BENIGN DISORDERS OF WBC o Chronic bacterial infections TB/viral/fungi

o Hairy Cell Leukemia = pathognomonic to monocytosis

Definitions Eosinophilic Leukocytosis
o Leukopenia = WBC o Allergic disease
o Leukocytosis = WBC o Parasitic diseases
Neutrophil maturation o Hypereosinophilic syndrome = if for 6 mo and not due to above 2
o Myeloblast promyelocyte myelocyte metamyelocyte o Chronic eosinophilic leukemia = Clonal
Band Neutrophil Basophil Leukocytosis
Neutrophil precursors o Chronic Myeloid Leukemia (CML)
o Myeloblasts seen in BM Langerhans Cells
o No seen in peripheral blood if so = AML o Dendritic cells that present antigens to nave T cells
o CD34, CD117 o In skin and mucosa
Neutrophils o Tennis racquet Birbeck granules
o Reserve pool in BM o Neoplastic prolif = Langerhans cell histiocytosis
o M:E in BM = 2:1 to 4:1 o CD1a and S-100
o In blood Langerhans cell histiocytosis
Circulating pool (in CBC) o Malignant prolif of Langerhans
Marginating pool (not in CBC) o Letterer-Siwe disease = multiple areas
Neutropenia o Eosinophilic granuloma = w/ eosinophils
o Causes o Hand-Schuller-Christian disease = Focal
Congenital Hemophagocytic Lymphohistiocytosis
Kastmanns = Body cant make PMN o histiocytes in BM (Macs in BM = histiocytes)
Myelokathexis = PMN cant leave BM o Caused by infection
Acquired o Fever, pancytopenia (b/c cells phag by macs), multiorgan fail,
Infections (bacteria), drug, toxins, autoimmune etc coagulopathy, CNS signs
o Clinical Sinus Histiocytosis w/ massive lymphadenopathy
Infection mouth/throat ulcer o Less fatal than previous one
Septicemia S. epiderm. in bowel o Lymph nodes w/ histiocytes that have lymphocytes inside their
Neutrophilic Leukocytosis cytoplasm but not eating them
o Causes o Rosai-Dorfman disease
Bacteria o Painless, chronic cervical lymphadenopathy
Inflamm/tissue necrosis myositis/vasculitis Lysosomal Storage Diseases
Any time stress hormone released o Gauchers Disease Auto Rec
Asplenia in last few days Accum of glucosylceramide in lysosomes of RES cells
Granulocyte leukocytosis (liver/BM)
o Leukemoid Reaction Def of glucocerebrosidase
Mimics leukemia 3 types baed on onset age
Reactive leukocytosis Chronic = adult / Acute infantile neuronopathic / Mixed
PMNs and immature PMNs (1st 3) in blood Assoc w/ Parkinsons disease, multiple myeloma
Should not be in blood = Left Shift Anemia, leukopenia, thrombocytopenia
Cause = bacterial inf / hemolysis Dx via assay of white cell glucocerebrosidease and DNA analy.
o Leukoerythroblastic Reaction o Niemann-Pick
Nucleated RBC + Left shift Sphingomyleinase def
Myelofibrosis Accum of sphingomyelin and cholesterol
Defects of PMN Fxn Most are infants that die in 1st few years of life
o In chemotaxis Hepatosplenomegaly w/ lung and cns involvement
Lazy leukocyte syndrome Cherry-Red spot in retina
Corticosteroid therapy = keeps PMNs in BV Pancytopenia
Myelodysplasia = PMN die in BM Foam Cells in BM aspirate
o In phagocytosis
o In killing
Chronic granulomatous disease
Abnormal oxidative metab
Recurring infections in early child
Myeloperoxidase defi
Chediak-Higashi syndrome
Abnormal White blood cells
o Neutrophilic toxic exchange = vacuoles/ongoing infections
o Dohle body = sign of ongoing infection
o Hypersegmented PMN = megaloblastic anemia
o May-Hegglin anomaly = Giant platelets
o Pelger-Huet anomaly = myelodysplastic syndrome
o Chediak-Higashi syndrome = giant granules in monocyte/PMN
o Alders anomaly = same but smaller granules in all cell types
Monocytosis
MYELOPROLIFERATIVE NEOPLASMS Chronic myeloid leukemia
o Most common MPN
Clonal prolif of hematopoietic marrow stem cells o Uncontrolled production of PMNs/Basophils/Eosinophils
o Hypercellular marrow o W/o Tx triphasic course
o PMNs, RBC, or platelets Chronic phase accelerated phase terminal blast crisis
o Hepatosplenomegaly marrow fibrosis or acute leukemia Terminal blast resembles acute leukemias = AML(2/3) and
o All result from acquired genetic abnormality in the stem cell ALL(1/3)
PV/ET/MF o Signs
o All 3 have mutation of tyrosine kinase JAK2 Asymptomatic - discovered when pt in for routine check
o JAK2 is needed for normal myeloid devel. Fatigue, malaise, weightloss, abd full, splenomegaly
Polycythemia Vera o Labs
o Myeloid clonal prolif RBC mass (Hb) Leukocytosis
o WBC may also occur Lots of immature cells in peripheral blood
o Symptoms Anemia and platelets
Symptoms due to viscosity BM = very hypercellular
Headache/dizziness/visual disturbances Philadelphia chromosome (22)
Facial plethora/erythromelalgia (burning pain in hands/feet) T9;22
Thrombosis or bleeding Fusion of BCR (22) and ABL1 (9) = BCR-ABL1 =
Pruritus after warm shower unregulated tyrosine kinase (210kD)
o Labs o Tx =Tyrosine Kinase inhibitors - blocks binding of ATP to protein
Normocytic RBCs Mastocytosis
BM hypercell w/ erythroid and megakaryocytic hyperplasia o Mast cell accum due to clonal disorder (KIT mutation)
JAK2 mutation o Cutaneous mastocytosis = only in skin
o WHO criteria = 2 major + 1 minor or 1 major +2 minor o Systemic mastocytosis = infiltrate multiple extra-cutanous organs
Major = Hb and JAK2 mutation o Signs
Minor = EPO, BM findings above Symptoms related to prostaglandin and histamine release
o Other causes need to be ruled out Flushing, pruritus, abd pain, bronchospasm
EPO, chronic hypoxemia (smoker), high altitude, dehydration o Can become = acute leukemia
o Tx = phlebotomy/hydroxyurea/ASA Chronic myelomonocytic Leukemia
o Can become = Primary myelofibrosis/Acute Myeloid Leukemia o Features of myeloprolif neoplasm and myelodysplastic syndrome
Essential Thrombocytosis/thrombocythemia o Peripheral blood monocytosis + BM dysplasia
o Presence of chronic non reactive thrombocythemic state not due to Anemia, thrombocytopenia, cytopenia and hepatosplenomegaly
one of the other MPNs o Labs
o Dx based on exclusion of other diseases BM hypercellular w/ <20% blasts
platelets No BCR-ABL
Megakaryocytic hyperplasia in BM o Becomes = AML aka poor prognosis
No Philadelphia chromosome o Cure = stem cell transplant
No causes for reactive thrombocytosis Juvenile Myelomonocytic leukemia
Absence of myodysplastic syndrome/Primary myelofibrosis o In first 4 years of life in
o Symptoms o Children w/ Noonans syndrome and Neurofibromatosis = risk
Vasomotor symptoms = light headed, syncope o Features of both MDS/MPN
Unusual thrombotic event/bleedings o Myelomonocytic prolif in BM/blood
o Labs o Hepatosplenomegaly/lymphadenopathy due to leukemic
High platelet # in peripheral blood infiltration of organs
Enlarged mature megakaryocytes in BM o No Philadelphia chromosome
JAK2 mutation o Cure = stem cell transplant
o Tx = hydroxyurea/ASA
o Can become = Primary myelofibrosis
Primary myelofibrosis
o Myeloid stem cell clonal prolif w/ reactive fibrosis of BM
o Marrow fibrosis due to abnormal megakaryocytes that secrete
cytokines that stim fibroblasts/fibrosis
o Extramedulary hemat = hepatosplenomegaly
o Signs
Fatigue
Splenomegaly = abd pain + weight loss
Symptoms of hypermetab state, fever, bone pain, night sweats
o Labs
Smear = Tear drop cells
BM reticulin stain shows fibrosis
JAK2 mutation
o Tx = supportive care/hypomethylating
o Cure stem cell transplant
o Can become = acute myeloid leukemia
MYELODYSPLASTIC SYNDROMES APLASTIC ANEMIA

