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Hematology 1
Anemia
Hematology 2
Overview
Definition – adults
Males: hgb < 13-13.5
hct < 41
Females: hgb < 12
hct < 36
Children Hgb: age-specific until 18
U.S. Preventive Services Task Force and AAFP
recommend screening Hgb or Hct between 6-12
months in high-risk infant
Insufficient evidence to recommend routine screening
in asymptomatic persons, except pregnant women
Hematology 3
Analysis of the Cause of
Anemia
Based on cause
Decreased production
Lack of nutrients – Iron, B12, Folate
Primary bone marrow involvement
Aplastic anemia
Myelodysplasia
Tumor
Suppression of bone marrow function
Drugs
Cancer
Irradiation
Hematology 4
Analysis of the Cause of
Anemia (Cont’d)
Increased destruction
Hemolytic anemia
Inherited – Hereditary Spherocytosis, Sickle Cell
Acquired – Coombs positive
RBC loss
Bleeding – GI, uterine or traumatic
Based on Morphology
Most helpful is evaluation by mean corpuscular
volume (MCV)
Microcytic < 80
Normocytic 80-100
Macrocytic > 100
Hematology 5
Microcytic Anemia
Serum
TIBC Ferritin
Fe
Iron
Decreased Increased Decreased
deficiency
Anemia of
Normal or
chronic Decreased Decreased
decreased
disease
Hemoglobin- Normal or
Normal Normal
opathies increased
Sideroblastic Normal or Normal or Normal or
anemia increased increased increased
Hematology 7
Iron Deficiency Anemia (Cont’d)
Most sensitive test - serum ferritin, but also
an acute-phase reaction
Fe/TIBC, soluble transferrin receptor
Few iron preparations have any advantage
over ferrous sulfate
Increase in hemoglobin of 2-3 gm/dl over 3-4
weeks defines acceptable response to
therapy. Reticulocyte count increases in 7-10
days
Treatment to rebuild iron stores may take 6
months
Hematology 8
Anemia of Chronic Disease
(ACD)
Except for acute blood loss, the most common cause
for normocytic anemia
Associated with chronic inflammatory, infectious, and
neoplastic disorders but 40% occurs in their absence
Occurs because t ½ of RBC is decreased and the
bone marrow is unable to normalize blood count
secondary to impaired iron processing
20-40% of ACD is microcytic; rarely MCV <72 unless
iron deficiency present
Erythropoietin (40,000-60,000 units sq weekly) and
iron therapy is usual therapy; iron is used to
overcome utilization problems
Hematology 9
Iron
The body has no way to remove excess iron either
obtained by abnormally high absorption or blood
transfusions
Body stores of 3800 mg in men and 2500 mg in women
Highly regulated absorption which replaces 1 mg/day in
men and 1.5 mg/day in menstruating women
Low levels of serum iron and transferrin saturation in
hospitalized patient more likely to be anemia of chronic
disease phenomenon, and high ferritin levels most likely
secondary to inflammation or liver disease
Most common etiology of iron overload
Blood transfusion
Hemochromatosis
Ineffective erythropoiesis - thalassemias and others
Hematology 10
HFE Hemochromatosis
Autosomal recessive, common in whites;
uncommon in blacks or Asians
Persistently high transferrin saturation of
>45% in women and >50% men, and serum
ferritin >300 mg/ml suggestive
Confirmatory testing is the HFE gene
mutation
Symptoms/signs
Arthritis of
Unexplained liver disease
metacarpal/phalanges
CHF
Weakness
Diabetes
Abdominal pain
Hematology 11 Cirrhosis
HFE Hemochromatosis
(Cont.)
