Chapter 44: Primary and Familial Thrombocythemia

• The upper limit of a normal platelet count is usually between 350 × 10⁹/L and 450 × 10⁹/L depending on the clinical laboratory and specific method used.

• Table 44–1 presents the major causes of elevation of the platelet count above the normal limit.

Pathophysiology

• Essential thrombocythemia is a clonal disorder of multipotential hematopoietic progenitor cell and is a chronic myeloproliferative disorder related to polycythemia vera and primary myelofibrosis.

• Approximately 50 percent of patients express a mutant form of the Janus (JAK)2 signaling kinase (JAK2 V617F) found in several myeloproliferative disorders (polycythemia vera, primary myelofibrosis, rare cases of myelodysplastic syndromes). The mutant allele is almost invariantly found in one copy per cell in patients with essential thrombocythemia, and leads in vitro and in vivo to hematopoietic growth factor hypersensitivity, a hallmark of the disease.

• A smaller fraction of patients display other mutations of JAK2, or of the thrombopoietin receptor, c-Mpl. Nearly one-half of patients fail to express one of these mutations, and usually display lower hemoglobin concentrations than patients with JAK2 V617F.

Clinical Features

• The criteria used for the diagnosis of essential thrombocythemia are shown in Table 44–2.

• Usually develops between ages 50 and 70. Sex distribution is slightly skewed toward women, especially in younger patients.

• Because platelet counts are now often done routinely, the disorder is being discovered in younger individuals and in patients who are asymptomatic.

• Rare familial cases have been reported.

• Constitutional or hypermetabolic symptoms are very uncommon.

• Mild splenomegaly is found in 40 to 50 percent of patients.

• Patients may have ecchymoses and bruising due to functional platelet deficiencies, or due to acquired von Willebrand disease if platelet counts are very high.

• Bleeding and thrombotic complications are major causes of morbidity and mortality. Table 44–3 summarizes the risks of thrombosis or bleeding.

• Bleeding is common and is characteristic of platelet or vascular disorders: mucosal, gastrointestinal, cutaneous, genitourinary, and postoperative.

• Use of aspirin may occasionally lead to serious bleeding complications, especially when platelet counts are above 1500 × 10⁹/L due to acquired von Willebrand disease.

• Thrombosis, more often arterial than venous, is most common in cerebral, peripheral, and coronary arteries.

• Twenty-five percent of all thrombotic events are lower-extremity deep venous thrombosis.

• Thrombosis in the myeloproliferative disorders often occur in unusual locations, such as hepatic artery (Budd-Chiari), sagittal venous sinus, upper extremity.

Erythromelalgia and Digital Microvascular Ischemia

• Caused by vascular occlusion with platelet thrombi.

• Patients have intense burning or throbbing pain, especially in feet.

• Symptoms are exacerbated by heat, exercise, and dependency, and relieved by cold and elevation of the lower extremity.

• Painful vascular insufficiency may lead to gangrene and necrosis with normal peripheral pulses and patent major vessels on angiography.

• These problems often respond dramatically and promptly to small doses of aspirin and/or reduction of platelet count.

Cerebrovascular Ischemia

• Symptoms may be nonspecific (headache, dizziness, decreased mental acuity), and signs may be focal (transient ischemic attacks, seizures, or retinal artery occlusion).

Recurrent Abortions and Fetal Growth Retardation

• Multiple placental infarctions may lead to placental insufficiency with recurrent spontaneous abortions, fetal growth retardation, premature deliveries, and abruptio placentae.

• May require use of aspirin during pregnancy, but avoid at least 1 week prior to delivery to reduce risk of maternal or neonatal bleeding complications.

Hepatic and Portal Vein Thrombosis

• Usually occur with polycythemia vera but may occur with essential thrombocythemia.

Blood and Marrow Findings

• Platelet counts may range from only slightly above normal to several million platelets per microliter.

• Platelets may be large, pale blue–staining, and hypogranular. Nucleated megakaryocyte fragments having a lymphoblastoid appearance may be seen occasionally in the blood film.

• Some patients may have mild leukocytosis with hemoglobin concentration ranging from normal to mild anemia.