MDS = heterogeneous group of clonal disorder of marrow stem cells Definition = diminished or absent hemat precursors in BM due to
Features injury to stem cell. Name is misnomer b/c all cell lines affected w/
o Dysplastic features pancytopenia
o Progs to AML possibly Causes
o Ineffective blood cell production leading to BM failure o Congenital
BM has prolif but apoptosis = hypercell marrow but Fanconis anemia auto rec
cytopenia Defect in DNA repair enzyme / chromosomal breakage
o De novo = primary Skeletal, renal, growth abnormal
o Others = therapy related MDS/tMDS/secondary MDS Prog to MDS or AML
o > 65 Years old and Male, risk w/ age Dyskeratosis congenital sex linked
Causes Nail/skin atrophy
o DNA damage to stem cell Disorder in enzymes involved w/ telomere length
o Environ factors benzene, radiation, tobacco, chemo o Acquired
o Inherited abnormal trisomy 21, fanconi anemia, bloom Idiopathic
syndrome, ataxia telangiectasia, PNH, congenital neutropenia Drug induced
Symptoms NSAIDS phenylbutazone, chloramphenicol
o RBC, platelets, mature granulocytes (PMN, eos, baso, mast) Gold, solfonamides, antiepileptics, nifedipine
o Anemia/fatigue Viruses = Parvovirus, HIV, EBC
o Neutropenia-infection/thrombocytopenia-bleeding Patho
Labs o Damage induced by above lymphocyte activation
o Anemia + low reticulocyte response o Unregulated lymphocyte activation of Cytotoxic T cells
MCV = macrocytic or normal directed against stem cells
o Leukopenia = WBCs Lab manifestations
o Thrombocytopenia = early manifest if del(20q) o Symptoms due to progressive cytopenias
o Smear Fatigue/hemorrhage/menstrual flow/petechial gum bleeding
RBC = normocytic or macrocytic o Hypocellular BM = lots of fat in BM
WBC = dysplastic PMN
Size change, abnormal lobation, abnormal granularity Paroxysmal Nocturnal hemoglobinuria
Pseudo-Pelger-Huet abnormality o Related to aplastic anemia
o BM = normal/hypercellular o Signs
o Ringed sideroblasts Hemolytic anemia/jaundice/pink-red urine
o Megakaryocytes large mononuclear forms Hypercoagulable state = due to free Hb, platelet activation and
hypogranular/multiple small lobes disconnected BM failure
o Granulocyte dysplasia hypogranular/hyposegmented o Patho
o Nucleus blebbing/multinucleation Mutation of PIG-A gene that makes GPI anchors in
o Howell Jolly bodies and Basophilic stippling platelets/WBC/RBCs
Diagnosis Loss of GPI
o Requires BM biopsy/aspiration loss of decay accelerating factor (DAF) (CD55)
o >10% of affected cells loss of membrane inhibitor of reactive lysis (CD59)
o Blast cells needs to be <20%
Both are complement regulatory proteins
WHO classification Leads to complement med lysis of RBCs (hemolysis) and
o Refractory cytopenia w/ unilineage dysplasia activation of platelets (thrombosis)
o Refractory anemia w/ ring sideroblasts (only erythroids) During sleep Resp Acidosis intravasc hemolysis
o Refractory cytopenia w/ multilineage dysplasia hemoglobinemia/hemoglobinuria
o Refractory anemia w/ excess blasts o Tx
o MDS w/ isolated del(5q) Immunosuppression to reverse marrow failure
Differential Dx mimic morph of MDS Stem cell transplant
o Vit B12 and folic acid def
o Heavy metal tox
o Viral infection
o Copper def
o Zinc excess
Prognosis
o Based on degree of cytopenias/ % blasts in BM, and cytogenetic
abnormalities
o High risk pts progress to cytopenias and/or acute leukemia
Treatment depends on prognosis
o Low risk = transfusion growth factors
o High risk = hypomethylating agent + stem cell transplant
ACUTE LEUKEMIA o AML not otherwise specified = classified by morphology
M5 = Acute monoblastic/monocytic leukemia
Transformed cell from myeloid stem cell Acute myeloid leukemia monoblasts in circulation
Transformed cell from lymphoid stem cell Acute lymphoblastic L Tissue invasion/gum hypertrophy
CD11c, CD14 + for NSE
Acute Myeloid Leukemia M6 = Acute erythroid leukemia
M7 = Acute Megakaryoblastic leukemia
Definition
BM w/ fibrosis and cells show pseudopod formation
o Clonal prolif of myeloid precursors accum of leukemic blasts
In pts w/ Downs syndrome
in BM and other tissues.
o Inhibition of normal RBC/platelet/granulocyte production Megakaroblasts = CD41, CD61
Most common acute leukemia in adults AML unique feature = Acute promyelocytic leukemia (M3) T15;17
o Retinoic acid receptor alpha (RARa) on 17
Assoc w/ env/chemicals/radiation/chemo/genetics (trisomy 21
o PML gene on 15
downs) and others
o PML-RARa fusion blocks normal differentiation by retinoic
Signs
acid
o Anemia/fatigue
Multiple granules and multiple Auer Rods
o Neutropenia/infections
mortality due to coagulopathy (DIC)
o Thrombocytopenia/bleeding/ecchymosis/epistaxis/menorrhagia
o Tx diff from other leukemia
o Fever/bone pain
Trans-retinoic acid + Arsenic
o Unusual Signs
Prognosis based on cytogenetics
Myeloid sarcoma = small tumors of leukemia cells/extramed
Leukemia Cutis Tx
Gingival hypertrophy = tissue infil seen w/ monocytic types o Fit pts = Good risk
Coagulation abnormalities Acute promyleocytic leukemia Induction initial chemo 7+3 Ara-C and anthracycline
(APL) T15;17 Consolidation = 3-4 cycles of Ara-C
In T15;17 use Atra/Arsenic
Labs
o Fit/High risk pt = Bone marrow transplant
o Normocytic anemia
o Not fit
o Platelet
Supportive care
o WBC low/high/abnormal
Hypomethylating agents
o Blasts
Immature cells/large nuclei
Prominent nucleoli
Fine granular chromatin
Auer Rods = Pathognomonic
Dx
o Marrow infil w/ >20% blasts (if <20% possibly MDS)
o Monotonous cell population clonality
o Stains = to diff from lymphoid precursors
Myeloperoxidase
Sudan Black
Non-specific esterase monocytes/myeloblasts
o Immunophenotyping = Flow cytometry
Myloid markers = CD13, CD33
Immature markers = CD34, CD117
o Cytogenetics/FISH
Abnormal karyotypes in the pts
Karyotype on dividing metaphase cels
FISH done on non-dividing cells
o Molecular markers
NPM, FLT3, CEBPA
Aids in prognosis
WHO Classification
o Dx requires only cytogenetic abnormality (no need for >20%
blasts) in following 3 = all good prog
T8;21 RUNX1
Core binding factor (CBF) needed for normal hematop.
Translocation chimeric protein / disrupted
T15;17 PML-RAR
Inv(16) involves CBF
o AML-MDS related features = poor prog
AML that came from previous MDS
o Therapy related AML/MDS = Poor
AML in pt w/ hx of cytotoxic therapy
Ex) pts txd for breast/ovarian/hodgkins have small chance of
developing AML
Acute Lymphoblastic Leukemia

