (553 plliurDICI' jntarf&nll.
ah pkls bN-dose cytmbine (553 palientsl.
Treatment
• symptomatic and cytDglllllic IISJXIIIIII, illic lftlcll, llld 11111
• allopurinol and antihistamines II prggranion.
• chronic phase llhlll: Altanmedilnfollow-up of 19 months.
• imatinib mesylate (Gleevec•) - inhibits proliferation and induces apoptosis by inhibiting the estirnallld 11111 of 11!111jor cy\llgenetic response
[0 11135\ of c* in lllltlfbal poWII for 1111
tyrosine kinase activity in cells positive for bcr-abl Plilildelphil duamosamellll 18 monltl- r1.1!1
• clinical success with imatinib (cytogenic remission) has resulted in fewer patients 84.1 1111l.DI in IIIII inudirib uraup and
requiring bone marrow transplantation 34.7!1 {95\ Cl, 29.311140.01 in 1be llniUP Given
• dasatinib (tyrosine kinase and src "dual inhibitor») or nilotinib (selective bcr-abll inhibitor) mtnron-1111 plu$ cylllllline (p<0.001 j. The
lllinHd IIIII af cylaglnltic r.panu
for those who fail imatinib
wn76.Z!I(MQ, 72.51117Uhnd 14.5\
• interferon-alpha- virtually obsolete with advent of tyrosine kinase inhibitors (95\Cl10.510 mpactMif(p<0.001(.
• hydroxyurea (for initial stabilization ofWBC counts >20) At 18 months. the es1inted life tllleedom 11om
• bone marrow transplantation (curative} ]JI"DGIIIIion 111 or bUt-ailis
• accelerated phase Ct.l. WIS 96.7!1 in 1be inwlilib llniUP 111d 91.5\ in
thll CGriillllion-1lllrlpyQITIUP jp<0.001].1mltilib
• 600 mg PO daily
- bellllrloi1R11id 111111 contirdJII1herlprf.
• blast crisis Clncbinl: In 1lrml af bln1lqic IIIII
• up to 800 mg PO daily ty1DGII1IIic !allbilly IIIIU.
• stem cell transplantation may be curative - to be considered in young patients who do not meet lblihaod rJprogressiln1D

therapeutic milestones crbllllt-criliiCML.

interferon-Ill plu$ bN-dose cyllnlbile 1$ first-line
• treatment success is monitored based on therapeutic milestones: tfmpy in nawly dilgnalad clrnfhllll CNL
• hematologic - improved WBC and platelet counts, reduced basophils
• cytogenetic- reversion of bone marrow to Philadelphia-chromosome negativity
• molecular - reduction/absence of bcr-abl transcripts in periphery and marrow .... ,,

Prognosis
The Sobl is usn ta calaa1m
• survival dependent on response prugnallia in CML ,.• • 1laHd ...
• those achieving complete cytogenetic response (CCR) on imatinib by 18 months of therapy - four prognclltic fltcton:
6 year overall survival >90% 1. AQe{YeiiiS)
• those who do NOT achieve CCR on imatinib - 6 year overall survival (OS} of 66% 2. Sp111811 Size (em]
• acute phase (blast crisis- usually within 3-5 years) 3. 'lr. Mya1ablam in pariphunll blood
4. P111talets > 700 x
• 2/3 develop a picture similar to AML
• unresponsive to remission induction The finrt thr&B criturill ara canlinua111
variables with progressively worse
• 1/3 develop a picture similar to ALL prognosis Ill higher Vlllues.
• remission induction (return to chronic phase) achievable
H40 Hematology Myeloproliferative Neoplaama (MPNa) Toronto Notes 2011

Idiopathic Myelofibrosis (IMF)

-----------------------------
Definition
• excessive bone marrow fibrosis leading to marrow failure
• characterized by anemia, extramedullary hem.atopoiesis,leuk.oerythroblastosis, teardrop red
cells in peripheral blood and hepatosplenomegaly

Epidemiology
,, I
• rare, median age at presentation is 65

Pathophysiology
Myelofibrosis can be eilher primary • abnonnal myeloid precursor postulated to produce dysplastic megakaryocytes that secrete
(idiopathic) or occur as a trlnsfonnation
of an PRV or ET. fibroblast growth factors
• stimulates fibroblasts and stroma to deposit collagen in marrow
• increasing fibrosis causes early release of hematopoietic precursors leading to:
• leuk.oerythroblastic blood film (primitive RBC and WBC present in blood)
,, I
• migration of precursors to other sites - extramedullary hematopoiesis (leading to

hepatosplenomegaly)
A "leukoerythroblastic" blood film
(RBC and granulocyhl precurwn;) Clinical Features
implies bone marrow inliltnrtion with
malignancy (e.g. laukamiu, 1olid • anemia (severe fatigue is most common presenting complaint, pallor on exam in >60%)
11m0ur matastasas) or fibrosis (a.g. • weight loss, fever, night sweats -+ secondary to hypermetabolk state
IMF). • splenomegaly (90%) -+ secondary to extramedullary hematopoiesis; may cause early satiety
• hepatomegaly (70%) -+ may get portal hypertension
• bone and joint pain -+ secondary to osteosclerosis, gout
,, I • signs of extramedullary hematopoiesis (depends on organ involved)

IMF is chlractariz8d by a dry BM Investigations

aspirate and tear drop RBCs. • CBC: anemia, variable platelets, variable WBC
• biochemistry: increased ALP (liver involvement, bone disease), increased LDH (2° to ineffective
hematopoiesis), increased uric acid (increased cell turnover), increased B12 (2° to increased
neutrophil mass), increased leukocyte alkaline phosphatase (LAP)
• blood film: leukoerythroblastosis with teardrop RBCs, nucleated RBCs, variable polychromasia,
large platelets and megakaryocyte fragments
• bone marrow aspirate: "dry tap" in as many as 50% of patients
• bone marrow biopsy (essential for diagnosis): fibrosis, atypical megakaryocytic hyperplasia,
thickening and distortion of the bony trabeculae (osteosclerosis)

Treatment
• allogeneic stem cell transplant is potentially curative
• symptomatic treatment
• transfusion for anemia
• erythropoietin - 30-50% of patients respond
• androgens (e.g. danazol has shown transient response with response rates of <30%)
• hydroxyurea for splenomegaly, thrombocytosis, leukocytosis, systemic symptoms
• alpha interferon (as second line therapy)
• splenectomy (as third line therapy; associated with high mortality and morbidity)
• XRT for symptomatic extramedullary hematopoiesis, symptomatic splenomegaly
• thalidomide, JAK2 inhibitors, etanercept

Prognosis
• International Prognostic Scoring System (IPSS) for IMP uses 5 factors to determine mean
survival:
• presence of constitutional symptoms; age >65; hemoglobin <100 g/L; leukocyte count
>25,000/mm3; circulating blast cells
• based on the calculated score, a patient's IMF is categorized as "loW: "intermediate 1
"intermediate 2': or "high" with a mean survival of 135, 95, 48 and 27 months respectively
• risk oftransformation to AML (8-10%)

Essential Thrombocythemia (ET) -----------------------

Definition
• overproduction of platelets in absence of recognizable stimulus
• must rule out secondary thrombocythemia

Epidemiology
• increases with age; F:M = 2:1 but F=M at older age
Toronto Notes 2011 Myeloproliferative Neoplasma (MPNs)ILymphoid Malignancies Hematology H41

Diagnosis (WHO Criteria)

• positive criteria:
• sustained platelet count >600 x 109/L
• bone marrow biopsy - proliferation of megakaryocyte lineage with enlarged, mature
megakaryocytes
• acquired JAK2 mutation
• criteria for exclusion:
• no evidence of PRY, CML, IMF, MDS
• no bcr-abl fusion gene
• no evidence of bone marrow collagen or reticulin fibrosis
• no evidence of reactive thrombocytosis due to inflammation, infection, neoplasm, prior
splenectomy

Clinical Features
.... ,

• often asymptomatic EliDIDtw af Suomluy
• vasomotor symptoms (40%) Thranllocy!Mmia
• headache (common), dizziness, syncope lnflc:tion
• erythromelalgia (burning pain of hands and feet, dusky colour, usually worse with heat, Inflammation {IBil, arthritis!
MllliQII8JIC'(
caused by platelet activation -+ microvascular thrombosis) Hamonhega
• thrombosis (arterial and venous) Iron deficiency
• bleeding (often GI; associated with platelets >1000 x Io9/L) Hemolytic anemia
• constitutional symptoms, splenomegaly l'o8t splenectomy
Post chamothlnpy
• pregnancy complications; increased risk of spontaneous abortion
• risk of transformation to AML {0.6-5%), myelofibrosis

Investigations
• CBC: increased platelets; may have abnormal platelet aggregation studies
• bone marrow hypercellularity, megakaryocytic hyperplasia, giant megakaryocytes
•
•
increased K, increased P04 (2° to release of platelet cytoplasmic contents)
diagnosis: exclude other myeloproliferative disorders and reactive thrombocytosis .... ,,.----------------.
.