• The leukocyte differential count is usually normal, without nucleated red cells.

• Pseudohypokalemia may occur with extreme thrombocytosis or leukocytosis.

• Marrow shows increased cellularity with megakaryocytic hyperplasia and masses of platelet debris ("platelet drifts"). Megakaryocytes are frequently giant, with increased ploidy, and occur in clusters. Significant megakaryocytic dysplasia is uncommon.

• Some patients who have otherwise typical essential thrombocythemia will have the Philadelphia chromosome or the BCR/ABL gene rearrangement.

Clinical Tests of Hemostasis

• Abnormal tests serve as a marker for the disease but do not predict bleeding and/or thrombosis and, thus, are rarely of clinical utility.

• The bleeding (closure) time is prolonged in less than 20 percent of patients.

• Platelet aggregation abnormalities are variable:

  — Total loss of responsiveness to epinephrine is characteristic.

  — Reduced responses to collagen, ADP, and arachidonic acid occur in less than one-third of patients.

  — Patient platelets may display hyperaggregability or spontaneous aggregation in vitro.

Differential Diagnosis

• The diagnosis is made by genetic testing for JAK2 V617F, another JAK2 or c-Mpl mutation, or in their absence by exclusion because there is no specific marker for the disease. The following should be demonstrated:

  — The platelet count is usually greater than 600 × 10⁹/L, on at least two occasions separated by 3 months, but some patients have platelet counts in the normal range or only slightly elevated.

  — The patient is not iron deficient or afflicted by an inflammatory condition.

  — There is no other recognizable cause for secondary thrombocytosis.

  — The Philadelphia chromosome is absent.

  — There is no evidence for myelofibrosis.

Therapy

Asymptomatic Patients

• The need to treat asymptomatic patients is controversial.

Symptomatic Patients

• Lowering the platelet count in patients with active bleeding and/or thrombosis is beneficial.

• Prompt reduction is especially warranted in patients with microvascular digital or cerebrovascular ischemia.

Treatment Options

• Urgent platelet count reduction can be achieved by plateletpheresis, but the benefit is short-lived, often with a rebound increase in platelet count.

• Hydroxyurea is highly effective as initial therapy. The usual starting dose is 10 to 30 mg/kg per day orally. Blood counts should be checked within 7 days of initiating therapy and frequently thereafter, seeking a maintenance dose that will maintain the platelet count at less than 400 × 10⁹/L. The major side effects of hydroxyurea are gastrointestinal upset and reversible painful leg ulcers, occurring in approximately 30 percent of patients.

• Aspirin should be added in nearly all patients requiring treatment, unless contraindicated by bleeding, allergic complications, or extremely high platelet counts.

• A large randomized study of hydroxyurea plus aspirin vs. anagrelide plus aspirin demonstrated the superiority of the hydroxyurea plus aspirin arm in reducing complications.

• Anagrelide inhibits marrow megakaryocyte maturation and is effective alternative second-line therapy for patients who do not tolerate hydroxyurea. The starting dose is 0.5 mg orally four times daily or 1 mg orally twice daily. Dosage adjustments should be made weekly, depending on the blood count. The maintenance dose is usually 2.0 to 3.0 mg/d. Side effects include neurologic and gastrointestinal symptoms, palpitations, and fluid retention in approximately 25 percent of patients.

• Recombinant interferon-α is also effective therapy. It suppresses the abnormal megakaryocyte clone. The starting dose is 3 million units subcutaneously daily with subsequent adjustments based on tolerance and response. Two major side effects are flu-like symptoms and psychiatric disturbance, especially in older patients. It has been recommended for patients less than 45 years because it is free from teratogenic or leukemogenic effects.

Course and Prognosis

• The major cause of morbidity and mortality are thrombosis and hemorrhage.

• Rarely, essential thrombocythemia may convert to another myeloproliferative disorder, or spontaneously convert to acute leukemia.

• A rare disorder usually inherited as an autosomal dominant trait.

• The disorder is occasionally due to mutations of the thrombopoietin gene, which lead to markedly increased serum thrombopoietin levels, or due to activating mutations of the thrombopoietin receptor.