Definition
o Clonal prolif of lymphoblasts accum of leukemic blasts in BM
and other tissues.
Can mimic AML
Overlap w/ lymphomas
o If its mainly marrow/leukemic phase ALL
o If its mainly lymph nodes Lymphoma
Most common cancer in Children
Types divided whether B cell line (majority) or T cell line
Signs
o Anemia/thrombocytopenia/neutropenia
o Fatigue/bleeding/infections/fevers night sweat, weight loss, bone
pain
o Heptomegaly/Splenomegaly and lymphadenopathy = more
common in ALL than AML
o Testicular swelling
o CNS involvement Cells seen in a CSF sample
Dx
o Morpho
Cells medium size/High N:C ratio
Nuclear folds/grooves
BM hypercell
No granules/No Auer Rods
o Stain
Myeloperoxide, Sudan Black, and nonspec esterase = Negative
PAS dot like positivity around nucleus
TdT Terminal deoxynucleotidyl transferase
o Flow cytometry
B Cell CD10, CD19, CD20, CD22
T Cell CD2, CD3, CD7
o Cytogenetics
T9:22 Philadelphia chromosome (seen in ALL and CML)
Pathognomonic of CML
Protein in ALL is 190 kD unregulated tyrosine kinase
T12;21
Hyperdiploidy good prognosis
Hypodiploidy Poor prognosis
Examples
o ALL B cell leukemia
Need flow and cytogenetics
Flow CD10, CD19, TdT+, Myloperox/Sud black Negative,
PAS positivity
Cytogenetics T9;22
o Burkitts lymphoma/leukemia overlap disease
Abnormal c-Myc oncogene on chromosome 8 to
T2;8
T8;14
T8;22
Round/multiple nuclei and cytoplasmic vacuoles starry sky
o T cell
More common in adolescent
Present w/ mediastinal mass
Heptosplenomegaly, lymphadenopathy
Nuclear folds
CD2, CD3, CD7, TdT
Treatment
o Regiments directed against lymphoblasts
o Induction, Consolidation, Maintenance, CNS prophylaxis, Stem
cell transplant
BENIGN LYMPHOCYTE DISORDERS Castlemans Disease

Lymphatic system Definition = lymphadenopathy due to angiofollicular hyperplasia

o Primary organs = BM and Thymus o Unicentric = localized
o Secondary = Spleen, Lymph nodes, Tonsils, Peyers patches o Multicentric = HHV 8 assoc 50% of the time
Disease course
Lymphocytosis/Lymphadenopathy o Indolent, benign = UCD
o Aggressive, lymphoma like = MCD
Presentation Subtypes
o Acute onset + young pt viral syndrome o Hyaline vascular type
o Asymptomatic older pt or constitutional symptoms malignant Most common / UCD / good prog
If symptomatic benign Onion peal mantle zone / lollipop appearance
o Assoc findings Lymphadenopathy > 5cm malignant o Plasma cell / plasmablastic type IL-6 driven
CBC MCD / more aggressive / symptoms / Tx like myeloma
o Mild anemia, mild thrombocytopenia benign o Mixed type
o Severe anemia, severe thrombocytopenia malignant Key events
Morphology o Viral homologue of IL6 drives B cell prolif
o CLL have normal morph o HHV 8 infects IgM + nave B cells
o Activated reactive lymphocytes can look like blasts o Cells go to mantle zone of node follicle
o Cleaved nuclei lymphoma o Cytokine release causes disease symptoms
o Red cell hugging Infectious Mononucleosis Tx
o UCD = surgical resection of node
Infectious Mononucleosis
o MCD = no standard tx
Definition self-limited, acute febrile caused by EBV Immunodeficiency/Lymphopenia Brutons Disease = X-linked
Patho expansion of T cells reactive against EBC infected B cells agammaglobulinemia
Clinically
o Affects young people/stiff neck Lymphopenia usually assoc w/ ID
Dx Downey cells When to suspect ID ? recurrent infections
Complications peripheral neuropathy/AIHA/thrombocytopenia How to Dx?
o Absolute Lymphocyte count (ALC)
Lymphadenopathy w/o lymphocytosis o T and B cell counts in PB (flow cytometry)
o Immunoglobulin quantitation in blood
Lymphatics divided into
How to Tx?
o Superficial nodes accessible to physical exam
o IV immunoglobulins monthly
o Axial nodes assessed by imaging
o Tx underlying cause / remove offending agent / gene therapy in
Causes mediastinal widening ADA deficiency
Onset
o Rapid (days) infection or very aggressive lymphoma Splenomegaly
o Very slow (mo/years) low grade NHL, CLL
Pain/tenderness Criteria need all 3
o Yes = infection or very aggressive lymphoma o Enlargement of spleen
o No = lymphoma o Reduction of at least 1 cell line in blood
Node consistency o Normal bone marrow function
o Soft = benign Indications for splenectomy
o Firm = NHL o Splenic rupture
o Rubbery = HL o Chronic immune thrombocytopenia
o Woody hard = metastatic carcinoma o Hemolytic anemia: hereditary spherocytosis, AIHA, thalassemia
Labs o Hypersplenism
o CBC, serology, cultures, flow cytometry Dont forget before splenectomy
o Node biopsy if all other work ups Negative o Pneumococcal vaccine 2 weeks before
Hyperplasia benign/reactive lymphadenopathy o Annual flu vaccine
Neoplasia malignant o Meningococcal vaccine
Types of Lymph Node hyperplasia
o Follicular = stim of B cells
Bacteria/viral/auto immune (RA)
o Paracortical = stim of T cells
Drug rxn/Inf Mono
o Sinus = expansion of sinus histiocytes
Sinus histiocytosis + massive lymphadenopathy = Rosai-
Dorfman Disease
Whipple disease
o Angiofollicular hyperplasia = Castlemans disease
MALIGANT LYMPHOCYTE DISORDERS Prolymphocytic Leukemia (PLL) B cell (3/4) and T cell (1/4)

