Hematology Board Review

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HematologyBoard Review

• Jeremiah Boles
• 6-4-08

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Agenda

• ITP diagnosis and management
• Recognize Auer rods on peripheral smear
• Brief overview of CML specifically how to
  diagnose
• CLL how to confirm
• Hyperhomocysteinemia and thrombosis
• Anemia
• Specifically Iron deficiency and how to
  diagnose/manage

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ITP

• Immune mediated disorder of platelet destruction
• Antibodies against glycoprotein IIb-IIIa, plt
  fibrinogen receptor and glycoprotein Ib.
• Blood smear decreased numbers of platelets with
  normal erythrocyte and leukocyte morphology
• In adults, classically disorder of young women

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ITP

• Idiopathic thrombocytopenic purpura also known as
  immune thrombocytopenic purpura and ITP
• Goal of treatment is to provide a safe platelet
  count to prevent major bleeding rather than
  correcting the underlying disease.
• Major bleeding is rare in pts with gt10,000

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ITP

• Autoimmune TCP not always idiopathic
• 30 drugs, 30 underlying disease,30
  idiopathic, 10 viral
• Underlying diseases Connective tissue d/o
  (SLE), lymphoproliferative d/o, hep C, HIV
• TCP in such situations is referred to as
  secondary ITP

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ITP Dx

• Careful peripheral smear examination to exclude
  morphologic abnormalities that would suggest
  alternative dx
• Examination of BM is not necessary, but is
  recommended if patient agegt60
• ?association with H.pylori controversial

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ITP

• General Treatment Goals - treat moderate to
  severe thrombocytopenia who are bleeding or at
  risk
• - limit duration of treatment unless symptoms
  persist
• - mild, asymptomatic thrombocytopenia should
  not be treated.

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ITP Treatment

• Individualized American Society of Hematology
• Rx when platelet count lt30
• Initial therapy prednisone 1 mg/kg/day, though
  some studies suggest treating initial
  presentations with high dose dexamethasone
  (40mg/kg/day for 4 days)
• Most respond to steroids

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ITP Treatment continued

• Those who dont respond or who require chronic
  high dose steroids, consider 2nd line therapy
• Splenectomy is classically second line
  initially effective in 85, 66 in remission at 5
  years
• Remember, all splenectomy patients need
  vaccinations against encapsulated (H. influenzae
  and N. meningitidis 2 weeks prior to sx)
• Splenectomy should be deferred for 4-6 weeks
  after diagnosis
• Younger patients in general respond better to
  splenectomy

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ITP Treatment continued

• Splenectomy sparing therapies
• Anti-D immunoglubin (WinRho) if Rh
• IVIG
• Rituxan (chimeric anti-CD20 monoclonal Ab)
• Others danazol, cyclophosphamide, azathioprine,
  vincristine

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ITP Transfusions

• Platelet transfusions are typically reserved for
  serious/severe bleeding.
• Generally will see rise in platelet count for up
  to 24 hours, but even if dont see bump in
  platelets, transfusions are often hemostatically
  effective

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Auer Rods

• These cytoplasmic inclusions were named by John
  Auer, an American physiologist (1875-1948)
• They are clumps of azurophilic granular material
  that form elongated needles seen in the
  cytoplasm of leukemic blasts. They are composed
  of fused lysosomes and contain peroxidase,
  lysosomal enzymes, and large crystalline
  inclusions
• Can be seen in the leukemic blasts of AML
• Classically M1,M2,M3,M4

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CML

• Most common adult leukemia in Western world
• Slight Male prodominance
• Median age at presentation 50
• Prototypic myelproliferative syndrome (remember
  others? ET, PCV, MF)
• Philadelphia Chromosome
• Balanced translocation t(922) that creates
  BCR-ABL
• BCR-ABL encodes protein that acts of tyrosine
  kinase
• This translocation is diagnostic of CML

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CML

• In patient with CML all cells of the
  hematopoetic lineage contain t(922) gt clonality
• Uncontrolled production of maturing granulocytes,
  predominantly neutrophils but also eosinophils
  and basophils
• 3 phases of CML- chronic phase, accelerated
  phase, and blast crisis.
• 85 of pts present in the chronic phase

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CML- Chronic Phase

• Chronic Phase years phase with proliferative
  advantage of this clone gain additional
  mutations
• large increase in the pool of committed myeloid
  progenitors leading to peripheral blood
  leukocytosis and often thrombocytosis
• Left shift
• Basophillia
• Splenomegaly, occasional hepatomegaly or
  adenopathy (myelofibrosis and extramedullary
  hematopoiesis)

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CML Chronic Phase

• Often asymptomatic
• Symptoms include fatigue, malaise, weight loss,
  excessive sweating, abdominal fullness, early
  satiety, sternal tenderness, gout, and bleeding
  episodes due to platelet dysfunction.

