Heme Flashcards
What mutations (in general terms) lead to myelodysplastic vs proliferative disorders?
Primary defects of maturation give rise to the myelodysplastic disorders, whereas loss of normal control of proliferation results in myeloproliferative disease. All of these disorders are preleukemic, with a variable but definite rate of transformation to acute leukemia.
What characterizes a myeloproliferative disorder?
Myeloproliferative neoplasms (MPNs), also known as chronic myeloproliferative diseases (MPDs), are clonal stem cell disorders characterized by leukocytosis, thrombocytosis, erythrocytosis, splenomegaly, and bone marrow hypercellularity. The hallmark of MPN is the failure of a transformed multipotent stem cell to respond to normal feedback mechanisms regulating hematopoietic cell mass.
Classification of myeloproliferative diseases?
- Acute myeloid leukemia
- Myelodysplastic syndrome (MDS)
- Myeloproliferative neoplasms (MPNs)
a. Chronic myelogenous leukemia
b. Polycythemia vera
c. Essential thrombocythemia
d. Primary myelofibrosis
e. Chronic neutrophilic leukemia
f. Chronic eosinophilic leukemia, not otherwise categorized
g. Hypereosinophilic syndrome
h. Mast cell disease
i. MPNs, unclassifiable - MDS, MPD
- Myeloid neoplasms associated with eosinophilia and abnormalities of PDGF-RA, PDGF-RB, or FGF-R1
Diagnostic Criteria for Polycythemia Vera
Major Criteria
1. Hemoglobin (Hgb) >18.5 g/dL (men), >16.5 (women); or Hgb or hematocrit (Hct) >99% reference range for age, sex, or altitude of residence; or Hgb >17 g/dL (men), >15 g/dL (women) if associated with a sustained increase of ≥ 2g/dL from baseline that cannot be attributed to correction of iron deficiency; or elevated red cell mass (>25% above mean normal predicted value) 2. Presence of JAK2 V617F or similar mutation
Minor Criteria
1. Bone marrow trilineage myeloproliferation 2. Subnormal serum erythropoietin level 3. Endogenous erythroid colony formation in vitro
Either both major criteria and one minor criterion or the first major criterion and two minor criteria must be met for diagnosis of polycythemia vera.
Clinical features of polycythemia vera?
PV occurs in 1 to 3 of 100,000 people, with a median age at onset of 65 years. Early recognition and treatment of PV are important because untreated patients with PV suffer significant morbidity and mortality from thromboembolic disease in the cerebral, coronary, and mesenteric circulations. Twenty percent of patients show symptoms of arterial and venous thrombosis, and thrombosis remains the most common cause of death. Typically, patients complain of headache, visual problems, mental clouding, and pruritus after bathing. Occlusive vascular events such as stroke, transient ischemic attacks, myocardial ischemia, and digital pain, paresthesias, or gangrene are common. In addition, pulmonary, deep vein, hepatic, and portal vein thromboses may occur. Paradoxically, patients are also predisposed to hemorrhagic events, which are presumably caused by abnormal platelet function, and such patients may exhibit gastrointestinal bleeding. Physical examination often shows retinal vein occlusion, ruddy cyanosis, and splenomegaly.
Treatment of polycythemia vera?
Without treatment, one half of all patients with PV die of thrombotic complications within 18 months of diagnosis. With therapy, PV is a chronic, progressive disease. The risk for transformation to myelofibrosis and myeloid leukemia is 5% to 20% over 20 years. Patients with advanced age, prior history of thrombosis, and high hematocrit values are at high risk for subsequent vascular events. Therefore, intermittent phlebotomy is the mainstay of treatment and usually results in iron deficiency anemia, which further reduces the rate of red blood cell production. Cytoreductive therapy is indicated for patients with intolerant or failing phlebotomy, with a prior history of or risk factors for thrombosis, or with symptomatic splenomegaly.
Current therapies include hydroxyurea (a low-dose cytotoxic agent that does not appear to increase leukemic risk), interferon-α (used in young patients and women during pregnancy), and anagrelide (a megakaryotoxic agent used for treating refractory thrombocytosis). Goals of therapy are hematocrit values less than 45% in men and less than 42% in women. As with all myeloproliferative disorders, initiation of cytoreductive therapy may precipitate hyperuricemia (resulting in secondary gout and uric acid stones), warranting treatment with allopurinol. Low-dose aspirin and treatment of asymptomatic thrombocytosis has been demonstrated to decrease thromboembolic events in patients with PV and is especially important in older patients with significant cardiac risk factors. In younger patients, nonsteroidal anti-inflammatory drugs and antiplatelet agents should be used judiciously because of the risk for gastrointestinal hemorrhage. With effective therapy, the long-term survival of these patients is excellent.
Criteria to diagonose Essential thrombocytosis
Major Criteria
1. Platelet count ≥ 450 × 10 9/L 2. Megakaryocyte proliferation with large and mature morphology. No or little granulocytic or erythroid proliferation 3. Not meeting WHO criteria for CML, PV, PMF, MDS or other myeloid neoplasm 4. Demonstration of JAK2 V617F or other clonal marker or no evidence of reactive thrombocytosis
Diagnosis of essential thrombocytopenia requires meeting all four major criteria.
Clinical features of essential thrombocytosis
ET is an uncommon disorder with an increasing number of cases found in patients who are asymptomatic on routine laboratory testing. Although the median age at onset is 60 to 65 years, 10% to 25% of patients are younger than 40 years of age. Up to two thirds of patients are symptomatic. Vasomotor symptoms include headache, dizziness, visual changes, and erythromelalgia (burning pain and erythema of feet and hands). Serious arterial thrombotic complications such as transient ischemic attacks, strokes, seizures, angina, and myocardial infarcts may occur. Patients may rarely have purpuric skin lesions or hematomas. The risk for gastrointestinal bleeding is less than 5%.
Treatment of essential thrombocytosis
In general, patients with this disorder have long-term survival rates similar to those of age-matched control patients. The risk for leukemic transformation is extremely low (3% to 4%) in comparison with other MPNs. However, morbidity from recurrent hemorrhagic and thrombotic complications is high and cannot be reliably predicted from the platelet count or platelet function abnormalities. Because treatment requires lifelong administration for disease control, assessment of risk factors and prior history of clinical signs and symptoms dictate therapeutic choices. All patients benefit from aggressive management of cardiovascular risk factors (such as smoking, hypertension, obesity, and hypercholesterolemia). Low-dose enteric aspirin may be used in all patients to relieve neurologic symptoms and carries a minimal risk for bleeding. Although young and pregnant patients are often not treated until they become symptomatic, older patients (>60 years) and those with a prior history of thrombosis or long disease duration may benefit from the addition of platelet-lowering agents. Hydroxyurea, a nonspecific myelosuppressive agent, is the most common first-line agent and is generally well tolerated with low long-term leukemogenic risks. Anagrelide (an oral antiplatelet agent that inhibits platelet aggregation and megakaryocyte maturation) is also used, primarily as a second-line agent after hydroxyurea failure resulting from associated acute side effects (fluid retention, palpitations), hemorrhage (with concomitant aspirin use), and risk for myelofibrosis transformation. Both of these agents are known teratogens and therefore cannot be used in the significant fraction of patients with ET who are young women of childbearing age. Because patients with ET have a high incidence of fetal wastage, interferon-α (a cytokine that alters the biologic mechanisms of the malignant clone but does not cross the placenta), in addition to heparin or aspirin, has been recommended to improve pregnancy outcomes in these patients.