Chronic Lymphoid leukemias (CLLs) Old age

o Chronic lymphocytic leukemia Splenomegaly* w/o lymphadenopathy
o Prolymphocytic leukemia High lymphocyte count - WBC
o Hairy cell leukemia More aggressive than CLL
o Large granular lymphocytic leukemia Cell morpho
o Adult T cell leukemia/lymphoma o 2x the size of CLL cells
Lymphomas o Large nucleolus = immature
o Hodkin o Clumed nuclear chromatin = sign of mature
o Non-Hodkins Sig+ [bright], CD5 (-), CD23-, FMC7+
Immunoproliferative disorders
o Multiple Myleoma Hairy Cell B cell
o Amyloidosis
o Hyperviscosity syndrome Old female
o MGUS Splenomegaly* w/o lymphadenopathy (like PLL)
o Waldenstroms macroglobulinemia Labs
o Pancytopenia = rule (the other 4 all have WBC, HC = WBC)
Chronic Lymphocytic Leukemia (CLL) B cell Due to BM replacement by leukemia cells, BM fibrosis,
splenomegaly
Old age, Men o Dry BM tap
Not assoc w/ radiation/chemicals/virals as cause Due to fibrosis of BM induced by hairy cells
Presentation o Tartrate resistant acid phosphatase (TRAP) stain +
o Asymptomatic incidental finding, WBC Hairy cells
o Constitutional weak/fatigue/fever/night sweat/weight loss o Tropism to BM and spleen
o Lymphadenopathy*, splenomegaly, hepatomegaly o Hair like cytoplasmic projections due to over expression of Rho
o Anemia, thrombocytopenia = BM failure late manifestation GTPase
o Infections late in Disease Flow cytometry
Staging o Lambda + / Kappa
o Low o CD103 w/ CD19
0 = ALC > 5000 o CD11c w/ CD19
1 = ALC > 5000 + Lymphadenopathy o CD25 (IL2) w/ CD19
o Intermediate Drug of choice = 2-chlorodeoxyadenosine + rituximab
2 = ALC > 5000 +/- lymphadenopathy + hepatomegaly and/or Good prognosis
splenomegaly
o High Large Granular Lymphocytic Leukemia (LGLL) T cell/NK cell
3 = ALC >5000 + Anemia +/- lymphadenopathy +/-
organomegaly Neutropenia/anemia
4 = ALC > 5000 + thrombocytopenia +/- lymphadenopathy +/- Splenomegaly/arthropathy/positive serology for RA
organomegaly CD3/CD56/CD57
Flow Cytometry = Standard for CLL Tx w/ steroids, cyclophosphamide or G-CSF Neupogen
o Weak surface IgM/D (kappa or gamma)
o CD23, Sig+ [weak] Adult T cell Lymphoma (ATLL) T cell
o CD 5 = T cell marker on B cell
CD23+ / Fmc 7 - = CLL Young
CD23- / Fmc 7 + = Mantle cell lymphoma WBC
Treatment Assoc w/ T cell virus type 1 HTLV-1, Japan and Caribbean
o Rules for incurable disease Hypercalcemia, skin lesions, hepatosplenomegaly, lymphadenopathy
Intent is palliative Clover leaf nuclei and T cell phenotype
Dont have to treat routinely CD3, CD4
Therapy Poor prognosis
o Stage 0 = observe
o Stages 1, 2 = treat selected
o Stages 3, 4 = Treat
Complications (Exam Q)
o Recurrent infections T/B cell def Pneumonia, Herpes Zoster
o Hypogammaglobulinemia = due to decerase in normal B cells
o AIHA = Warm Ab Coombs + w/ microspherocytes and
polychromatophilic RBCs
o Autoimmune thrombocytopenia (ITP)
o AIHA + ITP = Evens syndrome (+ Coombs/platelets)
o Transformation to Diffuse Large cell lymphoma = Richters
syndrome or prolymphocytic leukemia
HUMAN LYMPHOMAS Follicular Lymphoma

Group of heterogenous diseases due to malignant transformation of Prototype indolent NHL

lymphocytes in usually lymph nodes (leading to lymphadenopathy) T14;18 and BCL2 overexpression (so inhibit apoptosis)
NHL has way more cases per year Incurable
When to suspect Germinal center markers CD10 and BLC6
o Painless, non-tender lymphadenopathy Small B cell markers CD20 and BCL2
o Spread by contiguity in HL, skip pattern in NHL
o B symptoms Marginal Zone Lymphoma
Fever, night sweats, weight loss
Presence of Bs = worse prognosis 3 subtpyes
Diagnosis o 1 - Involves lymph nodes
o Priority 1 = Diagnosis lymph node biopsy o 2 primary Massive splenomegaly w/o lymphadenopathy
Excisional is best o 3 primary extranodal presentation
o Priority 2 = Staging/work up after diagnosis is done Most common mucosa associated lymphoid tissue MALT
o Priority 3 = Treatment after determining stage Assoc w/ H pylori infection
Staging Use of antibiotics complete remission of lymphoma
o Stage 1 = one group of nodes CD20 and BCL2
o Stage 2 = 2 or more groups on same side of diaphragm
o Stage 3 = 2 or more groups on both sides of diaphragm Mantle Cell lymphoma
o Stage 4 = organs/tissues not next to nodes and the outside
lymphatic system (Liver BM) T11;14
o Then for that stage, see if B symptoms present or not Overexpression of Cyclin D1/BCL1
o PET/CT very useful in staging CD19, CD5, CD22, FMC7
Fast growing, incurable
Hodgkin Lymphoma (HL)
Very Aggressive NHL Burkitt Lymphoma
Itching and alcohol induced pain at site of disease are unique to both
HL and NHL 2 forms
Malignant cell = Reed-Sternberg cell o Endemic(African) Jaw presentation in children, EBV+
in all other cells in biopsy are reactive o Sporadic (anywhere in world)
Flow cytometry not helpful here since so many cells reactive o T8:14 and Myc overexpression
immunohistochemistry is standard o Starry sky and vacuolated cell
R-S cells in HL CD15 and CD30 w/o CD20 o Curable w/ aggressive chemo
Nodular lymphocyte predominant type (NLPHL) has CD20 w/o T-Cell Lymphoma Mycosis Fungoides
CD15 and CD20
Labs Chronic cutaneous T cell lymphoma
o Normocytic CD4 = Sezary cell ceribriform/folded nuclei
o Leukocytosis Reactive in HL Pruritic, psoriasis like plaque lesions
o Lymphopenia advanced HL
Skin infiltration by lymphoma cells
o Platelets - early and advanced stage
Sezary syndrome = MF + circulating lymphoma cells
o Disease markers
ESR and C-reactive protein in Chronic/incurable
Management Anaplastic Large Cell Lymphoma (ALCL)
o Curable Disease
Skin, bone, lung, liver
Non Hodgkin Lymphoma Diffuse Large B cell Lymphoma (DLBCL)
CD30 (R-S cells also CD30 but its CD30 and CD15) here only 30
Effacement of lymph node Anaplastic large cell kinase (ALK)
Diffuse proliferation of large atypical lymphocytes o T2;5 NPM-ALK most common (NPM = nucleophosmin)
CD19, CD20, and lambda chain
Curable Disease