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CML Accelerated Phase

• Neutrophil differentiation becomes progressively
  impaired and leukocyte counts are more difficult
  to control with myelosuppressive meds

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CML Blast Phase

• Blast Phase mutations lead to loss of
  differentiation and progression into acute
  leukemia (may resemble ALL or AML)

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CML Diagnosis

• Typically patient is noted to have leukocytosis
  on routine CBC
• May have fatigue, weight loss, splenomegaly,
  thromocytosis
• Diagnosis confirmed by demonstrating t(922) by
  FISH or PCR of blood or bone marrow aspirate

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CML - Treatment

• Imatinib meylate (Gleevec) STI 571
• Inhibits the tyrosine kinase BCR-ABL
• Suppresses or eliminates CML clone
• Initial numbers Gleevec vs previous standard
  therapy 95 vs 56 hematologic remession, 85 vs 22
  complete cytogenetic remission
• Longer f/u with determine durability of response
• Allogenic stem cell transplant best results in
  early, chronic phase
• Blast phase chemo to induce remission, if
  return to chronic phase - xplant

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CML - Recap

• Myeloproliferative disorder
• Philadelphia Chromosome t(922)
• BCR-ABL Tyrosine Kinase
• Chronic Phase years gain mutations
• Blast Phase loss of differentiation resembers
  acute leukemia
• Gleevec Imatinib tyrosine kinase inhibitor

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CLL Chronic Lymphocytic Leukemia

• CLL and its lymphomatous cousin, small
  lymphocytic leukemia (SLL), are characterized by
  an abnormal accumulation of morphologically
  mature (chronic) appearing lymphocytes
• Characteristic phenotype CD19,CD20, CD23 B
  cells and also CD5 (Tcell assoc antigen)
• In blood (gt5000/mm3), bone marrow, or lymph nodes
• Smudge cells on peripheral smear - reflect
  fragility of cells

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CLL - diagnosis

• Characteristic phenotype CD5,CD19,CD20,CD23 B
  cells by flow cytometry
• Flow often obviates need for BMBx
• Patients often noted to have lymphocytosis (gt5000
  lymphs) on routine CBC

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CLL - diagnosis

• 1 point for each of below, 4-5 points 97
  accurate
• Weakly positive surface immunoglobulin stain
• CD5
• CD23
• CD79b or CD22 weakly
• FMC7 negative

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CLL minimum diagnostic criteria

• ALC in the peripheral blood gt10,000 with a
  preponderant population of morphologically mature
  appearing small lymphocytes
• Normo to hypercellular bone marrow with
  lymphocytes accounting for gt30 of all nucleated
  cells
• low levels of surface membrane immunoglobulin,
  expression of 1 or more B cell antigens, and
  expression of CD5

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CLL - Mortality

• Major complications of CLL arise from cytopenias
  and immune dysfunction, anemia, and
  thrombocytopenia
• Infections lead to 50 of deaths from CLL
• Depressed immune function from hypogammaglobulinem
  ia can be improved with IVIG for patients with
  pattern of repeated infections, especially
  pneumonia and sepsis.

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CLL Prognosis/Treatment

• Important prognostic factors
• Cytogenetics
• Immunoglobulin mutational status CLL with
  somatic mutations of immunoglobulin heavy chain
  have particularly indolent course (median
  survival 25 years vs 8 without)
• Treatment options mirror those for Follicular
  lymphoma indolent very successful in inducing
  remission, but not cure

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Hyperhymocysteinemia

• Hyperhymocysteinemia is associated with increased
  risk of venous as well as arterial thrombosis
• Plasma homocysteine levels are determined by
  genetic and environmental factors
• Dietary intake of folic acid, b12, b6
• Supplementation of these vitamins can lower
  plasma homocysteine levels, but it hasnt been
  shown if this reduces risk of recurrent vascular
  events

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Anemia

• Deficiency in oxygen carrying capacity of blood
  (decreased erythrocyte mass)
• General Categories
• Production Defects
• Maturation Defects
• Survival Defects
• Sequestration
• Blood Loss

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Anemia Production Defects

• Anemia of Chronic Disease
• Most common cause of anemia in hospitalized
  patient
• Impaired iron utilization despite normal or
  increased iron stores
• Epo levels are usu lower than expected for degree
  of anemia
• Chronic rheumatic, infectious, neoplastic d/o
  usually at play

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Anemia Production Defects

• Anemia of Renal Disease
• Normochromic and normocytic with low retic count
• For epo to be effective need normal iron stores
  - (ferritin gt100 and sat gt20)
• Anemia of Hypometabolic States
• Hypothyroid, Addison (deficient glucocorticoid),
  hypogonadism, panhypopit (low growth hormone)
• Anemia from bone marrow damage
• Aplastic anemia, marrow infiltrative disorders

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Anemia Maturation Defects

• Can further divide into Cytoplasmic and Nuclear
• Cytoplasmic
• Impaired hgb synthesis iron deficiency
• Protoporphyin deficiency sideroblastic anemia
• Globin synthesis deficiency - thalassemias
• Nuclear
• DNA synthesis defects folate,b12