Liver biopsy
If ferritin >1000 mg/ml or abnormal liver function testing
If cirrhosis present - lifetime increased risk of
hepatocellular carcinoma
Family members should be screened
Treatment of iron overload
Phlebotomy of 450-500ml 1-2 times weekly until iron
stores depleted (ferritin <20mg/ml)
Maintenance phlebotomy (once 2-6 months) to keep
ferritin <50mg/ml
Parenteral iron chelation (desferrioxamine) used if iron
overloaded and anemia
Hematology 12
Macrocytic Anemia
Megaloblastic – > 5 lobes on neutrophils
B12 deficiency
Folate deficiency
Inadequate intake – alcoholism
Increased requirements
Decreased absorption
Bone marrow disorders
Drugs
Phenytoin Hydroxyurea
Methotrexate Zidovudine
Sulfasalazine Sulfamethoxazole
Oral contraceptives Phenobarbital
Hematology 13
B12 Deficiency
Glossitis, peripheral neuropathy, weakness,
hyperreflexia, ataxia, loss of proprioception,
poor coordination, affective behavior
changes, myelopathy, abdominal pain
Tests - Schilling test, methylmalonic acid
assay, intrinsic factor blocking antibody,
serum gastrin assay, homocysteine
Treatment – 1mg vitamin B12 po q day
Hematology 14
Schilling Test
Positive - pernicious anemia
Negative - inadequate intrinsic factor,
gastrectomy, gastric bypass surgery,
ileal disorders - sprue, fish tapeworm,
inadequate intake
Rarely used secondary to clinical utility
Hematology 15
Hereditary Spherocytosis
Most common of hereditary hemolytic
anemias
Autosomal dominant
Neonatal hyperbilirubinemia
Cholelithiasis 40% by 3rd decade of life
“Aplastic crisis” – parvovirus
Hematology 16
Hereditary Spherocytosis
(Cont’d)
Blood smear
Spherocyte
MCHC elevated 37-39 g/dl
Osmotic fragility test
Splenectomy is cure
Folic acid supplements
Hematology 17
Glucose – 6-Phosphate
Dehydrogenase Deficiency (G6PD)
X-linked disorder – black males
Avoidance of oxidative drugs should
prevent hemolysis (sulfa)
Splenectomy not indicated
G6PD levels helpful – beware of false
normals during attack secondary to
higher level in reticulocytes
Hematology 18
Warm Autoimmune
Hemolytic Anemia
Primary or secondary (collagen vascular,
lymphoproliferative, HIV, ulcerative colitis)
IgG antibodies lead to positive direct antiglobulin test
90% of the time
Prednisone – first-line treatment
1-1.5 mg/kg daily
weeks
Slow taper to <10 mg daily
Hematology 21
Sickle Cell Disease –
Recommendations
Infant should be screened for hemoglobinopathies
Children should be screened at 2 years of age by
transcranial doppler (TCD) to assess for risk of stroke that
can be reduced by chronic transfusion therapy serial testing
recommended
Retinal exam at school age to detect early proliferative sickle
retinopathy
Folic acid 1 mg/daily
Vaccines
Influenza starting at 6 mo and yearly
7-valent PCV (routine childhood immunization)
23-valent pneumococcal vaccine at 2 years of age and repeated 3-5 years
later
Meningococcal vaccine at 2 years of age
Infection control
Prophylactic penicillin until age 5 starting at 2 months of age – 125 mg bid
Hematology 22 until age 2-3 then 250 mg bid
Sickle Cell Disease –
Recommendations (Cont.)
Management of painful episodes
Exclusion of causes other than vasoocclusion-infection
Opiates, other analgesics
Optimal hydration – po or I.V.
Hematology 23
Paroxysmal Nocturnal
Hemoglobinuria
Chronic hemolytic anemia complicated by
iron deficiency due to urinary loss
Associated with venous thrombosis,
pancytopenia
Diagnosis
Acid-induced hemolysis (Ham’s Test)
Cytogenetics
Treatment
Anticoagulation, iron and folic acid
supplements, monitoring blood counts
Hematology 24
Aplastic Anemia
Rapidly progressive disorder
50% of the time no obvious cause
Differential
Acute leukemia
Myelodysplastic syndrome
Drug-induced
Nutritional
Treatment
Allogeneic stem cell transplantation with 75-90% long-
term survival. Limited to those <50 yr and HLA-identical
sibling donors
Avoid transfusion of blood products from family members
Hematology 25
Stem Cell Transplantation
Used for treatment of malignant disorders (CML,
AML, ALL, myelodysplastic syndromes) and
nonmalignant disorders (aplastic anemia, metabolic
disorders, hemoglobinopathies)
Types
Autologous - harvesting and cryopreservation of
patient’s own cells
Allogenic - from donor
Best results
Younger age <40-50
Well-controlled malignancy
HLA - identical sibling donor - chance less than 30-35%
Hematology 26
Stem Cell Transplantation
(Cont.)
Graft-versus-host disease
Major toxicity from allogeneic stem cell
10-15% death rate
30-40% chronic morbidity
Early <100 days: rash, cholestatic hepatitis,
enterocolitis
Late >100 days: hepatitis, scleroderma, arthritis,
bronchiolitis, malabsorption, sicca syndrome
Hematology 27
Stem Cell Transplantation
(Cont.)
