Medicine 5th year, 9th lecture/part one (Dr. Sabir)
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Medicine 5th year, 9th lecture/part one (Dr. Sabir)

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The lecture has been given on Apr. 10th, 2011 by Dr. Sabir.

The lecture has been given on Apr. 10th, 2011 by Dr. Sabir.

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  • Figure 3. Pathological Features of Peripheral Blood and Bone Marrow in Patients with Myelofibrosis with Myeloid Metaplasia. Panel A shows myelophthisis of the blood. Immature granulocyte precursors, a nucleated red cell, and teardrop-shaped red cells are visible (Wright-Giemsa, x200). Biopsy specimens of the bone marrow core show stromal stranding and atypical megakaryocytes (Panel B; hematoxylin and eosin, x128), collagen fibrosis on silver-impregnation staining of reticulin (Panel C, x128), and thickening of the bone trabeculae (osteosclerosis) and intramedullary sinusoidal hematopoiesis (Panel D; hematoxylin and eosin, x128).

Medicine 5th year, 9th lecture/part one (Dr. Sabir) Medicine 5th year, 9th lecture/part one (Dr. Sabir) Presentation Transcript

  • Myeloproliferative Disorders
  • Overview
    • The Myeloproliferative disorders:
      • Polycythemia vera
      • Essential Thrombocytosis
      • Myelofibrosis
      • CML
  • Polycythemia
    • Erythrocytosis is an increase in the concentration of erythrocytes, whether measured as number of cells, hemoglobin, or packed cell volume (hematocrit)
    View slide
    • Erythrocytosis may be the result of
    • an increase in the red cell volume or mass (absolute erythrocytosis), or
    • may be the result of a reduced plasma volume (called relative or spurious polycythemia or Geisböck's syndrome )
    • Polycythemia accompanies increased total blood volume, whereas relative erythrocytosis does not
    View slide
    • Secondary polycythemias are caused by factors extrinsic to red cell precursors
    • Physiologically-appropriate (in response to tissue hypoxia )
    • Physiologically-inappropriate
  • Polycythemia
    • ERYTHROPOETIN (EPO)-mediated :
    • Hypoxia driven :
    • Central hypoxic process
    • Chronic lung disease
    • Rt-to-lt cardiopulmonary shunts
    • High-altitude habitat
    • Carbon monoxide poisoning
    • Smoker’s polycythemia (long-term CO exposure)
    • Hypoventilation syn including sleep apnea
    • Hemoglobinopathy(High–O² affinity variety)
    • Peripheral hypoxic process :
    • Localized:
    • Renal artery stenosis
    • Diffuse:
    • High oxygen-affinity hemoglobinopathy
    • Hypoxia independent (pathologic EPO production):
    • Malignant tumors :
    • Hepatocellular carcinoma
    • Renal cell cancer
    • Cerebellar hemangioblastoma
    • Parathyroid carcinoma
    • Nonmalignant conditions :
    • Uterine leiomyomas
    • Renal cysts (polycystic kidney disease)
    • hydronephrosis
    • Pheochromocytoma
    • Meningioma
  • Polycythemia vera
    • Definition: A neoplastic disorder arising from a pluripotent stem cell, generally characterized by erythrocytosis, with or without thrombocytosis and leukocytosis.
    • Incidence 10 new cases per million
    • Highest incidence in ages 50-75, but 5% occur in pts < 40 y.o.
  • P vera - natural history
    • Latent phase - asymptomatic
    • Proliferative phase - pts may be hypermetabolic or have sx of hyperviscosity or thrombosis
    • Spent phase - anemia, leukopenia, secondary myelofibrosis, increasing liver and spleen size
    • Secondary AML
      • 1-2% of pts treated with phlebotomy alone
      • Certain drug therapies increase risk
  • P vera - symptoms
    • Sx common to all erythrocytosis
      • Headache,  mental acuity, weakness
    • Sx more specific to P vera:
      • Pruritus after bathing
      • Erythromelalgia
      • Hypermetabolic symptoms
      • Thrombosis (arterial or venous)
      • Hemorrhage
  • Erythromelalgia
  • P vera – signs:
    • Facial plethora
    • Splenomegaly (70%)
    • Hepatomegaly (40%)
    • Distension of retinal veins
  • P vera - Lab Findings
    • CBC
      •  Hgb/Hct
      • î red cell mass
      •  WBC in 45%
      •  Plts in 65%
      • Basophilia (seen in all MPDs)
    •  Uric acid (can lead to gout) and îB12
    •  Leukocyte alkaline phosphatase score
    • Low Epo levels
    • Positive JAK2
  • Diagnosis
      • Major Criteria
        • Increased Red Cell Mass (>36ml/kg males, >32 ml/kg females)
        • Arterial oxygen saturation > 92%
        • Splenomegaly
      • Minor Criteria
        • Platelets > 400,000
        • WBC > 12,000
        • LAP score > 100
        • Serum B12 > 900 or serum unbound B12 binding capacity >2200
  • WHO criteria
    • A criteria
    • A1 - Elevated red blood cell mass (>25% more than the mean normal predicted value) or Hb >18.5 g/dL in M or >16.5 g/dL in F
    • A2 – No cause of secondary erythrocytosis
    • A3 - Splenomegaly
    • A4 - Clonal genetic abnormality other than Ph-chromosome or BCR/ABL fusion gene in marrow cells
  • WHO criteria
    • B criteria
    • B1 - PLT > 400000 and WBC >12000
    • B2 - BM biopsy showing panmyelosis with prominent erythroid and megakaryocytic proliferation