Indolent/Low Grade NH Lymphomas

Follicular lymphoma grade 1, 2

Small lymphocytic lymphoma (SLL)
Marginal zone lymphoma (MZL)
Lymphoplasmacytic lymphoma Waldenstroms
macroglobulinemia
Features of above 4
o Slow growing
o Indolent, affects older patients
o Advanced stage at presentation
o Incurable
IMMUNOPROLIFERATIVE DISORDERS o Bone resorption
Myeloma cells interact w/ BM stromal cells generate
Definitions differentiated and activated osteoclasts Bone resorption
o Malignant prolif of Ig secreting B lymphocytes (plasma cells) and fracture/collapse Pain
assoc w/ paraproteinemia (secreted) Epidemiology
o Serum protein electrophoresis (SPEP) analyze proteins in serum o African Americans, pacific islanders
o Polyclonal gammopathy = benign reactive plasma cell response to o Old people
antigen o Petroleium products and pesticides
o M-protein or paraprotein = monoclonal band that reflects Ig MM clinical features
synthesis from single clone Monoclonal gammopathy. o Bone pain (backache)
o Polyclonal = broad based band Skeletal survey is standard test
o Monoclonal = narrow based band Multiple punched out lytic lesions, osteopenia (bone thinning),
Plasma cell disorders classification compression of vertebral bodies and pathological fractures
o Monoclonal gammopathy of undetermined significance (MGUS) Bone scan underestimates bone disease b/c its measuring
o Plasma cell myeloma osteoblasts
o Plasmacytoma o Anemia
o Immunoglobulin deposition disease BM infiltration by MM
Primary amyloidosis Renal fail EPO
Diagnostic Criteria o Recurrent infections
o Symptomatic myeloma Neutropenia due to MM
Monoclonal protein in serum/urine Deficient immunity
>10% plasma cells in BM o Hypercalcemia
CRAB Due to bone resorption
Calcium (hypercalcemia) o Amyloidosis
Renal impairment o Hyperviscosity syndrome
Anemia Labs for MM
Bone Disease o Presence of paraprotein
o MGUS SPEP presence of monoclonal spike
M protein level <3 IEP type of isotype usually IgG
<10% plasma cells in BM o serum free light chain
No CRAB FLC assay has replaced bence jones protein detection in urine
MGUS becomes MM o normal Ig
o Peripheral blood smear
Multiple Myeloma Rouleaux formation
erythrocyte sedimentation rate (ESR)
Definition serum B2 microglobulin made by plasma cells
o Expansion of malignant plasma cells in BM Prognostic marker
o Destructive (lytic) bone lesions MM is incurable
o BM failure
o Consequences of secreted proteins Plasma Cell Leukemia
Plasma cells are in a cluser w/ a perinuclear halo and eccentric nuclei
Myeloma cells normal counterpart is post germinal center plasma >20% plasma cells in blood
cell Combined features of
Like their counterpart, they home to bone marrow o Acute leukemia = anemia, thrombocytopenia
With time they expand in the BM and replace normal hemato o Multiple myeloma = Ca2+, renal fail, bone disease
Clinical manifestations result from Progresses from MM to this disease
o BM replacement by myeloma
Plasma cells express CD38 and CD138 Amyloidosis
Infiltration leads to Anemia, Neutropenia, Thrombocytopenia
which is classic triad for BM failure Definition = extracellular deposition of protein in abnormal fibrillary
o Monoclonal Ig secreted by myeloma cells form
Rouleaux formation stacking of RBCs Systemic Amyloidosis (AL)
Erythrocyte sedimentation rate (ESR) o Assoc w/ clonal plasma cell prolif
Immune paresis - in normal serum Igs o Caused by deposition of monoclonal light chains
Renal injury Clinically Organ enlargement and dysfunction
Bence Jones light chain(k or gam) protein deposition o Tongue macroglossia
Amyloid deposition o Heart cardiomegaly
o Peripheral nerves neuropathy
Calcium deposition (nephrocalcinosis) due to Ca2+
o Kidney renal fail
Pyelonephritis
Uric acid crystal deposition
IV contrast should be avoided
MM treatment = bisphosphonates
Waldenstroms Macroglobulinemia BONE MARROW TRANSPLANTATION

Malignant prolif of IgM secreting plasmacytoid lymphocytes in BM Hematopoietic stem cell transplant (HSCT)
Assoc w/ soft tissue and not bone disease o 2 phases
When BM infiltration cytopenia Administer high dose chemo and/or radiation elim of tumor
When liver/spleen hepatosplenomegaly and pts BM
Monoclonal IgM Hyperviscosity syndrome Infusion of hematopoietic stem cells reconstitute
Clinically lymphohematopoietic system
o Hyperviscosity syndrome Types
Visual disturbances o Autologous Pts own marrow/stem cells are removed,
Retinal changes cryopreserved and reinfused after high dose chemo
Epistaxis Done in Multiple Myeloma/NHL/HL
Tx = plasmapheresis Mechanism of cure = high dose chemo. Allows for dose
intensification and marrow tox is dose limiting
Adv = pt is donor and less toxicity
Disad = pts own stem cell may be abnormal b/c of previous
chemo or contamination w/ tumor cells
o Allogenic Stem cells from a donor
HLA matched sibling donor
HLA mismatched family donor
HLA matched unrelated donor
Done in AML/ALL/MPD/MDS/aplastic anemia/Hb-opathy
Mechanism of cure = high dose chemo and/or radiation
Can replace genetically abnormal (not cancerous) HSC w/ a
normal one ex) Sickle Cell
GVT new stem cell can recognize cancer cell as foreign and
remove them
o Syngeneic from a twin
o Cord blood rich source of stem cells
Hematopoietic Stem cell
o Gives rise to entire system
o Unique property of self renewal so few number of cells needed
o CD34
o Normally in BM but in equilibrium w/ blood
Harvesting stem cells
o BM harvest posterior iliac crest
o Peripheral blood harvest mobilization of stem cells into
peripheral blood followed by apheresis
Use of G-CSF causes this
Other use
o Marrow fail/Hb-opathy/enzyme def/Aplastic anemia/Sickle
cell/Thalassemia
HLA antigens
o Chromosome 6 w/ antigens A, B, C, DR
o Can differentiate self from non self
o Siblings have 25% chance of matching
Phases of Transplantation
o Condition
chemo/rad done to tumor burden and immunosuppress pt to
allow engraftment
o Transplant
harvested cells infused into vein, cells go to BM
o Recovery
2 weeks of intense supportive care
Pt is cytopenic needs platelet and blood transfusion
Reversible damage to skin, liver, GI, lung due to chemo
o Infections
Susceptible to infections
Bacteria = Gram neg/pos
Viral reactivation = HSV, CMV, Epstein Barr
Funal Candida / aspergillus
Unique aspects of Acute Graft vs Host Disease
o Antigenic differences cause donors immune system to attack
patient as a foreign
o Skin, liver and GI are usually attacked
o But theres also anti-tumor activity
PHARMACOLOGY
Degrades clots
Warfarin o Indirect Factor 10 inhibitor = Fondaparinux
o Inhibits Factors 2, 7, 9, 10 } all vit K dependent factors o Direct factor 2 inhibitor = argatroban, desirudin and bivalirudin
o Protein C and S are natural anticoags and they are inhibited by o Thrombolytics
warfarin in first time users Generates clots
Because C and S are depleted first, it is prothrombotic state in o Factor 7
the beginning o Anti-fibrinolytics
o Monitoring
Target INR = 2-3 UFH and LMWG and indirect inhibitors because they need help of
Below 2 = Clotting antithrombin
Over 3 = Bleeding o aPTT to monitor heparin
Gut flota and liver disease also INR o intrinsic and common pathway assessed
o Ne renal clearance o if pt is going to surgery, stop UFH 4-6 hours before
o Vit K intake effect of warfarin o Protamine is reversal agent for UFH, partially effective for
o Metabolic inducer = Rifampin LMWH
o Metabolic inhibitor = Amiodarone, Quinolones, TMP-SMX, HIT
Metronidazole o Drop in platelet but also a pro thrombotic state
o Acetaminophen INR via pharmacodynamics interaction o HIT is seen 3x more in surgical pts than medical pts b/c surgery
o Need to overlap w/ heparin b/c provides a sensitizing environemtn
It takes 5 days for steady state / for factor 2 depletion o Besides HIT, TTP and Lupus thrombocytopenia also cause a pro
Initially prothombotic b/c C and S are depleted thrombotic state but also cause a drop in platelets b/c they are
o Pharmacokinetic interaction = result in warfarin build up being consumed
TMP-SMX, Amiodarone etc o Do not use LMWH if pt has history of HIT due to cross reactivity
o Pharmacodynamics interactions = when a drug is known to cause
bleeding is added to warfarin Indirect factor 10 inhibitor = Fondaparinux = smallest compared to
Aspirin and clopidrogrel UFH and LMWH
o For High INRs o Fondaparinux does not cause HIT
w/ no bleeding hold warfarin and give Vit K
Smaller the size = risk of HIT
w/ life threatening bleeding give FFP
Bigger the molecule = shorter the half life
o Purple toe syndrome/skin necrosis
Due to protein C deficiency Smallest has most renal elimination
Onset = 1-10 days after starting warfarin Protamine actually works best against UFH more than Fondaparinux