Complications
<100 days
Infections - bacterial, fungal, viral - CMV, herpes
Hemorrhage
Veno-occulsive disease
Engraftment failure
Angiopathy
>100 days
Infections - encapsulated bacteria, varicella-zoster,
Pneumocystis carinii
Cataract
Autoimmune
Hematology 28
Thrombocytopenic Purpura
(TTP)
Pathognomonic pentad
Microangiopathic hemolytic anemia
Thrombocytopenia
Neurologic abnormalities
Fever
Renal dysfunction
Can be associated with bone marrow
transplant, gastric adenocarcinomas, shiga-
toxin enterocolitis, pregnancy, HIV and drugs
Treatment
Plasma exchange therapy
Hematology 29 No platelet transfusions
Immune Thrombocytopenic
Purpura (ITP)
Usually a self-limiting bleeding disorder of childhood
2/3 of cases are preceded by viral infections
80% recover normal platelet counts by 6 months
Autoantibodies attach to the membrane receptors on the
platelets but not accurate for diagnosis
Present with spontaneous nonpalpable bruises and
petechiae
Intracranial hemorrhages possible if platelets <10,000/µL
Hematology 30
ITP
Bone marrow not necessary when
Age <60
Typical presentation
Treatment
Doesn’t alter the duration of illness
Does shorten period of profound
thrombocytopenia
Indicated if platelets <30,000/µL Prednisone 1
mg/kg daily
Response within 4-7 days, usually by 2-3 weeks then
taper
50-75% response rate
Hematology 31
ITP (Cont.)
Anti-D immune globulin used in Rh-positive
patients with an intact spleen
Associated with 1g/dl hemoglobulin drop (rare cases of
severe hemolysis)
70-80% response rate
Intravenous immunoglobulin (IVIg)
70-80% response rate
Splenectomy
80% response rate but relapse in 20-30% of those
Used if unable to taper prednisone to <10-20 mg daily
Hematology 32
Thrombocytopenia
20-40% hospitalized patients who are critically ill
have platelets <100,000 µL. Common reasons
include drug-induced and infection. Treatment to
maintain >10,000/µL or >20,000 µL in those at
higher risk for bleeding
Incidental thrombocytopenia in pregnancy
Most common cause of isolated thrombocytopenia
Usually >100,000/µL and by definition >70,000/µL
Not associated with adverse events
Hematology 33
Thrombocytopenia (Cont.)
ITP in pregnancy
No correlation between maternal and fetal values
No reliable treatment to increase fetal platelets
Risk of fetal blood sampling to assess fetal platelet
levels is equal to fetal injury by vaginal delivery
Cesarean delivery not proven effective
Most recommend trial of labor without fetal platelet
assessment
Hematology 34
Heparin-Induced
Thrombocytopenia (HIT)
30-50% of HIT is associated with thrombosis
(HITT)
Decrease in platelets of 50% after 5 to 10
days of heparin or <1 day after re-exposure to
heparin within 3 months
Platelet factor 4/heparin complexed
antibodies is sensitive but not specific
Present in 10% of medical or surgical patients with recent
heparin exposure and 50% of patients after CABG
Hematology 35
Heparin Induced
Thrombocytopenia (HIT) (Cont.)
HITT
20% mortality
10% limb amputation
30% rethrombosis
HIT/HITT Treatment
Immediately stop all heparin
Lepirudin
Renal excretion
PTT to 1.5-2.5 x normal
Argatroban
Liver metabolized
May prolong INR when starting with warfarin. Continue til
INR is >4
Hematology 36
Von Willebrand Disease (VWD)
Most common inherited bleeding disorder
Autosomal dominant trait
Affects females and males equally
Clinical presentation
Low incidence of bleeding common
Epistaxis, lifelong easy bruising, dental bleeding,
postpartum bleeding, menorrhagia
Aspirin or NSAID can precipitate bleeding
Hematology 37
Von Willebrand Disease (VWD)
(Cont’d)
Lab testing for screening
Plasma VWF antigen
Plasma VWF activity (Ristocetin cofactor activity)
aPTT
Factor VIII activity
Bleeding time/platelet function analyzer (PFA 100)
Lab testing if screening testing abnormal
include VWF multimers and Ristocetin-
induced platelet aggregation
Determine subtype of VWD
Subtype of VWD directs treatment
Hematology 38
Von Willebrand Disease (VWD)
(Cont’d)
VWD Types
Type 1 – most common – 70%
Quantitative deficiency
Type 2
25% of cases
Qualitatively abnormal
4 subtypes
Type 3
Rare
Treatment
DDAVP
Useful in most patients with Type 1, variable with Type 2
Can be given s.q. or by nasal spray
Replacement therapy with VWF
Hematology 39 Antifibrinolytic therapy
Hemophilia A and B
X-linked recessive disorder with deficiency of:
Factor VIII in Hemophilia A
Factor IX in Hemophilia B
Hematology 41
Hemophilia Bleeding
Emergencies
Hemophilia
Mild (hemarthrosis, hematuria)
Moderate (epistaxis, GI bleeding)
Severe (CNS, Retroperiotoneal)
Recombinant factor VIII initial doses
12.5 units/kg – mild
25 units/kg – moderate
50 units/kg – severe
Factor IX initial dose
25 units x 1 kg – mild or moderate
50 units 1 kg - severe
Hematology 42
Iatrogenic Bleeding
Complications
Heparin
Stop heparin
Protamine 1 mg per 100 units of heparin
given over last 4 hours; max dose of 50 mg
(slow i.v. push)
Lovenox
Protamine (partially effective) 1 mg per mg
of Lovenox given if <8-12 hours; 0.5 mg
per mg of Lovenox if 8-12 hours; none if
>12 hours
Hematology 43
Iatrogenic Bleeding
Complications (Cont’d)
Coumadin
INR 2-5
No bleeding or minor bleeding
Lower dosage
INR 5-9
No bleeding withhold x 1-2 days
Restart at lower dose – consider
Increased risk of bleeding or minor bleeding
Vit K 1-2.5 mg p.o. withhold x 1-2 days
Restart lower dose - consider
Hematology 44
Iatrogenic Bleeding
Complications
Coumadin
INR >9
No bleeding or minor bleeding
Vit K 3-5 mg p.o. withhold x1-2 days
Restart lower dose – consider
Severe
Vit K 5-10 mg
FFP
Prothrombin complex concentrate if insufficient time
to thaw FFP
Hematology 45
Iatrogenic Bleeding
Complications (Cont’d)
TPA
Amino caproic acid (Amicar)
Competitively inhibits activation of plasminogen
to plasmin
Aprotinin (Trasylol)
Inhibits plasmin, antifibrinolytic effects
PRBC, cryo, FFP, Platelets
Hematology 46
Neutropenia
Normal
>2500 mcL in most populations
>1500/mcL in African and Middle Eastern
populations
Etiology
Acquired infections (HBV, CMV, EBV, Gram-
negative sepsis, Rickettisal, malaria, ehrlichosis)
Drugs (NSAID, Antithryoid drugs, clozapine, gold)
Chronic autoimmune
Congenital
Cyclic neutropenia – 3 to 6 days of neutropenia every 3
weeks
Chronic benign
Severe congenital neutropenia – severe infections in 1st
Hematology 47 months of life
Neutropenia (Cont’d)
Risk of infection
Related to degree and duration of neutropenia,
especially absolute neutrophil count ANC <100/µL
for >5 days in those with chemotherapy/marrow
failure
Children with benign chronic or adults with
immune neutropenia don’t have high risk of
infection
Common sources – oral cavity and mucous
membranes
Hematology 48
Neutropenia (Cont’d)
Diagnosis
Different for infants/young children than adults
Mild neutropenia without infections
Rule out infection or medication-related
Rule out cyclic neutropenia
Check CBC 3x/wk for 6-8 wks
If persist after 8 weeks – bone marrow
Moderate to severe with infections
Bone marrow and rule out cyclic as above
ANA, C3, C4 to screen for collagen vascular disease
Immunoglobulins, HIV, B12/folate
Hematology 49
Neutropenia (Cont’d)
Treatment
Febrile patients should be treated immediately
(see oncology slides on fever/neutropenia)
Myeloid growth factors (G-CSF, Neopen) can
correct neutropenia and reduce infectious
complications in chemotherapy-induced cases
who are high risk (ANC <100), uncontrolled
cancer, pneumonia, multiorgan dysfunction,
pneumonia and hypotensive episodes
Hematology 50
Hematologic Cancers
Hematology 51
Hematologic Cancers
Leukemia
31,500 new cases / year in US
1/2 chronic, 1/2 acute
Lymphoma
63,600 new cases / year in US
7400 Hodgkin’s, 56,200 non-Hodgkin’s
Other
Hematology 52
Leukemia
Originates in bone marrow
Proliferation of abnormal white cells
Classified by cell type and time to death
(if untreated)
Myelogenous (granulocytes) vs.
Lymphocytic (lymphocytes)
Acute (months) vs. Chronic (> 1 year)
Most common cancer in children
Hematology 53
Acute Leukemia
Rapid uncontrolled proliferation
(Usually) functionless cells
Replacement of normal bone marrow
Bleeding (thrombocytopenia)
Infection (neutropenia)
Fatigue (anemia)
Generally treatable and potentially
curable (chemotherapy)
Hematology 54
Acute Leukemia (Cont.)
Usually seek care secondary to bacterial
infection or bleeding
Bleeding usually minor
Petechiae
Gingival bleeding
Epistaxis
Labs
WBC - equal presentation of normal, low and elevated counts
Anemia - usually moderate
Platelets - usually severally reduced
Immature blast cells diagnostic of leukemia almost always seen on
peripheral smear
Bone marrow superior for cytogenetic and immunophenotyping
Hematology 55 studies
Acute Leukemia (Cont.)