    • B3 - Low serum EPO levels
    • A diagnosis of PV is made when
    • A1 + A2 + any one A
    • A1 + A2 + any two B
  • P vera - Treatment
    • Phlebotomy
    • Myelosuppressive agents
      • Hydroxyurea
      • Alkylating agents such as busulfan
      • 32 P
    • Interferon alpha
  • P vera - phlebotomy
    • Generally, the best initial treatment:
      • No increase in progression to AML
      • Rapid effect
      • No BM suppression
    • Remove 500 cc blood 1x/wk to target Hct <45%, then maintain
    • Downsides:
      • Increased risk of thrombosis
      • No effect on progression to spent phase
      • May be insufficient to control disease
  • P vera - Myelosuppression
    • Hydroxyurea
      • can be used in conjunction with phlebotomy
      • May increase the risk of leukemic transformation from 1-2% to 4-5%
    • 32 P
      • increase the risk of leukemic transformation from 1-2% to 11%
      • May be appropriate for pts intolerant of medications or for elderly patients
      • Single injection may control hemoglobin and platelet count for a year or more.
  • P vera - interferon alpha
    • Benefits
      • No myelosuppression
      • No increase in progression to AML
      • No increase in thrombosis risk
      • OK in pregnancy
    • Drawbacks
      • Must be given by injection
      • Side effects may be intolerable in many pts, include flu-like symptoms, fatigue, fever, myalgias, malaise
  • Essential Thrombocythemia
    • Only 50% of these pts have a clonal disorder--the rest have polyclonal increase in megakaryocytes
    • Incidence is similar to P vera
    • 20% of pts are <40 y.o.
    • Exact pathophysiology is unclear
  • ET - Diagnosis
    • First, rule out secondary causes of thrombocytosis : cancer, infection, inflammation, bleeding, iron deficiency
    • Pts may have splenomegaly
    • Plts count should be >600000 on 2 separate occasions, at least 1 month apart
    • Exclude CML by absence of Philadelphia chromosome
    • Exclude P vera by normal Hb without iron deficiency.
  • ET - natural history
    • Rarely progresses to AML (<1% of pts)
    • May progress to myelofibrosis
    • Major complication is thrombosis
      • in 20-30% of pts
      • - may be arterial or venous
  • ET - Symptoms
    • Many patients are asymptomatic
    • Digital ischemia from microvascular thrombi
    • Erythromelalgia
    • Pruritus
    • Hemorrhage - in 40% of pts
  • ET - Labs
    • Iron studies should be normal, as should the ESR, which is a measure of inflammation.
    • If the plt count is very high, there may be pseudohyperkalemia and pseudohypoglycemia . This goes away if the blood is drawn into a heparinized tube.
    • Plts can be very large and bizarrely shaped
    • Marrow shows clusters of abnormal megakaryocytes.
    • 50-75% may have JAK2 mutation
  • ET - Abnormal Megakaryocytes Arrows indicate some of the abnormal mega-karyocytes
  • ET - Treatment
    • Treatment targeted at reducing the platelet count.
    • Treat those who have had or are at risk for thrombosis , those >65 y.o ., or pts with plts > 1-1.5 million
    • Why treat?
      • In pts at risk for thrombosis, Rx reduces risk of thrombosis and may reduce 2º myelofibrosis.
  • ET - therapeutic agents
    • Anagrelide
    • Hydroxyurea
    • Interferon alpha
  • ET - anagrelide
    • Interferes with megakaryocyte development without causing depression of other cell lines
    • Side effects include: hypotension, severe headache, fluid retention, palpitations/arrhythmias, severe headaches, CHF, bloating/diarrhea (in lactose intolerant patients)
  • Myelofibrosis
    • Clonal stem cell disorder affecting megakaryocytes predominantly
    • All myeloproliferative disorders can result in a spent phase which can be difficult to distinguish from primary MF
    • Myeloid metaplasia refers to earlier proliferative phase where extramedullary hematopoiesis predominates.
  • MF - Natural Hx and Sx
      • Median survival is 5 yrs
      • Transforms into AML in 5-20%
      • >50% pts present with sx of anemia and thrombocytopenia
      • Pts may have fever, sweats, wt loss
      • As spleen enlarges (from EMH), pts may have abdominal pain, early satiety.
  • MF - Physical Findings
    • Massive splenomegaly
    • Hepatomegaly
  • MF - Lab findings
    • Early on, pts may have  Plts and normal Hb and WBC.
    • Anemia, and  Plts and  WBC seen as disease progresses
    • Peripheral smear shows leukoerythroblastic picture, with teardrops, NRBC and early granulocytes
    • “ Dry tap” or inability to aspirate liquid marrow frequently seen
    • Increased collagen and reticulin fibrosis on BM biopsy
    • 40-75% may have JAK2 mutation
  • Tefferi A. N Engl J Med 2000;342:1255-1265 Pathological Features of Peripheral Blood and Bone Marrow in Patients with Myelofibrosis with Myeloid Metaplasia
  • MF - Treatment
    • There is no definitive therapy
    • If patient is young, BM transplant can be done, but older patients have too high mortality
    • Rx is supportive, with transfusions
    • Splenectomy can be done for sx of abdominal pain, but frequent complications of thrombosis, hemorrhage, and infection.