Treatment There is an IISymptnmatic "benign- form

• low dose aspirin if previous history of thrombotic event, cardiovascular risk factors, older or of assantial tllrombocylhlllllil with a
symptomatic stabla or slowly rising plat.llt count.
• cytoreductive therapy if thrombosis or thrombotic symptoms: hydroxyurea (HU) (1st line Tlllltment includes observation, liSA,
therapy), anagrelide, interferon-alpha, or 32P (age >80 or lifespan <10 years) sul!inpyriZOIIa or dipyridamole.
• splenectomy not recommended (increased risk of bleeds, thrombosis)

Lymphoid Malignancies
Acute Lymphoblastic Leukemia (ALL) - - - - - - - -

Definition
• malignant disease of the bone marrow in which early lymphoid precursors proliferate and
replace the normal hematopoietic cells of the marrow
• WHO subdivides ALL into two types depending on cell of origin
• B cell - precursor B lymphoblastic leukemia
• T cell- precursor T lymphoblastic leukemia

Clinical Features .... ,,._________________

• see Acute Myeloid Leukemia, IDS for full list of symptoms

• distinguish ALL from AML based on Table 21 FAB ClasslliNIIn of ALL
• 75% ALL occurs in children <6 years old; second peak at age 40 L1 blast cells small, uniform high N:C
• clinical symptoms usually secondary to: l'lllio
• bone marrow failure - anemia, neutropenia (SO% present with fever; also infections of LZ blut cells l11r1J8r, hster01J81180UI,
oropharynx, lungs, perianal region), thrombocytopenia I-N:Cra1io
• organ infiltration - tender bones, lymphadenopathy, hepatosplenomegaly, meningeal signs L3 vacuolallld blasts. basophilic
cytoplurn (usually B·All)
(headache, N/Y, visual symptoms; especially in ALL relapse)

Investigations
• CBC: increased leukocytes >10 x 109/L (occurs in 50% of patients); neutropenia, anemia or
thrombocytopenia
• may have increased uric acid, K. P04, Ca, LDH
• PT, aPTT, fibrinogen, D-dimers for DIC
• leukemic lymphoblasts lack specific morphological (no granules) or cytochemical features,
therefore diagnosis depends on immunophenotyping
• cytogenetics: Philadelphia (Ph) chromosome in -25% of adult ALL cases
• CXR: patients with ALL may have a mediastinal mass
• LP prior to systemic chemotherapy to assess for CNS involvement
H42 Hematology Lymphoid Malignanda/Lymphomas Toronto Notes 2011

..... ,

Treatment
• eliminate abnormal clone:
r-tmlllt of Allw. AML 1. Induction - to induce complete remission (undetectable leukemic blasts, restore nonnal
1. No proven benefit of maintBIIIInce hematopoiesis)
chamatharepy in AML • e.g. Dana-Farber regimen- vincristine (Oncovm•), prednisone, methotrexate,
2. No routine CNS prvphylaxi1 in AML lencovorin, L-asparaginase, intrathecal methotrexate and ara-c
• in Philadelphia chromosome-positive ALL, add imatinib mesylate (Gleevec•, a bcr-abl
tyrosine kinase inhibitor); found to induce complete remission in up to 95% cases
2. Consolidation and/or intensification chemotherapy
• consolidation - continuing same chemotherapy to eliminate subclinical leukemic cells
• intensification -high doses of different (non-cross-reactive) chemotherapy drugs to
eliminate cells with resistance to primary treatment
3. Maintenance chemotherapy -low dose intermittent chemotherapy over prolonged period
(2-3 years) to prevent relapse
4. Prophylaxis: CNS radiation therapy or methotrexate (intrathecal or systemic)
• hematopoietic stem cell transplantation- potentially curative (due to pre-implant
myeloablative chemoradiation and post-implant graft-versus-leukemia effect) but relapse rates
and non-relapse mortality high

Prognosis
• depends on response to initial induction or if remission is achieved following relapse
• good prognostic factors: young, WBC <30 x 109/L, T-cell phenotype, absence of Ph
chromosome, early attamment of complete remission
• achievement of first remission: 60-90%
• childhood ALL: 80% long term remission (>5 years)
• higher cure rates in children because of better chemotherapy tolerance, lower prevalence of
bcr-abl fusion gene (associated with chemotherapeutic resistance)
• adult ALL: 30-40% 5-year survival

Table 21. Diffarentiate AML Fram ALL

AML AU
Big people (IIIUts) Small people (kids)
Big blasts Small blam

Big mortality rata Small mortality rata

To Dlffertlntiatl AML From ALL:
Remember Big and SmALl
Lots of cytoplasm Less cytoplasm
(UI Tllbll21) Lots of nucleoli (3·51 Few 11.1cleoli (1-3)
Lots of gra11.1les 111d Auer rods No granules
Myeloperoxidase, Sudan black stain PAS (periodic acid schiff)
Maturation defect beyond myeloblast or promyelocyte Maturation defect beyond lymlilablast

Lymphomas
Definition
• collection oflymphoid malignancies in which malignant lymphocytes accumulate at lymph
..... ,
..}-----------------,
nodes and lymphoid tissues
• leading to lymphadenopathy, extranodal disease and constitutional symptoms

• Ann Arbor staging- can be used for
both Hodgkin's and non·Hodgkin's
lymphoRII, but gradll/hiltology is
more important for non-Hodqkin's
lymphoRII b8CBUI81hu outcome
differs significanllv dependinq on type
of lymphoma.
• Prog-nostic scorn are difflrent
for indolent VBm11i 111J111111SiV8
lymphoRIIS.
• Highly aggressive lymphoma act like
acutllaukamin.
......
.. ,
}-----------------,
Hodgkin' a ia diatinquilhud from non-
Hodgkin's lymphoma by 1he presence of
Reed-Sternberg cells.
Staging (Ann Arbor Staging System)
• Stage I
• involvement of a single lymph node region or extralymphatic organ or site
• Stage II
• involvement of two or more lymph node regions or an extralymphatic site and one or more
lymph node regions on same side of diaphragm
• Stage III
• involvement of lymph node regions on both sides ofthe diaphragm; may or may not be
accompanied by single extra lymphatic site or splenic involvement
• Stage IV
• diffuse involvement of one or more extralymphatic organs including bone marrow
• subtypes:
• A = absence of B symptoms
• B = presence of B symptoms
• unexplained fever >38"C
• unexplained weight loss (> 10% of body weight in 6 months)
• night sweats
Toronto Notes 2011 Lymphomas Hematology H43

T1ble ZZ. Chromosome Tr1nslocations

Translocation Gena Activltion Auociatad Neoplasm
l(8;141 e>mye activation Burkitt's lyqJhoma
l(14;18l bcl-2 activation Follicular lymphoma
l(9;221 Philadelplia clromosome (bcr-MJ/ i¥Jridl CML. ALL in adults (25% of the limel
l(11;141 Overexpression protein cyclin 01 Mantle cell lymphoma

Hodgkin's Lymphoma
Definition
• malignant proliferation oflymphoid cells with Reed-Sternberg cells (thought to arise from
germinal centre B-cells)

Epidemiology
• bimodal distribution with peaks at 20 years and >50 years
• association with Epstein-Barr virus in up to 50% of cases

Clinical Features
• asymptomatic lymphadenopathy (70%)
• non-tender, rubbery consistency
• cervkallsupraclavi.cular (60-80%), axillary (10-20%), inguinal (6-12%) .... ,,

• splenomegaly (50%) ±hepatomegaly
• mediastinal mass Hodgki'l's Lymphoma classically
• found on routine CXR, may be symptomatic (cough) pments as a painless, non-ttnder,
film, rubbery llllqam11111: of superficial
• rarely may present with SVC syndrome, pleural effusion lymph nodls, mort ofbln in the mvical
• systemic symptoms rag ion.
• B symptoms (especially in widespread disease; fever in 30%), pruritus
• non-specific/paraneoplastic
• alcohol-induced pain in nodes, nephrotic syndrome
• starts at a single site in lymphatic system (node), spreads first to adjacent nodes
• disease progresses in contiguity with lymphatic system

Investigations
• CBC
• anemia (chronic disease, rarely hemolytic), eosinophilia, leukocytosis, platelets normal or
increased early, decreased in advanced disease
• biochemistry
• LFTs (liver involvement)
• RFTs (prior to initiating chemotherapy)
• ALP, Ca (bone involvement)
• ESR, LDH (monitor disease progression)
• imaging
• CXR, CT chest (lymph nodes, mediastinal mass), CT abdomen/pelvis (liver or spleen
involvement), gallium scan (assess treatment response)
• cardiac function assessment - (MUGA or echocardiography) for patients at high risk of pre-
treatment cardiac disease (age >60, history of HTN, CHF, PUD, CAD, MI, CVA)
• PFI's -if history oflung disease (COPD, smoking, previous radiation to lung)
• excisionallymph node biopsy confirms diagnosis
• bone marrow biopsy to assess marrow infiltration (only necessary if B symptoms, stage III or rv;
bulky disease or cytopenia)

Treatment
• stage 1-11: chemotherapy (ABVD) followed by involved field radiotherapy (XRT)
• stage III-IV: chemotherapy (ABVD, BEACOPP) with XRT for bulky disease
• relapse, resistant to therapy: high dose chemotherapy, bone marrow transplant
• PET scans used to follow response to treatment
CHOP = cyclophosphamida,
Complications of Treatment hydroxydoxorubicin (Adriamycin),
• cardiac disease -secondary to XRT (adriamyctn is cardiotoxic) vincrirtina (Oncovin), prednisone
• pulmonary disease - secondary to bleomycin (interstitial pneumonitis) VAD = vincriltine, adrillmycil,
• infertility- recommend sperm banking daxamlllhasone
• secondary malignancy in irradiated field ABVD = ldriamycin, bleomycin,
vinblastirw, dacarbllzine
• <2% risk of MDS, AML (secondary to treatment, usually within 8 years)
BEACOPP = biBDmycin, etopolida,
• solid tumours oflung, breast; > 10 years after treatment acmmycin, cydophosphamidl,
• non-Hodgkin's lymphoma vincristine, procarbazine and prednisone
• hypothyroidism - post XRT
H44 Hematology Lymphomas Toronto Notes 2011

..... '.. ,

Prognosis
• adverse prognostic factors:
lm.rnatio111l Proallllltic Facton 1. serum albumin <40 giL (4 gldL)
Projec:t1118 2. hemoglobin <105 giL (10.5 g/dL)
Proa-tic F8C1o11 FFP 3.male
0 84"' 4. stage IV disease
1 77'fo 5. age :?:45 years
2 67'fo 6.leukocytosis (WBC >1.5 x 109/L)
3 60'L
4 51"' 7.lymphocytopenia (lymphocytes <0.06 x 109/L or <8% ofWBC count or both)
5-7 42'L • prognostic score
FFP = freedom from prognMion at • each additional adverse prognostic factor decreases freedom from progression at 5 years
5 yell1.