Dabigatran Anti-thrombin : Direct Thrombin inhibitor = Argatroban

o Direct Factor 2 inhibitor o Argatroban = 1st line Tx for HIT
o No INR monitoring o Elim via Hepatic
o Ads o Monitor via aPTT
Fewer drug interactions, no monitoring, less intracranial
bleeding Factor 7
o Disad o To control bleeding
Short half life(in case pt missed a dose, no anticoag protection) o Either through tissue factor independent pathway
No antidote o Or tissue factor dependent
Heavily Renally cleared o SE = thrombosis
More GI bleeding compared to warfarin o Thrombotic events assoc w/ factor 7 occur more in non-
Should not beused w/ mechanical heart valves use warfarin Hemophiliac pts vs their hemophiliac counterparts
instead Critically ill pts have activated platelet all over and this wide
o Pts having surgery who have CrCl>50 should stop 1-2 days before spread activation results in a higher thrombin burts even outside
and if CrCl <50 mL/min should stop 3-5 days before the site of injury aka puts them in a pro-coagulant state

Rivaroxaban/Apixaban Anti-Fibrinolytics = Aminocaproic acid and Tranexamic acid

o Same as dabigatran except this is factor 10 inhibitor
o And theres more drug interaction b/c this also interacts w/
CYP3A4
o No antidote
o Times when you need real time assessment of level of anticoag
but cannot w/ these
Before surgery, Drug-Drug interaction, if pt is noncompliant
o Renal elimination
o MOA = saturation of the bidning site by anti-fibrinolytics
displaces plasminogen from surface of fibrin
o This prevents binding of fibrin to plasmin and preserve the matrix
structure of fibrin
Aspirin
o Cause a qualitative defect in platelet and not quantitative
o So aspirin cannot cause thrombocytopenia
o Monitoring = Optical aggregometry
o Aspirin inhibits COX1/2 TXA2 Platelet aggregation
o Aspirin antiplatelet effect at 80-100 mg/day
o Good for arterial thrombosis but ok for venous thrombosis
o Hold for 5 days befoe an invasive procedure
Be/cause of platelets half life and irreversible inhibitor effect by
aspirin
 P2Y12 Receptor Antagonist antiplatelets Pyrimidine antagonists Cytarabine and Gemcitabine
o Clopidogrel o Incorporates into DNA replication
o Prasugrel
o Ticagrelor (reversible) Purine Antagonist = 6 Mercaptopurine and 6 thioguanine
o Block ADP from binding at receptor o Decoy for hypoxanthine and guanine
o Clopidogrel
Hold for 5 days before surgery Anti metabolite Hydroxyurea
Poor absorption o In sicke cell , it helps by stimulating production of HbF
Gets effected by CYP219 metabolizers o Antimetabolits have immunosuppressive effect by inhibiting
o Prasugrel lymphocytes
1 step activation instead of 2
No interactions w/ genetic polymorphisms like clopidogrel
Quicker and more potent/prolonged anti-platelet response
o Ticagrelor (reversible)
Quicker offset
Incase you want to stop antiplatelet shortly before a procedure
SE = Bleeding, Dyspnea, Ventricular pauses
Latter 2 due are caused because ticagrelor ATP which
causes an increase in adenosine in the blood

Targeted therapy
o Tyrosine kinase inhibitors
o Hypomethylating agents
o Anti-CD20 monoclonal antibodies
Anti-metabolites
o Anti-folates
o Anti purines
o Anti pyrimidines

Tyrosine Kinase inhibitors = Imatinib, Dasatinib, nilotinib

o Inhibits prolif of bcr-abl fusion protein/Philadelphia chromosome
o Helpful in CML
o Dasatinib
Dual specific ABL and Src kinaser so even stronger
o SE: Edema seen in Imitinib and Dasatinib = off-targets

Hypomethylating agents = Azacitidine and Decitabine

o Inhbit DNA methyltransferase hypomethylate dna
epigenetic silencing
o Helpful in MDS

Anti-CD20 Monoclonal antibodies = Rituximab

o Opsonized B cells in 3 diff ways
o But also decreased Ig
o So vaccines given after rituximab dont work

