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Hematology

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

Consider Lead Poisoning


Hematology 6
Iron Deficiency Anemia
„ Most common causes: menstrual or GI
blood loss (PUD, cancer, diverticulosis,
IBD, angiodysplasia)
„ Other causes: pregnancy and infancy
secondary to increased iron needs
„ 50% with pica – unusual compulsive
craving for chewy or crunchy items –
ice, clay, etc. (phagophagia)

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

„ Response usually 1-2 weeks and unlikely after 3

weeks
„ Slow taper to <10 mg daily

„ Splenectomy for prednisone failures or unable to


wean (50% success)
„ Transfusions – temporizing measure
Hematology 19
„ Chelation therapy may be needed for iron overload
Cold Autoimmune
Hemolytic Anemia
„ Primary or secondary (mycoplasma,
mononucleosis, lymphoproliferative)
„ IgM antibodies
„ Prednisone and splenectomy – not helpful
(destroyed in liver not spleen)
„ Preventive measures – avoid cold
„ Treatment – plasmapheresis
„ Indications
„ Severe hemolysis
„ Preoperative for surgery
„ Duration of effect 5 days
Hematology 20
Sickle Cell Anemia
„ Inherited blood disorder – African Americans most
commonly affected
„ Dx – prenatally by fetal DNA on chorionic villus
sampling at 8-10 wks, newborn screening and
hemoglobin electrophoresis
„ Clinical hallmarks
„ Vaso-occlusive phenomena – sickled RBC block small blood
vessels and cause periodic episodes of pain and ultimately
extensive organ damage. Treat pain.
„ Hemolysis - sickled RBC have life span of 10-20 days
(normal 120 days)

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.

„ Management of chest syndrome


„ As above
„ Correct hypoxia
„ Antibiotic treatment
„ Blood transfusion
„ Episodic – progressive chest syndrome, splenic or hepatic sequestration,
prophylactic preoperative, acute stroke
„ Chronic – primary or secondary stroke prevention

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

„ Bleeding most common in joints (elbows, knees,


ankles), muscles and GI tract
„ Mild
„ > 5% normal factor = bleeding with significant
trauma
„ Moderate
„ 1-5% normal factor = bleeding with moderate
trauma
„ Severe
Hematology 40 „ <1% normal factor = spontaneous bleeding
Hemophilia A and B (Cont’d)
„ Labs
„ PTT, factor VIII and IX levels
„ Treatment goals
„ Prevent long-term disability from hemarthroses
„ Treatment
„ DDAVP releases factor VIII from tissue stores
„ Specific factor replacement based on severity of
bleeding

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)

„ 80% of all leukemias of childhood


„ Peak incidence 3 - 7 years old
„ Treatment
„ Excellent response to chemotherapy

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
ƒ Tender ƒ > 2 cm size
ƒ Cervical, axillary, ƒ Supraclavicular
ƒ inguinal ƒ > 40 yrs – hard, matted, fixed
ƒ < 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

Apply Wells Criteria

Low Risk: <2 High Risk: >2

D-Dimer D-Dimer and Compression Ultrasound

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

Clinical Probability of P.E. Score


Low <10% <2
Intermediate – 30% 2-6
Hematology 96 High >70% >6
Specific Testing for P.E.
„ Ventilation-Perfusion Testing
„ Normal scan essentially rules out P.E. but
it is an uncommon test result
„ High-probability scan can be considered
definite only on high-probability patients
„ Most scans are non-diagnostic,
intermediate probability
„ Not test of choice with lung diseases

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

„ 70-85% for sublobar or lower

„ Accounts for 10-30% of all P.E.


„ Therefore, filling detects can be considered diagnostic
and normal CT scan lowers the likelihood but doesn’t
rule it out
„ A negative CT scan and negative compression
ultrasound of the leg rules out P.E. except in the
patient with high clinical probability of P.E.
Hematology 98
Specific Testing for P.E.
(Cont’d)
„ Conventional Pulmonary Angiography
„ 0.5% die and 1-5% have major nonfatal
complications (respiratory failure, renal failure,
blood transfusion)
„ Reserved for subgroup of patients in whom
diagnosis cannot be established by noninvasive
routes
„ Magnetic Resonance Angiography
„ Sensitivity similar to CT
„ Currently more technical issues and costs limit
Hematology 99 its use
Specific Testing for P.E.
(Cont’d)
„ D-Dimer
„ The role is limited to ruling out embolism if test is
negative
„ Evaluation of the leg veins
„ Most P.E. arises from the leg veins
„ Abnormal in only 50% of patients with proven
P.E., but 90% of P.E. thought caused by lower
extremity DVT

Hematology 100
Low Clinical Probability of P.E. (<10%)
D-Dimer

Negative P.E. ruled out Positive


V/Q or Helical CT

Positive V/Q high Negative Helical CT V/Q - normal


Helical CT probability or V/Q – low,
intermediate
P.E. ruled out
P.E. Confirmed Compression US Compression US

Negative Positive Negative

Pulmonary P.E. confirmed P.E. ruled out


Angiography

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

Pulmonary P.E. confirmed


Angiography

Negative Positive

Hematology 102 P.E. ruled out P.E. confirmed


High Clinical Probability of P.E. (>70%)
V/Q or Helical CT (preferred)
Positive Helical or Negative Helical CT or V/Q – low, Negative V/Q scan
V/Q – high intermediate
probability
P.E. ruled out

P.E. confirmed Compression US

Negative Positive

Pulmonary P.E. confirmed


Angiography

Negative Positive

Hematology 103 P.E. ruled out P.E. confirmed


Treatment – Venous
Thromboembolic Disease
„ Long-term anticoagulation goal
„ Goal INR 2-3
„ Ideal INR 2.5
„ Risk factors for bleeding: age >65, CVA, GI bleed,
MI, anemia, CRF, DM
„ Low-Molecular-Weight-Heparins (LMWH) or
Heparin for 5 days
„ Start Warfarin on day 1 and overlap with
LMWH/Heparin for 2 days with therapeutic INR

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)

>6 months Idiopathic, first event

12 months to First event with life threatening lifetime


„ Life threatening episode
„ Cancer, until resolved
„ Anticardiolipin antibody
„ AT III deficiency
„ Multiple thrombotic abnormalities
Recurrent event, idiopathic or with
thrombophilia
Hematology 105
Treatment – Venous
Thromboembolic Disease (Cont’d)
„ Thrombolytic agent use must be
individualized. Best candidates are with
hemodynamically unstable PE or massive
iliofemoral thrombosis
„ IVC – Inferior Vena Cava Interruption
recommended when anticoagulation
contraindicated or recurrent
thromboembolism despite adequate
anticoagulation, chronic recurrent with
pulmonary HT, situations with high risk of
recurrent events, and when performing
Hematology 106 pulmonary embolectomy
Treatment of Massive
Pulmonary Embolus
„ PE accompanied by
„ Hypotension, shock, severe hypoxemic
respiratory failure, acute right HF or
obstruction >50% pulmonary vasculature
„ Treatments
„ Oxygenation / ventilatory support, close
fluid management, consider
norepinephrine, thrombolytics followed by
heparin especially in cases of
hypotension, surgical and catheter
embolectomy, consider IVC filter to
Hematology 107 prevent another event
References
Evidence Based Medicine
Practice Points

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