Non-Hodgkin's Lymphoma (NHL)

Definition
• malignant proliferation oflymphoid cells of progenitor or mature B or T cells

Classification
• multiple classification sym:ems exist at present and may be used at different centres
• can originate from both B- {85%) and T-or NK- {15%) cells
• B cell NHL - e.g. Burkitt's lymphoma, mantle cell lymphoma, follicular lymphoma
• T cell NHL - e.g. mycosis fungoides, anaplastic large cell lymphoma
• WHO/REAL classification sym:em - 3 categories of NHLs based on natural history
• indolent (35-40% ofNHL) - e.g. follicular lymphoma, small lymphocytic lymphoma/CU.,
mantle cell lymphoma
• aggressive (-50% ofNHL) - e.g. diffuse large B-celllymphoma
• highly agreasive {-5% ofNin.) - e.g. Burkitt's lymphoma

Clinical Features

..... ',

•
•
•
painless superficial lymphadenopathy, usually> !lymph node region
usually presents as widespread disease {exception is aggressive lymphoma)
constitutional symptoms not as common as in Hodgkin's disease
NHL: "-ocimd ConditiDM • cytopenia: anemia ± neutropenia ± thrombocytopenia can occur when bone marrow is involved
1. lmmunoduficiem:y (e.g. HIV)
2. diseases (e.g. Sl.E) • abdominal signs
3.1nfections (e.g. EBV) • hepatosplenomegaly
• retroperitoneal and mesenteric involvement (2nd most common site of involvement)
• oropharyngeal involvement in 5-10% with sore throat and obstructive apnea
• extranodal involvement - most commonly GI tract; also testes, bone, kidney
• CNS involvement in 1% (often with HIV)

CIIDNIICII!ulbnpy l'llllllmilllb-
CIIDNII ClllulbnpJ Allie in PlliiiD with
. .1)
t..rc« Ont:d 2006; 7:37S-91
Study: RlndiriBd canlrallad 1rill with 1 n1llliln
lai!M'It. 341!11Rhs.
824 • increased LDH (rapidly progressing disease, poor prognostic factor)
dillu•llrge-B-CIIIfmpbaml who hid S1 ritt
lictDr, AQB I-IV or &llgllliiBue with
buk(IQB: 1811
Palilm ..:li¥edeilher6cydes
al chamaiunpv ll1d ribmimab (CCR;
n=413) 1116 cycles afCHOP-Ib c:hemalllnPV
IIana ltlC; n=411). Uty lllllldmadlllilll
received addilianll !ldialllmpv.
P*IJy o.....: Event-llle!U\WII. Sec:anduy
lllleom• incblld: fllllllll•, p!Dgllllion oodlr
ltalpv, piUQI8IIiaDfTw IJYIIIIIIIVMI
llld frlquiiiC'(af1Dxic aflac1s.
111111111: l'l1ierQ receiviv cal hid .. incleaed
3-..... IWII.fnl uvivll campllld wiil U. Cl£
(79'4 111. 59'4; P<O.IDI1) lll1d 1111 irmued
3-,.-MIIII-w.l{lmw. P=O.OOOI).
frequency af IIINerJe Mills did not 4lleT between
groups.
Clllllbia1: Riluximlh addld 1D six C¥CI• af CHCI'
il111 .tr.:M tJJmnart for yooou plli8rQ with
Investigations
• CBC
• normocytic normochromic anemia
• autoimmune hemolytic anemia
• advanced disease: thrombocytopenia, neutropenia and leukoerythroblastic anemia
• peripheral blood film may show lymphoma cells
• biochemistry
• increase in uric acid
• abnormal LFTs in liver metastases
• CXR, CT chest, abdomen, pelvis for staging
• gallium scan is useful for monitoring response to treatment and evaluation of residual
tumour following therapy in aggressive histological disease
• diagnosed by
• lymph node biopsy- exdsional biopsy preferred. FNA unreliable
• bone marrow biopsy- not optimal for diagnosis as BM may not be involved
Treatment
• localized disease (e.g. GI, brain, bone, head and neck)
• radiotherapy to primary site and adjacent nodal areas
• adjuvant chemotherapy
• surgery: splenic marginal zone lymphoma
• indolent lymphoma- goal of treatment is symptom management
• watchful waiting
• radiation therapy for localized disease
• chemotherapy for advanced stage disease [single agent or combination with ritwdmab
{Rituxan•), an anti-CD20 antibody]
Toronto Notes 2011 Lymphomas Hematology H45

• aggressive lymphoma- goal of treatment is curative

• combination chemotherapy: CHOP is mainstay, plus rituximab ifB-celllymphoma
• radiation for localizedJbulky disease
• CNS prophylaxis with high-dose methotrexate sites involved
• relapse, resistant to therapy: high dose chemotherapy, BMT
• highly aggressive lymphoma .... , ,I
• Burkitt's Lymphoma - short bursts of intensive chemotherapy
• "CODOX-M" chemotherapy regimen also often used± IVAC Treidment at HL depends on s1llge;
• CNS prophylaxis and tumour lysis syndrome prophylaxis trwtment of NHL depundl on hiltologic
subtype.
Complications
• hypersplenism
• infection
• autoimmune hemolytic anemia and thrombocytopenia
• vascular obstruction (from enlarged nodes)
• tumour lysis syndrome (particularly in very aggressive lymphoma) - see HSO

Prognosis
• follicular lymphoma- Follicular Lymphoma International Prognostic Index is used (5 adverse
prognostic factors): age >60; number of nodal areas >4; elevated LDH; Ann Arbor stage III-IV;
hemoglobin <120 giL
• based on calculated risk, mean 5 year survival ranges from 53-9196
• diffuse large B-celllymphoma -The International Prognostic Factor Index is used (5 adverse
prognostic factors): age >60; Ann Arbor stage (III-IV); performance status (ECOG/Zubrand 2-4);
elevated LDH; >1 extranodal site
• based on calculated risk, mean 5 year survival ranges from 26-7396

Tabla 23. Characteristics of Salactad Non-llodgkin's Lymphomas

Follicular Diffuse Large B-Cell Bulllitt's Militia Cell
I..JIIphoma(DLBCL)
Pen:enllgll of NHLI 33% < 1% ali.llt NHLs 6%
30% chidhood NHLs
Genetic Mulltion Bcl-2 activation Bcl-2, Bcl-6, MVC c-myc activation Overaxpression of cyclin
raman game niB D1 (Bcl-1 activatioo)
Clnsilicllion Indolent Ag1J'e5Sive Very aggressive ndolerrt
(high-grade)
Riskfadln Middle'ilge - BldBriy Pravious Cll 1. Endemic- African Male (mllle:fernale 4:1)
(Richter's lrllnsf.: origin. EBV-assacillled
5% Cll patients 2. Sptndic- no EBV
pni!J'llSS to ll.BCL) 3. HIV-rela1ed-
AIDS-dllfining illness
Clinical Features • Widespread painless • Rapidly pni!J1lSSive • Endemic form - • Oftl!n presents Stage IV
LAD* :!: bone marrow LAD and extranodal massive jaw LAD with palpable LAD
involvement i1filtration • "Starry-sky" histology • Involvement Dl Gl tract
• Frllqullllt 1ri1151ormation • 50% pmllllt at mge • High ri&k Dl tumour
to aggressive lymphoma VII, 50% widely lysis syndrome upon polyposis), Wllldeyer's
• Very responsive to disseminated treatment Ring
chernoradiation tx • Extremely aggressive,
5-yaar survival 25%
H46 Hematology Malignant Clonal Proliferations of Mature 8-Cells Toronto Notes 2011

Malignant Clonal Proliferations of

Mature B Cells
Table 24. Characteristics of B-Cell Malignant Proliferation
Cll Macraglobuln1111i1 Mv-1111111
CIIIType Lyrqlhocyte Plasmacytoid Plasma cell
Pratein lgM present lgM lgG, A, liltrt chain, M, Dor E

..... ,, , Nodes
llaplltlllplallllllllllaly
VfJry rommon
Cammon
Common
Common
Rn
Rare

Rouleaux forTMtion on Bona Liliana Rare Rare Common

blood smear, if not anifllct. danotes Hypercalcania Rare Rare Common
hyperglobulinemia (but not necessarily
monoclonality). a-lflilun Rare Rare Common
nmunoglobulin CampliCIII:i- Cammon lnfrequant Rn

Chronic Lymphocytic Leukemia (CLL) -----------------

Definition
• indolent disease characterized by clonal malignancy of mature B-cells

Epidemiology
• most common leukemia in Western world
• mainly older patients; median age 65 years
• M>F

Pathophysiology
• accumulation of neoplastic lymphocytes in blood, bone marrow, lymph nodes and spleen

Clinical Features
• 25% asymptomatic (incidental finding)
• 5-10% present with B symptoms (:2:1 of. unintentional weight loss :2:10% ofbodyweight within
previous 6 months, fevers >38°C or night sweats for <!:2 weeks without evidence of infection,
extreme fatigue)
• lymphadenopathy (50-90%), splenomegaly (25-55%), hepatomegaly (15-25%)
• immune dysregulation -autoimmune hemolytic anemia (Coombs positive), immune
thrombocytopenic purpura (ITP), hypogammaglobulinernia ± neutropenia
• bone marrow failure -late, secondary to marrow involvement by Cll cells

Investigations

..... ,...----------------,
,
• CBC: absolute lymphocytosis >5 x 109/L
• peripheral blood film
• lymphocytes are small and mature
• smudge cells
Smudge calls ara artifact& of damaged
lymphocytes from slide preplllllliofl • :O.ow cytometry
• cytogenetics - FISH
• bone marrow aspirate
• lymphocytes >30% of all nucleated cells
• infiltration of marrow by lymphocytes in 3 patterns: nodular (10%}, interstitial (30%}, diffuse
(35%, worse prognosis) or mixed (25%)

Natural History and Treatment

• natural history - indolent but incurable, with slow progression; thus select gentlest
treatment that will control symptoms
• observation if early, stable, asymptomatic
• intermittent chlorambucil or fludarabine chemotherapy combined with Ritxuirnab
• corticosteroids, MG - especially for autoimmune phenomena
• radiotherapy
• small minority present with aggressive disease; usually associated with chromosomal
abnormalities (e.g. p53 deletion)
• 9 year median survival, but varies greatly
Toronto Notes 2011 Malignant Clonal ProliferatioDS of Mature B Cells Hematology H47

• prognosis predicted by Rai staging

• low risk: lymphoqtosis in blood and bone marrow only
• intermediate risk: lymphoqtosis with enlarged nodes in any site or splenomegaly, hepatomegaly
• high risk: lymphocytosis with disease-related anemia (<110 giL) or thrombocytopenia
(<lOOx 109/L)

Complications
• bonemarrowfailure
• immune complications - autoimmune hemolytic anemia. immune thromboqtopenic (ITP),
immune deficiency (hypogammaglobulinemia. impaired T-cell function)
• polyclonal or monoclonal gammopathy (often IgM)
• hyperuricemia with treatment
• 5% undergo Richter's Transformation - aggressive transformation to Diffuse Large B-Cell
Lymphoma (see Table 23}

Multiple Myeloma (MM)

--------------------------------------
Definition
• neoplastic proliferation of a clone of plasma cells producing a monoclonal immunoglobulin
• usually single clone of plasma cells, although biclonal myeloma also occurs
Multip.. Mylllarn•
Epidemiology CRAB
• incidence 3 per 100,000, most common plasma cell malignancy lnci88Md Calcium
Renal failure
• increased frequency with age; median age of diagnosis is 68; M>F Anemia
larry lesions {lytic or osteoporosis felt
Pathophysiology to be ca111ad by myeloma)
• malignant plasma cells secrete monoclonal antibody
• 95% produce M protein (monoclonal Ig = identical heavy chain + identical light chain, or
light chains only)
• IgG SO%, IgA 20%, IgD 2%, IgM 0.5%
.... ,,

• 15-20% produce free light chains or light chains alone found in either:
- serum as an increase in the quantity of either kappa or lambda light chain (with an Raulina urinalysis will nat datact light
abnormal kappa:lambda ratio) chains as dipstick detects albumin.
Nead sulfosalicylic acid or 24 hour
- urine as Bence-Jones Protein ume prciBin far or
• <5% are non-secretors electrapharasis.