Treatment
Specific antineoplastic regimens
Supportive care for nausea/vomiting
Xanthine oxidase (allopurinol) used before chemotherapy to
prevent urate nephropathy
“Routine” transfusion when platelets <10,000/ mcl
Hematology 56
Acute Lymphoblastic
Leukemia (ALL)
Hematology 57
Acute Myelogenous Leukemia
(AML)
Primarily adult disease
Median onset 50 years old
Increasing incidence with age
Treatment
Chemotherapy – 70% response; 30% cure
Post-remission therapy – chemo or bone
marrow transplant
Hematology 58
Chronic Lymphocytic
Leukemia (CLL)
History
Adult onset (90% > age 50), most common leukemia
Symptoms
Clonal proliferation of defective B lymphocytes
Immunosuppression
Bone marrow failure
Organ infiltration
Lymphadenopathy (80%)
Hepatosplenomegaly (50%)
Treatment
Early in disease of no benefit
Indicated for progressive symptoms or decreasing cell
counts (platelets, hemoglobin)
Hematology 59
Hairy Cell Leukemia
Cancer of B lymphocytes
Pancytopenia
Including monocytopenia (unusual)
Disease of middle aged men
Median age 55
5:1 male
Fatigue, infection, splenomegaly (often
massive)
Prognosis good with chemotherapy
Hematology 60
Lymphomas
Any neoplasm of lymphoid tissue
Types
Hodgkin’s Disease
Non-Hodgkin’s Lymphoma
Burkitt’s Lymphoma
Cutaneous T-Cell Lymphoma
Mycosis Fungoides / Sezary Syndrome
Primary CNS Lymphoma
Waldenstrom’s Macroglobulinemia
>2 gm/dl IgM monoclonal
Hematology 61
Hodgkin’s Disease
(Lymphoma)
Painless lymphadenopathy
Initially single node
Spread to contiguous nodes
Late dissemination
Subtypes by lymph node biopsy
Lymphocyte predominance
Nodular sclerosis
Mixed cellularity
Lymphocyte depletion
Hematology 62
Hodgkin’s Disease
(Lymphoma) (Cont’d)
Staging by spread + symptoms
Stage I: one lymph node region
Stage II: two lymph node areas, one side
of diaphragm
Stage III: lymph node regions, both sides
of diaphragm
Stage IV: disseminated disease with bone
marrow or liver involved
Stage A: no constitutional symptoms
Stage B: weight loss, fever, or night sweats
Hematology 63
Hodgkin’s Disease
(Lymphoma) (Cont’d)
Reed-Sternberg cells for diagnosis
Radiotherapy for stage IA & IIA
> 80% 10-year survival
Chemotherapy for higher stages
Poorer prognosis w/
Age, bulky disease
Lymphocyte depletion, mixed cellularity
Hematology 64
Non-Hodgkin’s Lymphoma
Group of lymphocyte cancers
Classification by behavior
Indolent to rapidly progressive
Can be isolated or widespread at diagnosis
Indolent with painless lymphadenopathy
(follicular)
Higher grade with adenopathy or symptoms
(diffuse large B-cell)
Fever, drenching night sweats, weight loss
Hematology 65
Non-Hodgkin’s Lymphoma
(Cont’d)
Diagnosis by excisional biopsy
Staged at diagnosis
Physical exam, chest x-ray, CT
abdomen/pelvis, bone marrow biopsy
Possible LP (high-risk morphology)
Serum LDH a prognostic marker
Treatment
Combination chemotherapy
Hematology 66
Lymphadenopathy
Most common – no cause is found and
spontaneous resolution over 2 weeks
Evaluation depends on risk factors and
presentation
Low risk High risk
Tender > 2 cm size
Cervical, axillary, Supraclavicular
inguinal > 40 yrs – hard, matted, fixed
< 40 yrs – 95% benign
Treatment
Observation
Hematology 67
Excisional biopsy
Monoclonal Gammopathy
Diagnostic criteria
< 10% bone marrow plasma cells
Asymptomatic
Monoclonal protein < 3 gm/liter
Normal bone x-rays – axial skeleton (skull,
spine, CXR, AP pelvis)
Normal hemoglobin, Ca++, creatinine
No light-chains in urine
B2 microglobulin < 3 mg/dl
Hematology 68
Monoclonal Gammopathy
(Cont’d)
5% of patients > 70 yrs
20% secondary to other systemic disorder –
cirrhosis, rheumatoid, sarcoidosis
Natural history usually benign
25% over 25 years develop myeloma,
amyloidosis, lymphoproliferative disorders
Follow up every 6 months for 2 years then yearly
Hematology 69
Multiple Myeloma