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Iron Deficiency Anemia

• Very low ferritin(lt10ng/ml) diagnostic of iron
  deficiency
• Ferritin - acute phase reactant - thus it may be
  falsely normal or elevated
• Serum ferritingt100ng/ml is rare in iron deficient
  patients
• Serum iron (lt35), TIBC (gt300), and TS (lt10) are
  helpful when ferritin10-100ng/ml and iron
  deficiency is still suspected
• Bone marrow iron stores is the gold standard
• Iron Deficiency is a symptom once diagnosed
  find the cause
• Most common cause of thrombocytosis in adults

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Iron Deficiency vs AOCD
Fe Deficiency AOCD
MCV lt85 72-100
MCHC lt32 lt36
FE Low (lt60) Low (lt60)
TIBC High (gt400) Low (lt250)
TIBC sat Low lt15 (usu lt10) Low to normal (2-20)
Ferritin Low (lt15) Normal to High (gt35)
Soluble Transferrin Receptor High Normal
Stainable Marrow Iron Absent Present
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Iron Deficiency Anemia

• Increased iron requirements
• Blood loss menstruation, GI bleeding, chronic
  blood donation
• Intravascular hemolysis (PNH, hemolysis secondary
  to prosthetic valve)
• Pregnancy, lactation
• Inadequate iron supply
• Poor nutrition
• Malabsorption gastric bypass surgery,
  achlorhydria, celiac disease

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Iron Deficiency Anemia - Treatment

• Replacement doses Recommended - 200mg of
  elemental iron per day
• Ferrous sulfate 66mg of elemental iron per 325mg
  tablet
• Niferex (iron polysaccharide) contains 150mg of
  elemental iron
• Better absorption in a more acidic environment
  empty stomach, absence of antiacid (ppi etc),
  vitamin C, OJ - but usually not significant
  enough to justify

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Iron Deficiency Anemia - Treatment

• Reticulocytosis in 4-7 days
• Increased hemoglobin in first several weeks (4-6
  classically)
• Anemia usually resolves in 4-6 months (depending
  on etiology of iron deficiency)
• Continue oral replacement for several months
  after anemia has resolved to replete iron stores

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Iron Deficiency Anemia - Treatment

• Reasons for failure of oral iron
• Non-compliance
• Incorrect diagnosis
• Malabsorption celiac disease, chronic
  giardiasis, small bowel infiltrative process, h/o
  small bowel or gastric resection.

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Iron Deficiency Anemia Treatment Failures

• What to do if No Response and have iron
  deficiency confirmed as diagnosis
• Attempt to Improve compliance decrease number of
  pills, treat constipation, take with food
• Oral iron challenge to determine if absorbing
  iron
• Parenteral iron
• Iron dextran can give total dose replacement in
  single dose, rate of anaphylaxis 0.6
• Ferrlecit (Sodium Ferric Gluconate) Usually do
  not give as a single dose as total replacement
  can cause hypotension from excess of free iron

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Anemia Survival Defects

• Further Divided into
• Intrinsic (inheritied defects)
• Membrane cytoskeleton - spherocytosis,
  elliptocytosis
• Metabolic enzymes G6PD
• Hemoglobinopathies Sickle Cell
• Extrinsic (acquired)
• Antibody or complement mediated Autoimmune
  hemolysis, malaria
• Microangiopathy DIC, vascular hemolysis

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Anemia - Sequestration

• Sequestration hypersplenism usually from portal
  hypertension or splenic sequestration crises

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Anemia Blood Loss

• Self explanatory when loss exceeds marrow
  production may result in a maturation defect
  (iron, b12, folate)

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Microcytic Anemias

• Iron deficiency
• Beta thal
• Trait hgb usually 9-11
• Hemoglobin electrophoresis persistent elevation
  of hgbF, variable levels of hgbA2, and absent
  HgbA.
• Alpha thal
• One gene absent RBC normal
• Two genes absent mild anemia with
  hypochromic/microcytic red cells
• Electorphores is normal. Globin chain analysis
• Sideroblastic anemia rare, hereditary disorder,
  X-linked mutation in ALA synthase.
• Lead poisoning

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Macrocytic Anemias

• Vitamin deficiency B12 and folate
• Medications hydroxyurea, methotrexate, 6MP, AZT,
  phenytoin
• Alcoholism direct toxic effect or via folate
  deficiency
• Liver disease
• Myelodysplastic syndrome
• Hypothyroidism
• Reticulocytosis

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Peripheral Smear
Finding Meaning
Shistocytes/RBC fragments Microangiopathic hemolytic Anemia (MAHA) TTP, HUS, HELLP, DIC Burns Valve hemolysis
Spherocytes Autoimmune hemolytic anemia Hereditary spherocytosis
Target Cells Liver disease, also in thalassemia and other hemoglobinopathies
Teardrop Cells Myelofibrosis and other infiltrative bone marrow processes Sometimes seen in thalassesemia
Burr Cells (echinocytes) Uremic patients
Spur Cells (acanthocytes) Liver disease
Howell-Jolly bodies Splenectomy or functionally asplenic patients result of fragmentationof nucleas occurs normally and usually removed by spleen
Hypersegmented PMNS Megaloblastic anemia (PA, b12, folate)
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