,,
Clinical Features and Complications
• bone disease- pain (usually back), bony tenderness, pathologic fractures .....
• lytic lesions are classical (skull, spine, proximal long bones, ribs)
• increased bone resorption secondary to osteoclast activating factors such as PTifrP
• anemia - weakness, fatigue, pallor Diag!Mil of MM {WHO)
• secondary to bone marrow suppression Maj•Cr*ria
• weight loss 1. Bane m.-raw >3D% piiUIITia callli
2. Plasmacytama an tissue biopsy
• infections 3. High parapruteins (elevated serum
• usually S. pneumoniae and Gram-negatives lgG. lgA or light chain excl'lltian)
• secondary to suppression of normal plasma cell function MiniM'Cr*ria
• hypercalcemia - NN, confusion, constipation, polyuria, polydipsia 1. Bona m.-raw plasmacytosis 10..:!0%
• secondary to increased bone turnover 2. Monoclonal protein leu than major
• renal disease/renal failure criteria lavels
3. Lytic bane lesions
• most frequently causes cast nephropathy (see N!ll?hrology. NP34} 4. Reduced nar..clanallg lavN
• bleeding
• secondary to thromboqtopenia. may see petechiae, purpura
• can also be caused by acquired von Willebrand disease
• extramedullary plasmaqtoma
• soft tissue mass composed of monoclonal plasma cells, purplish colour
..... ,,
.
• hyperviscosity- may manifest as headaches, stroke, angina. MI
• secondary to increased viscosity caused by M protein Amyloid
• amyloidosis The gennl term far a wriety of
• accumulation of insoluble fibrillar protein (Ig light chain) in tissues; can cause infiltration of proteinaceous matarials that have a
similar structural arganiZitian and are
any organ system: cardiac infiltration - diastolic dysfunction, cardiac arrhythmias, syncope, abnormally dapasited in tissllls.
sudden death; GI involvement - malabsorption, beefy large or laterally scalloped tongue; Found in a varisty of clinical di&ardars
neurologic involvement - orthostatic hypotension, carpal tunnel syndrome and can causa systemic [e.g. MM [light
• may cause Factor X deficiency if fibrils bind Factor X -+bleeding (raccoon eyes} cilains)] or localized amylaidasi• [e.g.
• neurologic disease - muscle weakness, pain, paresthesias Alzheimer disease (AB amyloid)].
• radiculopathy caused by vertebral fracture, extramedullary plasmacytoma
• spinal cord compression (10-20% of pts) is a medical emergency
H48 Hematology Malignant Clonal Proliferations of Mature B Cella Toronto Notes 2011

AullilqiiiiS.
....
.........
_...,... wr.....-..,
Mllphllll .......... :l:

•IWiipl• ..,....

ila.ly
Investigations
• CBC
• normocytic anemia, thrombocytopenia, leukopenia
• rouleaux formation on peripheral film
lancet2007; 370:12Dt-18
llldy: Randomilld Clllllnlllrilll willllllllliln
• biochemistry
• increased Ca, increased ESR, decreased anion gap, increased Cr, albumin, beta2-
lalluw " . 51.1 rncmltl.
IWticipiiD: pravilully urmllfld patilnll microglobulin (as part of staging), proteinuria (24 hour urine collection)
'flrith ndiple rrr;eloma (age 65 to 75 yen). • monoclonal proteins
........
plusp!ldrisn IMP: MP pUI llllidaril•
• serum protein electrophoresis (SPEP) - demonstrates monoclonal protein spike in serum in
(t.I'T; n= 125)111 Riducudftnlily allll 80% (ie. M protein)
tnwlsplanlatioll using ma..-n 100 • urine protein electrophoresis (UPEP) - demonstrates light chains in urine = Bence-Jones
(t.ll.100; n=12SJ. Protein (15% only secrete light chains)
......., .._.: Slniirllllll
. . . .: Medi1111111'1i¥1l rills were 33.211111Mhs
• immunofixation - demonstrates M protein and identifies Ig type; also identifies light chains
(13H4.8)1orMP. 51.6 months (26.&-not reiCIIed) • serum free light chain quantification - kappa and lambda light chains, calculated ratio
lo! MI'T.IIId 38.3 rrmhs II 3.0-61.61 fw MB.IOO. • bone marrow aspirate and biopsy
SliVivll-!iPiasnlly higt. Mil lila MPT • often focal abnormality, greater than 10% plasma cells, abnormal morphology, clonal plasma
1lllllpy lhlll MP (HII 0.59; MB.100
(0.611; P=OJl27).
cells; send for FISH or cytogenetics (prognostic implications}
c:.llllan: Thllidonidl i1 aiiiDnetion Mh • skeletal series (x-rays), MRI if symptoms of cord compression
meljiUD 111d is more efficiiCiouslo! • presence oflytic lesions and areas at risk of pathologic fracture
pmiaus. Llllllltld llilllty pililull Mil nUiipll • bone scans are not useful since they detect osteoblast activity
myebrll.
• beta-2 microglobulin, LDH and CRP are poor prognosticators

.... , Diagnosis
• International Myeloma working group criteria
1. serum or urinary monoclonal protein
Light Clllin 2. presence of clonal plasma cells in bone marrow or a plasmacytoma
15% of MM produce only light chains. 3. presence of end-organ damage related to plasma cell dyscrasia, such as:
Renal failun is a major problem. • increased serum Ca
Kappa > lambda light chain betlllr
prognosis. • lytic bone lesions
•anemia
• renal failure

Treatment
• treatment is non-curative
• treatment goals:
• improvement in quality of life (improve anemia, reverse renal failure, bony pains)
• prevention of progression and complications
• increase overall survival
• autologous stem cell transplant if <70 years old
• usually preceded by 4-6 months of cytoreductive therapy utilizing a regimen that includes
steroids (prednisone or dexamethasone)
• chemotherapy if> 70 years old or transplant-ineligible
• consider melphalan and prednisone alone if>75 years old
• melphalan, prednisone and thalidomide or melphalan, prednisone and bortezomib if
65-75 years
• dexamethasone and bortezomib if ARF; bortezomib ± dexamethasone in light chain
amyloidosis
• supportive management:
• bisphosphonates for those with osteoporosis or lytic bone lesions
• local XRT for bone pain, spinal cord compression
• kyphoplasty for vertebral fractures to improve pain relief and regain height
• treat complications: hydration for hypercalcemia and renal failure, bisphosphonates for
severe hypercalcemia, prophylactic antibiotics, erythropoietin for anemia
• all patients will relapse; choice of retreatment regimen depends on duration of remission, organ
involvement, patient's comorbidities and preferences

Prognosis
• Salmen-Durie (Hb, calcium, M protein, radiograph appearance and creatinine) and
International Staging System (beta-2 micoglobulin, CRP, chromosome 13 status, serum IL-6,
duration of initial plateau phase) used to stage and estimate prognosis
• median survival based on stage usually 16-70 months
Toronto Notes 2011 Malipant Clonal ProJiferaliona ofMature BCelb/Compllcatimu of Hematologic Malipandes Hematology H49

Monoclonal Gammopathy of Unknown Snn FlwliPtCW.IIIIio ilu

llilkflcafw .........

Significance (MGUS)
IIIGIJSI

lood 106:112-7.
Definition s..ly. ArllrDij1lclM lludy dlllrriling whlk
• presence of M protein in serum in absence of any clinical or laboratory evidence of a plasma the presm:e al DIJIIocbnllfile lilpplcrllnmda
cell dyscrasia or lymphoproliferative disorders cbli111 in rnonoclunll

• incidence: 0.15% in general population, 5% of people >70 years of age !IIII'II1JPIIh¥ Dfundetemined li!Jiific:lnce{MGUSL
._... tt. risk al progrmion llllllllipnl;y.
• asymptomatic IIIIIIWI: Blllin1arum 1111111• abllillld lnlm
1383 pllilnlllllllllthe Mayo dinic:
Diagnosis 1!111).1994. 114Bblsllillttll!'llleswara
• presence of a serum monoclonal protein (M-protein) at a concentration <30 giL oblailed within 30 dlys of diagnosl.
lllllulll: Mllgnlnt progrlllian t.d ocamd in 87
• <10% plasma cells in bone marrow {7.1i'Jol pitienls Ill lallll\'q)af 15 yelll.
• absence ofhyperCalcemia, Renal insufficiency, Anemia, Bony disease related to the plasma cell ., 319 133\1 plliaflllllllllinonNIIarumfrae
proliferative process (absence of "CRAB•) light chllin {R.CIIIIio WIS deteciBd. l"llere WISI
• 0.3-1% of patients develop a hematologic malignancy each year riskofpmgreaion in plliiiD
with mlllnlml Fl.C 1lliD raiiM 1D pdlflll with
• patients with M protein peak giL or patients with IgA or IgM MGUS are at higher risk I nonnlllltio {'-d l"ltiO. 3.5; M 2."5;
of malignant transformation p<O.OOII. This 1ildilg wu indapaJIIIari altt.sill
• patients with serum free light chains are at increased risk of malignant transformation IIIII type al the senwn monodOIIII (MJ plllein.
Canalllilnl: in higiHill: pants (llmannll
• monitor with annual history, physical, CBC, Cr, calcium, albumin, serum protein serum R.C lllio.11111¥ MWS.Iigh SIMI!
electrophoresis (considered pre-malignant) MpiHn IMI (>/=1.5 p\l.ll111eriskof
progn!stiollll20 yeii1WIS 58\ c:ornpll\ld lo 37,
in bigll-ironn.ilbl·rilk MGUS (1wll rist lldllrsf,
Waldenstrom's Macroglobulinemia 21\ IIM'inllrmldilll risk (Mil 1111 risk flc1Drj 111111
5\ loi\Yilk (no rill llcknl.

