Simple and Complex

Posted by • January 4th, 2013

In the latest article in our Clinical Problem-Solving series, a 44-year-old man presented to the emergency department with chest pain that had started 1 hour earlier and had awakened him from sleep. The pain was severe, substernal, burning, radiating to the left arm, and accompanied by nausea and vomiting.

When a myocardial infarction occurs in a patient who does not have traditional risk factors for coronary artery disease, alternative causes should be sought. Important causes include hypercoaguable states, coronary vasospasm (e.g., from cocaine use), coronary inflammation, anomalous coronary arteries, coronary dissection, and embolization.

Clinical Pearls

• What is the difference between primary thrombocytosis and secondary thrombocytosis?    

Primary thrombocytosis results from a clonal hematologic disorder, whereas secondary thrombocytosis is a reactive process commonly due to conditions such as infection, inflammation, cancer, drug reaction, or iron deficiency. The most common primary causes are myeloproliferative, but in rare cases, a form of myelodysplasia may underly this finding. Patients with clonal processes may report pruritus, usually after bathing. On physical examination, splenomegaly is more common with clonal than with reactive thrombocytosis.

• Is there an association between the myeloproliferative disorders and thrombosis?    

The myeloproliferative disorders, consisting primarily of polycythemia vera, essential thrombocythemia, primary myelofibrosis, and chronic myelogenous leukemia, are associated with hypercoagulability. The incidence of thrombosis in patients with myeloproliferative neoplasms remains unclear but is significantly elevated, as compared with the incidence in a general population. Arterial thromboses are more common than venous thromboses; strokes are most frequent, followed by myocardial infarction and peripheral arterial occlusion. Paradoxically, patients with myeloproliferative neoplasms are also prone to bleeding, which is typically mucocutaneous and is less frequent and severe than thrombosis.

Morning Report Questions

Q: What is the clinical significance of the JAK2 mutation in patients with myeloproliferative disorders?    

A: The JAK2 V617F mutation (an acquired somatic mutation in the JAK2 gene) results in a mutated tyrosine kinase capable of independently activating downstream pathways in thrombopoietin and erythropoietin signaling, as well as other cell and cytokine receptors. Cells expressing the mutation have a proliferation and survival advantage and are hypersensitive to hematopoietic growth factors. This mutation is present in more than 95% of patients with polycythemia vera and in 50% of patients with essential thrombocythemia and myelofibrosis. Its presence is diagnostic of a myeloproliferative neoplasm but cannot be used to distinguish among the various disorders.

Q: How is thrombocytosis managed in patients with myeloproliferative neoplasms?

A: The management of thrombocytosis in patients with myeloproliferative neoplasms currently entails the use of antiplatelet and cytoreductive therapies. In a randomized trial, aspirin was found to reduce the risk of thrombosis in patients with polycythemia, but it did not reduce mortality. There is no similar evidence to support the use of aspirin in patients with other myeloproliferative neoplasms. Cytoreductive therapies are considered for patients with polycythemia vera and for patients with other myeloproliferative neoplasms who are considered to be at high risk for thrombosis or bleeding, including those older than 60 years of age, those with a history of major thrombosis or hemorrhage, and those with platelet counts greater than 1.5 million per cubic millimeter. Cytoreductive therapies include phlebotomy, hydroxyurea, and interferon alfa. Hydroxyurea effectively reduces elevated cell counts, spleen size, and thrombotic risk. There is concern that hydroxyurea increases the risk of leukemic transformation, but no definitive evidence has established an association. Neither hydroxyurea nor inferferon has been shown to improve survival. The drug ruxolitinib, an inhibitor of both JAK1 and JAK2, has shown efficacy in reducing splenomegaly and constitutional symptoms in patients with intermediate-2 or high-risk myelofibrosis.

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