Diagnostic Criteria
(1 major + 1 minor or 3 minor)
Major Minor
Plasmacytoma on 10-30% plasma cells in
tissue biopsy bone marrow
> 30% plasma cells Monoclonal proteins less
in bone marrow than above
Monoclonal (M) Lytic bone lesion(s)
proteins Low immunglobulins
> 3.5 gm/dl IgG < 0.5 gm/dl IgM
> 2.0 gm/dl IgA < 0.1 gm/dl IgA
> 1.0 gm/24 hour < 0.6 gm/d IgG
urine of light
chains
Hematology 70
Multiple Myeloma
Median age 70 at diagnosis; median survival
2-3 years
Critical test
Bone marrow biopsy
Bone x-ray, not bone scan
Renal failure secondary hypercalcemia, light
chain deposit
Anemia – bone marrow decrease
Infection – hypogammaglobulinemia
Bleeding – dysfunctional platelets
Hematology 71
Multiple Myeloma (Cont’d)
Not all patients should be treated –
smoldering MM – no anemia, lytic lesions, or
hypercalcemia
If patient is <70 years of age and “healthy”
autologous stem cell transplant should be
discussed
If stem cell transplant not an option
>75 year melphalan and prednisone
65-75 melphalan, prednisone, thalidomide
Hematology 72
Myelodysplastic Syndrome
Common cause of cytopenias,
especially elderly
Stem cell clonal abnormality associated
with enhanced apoptosis, ineffective
hematopoiesis resulting in cytopenias
Diagnosis
Abnormal RBC morphology
Pelger-Huet deformity (bilobed neutrophilis)
Bone marrow aspirate - dysplasia
Cytogenetic studies
Hematology 73
Myelodysplastic Syndrome
(Cont’d)
Differential
Nutritional deficiencies - B12
Drug-induced
Myeloproliferative syndromes
Prognosis
Indolent chronic anemia to rapid death from
transformation to acute leukemia
Relative abundance of blasts in bone marrow
associated with aggressiveness of disease
Few blasts and only anemia - 6 yr survival
>10% blasts and pancytopenia - 1 yr survival
Hematology 74
Myelodysplastic Syndrome
(Cont’d)
Treatment
Curative with stem cell transplant but rare
secondary to not beneficial in those >50 yr
Symptomatic care
Erythropoietin (especially if baseline level <500)
Transfusion of RBCs, platelets
Treatment of infection, G-CSF
Lenalidomide (Revlimid)
In 5 q minus syndrome
Decreased transfusion
$6000-$7000/month
Azacitidine (Vidaza)
Cost $30-45,000
No difference in survival, improved quality of life, delay in
Hematology 75 leukemic transformation
Myeloproliferative Disorders
Clonal stem cell disorders
In contrast to myelodysplastic syndrome there
is no cellular dysplasia and normal
differentiation into mature blood cells and no
cytopenia
Includes
CML
Polycythemia vera
Myelofibrosis
Essential thrombocytosis
Hematology 76
Chronic Myeloid Leukemia
(CML)
A balanced translocation between
chromosomes 9 and 22 (Philadelphia
chromosome) creates a unique protein,
bcr-abl.
Onset in middle age by
Fatigue, night sweats, low-grade fever
Routine blood counts - demonstrating leukocytosis
and myeloid precursors, thrombocytosis
Splenomegaly
Hematology 77
CML - Therapy
Medical therapy is used to suppress malignant
clone, normalize blood counts, and delay blast
crisis
Hydroxyurea - 35-50% 5 yr survival
Interferon alfa daily injections 50-70% 5 yr
survival
Imatinib mesylate (Gleevac)
Inhibits bcr-abl tyrosine kinase
90% normalized blood counts
30-40% no detectable CML
Side effects - leukopenia, nausea, muscle cramps, rash,
hepatitis, fluid retention
Allogeneic stem cell transplantation
Hematology 78
Blast crisis treated similar to acute leukemia
Polycythemia Vera
Criteria
Hematocrit >60% male or >56% female in absence of
secondary causes
Normal O2 saturation >92%
Splenomegaly or two of the following
Leukocyte alkaline phosphatase Platelet >400,000/ µL
score >100 Leukocyte >12,000/ µL
High B12 >900 pg/ mcl
Symptoms - headache, pruritus, dysuria, blurred vision,
night sweats
Bleeding and thromboembolic events (venous and
arterial) major adverse effects
Hematology 79
Polycythemia Vera (Cont.)