Definition
• proliferation oflymphoplasmacytoid cells
• presence ofmonoclonal IgM paraprotein

Clinical Features
• chronic disorder of elderly patients; median age 64
..... ,,

• symptoms: weakness, fatigue. bleeding (oronasal), weight loss, recurrent infections, dyspnea, Waldunllrom"1 mac:ruglobulinurnia
CHF (triad of anemia. hyperviscosity, plasma volume expansion), neurological symptoms, accounts for 85'l!. of all ca- of
peripheral neuropathy, cerebral dysfunction hyperviscosity ryndrome.
• signs: pallor, splenomegaly, hepatomegaly, lymphadenopathy, retinal lesions
• key complication to avoid: Hyperviscosity Syndrome (see below)
• because IgM (unlike IgG) confined largely to intravascular space

Investigations and Diagnosis

• bone marrow shows plasmacytoid lymphocytes
• bone lesions usually not present
• bloodwork- rarely see hypercalcemia
• cold hemagglutinin disease possible - Raynaud's phenomenon, hemolytic anemia precipitated
by cold weather
• normocytic anemia. rouleaux, high ESR if hyperviscosity not present

Management
• alkylating agents (chlorambucil), nucleoside analogues (fludarabine), thalidomide, rituximab, or
combination therapy
• corticosteroids
• plasmapheresis for hyperviscosity- acute reduction in serum IgM

Complications of Hematologic Malignancies

Hyperviscosity Syndrome
------------------------------
Definition
• refers to clinical sequelae of increased blood viscosity (when relative serum viscosity >5-6),
resulting from increased circulating serum Igs or from increased cellular blood components in
hyperproliferative disorders (e.g. multiple myeloma, leukemia. PV)
• Waldenstrom's macroglobulinemia accounts for 85% of cases
H50 Hematology Complications of Hematologic Malignancles/Blood Products and 'Ii'anafuaions Toronto Notes 2011

Clinical Features
• hypervolemia causing: CHF, headache, lethargy, dilutional anemia
• CNS symptoms due to decreased cerebral blood flow: headache, vertigo, ataxia, stroke
• retina shows venous engorgement and hemorrhages
• bleeding diathesis
• due to impaired platelet function, absorption of soluble coagulation factors (e_g_ nasal
bleeding, oozing gums)
• ESR usually very low

Treatment
• plasmapheresis

Tumour Lysis Syndrome

Definition
• group of metabolic complications that result from spontaneous or treatment-related breakdown
of cancer cells
• more common in diseases with large tumour burden and high proliferative rate (high grade
lymphoma, leukemia)

Clinical Features
• metabolic abnonnalities
• cells lyse, releasing K, uric acid, P04 (increased levels)
• P04 binds Ca (decreased Ca)
• complications
• lethal cardiac arrhythmia (increased K)
• acute renal failure (urate nephropathy)

Treatment
• prevention
• aggressive IV hydration
• alkalinization of the urine
• allopurinol
• correction of pre-existing metabolic abnormalities
• dialysis

Blood Products and Transfusions

..... ,
9
Blood Products
BloedGrou...
Group Antia•n Antillady • RBCs, platelets and coagulation factors (fresh frozen plasma, cryoprecipitate, factor
0 H Anti-A, anti-B concentrates) are available for transfusion
A A Anti-8
• donated blood (1 U = 450-500 mL) is fractionated into these various components
• centrifugation separates whole blood into RBCs and platelet-rich plasma
B B Anti-A
• platelet rich plasma is further fractionated into platelets and plasma
AB Alll!dB Nil • need to pool together multiple units to obtain therapeutic amounts
• FFP is plasma frozen within 8 hours of collection
..... , • cryoprecipitate is the high MW precipitate generated when FFP is thawed at low
..
temperatures

In Caflllll, blood products n Specialized Products

leliodepletecl via filtration immediately
lifter donation. 1her8fore it is
consid111ed:
• Low in lymphoki'le&, mLitinu
in a lower incidanca of fabrila
nonhemolylic lmllfusion f811ctions
• CMV n.gatiw (biCiulll CMV found in
leukccytes)
• irradiated blood products
• prevent proliferation of donor T-cells in potential or actual BMT recipients
• used for immunocompromised patients
• CMV-negative blood products
• potential transplant recipients
• neonates
• AIDS patients
• seronegative pregnant women
Toronto Notes 2011 Blood Products and Tranafusions Hematology HSI

Red Blood Cells

Packed Red Blood Cells
...... ,

• stored at 4"C
• transfuse within 35 days of collection, otherwise cell lysis may result in hyperkalemia 1 unit Df pRBC wllapproldmately
inellll11$11 Hb by 10 ;ll or inCIVQ8 Hct
• transfuse within 7 days of collection if renal failure or hepatic failure is present to reduce by4%_
solute load
• infuse each unit over 2 hours, max of 4 hours
T................ iiCrilii:IIC..
Indications for pRBC Transfusion (TIICCJ
• Hb <70 giL (7 gldL) IIEJII11119; :wl:U-17
• maintain Hb between 70 and 100 giL during active bleeds (7 gldL to 10 gldL) Slldr. t.Uicentre.lllldomilld allllnll trill
• consider maintaining a higher Hb for patients with: 838aiticlllv iiPitienlsMh
uollmi11f11r initilllll'lltnWII IIIII Mlnoglobii
• CAD/unstable coronary syndromes less ltln 9!1"dl witMI72 hOOI$ aiiCU 11Dii1ion.
• uncontrolled, unpredictable bleeding 1--.n: a1llnlfllsiun
• impaired pulmonary function llt:iMcl either (1 Iareslri:tive slnilell't' IRS;

• increased 0 2 consumption
hllmulobin wulasltln 7.0 !l"'l•nd 111111
MlliDined 111 71119 WdU or 121 • iball llrll8lfl'
Frozen Red Blood Cells (LS; n=42DI in whkli 1lllllfusions ocamd v.lim
• used for recipients with rare blood groups or multiple auto-antibodies lhe 10..0 ll"dl
MlliDined 1111011112il"dL
PriMly Oub:Gma: Mcnlty d 30 dlys and
Selection of Red Cells for Transfusion -ny alf19111 dylfooctian.
• when a need for RBC transfusion is anticipated, the following should be ordered: Reaulll: Morlllily !lin d 30 da¥S- similar
• group and screen biiMen lllllliPL "-at, mlllblily l'lfllwn
iglificlnlly lawl! l'lilllthl RS 1111111V lllllladliy
• determines the blood group and Rh status of the recipient as well as the presence of
il patients 1111 RS uraup and 16.111 in IS
autoantibodies vs. major/minor blood group antigens uraup; P=O.D3IIIIIIIamoa;b 111111han 55
• crossm.atch '1\WIS ohae (5.7ll RS IIIII 13lll.S; P=OJ)21, but
• involves mixing the recipient's blood with potential donor blood and looking for clotting did IIIII cillr ila111bgroup with cli!EIIy siglliicllll
• takes 30-45 min caniacdisease.
Cani:Miln: ARS al rad eel I!WiJsim ill!
• when blood is required, several options are available laut • afllclive u, and poailtf superior to, a
• 1st line: fully crossmatched blood (not always available in emergency situations) l.S11'1111Uian in IJitic:dyil plliln1s. Tlllllfulion
• 2nd line: donor blood of the same group and Rh status as the recipient lfllllgia il plliln1s with ICidlmyoandilll
• 3rd line: 0- blood for females ofreproductive age; 0+ blood for all others inllrdion and ul'lillbll.a1181d furlbat Aldy.

Platelets
Table 25. Platelet Products
Product
Random dCIIDr (pooled)
Single donor platelets
HLA 11111tdied platelets
Indication
lli'Dmbocytopenia with bleeding
Potential BMT recipients
Refractory to pooled or single donor

• stored at 20-24•C
• random donor platelets are transfused in groups of 5 units; this should increase the platelet
count by at least 15 x 109/L
• single donor platelets (transfused as single units) should increase the platelet count by
40-60 X 109/L
• if an increase in the platelet count is not seen post-transfusion: alloantibodies, bleeding, sepsis
or hypersplenism may be present

Table 26. Indications for Platelet Transfusion

Pit (x 1QIA.} lndiCIIions
<10 Nan-immune thrombocytopenia
<20 Procelklres nat associated with significant blood lass
<50 Proclllilres associated with blood IDSS or major 8urgery (> 500 ml EBU
<100 Pre-neurosurgery or heed trauma
My Plllhlet dyafunction and rrabd blll8ding

Relative Contra-indications of Platelet Transfusion

• TTP, HIT, post-transfusion purpura, HELLP
H52 Hematology Blood Products and Tranafusions Toronto Notes 2011

Coagulation Factors
Tabla 2'1. Coagulation fllc:tar Products
Product lldicatilll
FrBiih F10Z8n Plasma (FFPJ Depletion of multiple coagulation facto11 (e.g. &epsis, DIC, dilution. TTP/HUS, liver dis!liiSII],
emergency reve11el of lie-1hreatening bleeding secondary ID Wllfarin overdose
Cryoprecipitate (enriched Factur VIII deficiency
fibrinogen, VM; VIII, XIIII wn Willebrand's disease
Hypofibrinogenemia
Hemate P wn Willebrand's disease
Factor VIII concentrate Factur VIII deficiency AI
Factor IX concentrate Factur IX deficiency (Hemophilia B)
Recombilant VIla Factur VII deficiency, CNS bleeds, severe traum11, Hemoplilia Aor Bwith inhibitors
Pro1hrombin Complex Rewnal of warfarin 1hempy or villmin Kdeficiency in bleBding peti&nt or in patient raquiring
urgent (<6 hoursj surgical procedure

Acute Blood Transfusion Reactions

IMMUNE
Acute Hemolytic Transfusion Reactions {AHTR)
• ABO incompatibility resulting in intravascular hemolysis secondary to complement activation
• most commonly due to incorrect patient identification
• occurs immediately after transfusion
• risk per unit of blood is <1 in 250,000
• presents with fever, chills, hypotension, back or flank pain, dyspnea, hemoglobinuria
• acute renal failure (<24 hrs) and DIC
• treatment
• stop transfusion
• notify blood bank and check for clerical error

.. ,
• maintain BP with vigorous IV fluids ± inotropes
.... • maintain urine output with diuretics, crystalloids, dopamine