Antimetabolites
o Interfere w/ DNA synth by falsely substituting in so they are
effective most in tumors that have high proliferation
Folate Antagonist = Methotrexate
o Impairs folic acid intake by tumor cell
o Inhibits DHF reductase
o Antidote = Folinic acid
Also given a day after to decrease Side effectsr
o Also used for immunosuppressive reasons
Treatment for Rheumatoid arthritis
o Toxic to normal healthy cells that are also rapidly proliferating
GI = diarrhea and mucositis
BM = myelosuppression
Pyrimidine antagonists = Fluorouracil or 5 FU
o Act as a fake pyrimidine base that inhibits thymidylate synthase
o Folinic acid given w/ 5-FU acts to help increase the effect of 5FU
o 5FU as IV bolus myelosuppression
o 5FU as continuous infusion skin toxicity Hand foot syndrome
D
HEMOSTASIS
Secondary Hemostasis
Platelet production o Coag starts by tissue factor exposure which then binds 7
o From cytoplasmic frags of BM megakaryocytes o 7+TF
o Live for 7-10 days Stim common pathway at factor 10
o Non nucleated Stim intrinsic pathway at factor 11
o Contain mRNA and all organelles and can make proteins o Formation of cross linked fibrin
o Megakaryocytes go through Endomitotic synchronous nuclear Fibrinogen thrombin fibrin that are non cross linked lattice
replication Factor 13 makes it cross linked
Replicate only nucleus and granules and keep getting big as 1 Natural anticoagulants
cell o Tissue factor pathway inhibitor inhibits TF
o Thrombopoietin o Antithrombin inhibits 9, 19, 2
Made by liver and kidneys o Protein C and S inhibit 8 and 5 and TPAI
Binds to c-MPL receptor of megakaryocytes Fibrinolysis
Platelet granules o tPA = serine protease that converts plasminogen to plasmin
o Dense Delta granules o Plasmin causes fibrin to break down into D dimers
Dark on EM
ADP, ATP, 5HTP, Ca2+
Def of these granules = Delta granule storage pool deficiency Disorders of Hemostasis
o Alpha granules o Disorder of 1 hemostasis
Adhesion proteins Vascular disorder (platelet dysfunction) immediate bleeding
Fibronectin, thrombospondin, vWF, fibrinogen into mucous membrane and skin
Growth promoting factors Manifestations
Coagulation factors Easy bruising
Platelet function Spontaneous bleeding from skin/mucous membrane
o Vasoconstriction Menorrhagia
o Platelet plug = primary hemo Excessive bleeding after trauma
o Clot/fibrin formation though coag cascade = secondary o Disorder of 2 hemostasis
o Dissolution of clot = fibrinolysis Clotting factor problem delayed bleeding into joint and soft
Platelet Adhesion tissue
o Blood is not exposed to subendothel collagen which induces Manifestation
platelet aggregation Hematoma collection beneath skin
o Adhesion to collegen via vWF
Hemarthrosis bleeding into joint
o Platelets have gp2b/3a receptor fibrinogen, VWF
Tests to Assess platelets
o Platlets have gp1b/5/9 receptor insoluble VWF
o CBC
Von willebrand factor
Platelet count
o Receptor for factor 8, collagen, gp1b/5/9 and gp2b/3a
Mean platelet volume inversely related to platelet count
o Produced in endothelium
o Blood smear
o Stored in Weibel Palade bodies in endothelium
o Bleeding Time
Formation of Thomboxane TXA2 time = defect in platelet, vWF or vascular defect but NOT
o Platelet adhesion and activation at cAMP and Ca2+ clotting factor defect
o Platelet adhesion Replaced by PFA-100 assay
Stimulated by ADP, TXA2 o Aggregation
Inhibited by NO, Endothelial ADPase, PGI2, aspirin, Add segregating agent to platelet rich plasma
prostacyclin
No agonist = more light scattering
Primary hemostatic plug
w/ agonist (to induce platelet aggreg) = less light scattering
o ADP is a potent recruiter of more platelets
o Platelet aggregation assay
o Clopidogrel works by inhibiting platelet ADP receptor P2Y12
ADP, Epi, Collagen and TXA2 aggregate platelets through
o ADP receptor P2Y12 is assoc w/ moderate bleeding
Gp2b/3a and fibrinogen
Defects in platelet aggregation
Ristocetin aggregates platelets through
o Glanzmann involves gp2b
Gp1b and vWF
o Von Willebrand and Bernard Soulie involve gp1b
Biphasic aggregation seen due to ADP being released twice
Coag Cascade
o PFA100
o Common = 10, 5, 2, 1
Tests adhesion and aggregation in response to agonst
o Extrinsic (PT) = 7 (inhibited by warfarin)
Measures time needed for occlusion
o Intrinsic (PTT) = 12, 11, 9, 8
Collagen + Epi prolonged by Aspirin
Vitamin K Collagen + ADP prolonged by Clopidagrol
o Coarboxylation of gamma carbon of glutamic acid
o Affect factors 10, 9, 7, 2, S, C
 Tests to assess clotting factors Platelet Disorders
o Prothrombin (PT) Time
Extrinsic and common pathway Quantitative Thrombocytopenia
Sensitive to Vit K factors 2, 7, 9, 10 Qualitative +/- thrombocytopenia
Used for monitoring warfarin Causes of thrombocytopenia
INR to standardize o destruction
o PT time in Autoimmune = ITP, TTP, HUS
Liver disease decreased clotting factors production o Production
Vit K antag Warfarin BM failure aplastic anemia, neoplasia
Fibrin or fibrinogen degradation products as in DIC o Sequestration
o Partial thromboplastin time (PTT) Splenomegaly
Intrinsic and common Autoimmune thrombocytopenic purpura ITP
Screen for detection of coag inhibitors (lupus anticoag) o Due to platelet destruction
Used for monitoring heparin and factor replacement therapy w/ o Chronic ITP
hemophilia More common
o PTT time in Cause of isolated thrombocytopenia
Heparin inhibits 10 and 2 Autoantibodies against platelet receptors
Fibrin or fibrinogen degradation products BM = megakaryocytic hyperplasia
Lupus anticoagulant Tx = steroid, IV IG, Rituximab
Liver Disease o Acute
o Mixed study In Children
Mix normal control plasma w/ patients plasma After vaccination or infection (chicken pox or mono)
If pts Pt or PTT value is corrected pts initially prolonged Due to nonspecific immune complex
time due to factor deficiency Post transfusion purpura
If not corrected its due to presence of inhibitor o Antibodies in recipient against HPA-1a on transfused platelets
o Thrombin Time (TT) Drug induced quinine, quinidine, heparin
Measures thrombin induced conversion of fibrinogen to fibrin Thrombocytopenia due to thrombotic thrombocytopenic purpura
o TT time TTP
Afibrinogenemia o Deficiency of ADAMTS13 ( usually breaks down large VWF)
Hypofibrinogenumia o Neurological symptoms
Dysfibrinogenemia o Tx = plasma exchange w/ FFP that removes the vWF and autoAb
Acquired o Platelet transfusion is contraindicated
Hemolytic Uremic Syndrome HUS
Disorders involving Primary Hemostasis o In children
o Kidney dmage
Vascular disorder
o Assoc w/ E coli 0157-H7 infection
o Easy brusing and spont bleeding from small BV
o Platelet transfucion is contraindicated
o Abnormality is vessels or pervasc CT
o Lifespan of platelet is normal so they dont bleed
o Inherited
Hereditary hemorrhagic telangiectasia LDH + adult + thrombocytopenia + neuro symptoms = TTP
Elhers-Danlos syndrome LDH + kid + thrombocytopenia + renal = HUS
o Acquired
Scurvy Disorders of platelet Function
Senile purpura o Hereditary
Purpura assoc w/ infection Glanzmanns Thrombasthenia
Henoch-Schonlein syndrome Bernard Soulier
Hereditary hemorrhage telang. Storage pool disorder
o Also called Osler Weber Rendu syndrome May Heggland
o Auto Dom o Acquired
o Dilated microvasc swelling Antiplatelet drugs
o Tx w/ laser, embolization, estrogen therapy Hyperglobulinemia plasma cell myeloma or Waldenstroms
Ehlers Danlos syndrome macroglbulinemia
Myeloprolif or myelodysplast disorder
o Mutation in collagen gene
o Purpura/hyperextensibility/dissecting aneurism
o USMLE gives this as a child abuse case Glanzmanns Thromboasthenia (GT)
Scurvy o Auto rec
o Vit C def defective collagen perifollicular petechiae (old) o Fail of platelet aggreg due to fibrinogen receptor def (gp2b/3a) on
platlets
Senile purpura = atrophy of supporting tissue of cutaneous bv
o Dx by platelet aggregation study
Purpura assoc w/ infection
Abnormal platelet aggreg w/ ADP, Epi and collagen
o Many diff ones. DIC meningococcal septicemia
Normal platelet aggreg w/ ristocetin (via gp1b)
Henoch-Schonlein
o In children w/ URTI
o Its a IgA mediated vasculitis
o Purpuric itchy rash on but and lower legs
 Bernard Soulier Labs for Hemophilia A and B
o Auto Rec Prolonged aPTT
o Failure of aggreg due to vWF receptor (gp1b) on platlets Low level of F8 (f9 for B)
o Smear = anemia, thrombocytopenia, large platelets Normal bleeding time and PT
o Dx by plat aggreg study o Detection
Normal aggreg w/ ADP, Epi and collagen DNA analysis
Abnormal aggreg w/ ristocetin DNA from chorionic biopsy
Same is seen in VWF disease Antenatal Dx possible
Bleeding tendency + thrombocytopenia + large platelets + no Treatment of HA
response to ristocetin = BSS o Bleeding episodes treated w/ Factor 8 replacement
Bleeding tendency + No thrombocytopenia + normal platelets + no o Spont bleeding controlled if F8 is raised above 20% of normal
response to ristocetin = vWD o For surgery it should be raised to 100%
Factor 9 Def
May Heggland anomaly o X linked
o Auto dom o Christmas disease
o Mutation in myosin heavy chain MYH9 o The 2 disorders only diff by coag factor assay
o Pts have Alport syndrome = hereditary nephritis w/ sensorineural o F9 has longer half life so infusions less frequently needed
o Smear
Giant platelets Von Willebrand disease Exam Q
Dohle bodies in WBC o Reduced level/fxn of vWF due to pt mutation or deletion
Thrombocytopenia o vWF has 2 roles
promote platelet adhesion to damaged endothel
Storage pool disorder Carry Factor 8 and protect from breakdown
o bleeding time
Grey platelet syndrome o Auto dom except 2N and type 3 AR
o Auto rec due to NBEAL2 gene mutation o Mucous membrane bleeding, blood loss from superficial cuts and
o Smear abrasions
Large platelets w/ no granules +/- Thrombopenia o Type 3 have no VWF at all
o Agranular platelets also seen in MDS Looks like clotting factor def
Delta SPD disorder Hemarthrosis and hematomas
o Hermansky pudlack oculo-cutanous albinism o Labs
o Chediak Higashi partial albinism; large granules bleeding time but normal platelet #
o Wiskott Aldrisch X linked, eczema, thrombpenia, repeated Factor 8
infection due to immune def) PTT
Platelet aggreg
Disorder of platelet function - acquired Defective aggreg w/ Ristocetin
o Antiplatelet drugs Normal aggreg w/ ADP, Epi, collagen
Aspirin, NSAIDS o Type O blood usually have lowest levels of vWF
o Hypergamaglobulinemia = plasma cell myeloma or o Type 1 all present but $
Waldenstromss o Type 2A = no large and intermediate
o Myeloprolif, Myelodysplast, PNH o Type 2B = No large and affin for Gp1b
o In aggreg assay o Type 3 = None at all
Aspirin aggreg w/ Epi o Type 2N
Clopidogrol aggreg w/ ADP Inability of vWF to bind to F8 low levels of 8
o In PFA100 assay vWF level is normal and aggreg normal w/ ristocetin
Aspirin prolonged closure time of coll + epi cartridge o Type 2M
Clopidogrol prolong closure time of coll + ADP cartridge Inability of vWF to bind to Gp1b on platelet
vWF antigen levels are normal w/ decreased ristocetin activity
Disorders involving Secondary hemostasis o Treatment
DDAVP for type 1
Hereditary Coag disorders F8 concentrate
o Hemophilia A (F8 def) Note WF is an acute phase reactant and could be due to preg,
o Hemohilia B (F9 def) exercise or stress
o VWD
Acquired Coag Disorders
Hemophilia A o Vit K def diet/drugs
o X linked o Liver Disease biliary obstruct cant absorb vit K
o Def in Factor 8
o Infants have profuse hemorrhage or develop joint/soft tissue
bleeds and brusing when they start to get active
o Recurrent painful hemarthroses Joint deformity
 Disseminated intravascular coagulation DIC Exam Q Antiphospholipid Antibodies APL
o Widespread deposition of fibrin w/ consumption of coag factors o Ab against plasma proteins bound to anionic surface
and platelets (phospholipid)
o Occurs due to many diseases Anticardiolipin
o Bleeding and thrombus Beta2 glycoprotein 1 (B2 GP 1)
o Labs o Occurs as thrombosis or recurrent miscarriage in assoc w/ APL
PT, PTT, TT Ab
fibrinogen, platelet count o 1 type is lupus anticoagulant
FSP and D dimers Prothrombin or B2 glycoprotein I
o Smear o Venous and arterial thrombosis
Hemolysis and RBC frags (schistocytes)
o Tx ISTH criteria for lab Dx of APL
Supportive care w/ FFP and platelet concentrates o Prolongation of atleast 1 phospholipid dependent screen test
Cryoprecipitate provides more concentrated source of PTT, Dilute Russell viper venom, Kaolin clotting
fibrinogen and RBC transfusion o No correction w/ 50:50 mix
DO NOT use heparin or antiplatelet drugs o Correction suggestions clotting factor deficicny
o Correction when excess phospholipid is added
General Roles in Thrombosis testing Children w/ APL Ab
o Tests affected by acute phase response and anticoag therapy o Post viral adenovirus, varicella
AT, PC, PS, clotting factors and fibrinogen o Autoimmune juvenile arthritis, SLE, AIHA
So test 3 months after episode and off therapy for 2 weeks o Prolonged PTT but no risk of bleeding
o DNA based tests and homocysteine test are not affected by acute
phase response
Testing for inherited thrombophilia
o Test for 5 leiden (most common)
o + ? = stop
o - = Test for prothrombin