Prognosis
Chronic disorder
Median survival of 15 years
Risk of acute leukemia or myelofibrosis
Higher risk of cardiovascular disease/mortality
Treatment
Regular phlebotomy to hematocrit of 42-45%
Maintain iron deficiency
Patients >70 yr, history of thrombosis or platelets
>400,000 treat with myelosuppressive therapy of
hydroxyurea
Aspirin 100 mg daily reduces risk of vascular
disease
Hematology 80
Myelofibrosis
Rare disease, older patients
Marrow fibrosis – end result
Leukoerythroblastic blood smear
Treatment
Supportive: transfusion, splenectomy
Curative – bone marrow transplant if
younger than 55 years
Hematology 81
Essential Thrombocythemia
Platelets >600,000/ µL usually
>1,000,000/ µL
Symptoms/signs
Erythromelalgia, livedo reticularis, headache
Venous and arterial thrombosis (20-30%)
Bleeding tendencies because of
“dysfunctional” platelets
Prognosis - near normal life expectancy
Hematology 82
Essential Thrombocythemia
(Cont’d)
Treatment
Low-risk (<60 yr, asymptomatic, no thrombosis
and platelets <1,500,000/µL) observation
Non-low-risk
Hydroxyurea to reduce platelets <400,000/ µL. Risk 3-
4% of developing acute leukemia after long-term use
Anagrelide - blocks megakaryocyte maturation
Aspirin - thrombosis history and no bleeding risk
Plateletpheresis for those with acute ischemic events
and platelets >1,500,000/ µL
Hematology 83
Syllabus Extras
Deep Vein Thrombosis (DVT)
and
Pulmonary Embolism (PE)
Hematology 84
DVT
Lifetime risk 2-5%
Of patients presenting with symptoms of DVT,
fewer than 30% have the disorder
Differential Dx
Muscle strain, tear
Leg swelling in paralyzed limb
Lymphangitis/Lymphedema
Venous insufficiency
Popliteal (Baker’s) cyst
Cellulitis
Knee abnormality
Unknown
Hematology 85
Drug-induced swelling
DVT (Cont’d)
History and physical exam are not reliable
enough by themselves to exclude the
diagnosis
Sequential evaluation strategies are helpful
and include the following:
History
P.E.
Clinical model for prediction based on history and
P.E.
Specific tests
Hematology 86
Risk Factors for Venous
Thromboembolism
Age > 40
History of venous thromboembolism
Surgery > 30 minutes
Prolonged immobilization
Cerebrovascular event
Cancer – Trousseau’s Syndrome
Investigation for occult cancer when it is clinically
suspected or routinely screened for
Fracture of pelvis, femur, tibia
Obesity
Pregnancy
Estrogen therapy
Inflammatory Bowel Disease
Hematology 87 Hyperhomocyteinemia
Risk Factors for Venous
Thromboembolism (Cont’d)
Genetic or acquired thrombophilia – detects
50% only
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Protime G 20210A mutation
Factor V Leiden
Anticardiolipin antibody
Lupus anticoagulant
Testing for thrombophilia should be considered
in patients below the age of 50 with recurrent
DVT/PE or in those with a strong family history
of proven DVT/PE
Hematology 88
Prevention of DVT
High risk – major orthopedic surgery on the
lower limbs without prophylaxis proximal DVT
10-30%, fatal PE 1-5%
Elective hip – LMWH (Low Molecular Weight
Heparin), warfarin, IPC (Intermittent Pneumatic
Leg Compression)
Elective knee – LMWH, IPC
Hip fracture – LMWH, warfarin
Spinal cord with paralysis – LMWH, IPC
Neurosurgery - IPC
Hematology 89
Prevention of DVT (Cont’d)
Moderate risk – general surgery in those >40
yr or <40 yr women taking OCP risk of DVT
2-10%, fatal PE <1%
General surgery LMWH, IPC
Low risk – minor surgery <30 min in patients
>40, or uncomplicated surgery <40 yr
Early ambulation
Hematology 90
Wells Criteria for Predicting The
Pre-Test Probability of DVT
Clinical Characteristic Score
Active cancer or within 6 mo. 1
Immobilization – paralysis, paresis, or casting 1
Bedridden > 3 days or major surgery < 12 weeks 1
Localized tenderness of venous system 1
Entire leg swollen 1
Calf measurement 3 cm greater measured 10 cm
below tibial tuberosity on symptomatic side 1
Pitting edema confined to symptomatic leg 1
Collateral superficial vein (non-varicose) 1
Alternative diagnosis at least as likely as DVT -2
Score: < 2 – 5% of DVT
Hematology 91 > 2 – 30% of DVT
Specific Testing for DVT
Compression ultrasound
Sensitivity >95%, specificity >95% for proximal DVT;
positive predictive value >95%
Can’t detect pelvic or calf DVT accurately
Can detect other diagnosis if not DVT – Baker’s cyst,
superficial phlebitis, muscle tear
Test remains abnormal (30-40%) for greater than 1 year
Impedance Plethysmography (IPG)
Sensitivity >90%, specificity >95%
False-positives greater than compression ultrasound;
positive predictive value 85%
May be helpful in evaluation of recurrent DVT in that IPG
Hematology 92
normalizes in 70% by 3 mo. and 90% by 9 mo.