DDx of Pust-Trensfusion Febrile Nonhemolytlc Transfusion Reactions {FNHTR)
• Acum hlmolytic 1nlnsfusion reaction
• Fallrila non-hamolytic 1nnsfusion • due to alloantibodies to WBC, platelets or other donor plasma antigens and release of cytokines
reaction from blood product cells
• Bacterilll conlllmillltion • occurs within 0-6 hours of transfusion
• Allargy • risk per unit ofblood is 1 in 100 (minor), 1 in 10,000 to 40,000 (severe)
DDx of Pust-Tnlnsfnlon Dyspnaa: • presents with fever ± rigors, facial flushing, headache, myalgia. hypotension
• Circulatory overload • treatment
• Transfusior..relatad acum lung injury
(TRALI}
• rule out hemolytic reaction or infection
• Allargy • if fever <38°C, continue with transfusion but decrease rate and give antipyretics
• if fever >38°C, stop transfusion, give antipyretics and anti-histamine

Allergic Nonhemolytic Transfusion Reactions

• alloantibodies (IgE) to proteins in donor plasma result in mast cell activation and release of
histamine
• occurs mainly in those with history ofmultiple transfusions or multiparous women
• risk per unit ofblood is 1 in 100
• presents mainly as urticaria and occasionally with fever
• can present as anaphylactoid reaction with bronchospasm, laryngeal edema and hypotension,
but this occurs mainly in IgA deficient patients that have anti-IgA antibodies
• treatment
• mild: slow transfusion rate and give diphenhydramine
• moderate to severe: stop transfusion, give IV diphenydramine, steroids, epinephrine, IV
fluids and bronchodilator&

Transfusion-Related Acute Lung lniury (TRALI)

• new-onset acute lung injury that occurs during transfusion or within 6 hours of the
completion of transfusion
• insidious, acute onset of pulmonary insufficiency
• profound hypoxemia (PaO:zfFi01 <300 mmHg)
• bilateral pulmonary edema on CXR
• pulmonary artery wedge pressure <18 mmHg
• no clinical evidence ofleft atrial hypertension
Toronto Notes 2011 Blood Products and Tranafusions Hematology H53

• pathogenesis uncertain; perhaps due to binding of donor antibodies to WBC of recipient and
rdease ofmediators that increase capillary permeability in the lungs
• typically occurs 2-4 hrs post transfusion and resolves in 24-72 hrs
• risk per unit of blood is 1 in 5000
• is currently the leading cause of transfusion-related morbidity and mortality
• treatment: supportive therapy (oxygen}
• inform blood bank; patient and donor testing will be arranged

NON IMMUNE

Bacterial Infection
• Gram positive: S. aureus, S. epidennis, Bacillus cereus
• Gram negative: Klebsiella, Serratia, Pseudomonas, Yersinia
• overall risk is 1 in 100,000 for RBC and 1 in 10,000 for platdcts
• never store blood >4 hours after bag has left blood bank
• treatment: stop transfusion, blood cultures, IV antibiotics, 1luids

Transfusion Associated Circulatory Overload

• due to impaired cardiac function and/ or excessive rapid transfusion
• presents as dyspnea, orthopnea, hypotension, tachycardia, crackles at base oflung and increased
venous pressure
• incidence is 1 in 700
• treatment: transfuse at lower rate, give diuretics and oxygen

Hyperkalemia
• due to K release from stored RBC
• risk increases with storage time and if blood is irradiated
• decreased risk if given fresh blood
• occurs in 5% of massively transfused patients
• treatment: see Ne.phrology. NP16

Citrate Toxicity
• occurs with massive transfusion in patients with liver disease - patients are unable to clear
citrate from blood
• citrate binds to Ca and causes signs and symptoms ofhypocalcemia
• treatment: IV calcium gluconate (10 m1 oflO%) for every 2 units ofblood

Dilutional Coagulopathy
• occurs with massive transfusion (>10 units)
• pRBC contains no clotting factors, fibrinogen, cryoprecipitate or platelets
• treatment: FFP, platelets and cryoprecipitate

Delayed Blood Transfusion Reactions

IMMUNE

Delayed Hemolytic
• due to alloantibodies to minor antigens such as Rh, Kell, Duffy, and Kidd
• level of antibody at time of transfusion is too low to cause hemolysis; later the level of antibody
increases due to secondary stimulus and causes extravascular hemolysis
• occurs 5-7 days after transfusion
• presents as anemia and mild jaundice
• treatment: no specific treatment required; important to note for future transfusion

Transfusion-Associated Graft Versus Host Disease (GVHD)

•transfused T-lymphocytes recognize and react against "host"' (recipient)
• occurs 4-30 days following transfusion
• most patients already have severely impaired immune systems (e.g. Hodgkin's or leukemia)
• presents as fever, diarrhea, liver function abnormalities and pancytopenia
• can be prevented by giving irradiated blood products

NON IMMUNE

Iron Overload
• due to repeated transfusions over long period of time (e.g. beta-thalassemia major)
• can cause secondary hemochromatosis
• treatment: iron chelators after transfusion
H54 Hematology Blood Products and 'I'ransfusiona/Common Medications Toronto Notes 2011

Viral Infection Risk

• HBV <1 in 82,000
• HTLV <1 in 1,000,000
• HCV <1 in 2,800,000
• HIV <1 in 4,000,000
• other infections include EBV, CMY, WNV

Common Medications
Tabla 28. Drugs for Anemia
Drug Cornman DOling Schadul1 lndcrio11 Cantraindic:daM
follllllary
iran Iron glucallllle Synthesis of 2-3 mWitg/day of elemental Iron deficiency anemia- Iron overload In children: acute
Iron sulphate hemoglobin iron treatment and prevention ion toxicity
Iron fumallla in 3 divided doses PO Pregnancy
Pai!Jfar<'
Femirona
C"flllOCobalamin Synthesis of flllic Up to 11Dlllf'day PO 812 deficiency llypenensitivity Diarrhea
hydmxycobalanin acid and DNA
BedCIP
Cobex8
falic acid Folic acid Synthesis of purines up to 5 mglday PO Folic acid deficiency Unoorreebld Rash
Novofolaci.P and 1hymidylate, Pregnancy pernicious anemia
FolviteCII thus DNA
epoetil EpogenCII Stimulation ol RBC 50-1 000 Ulkg SCJJV; Renalfaiure Uncontrolled Hypertension
Eprex3 synthesis 3 times weekly MIITUW failure hypBrtausion
dabrepoetil Autulagous blood donation Myelodysplastic
syndrome

A1pit1 pg DWiANI-•nAal
• Crinlllclulil of hrlllllllein
(fSI'III): R.dllliled C.llhllll Tlill
!Mm2lll6;
llldr.RIIIdonised. coolraled. apen-1Jallment.
lllditi'Q-hindad trill wi1h ll'llln folow-up of
3.5\'llln.
11orisienl iscllernic lUick Ill .... slroiB of
paiUIIIIIdlllblrillD!igil.
lnllmnllan: l'llilrD wnasignld 1D 1111irin
(»325 nv dlil11 v.illlln=1363) 111Mholi
(n=1376) dVIridlmail(200 nv twicl dlilyl.
......., carqxJiill oldellli
from d VMCUillr Ct.ISII, non.fllll strokl,
non-1111liii'J'I)CIIIill irRrdiJn. 1111111jor bleedilg
compicltion. lllflplned li1t
....: Primlry auk:ame lll'eJ'G 1111111 in 113
plliela on 111pirilll'ld dipyridlmola ll'ld
in IISpirin alonl(hlllrd lllioO.IO,
SCI0.66.0.J8;abaidllriskllllb:licm 1.0'1.J*
Yilt S Cl 0.1·1.8). Adiltillifl ttw ESPRIT IIIII
1D 1he mell-ftttsis af pm;ioos trials resubd in
11niMIII rilt lllio 1111 ile COJI'IIOiill of vnculr
dellb, stroke, or III)'IICirdill inlltclion of D.8Z (IS..
Cl 0.74.4J.11I. l'lllilnll onllpiin end dil¥idunall
cfiamrud 1rill mlllblian mDII aftlm ttwn lhuse
on uprilllble VI. . . . beCIUII of
ballllchl.
c.tailn: 1111 ESPRIT 1111111s. canmined v.illllhe
lids Df pfllliaus trials. pmida dicilnt ll'idlnc1
1D prefer 111e c:unDnllian regnn of up;n pu
diwidlmofe -llpirin alonl a llllli1lnrriiGt
tfwrlpy Iller CQbrll iWieemil olllllilrill origin.
Antlplatalat Therapy
Aspirin (ASA)
• irreversibly acetylates COX, inhibiting TXA2 synthesis, thus inhibiting platelet aggregation
• ASA is currently indicated for:
• stroke and MI prophylaxis
• to reduce the incidence of recurrent MI
• to decrease mortality in post-MI patients
• dosage: single loading dose of 200-300 mg PO, followed by daily dose of 75-100 mg PO OD
Aggrenox41'
• combination of ASA and dipyridamole
• dipyridamole increases intracellular cAMP levels, which inhibits TXA2 synthesis, leading to
decreased platelet aggregation
• hypothesized that the effects of dipyridamole potentiate antiplatelet actions ofASA
• Aggrenox" is more effective than aspirin in secondary prevention of stroke
• ongoing clinical trials will determine the best indications for this agent
Clopidogrel (Piavix•)
• ADP activates GP lib/Ilia. allowing platelets to bind fibrinogen and aggregate
• dopidogrel and tidopidine (Ticlid•) inhibit ADP binding to platelets, thus inhibiting
aggregation
• useful for prevention of cardiovascular events in high-risk patients
• cl.opidogrel may cause TTP
• ticlodipine (Ticlid•) is associated with a risk of agranulocytosis and is rarely used
Glycoprotein lib/lila Inhibitors
• Reopro• (abciximab), Integrelin• (eptifibatide), Aggrastat• (tirofiban)
• blocking GP Ilb/IIIa receptor inhibits fibrinogen and vWF binding, leading to decreased platelet
aggregation
• used most commonly in patients undergoing cardiac catheterization
Toronto Notes 2011 Common Medications Hematology H55

Anticoagulant Therapy
• see Approach to 'ITeatment of Venous Thrombosis, H32
,,9.----------------,
,
Cammon Mlldlutiona tlnrt lntllrut
Absolute Contraindication• withWamrin
• active bleeding Acellminophen (interference K
m81llbolilm)
• severe bleeding diathesis or platelet count <20 x 109/L (<20,000/mm3) NSAIDS {GI injuty)
• intracranial bleeding, neurosurgery or ocular surgery within 10 days Fluconazola
Matronidazola
Relative Contraindication• Sulfamethoxazole
• mild-moderate bleeding diathesis or thrombocytopenia
• brain metastases
• recent major trauma
rl Rxlll-0.. Ylalhi-Ad;.tlll
• major abdominal surgery within the past 2 days
• GI or GU bleeding within 14 days T......._...,.._. .........
lWnctilnltlll ....... lMWII .. ADatl

• endocarditis ..IWo\ 2006; 296:m.42

llldy. r.uic:enb!, Rlllllomilllll, open-libel
• severe hypertension (sBP >200 or dBP >120)
llljdclfill·bhled. IIOIHIRriolily trill Mh follow
• recent stroke upof3Tnllllhs.