Factor 5 Leiden
o Factor 5 gene w/ single base pair substitution, Arg to glut
o Protein C = natural coag and usually inactivates 5 but after this
mutation, its less susceptible (activated protein C resistance)
o FVL mutation hypercoagulable state = risk for VTE
o Heterozygous for factor 5 are 5 fold risk for VTE
o Homozygous are 50 fold
o Test methods
APC resistance assay
DNA based assay PCR
Activated protein C resistance assay
o APC will prolong PTT of normal but not of FVL = resistant

Prothrombin G20210A mutation

o Prothrombin Factor 2 = precursor of thrombin
o Made in liver
o prothrombin levels thrombotic risk
o Test = PCR
Protein C deficiency
o Auto dom
o Vit K dep
o Develop Skin necrosis due to Dermal vessel occlusion when
treated w/ warfarin therapy
o Def occurs during liver disease, DIC and sepsis
Protein S deficiency
o Cofactor to C
o Same necrosis w/ warfarin
Antithrombin Deficiency
o Natural anticoag that inhibits 2a and 10a
o Arterial thrombosis occurs
o Heparin ineffective
o Seen in pts w/ Nephritis
Homocysteinemia
o levels of homocysteine = Both venous and arterial thrombosis
o Mutation in methylene tetrahydrofolate reductase = MTHFR