Specific Testing for DVT
(Cont’d)
D-Dimer
D-Dimer is the final product of complete
fibrinolysis and is a tell-tale sign of the presence
of blood clotting
Highly sensitive but not specific; may be
present with:
Infection Trauma
Inflammation Surgical incision
Vasculitis Wound healing
Pregnancy Malignancy
Liver disease
Hematology 93
Specific Testing for DVT
(Cont’d)
D-Dimer (Cont’d)
3 different methods to measure and it is important to
know 2° to various sensitivities – tests recommended
ELISA
Latex-agglutination – IL-Test
Whole-blood agglutination - SimpliRED
Contrast venography
Most sensitive and accurate
1-2% risk of DVT 2° procedure
Usually not used 2° to accuracy and simplicity of
compression ultrasound
Magnetic resonance venography – available but
expensive
Hematology 94
DVT Protocol
Patient presents with possible DVT
1) Ultrasound
Negative: Positive positive: + DVT
DVT ruled 2) Negative D-Dimer
out & ultrasound: -
Compression Ultrasound Negative DVT
3) Negative
ultrasound and
positive D-Dimer:
Positive: Negative: DVT repeat ultrasound
DVT ruled in ruled out 1 week
Hematology 95
Evaluation of Suspected P.E.
Wells Criteria for Predicting Probability of Embolism
Risk Factors No of Points
Clinical signs and symptoms of DVT 3
An alternative diagnosis less likely than P.E. 3
Heart rate >100 1.5
Immobilization or surgery in last 4 weeks 1.5
Previous DVT/PE 1.5
Hemoptysis 1
Active cancer or within 6 months 1
Hematology 97
Specific Testing for P.E.
(Cont’d)
Helical CT scan
Wide ranges of sensitivity (57-100%) and specificity
(78-100%) reported secondary to:
Different technologies – higher resolution, scan times, better
peripheral visualization, motion artifact
Sensitivity – varies on location
90% for main or lobar
Hematology 100
Low Clinical Probability of P.E. (<10%)
D-Dimer
Negative Positive
P.E. ruled
Hematology 101 out P.E. confirmed
Intermediate Clinical Probability of P.E. (30%)
V/Q or Helical CT (preferred)
Positive Helical CT Negative Helical CT or V/Q – low, V/Q – normal
intermediate, high (if high 90%
+ for P.E.
P.E. confirmed
P.E. ruled out
Compression US
Negative Positive
Negative Positive
Negative Positive
Negative Positive
Hematology 104
Duration of Anti-thrombotic
Therapy
3-6 months First episode with reversible or
time-limited risk factors (patient may have
factor V Leiden or protime G 20210
mutation)
Hematology 108
SLIDE 12
All patients with hereditary hemochromatosis (HH) who have evidence of iron overload
should be strongly encouraged to undergo regular phlebotomies until iron stores are
depleted.
Name of AAFP-approved source of systematic evidence review: National Guideline
Clearinghouse
Specific web site of supporting evidence from the approved source identified immediately above
http://www.guideline.gov/summary/summary.aspx?doc_id=3448&nbr=002674&string
=Diagnosis+and+%22management+of+hemochromatosis.%22
Strength of evidence (description and/or grade as provided by the approved source): Grade II:
Evidence from at least one large well-designed clinical trial with or without
randomization, from cohort or case-control analytic studies, or well-designed meta-
analysis.
Evidence to Support Use:
A: Survival benefit
B: Improved diagnosis
C: Improvement in quality of life
D: Relevant pathophysiologic parameters improved
E: Impact cost of health care
Hematology 109
SLIDE 19
Parenteral chelation therapy with deferoxamine is currently the treatment of choice in
patients with chronic dyserythropoietic syndromes or chronic hemolytic anemia.
Monitoring the efficacy of therapy during chelation may require repeat liver biopsies to
confirm adequate reduction of hepatic iron concentration.
Name of AAFP-approved source of systematic evidence review: National Guideline
Clearinghouse
Specific web site of supporting evidence from the approved source identified immediately above
http://www.guideline.gov/summary/summary.aspx?doc_id=3448&nbr=002674&string=
Diagnosis+and+%22management+of+hemochromatosis.%22
Strength of evidence (description and/or grade as provided by the approved source Grade II:
Evidence from at least one large well-designed clinical trial with or without
randomization, from cohort or case-control analytic studies, or well-designed meta-
analysis.
Evidence to Support Use:
A: Survival benefit
B: Improved diagnosis
C: Improvement in quality of life
D: Relevant pathophysiologic parameters improved
E: Impact cost of health care
Hematology 110