Heparin and Warfarin 551 mU.1111111 weight 831qj) MIIIIICUie YllllUS
lhromollolmbolism fVTE).
IIIIIMidln: l'ltiarDWIII randonilld ID rave
Tabla 29. Comparison of Heparin and Warfarin llillwfixlld.dola. Miglll.......... .man-
Heparin Warfarin lrilctilntld lllplrin 111 LMYt'H (dlllllplrin 111
e!ampllil). Thenpv iu1ld fur I ninirun of
Stnlcture large anionic polymer, acidic Small lipid soluble molecule 5days 111d corm.d 11111 the INII was lladlt
within the lbempeutic range will! !be inililllion rl
Roubl Mninillrlli1111 Parentnl {IV, SC) Oral (PO) IWiflrin llalpy.
PriMly Oub:Gml: lleiJIIreiiiVIE over 3rncJr'&
Site of Al:ti1111 Blood (via Antithrombil) Liver rillolllw up lll1d major 10 dl'fS of
randoailllion.
Onset Rapid (seconds) Slow {limited by of clotting factors)
llllulll: 1hR wasl'ID liGnificlnlllllnlca in
Mechlnism Accslsllll8s BCtivity of Antitlrormin V'lllmin Kanlllgonist. inhibits production of II, VIL IX. the rill of in 1hllltrac:1ianllld
X. Protein Cand S heplril P4J (13 plllients, 3.1W.) vs.lhe LMWH
!.'OUPI12PIIi11D.3.4'l.l'hlllwas-.ol'ID
Dul'llian of Actian Acute {hours) Chronic (days) siPicanlcilhqnce in the i..:idln:e rl major
blleding Millin IDdlyS rl mdanilltion in 1111
Acutlllhenlose Protamine sulphate IV Vitamin K+ FFP lrilctilntld lllplrin I.'OUP 14 palin. 1.I'!
VI. the lMWH group (5 plliants. 1.4\1. ., 721
Monilllrilg am (intrinsic pethway) PTJINR {extrilsic pathway)
of palilla riCIMng Ll1frlclilntld hlllarin and
PreaniiiCY Sale (does nat cross placm) Nat used (can cross placm), t&nltogenic 68\ of pllilnll riCIIMng LMWII. trutmllllwas
lldniiiiiiiCI autsidl of hllspital

Advene Reactions of Heparin IUbwllneiU ul'inlc:tiooalld hlplrin is 11lffilctiw
• hemorrhage: depends on dose, age, and concomitant use of antiplatelet agents or thrombolytics • llll!dlrd 1r811mantwillllM'NH inpllilniiMh
• heparin-induced thrombocytopenia: associated with venous or arterial thrombosis (see Table 16) ICUIIIVIE.
• osteoporosis: with long term use

Low Molecular Weight Heparin (enoxaparin, dalteparin, tinzaparin}

• increased bioavailabillty compared to normal heparin ., ....... lll..........

• increased duration of action Ortlpedic Sir1rt: A

. . . . . Daulllt* ......
• SC route of administration Jn:h i1ttm Med. 2002;1 62:183HO
• do not need to monitor aPTT Ja det!nnile IWetlilr 1Nic1Die!u
• adverse reactions less common than UFH 2.5 mg. llgiman rllondlplrirux slllliln
• patients with renal failure (CrCl <30) can accumulate LMWH tlriig 5 him IIIII aR1111Y was1111n ei1CIM
Q IS..,. ISippiMd 8f10IIPI'ii
• only minimally reversible with protamine sulphate
lludy W.ctiln: Rill' nUiic:er'm, nrlllomillll,
Heparin Alternatives dadn·blild trials in PllilniJII'idQiing U:tM
It replacement. !leclive lllljarbee Qlii!IY,IIId
Danaparoid lllrgaryfurliipfilcbn (n=7344).
• indicated for mT, stable patients a-1111: Fandlpuiu. sjpiclnly reduced 1lie
• inhibits Factor Xa via antithrombin III iilcidenceriVIEiiydly11 (182[6.Kiof2682
• SC route of administration prilnlsJ C01111111d witlunaxaperin (371
rl 2703 will! acamrnon Drldllllllction
• monitor anti- Xa levels if renal failure or extremes in weight; cannot monitor aPTT rl 55.2\{l!i'I.CI, 45.KID 6.'1.1'1; this
ellectwas
Hirudin lllrvmY 11'11111 Although maj!r IHediiQ
• indicated for lllT, unstable patients (ICU/CCU) requiring procedures OCQjfled
trBI1iid group (p=.DOB), tlis ilcidlnca rl clialy
• direct thrombin inhibitor (natural) !!lmnt hteaq (Ieiding to dedi Ill reapenlion Ill
• IV route of administration ocamilg ill acrilicll organ) lid not diffilr hatwa•
• monitor aPTT levels grwps,
• risk of anti-hirudin antibodies (40-60%) Clncbinl: In petiliilllllidlli'QDing Dr1hoplli:
lllrgmy. 2.S mg offandlplri'axaodiln anal
• increases INR (difficulty switching to warfarin) dliy, aq 6 illlwldl
• blnafit an Milll
ristraGiction
incrHiing lila rilk rl clnically raiMnt
H56 Hematology Common Medications Toronto Notes 2011

Argatroban
• indicated for HIT, renal failure and unstable patients
• direct thrombin inhibitor (synthetic)
• IV route of administration
• monitor aPTT levels
• increases INR (difficulty switching to warfarin)

Fondaparinux
• selective inhibitor of Factor Xa
• heparin pentasaccharide analogue
• one of the newer drugs for prevention and treatment ofVTE

Tabla 30. Recommended Tha111peutic INR Ranges of Common for Oral Anticoagulant Therapy
lndil:alian INR llqa
Prophylaxis Ill venaus thrombosis {high-fisk suriJI!IYI Z.G-3.0
Treatment Ill venous thrombosis
Most ca&e& Ill thrombosis with antiphospholipid antibody syndrome
Treatment of embolism
Prewntion of systemic enilolism
1issue heart valves
AMI (ID pr8VIIIIt syslllmic embolisml
Valwar heart disease
A1rial fibrillation
Bileaflet mechanical valve in aortic position
Mechanical prosthetic mittal valves (high risk) 2.5-3.5
Prophylaxis Ill recurrent myoCIIdilll infarction

Tabla 31. Recommended Management of 1 Suprlltherapeutic INR

INR Blaading Praent llecommandad Action
>Ther to 5.0 No Lower warfarin dose, OR
Omit a dose and reswne warfarin at a lower dose when INR is in tharapeutic range, OR
No dose reduction naeded if INR is minimelly prolonged
>5.0 1D 9.0 No Omit the nert liD 2 doses of warfarin, monitor INR more frequently Mld reswne trealment
at a lower dose when INR is in thempeutic mnge, OR
Omit a dose and administer 1 ID 2.5 mg ami vit Kin petients with ilcreased risk of bleeding
>9.0 No Hold warhril and administar 51D 10 mg Dllll vit It Monitor INR more frequently and
administer more vit Kas needed. Resume warfarin at alower dose when INR is in
therllpeUtic range
Serious or life Hold warhril and administer 10 mg vit Kby slow IV infusion; supplement with pruthrombil
threatening c1JR1)1ex. concentrate, fresh frozen plasma. or recombinant human factor VIla, depending on
clinical urgency. Monitor illd repeat as needed.
hllp1ed fnlm: Ansell J, Hnh, J, E. et 1L I'IBmlcalagy 1nd at the Yi11min llllllgorlisb: AmeriCI11 Colege at Chest Physi:ims E<lidenc:e·Based
Cliniclll'rlcticelluidllilas (8tll EditiDII). Chest 210; (6 Suppl):160t.
Toronto Notes 2011 Common Medications/Landmark Hematology Trials Hematology H57

Chemotherapeutic Agents
Tabla 32. Selected Chemotherapeutic Agents
Mec:hanilm of Ac:tiaa ar Target
Alllylatmg Agent • chlorarrtucil, cyclophosli!amide. Damage DNA via alkylation of base pairs
melphalan (nitrogen mUSWds) Leads 111 of beses, abnormal base-
• cisplatin pairing. DNA breakage
• dacarbazine, prucarbazine
• bu&ulhm
AntimiiUalillls • metholrexste (folic acid antagonist) Inhibit DNA synthesis
• 6-mercaptopurine, lludarabina (pLiine
antagonist)
• !).FU (pyrimidine antagonist)
• hydroxyurea
• adriamycin (anthracycline) Interfere with DNA and RNA synthesis
• bleomycin
• mitomycin C
Juana • paclitaxel Stabilize microtubule& against braakdown once cell
• docetaxel division complete
Vinca-elklloids • vinblastine Inhibit microtubule assembly (mitotic spindles),
• vinaistine blockilg cell division
• vinorelbine
Topoisoiiiiii"ISIImibitDn • irinotecan, topotecan !topo I) Interfere with DNA unwinding neceswy lor nonnal
• lltoposide (topo II) and transcription

Monoclonal An1ibodls • trastuzwnab (Herceptine) Hmz

1111111 Mala!Da Inhibitors
• bevacizumab (Avastinfll) VEGF
• rittlximab {Rituxan41J CD2D
• celuximab (&bitux") EGFR
• imatinib mesylata Bcr-Abl
• erlotinib {Tarcevalll] EGFR
• gefitinib (nssa®J EGFR
• bortazomib {Velcade111) 26S prolllasome
• sunitilib (Sutent') VEGFR, PDGFR

Landmark Hematology Trials

Trill llafaru:e
CML: lmatinib w. NEJM 2003; In patients with chranic-lilllse CML, imatnib wes roore effactiw than IFNa +
IFN + Cytarabine 348:994-1 004 cylllrabine in inducing cytogenetic response and freedom from progression to
accelerated phas!Piblast crisis
Hodgkin's Lymphoma: NEJM 1992; In Lymphoma, ABVD regimen has equal fllilure.free and oV81"1111 survival to
ABVD w. MOPP 327: MOPP + ABW, but less myelotuxicity. ABVD is standard chemotherapy for Hodgkin's
CHOP NEJM 1993; In NHL CHOP has lowest incidence of fatal toxic reactioll& and shOW& no significant
328:1002-6 difference lmm 3 lither regimens in response or disease-free/overall survival. CHOP is
the stllndard for advanced NHL
CLOT NEJM2003; In patients with cancer and acute venous thromboembolism, LWMH was more effective
349:146-53 then coumadn in reducing the risk of ll!CIITent thromboembolism without increasilg the
risk of bleeding
ITP: Dexamethasone NEJM2003; Afour-day course of higt..dose dexamethasone is effective initial therapy for adults with
349:831-6 imrnme thrombocytopenic purpura
MRC NEJM2005; Hydroxyurea plus IOYMlose aspirin is superior to anagrelide plus low-dose aspirin for
353:85-6 patients with essential thrombocythemia at high risk for vascular events
TRICC NEJM1999; Arastrictiw strategy of red-cell tnrlslusion (when Ill < 70) is at least as elfective as
340:409-17 and possibly superior to a liberal transfusion strategy (when Hb <100) in ICU patients;
one possible exception is patients with an acute Ml or unstable angina
Platelet transfusion NfJM1997; The risk of major bleeding in patients with AML undellloing induction chemotherapy
threshold 337:1870-5 was similar whether the threshold was sat at 20 or 1C. Use of the
lower threshold reduced usage by 21.5 percent
Dose of platelet NEJM2010; Low dose prophylactic platelet transfusion decreases total number of
transfusion 362:600-13 transfused but incraases number of transfusions without increased incidence of bleeding
in patients with hypoproliferatiw thrombocytopenia
H58 Hematology References Toronto Notes 2011

References
ID Ilia plliant with ttrambocytasiL UpTolllta, RDI8, BD [fdl. w..m, MA 2009.
AniUae JO. T1811ment rJ Non-Hodgkin'• NEJM. 1983;328:1023-1030.
Balaiile R. Harausseua J. fv\lltiple lltillon. r£JM. 1997;336:165H4.
illllls SM and <ii'*l! JS. Tllllmantof dellp-vail ttmmollii. NEJM, 2004;351 :268-277.
lllmmDre AW, Snu:br Ill. L'l11'41lildenopathyand MalignaiiC:y.Arnericlll flmily l'h'/sicin 2002:66;210:1-21 10.
llaltmnllySS. Cau111 oftfw hnlillryand acquired sidarobllllic1111111i1L In: UpTDilltl, IIDII, BD [fdl. UpTDilllll, Waltlwn, MA 2000.
Calkin. JL Idiopathic Furpn.
lhiOII'IIoi;ytopenil+purpuA.pdf
Calkin JL. PI...I'IDII PH.IIIIody Eu¥: Blood Transfusions, Blood Altamalivls and Tnnsfulion Reactions. Surmylrook and Woman's !AIIIga Health Sciancea Cantra:
Taronto, 2003.
Car.dillll'ldiltric Socia!y. T1111slusim and risk of idaction il Cllllda: Up datil 2006. Padilllriculld Child Haalth. 2005;1 1131:158-162.
Carllll11111l. Enklllian al Bllading DisaniBTL In S.undln Milllual rJ Clinical Lalxntmy SciallCI. Cllig Lehman mWB Saundars CO, PA. 1118.
Cacir• Enanlial5 aiMedicina. Tlrombocytopania.
Christiansen SC.IIal. Tlmlmbophilil. Clinicall'lctDI-..and Recurrent ThrDmbotic Events. JAMA. 2005; 293(181:2353-2361.
Cina511111ld Bllnchatlii 'IS.IOIIUIB furpurL NEJM.
CllltBs TDand BaelmerRL. Causes afneutluphilia. UpTDillle, Rase, Ill (EdL UpTaDitB, Wdhim, MA2006.
Cahan K. Scadden D.T. Non-Hodgkin'slfmphama: pllhaglllllil, clinical prasaniBiilll, and 1llltmR. Cancar Tlllt RBL 2001;104101-203.
Decou IUs elll. Acnca11rial rJ vena CMI fillers in ttw rJ pumon•l'f embolism in pllienl$ with proximal tlranilasis. NEJM. 1988; 338: 401·415.
!Qcoll MC. Sickle l'edillrics illleview. 28:7 ng- 286
Gearts WH, Pineo IJ. JA. at II. Prevanlion rJ vtnDIJI tlir!IIIDiambalilm. Swdl ACCP conlarenca on antithrDmbalic and tlirombDiytic 1herlpy. Cbast 2004; 1261.

GlorgaJN. TI'Eimlnt IIIII prGgiiJiis of idiapelhic ttrambocytopani: P11J11111. Uplolllta, Rasa BD IEdL UpTallltt, Wllthun. MA 2005.
Gc*lmen J. ABC of clinical h11111'111D1ogv: Clrlnic m'l'ioid ld:almia. BMJ. 1997; 314:657.
Hllbe11111nn TM, Sbsan... IF. LYR1Jilldenapalhy. Ml¥0 Clinic l'nlc, 2000: 75ln723-732.
Haen:lever O.lleill V, etal. AprognasticscorefoniMnced Hodgkil's Prognostic Factors l'lojecl on AcMnced Hodgtin's Disease. NtJM. 1918;
338:1506-14.
H111th Canada. Eflecb; ct Lead on Health. 111111/Www.hc-K.ge.ca/IHffl'j!l-vsvfenYian'llldiibniH!v.php
H•nlll' M.L, Golda D.W. Myalad'IIPI•ia. r£JM. 1119; 340:1641-110.
111111/cenCimlll.nci.nil.gov
ICcro'ICS MJ et II. Comparison of 1G-mg and Wllrflrin initiation Jn11D1P11S logethet witli hepaJil far aut patient treatment rJ acu1e wenaus
lhrorrlicientDiism. Ann lnllm Mad. 2003; 138: 714·719.
Ky» RAand Rlljlumn SV. ChamatliaraP'I in 11111tipla ""'lllama· Uplollla1B, llaiB BD (EdL UpTollla1B, W.lth11111, MA 2006.
Ky» RAand Rejlii.ll'lr SV. Cili:al manillstatians and diagnais ctW.Id11111bom's Uplolll!t, I!DI8, BD [EdL UpTalllta. Walhun. MA 2006.
Landaw, SA. Appralchtotlia aUpetilntwithtlirombcJc¥tDplllia.ln: Up TaD1111,11asa, BD t£d1 UpTa d1111. MA2005.
l.aonlldi.S. J, Belli PM, BDU-MG, Ill al. Dipyridamole ar v.ithaut aspiin WJC11518curranl .._In ACP Jaumal July{Aug 2005; 143
111:10.
lMIB' RJ and Machi! SJ. ABC rJ cinical haematologv: PlatBiat dimlm. BMJ. 1997;314:809.
Liesnel RJ and Goldstone AH. ABC rJ clinicalamllalogv: The acute I!Wemiu. BMJ. 1997;314:7:13.
l.cMnmb1111 B. Downing JR,IknnattA.Acutl fll'lllail I!Uiilnia. 1911. NEJM. 341:1051-lZ.
LJ. and Bull HA. Norrral hlamDIIUislllll ragulllion. Blood Rllv. 11181;3:237.
Marbvic M. at al. Usaful1111s of salibla transfrilraceptor and ferritin in iTon deficilncy and dloric di-e. Seen J Cin Lib Invest 2005; 65:571·576.
Mllld GM. ABC rJ cili:al haami1Dklgv: Malgnlnt WDmll and chronic lfmphocytic ldaer!Ma. BMJ. 1997;314:1 103.
M&Ainazy Mand l'amon TC. ABC ct clilical haamllalogv: l'alyqotillllll'il, priml1y laRIIItiall ttrambiJC'IIhaamiland '"'llllafibruiis. BMJ. 1997; 314: 587.
MechaniiiN rJ -lrenllfusian reactians. Tlllllfus Cil Bioi. 2001;8:278-81.
GA. Vulilakopaulas TP, Bau111ialill VA. Ft1111 P. Samin Oncol1993; 20:570
l'lal G, Ch•ntler M, Magiera H, 81 II {Eds]. The W.hington Mllnual H.-.tologv llld Oncology Subspecialty (Anajl Upincatt Wiliamsllld wan., Philldalphi1 PA,
2004.
l'li C., E¥ln5 W.E. Acutllymphablulic leukemiL NEJM. 1988;339:1105-15.
Razman C.. MantsemrtE. ClrDiie lymJDqlic IUemia. NEJM. 1995;333:1052-57.
Sablti111 MS [fdl. H11f118100gy·Oncalagy.ln Packat Mldicina, 2nd ICI!icm: The M11111Chuslltl GIIIWII Haspol Handbaol: of lnlamal Madicilll. Wiliams and
Wains: PhiildaiPiia PA. 2004.
Slllllte Nllld Sakamoto K. AM Leukemia. E-medicille 2006acmsed Ill:
SIW¥8rs C. Chnric m.,..allaWnia. r£JM. 1999;340:13Jl.40.
Slralf MB, Smith B, SpivU JL "'!'he dilgnallii and managiOilln! rJ paltcyttaria vn in 1ha Bill linea tfw l'alyqotilamia Veri Stud¥ Gruup: asurwv of AmariCITl
Society ct Hemataagy rneriels' practice pil!lms". Blood 91 (41: 1144-9.
Tha Marek Manual; Ssction 11, ChaptBr 133: plllllllat disorders.
Tham• RH. 1n1Bm Mad. 2001;161:2433-2438.
U.S. Cansumer Product Ssfety !Ammission. Ban rJ Lead-Containing Paint and Cer1ail Consumer Products Belring Lead-Can!lining Paint httii:/h'Mw.cpsc.gov/
BUSIIf'O/regsmlladpmpdf
Vllenline ItA 1nd Hull RD. Clric:ll use of Wllrflrin. Uplalllte, Rase BD !EdL UpTDillle, Wlllth11111, MA 2006.
Valentine ItA and Hull RD. Clric:ll Ull of haperin and law mallcullr Wligllt haperin. Uplalll1t, R1111 BD IfilL UpTDilltl, Waltham MA 2006.
Will I'S,atal Ev11Uti011 rJ D-cinel in tha diagnlllis rlaJIIflllcbld daep-wintlrambasis. NtJM 2003;3411:1227-1235.
Wlson SE, Watson HG, Crowther MA.lrfN.dCIII Drll vitamin K for Ilia rJ ISYfl1l(gmatic plllilntl with lllevatsd inllmational narmaliztd m: 1
brill raviMY. CMAJ. 2004;170:821 -4.