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Leukocytosis Associated with Thrombosis

Essential thrombocythemia is not just a disease of the platelets — elevated leukocyte counts contribute to thrombotic complications.

In 2005, Barry Coller wrote a prescient article in which he reviewed the evidence showing that an elevated leukocyte count was a risk factor for ischemic vascular disease (Arterioscler Thromb Vasc Biol 2005; 25:658). He cited many examples of the association of leukocytosis with acute thrombosis, including high white blood cell (WBC) counts associated with myocardial infarction mortality and stroke severity, and high leukocyte counts in sickle-cell patients who developed ischemic vascular complications. Now, the European Collaboration on Low-dose Aspirin in Polycythemia vera (ECLAP) group reports that leukocytosis is a risk factor for thrombosis in essential thrombocythemia (ET).

The investigators recorded age, sex, blood counts, JAK2 mutation status, and history of vascular events in 439 patients (median age, 54; 264 women) with confirmed ET who were evaluated from 1981 through 2006. The median platelet count was 784x10⁹/L, WBC count was 8.7x10⁹/L, and hemoglobin was 14 g/dL. The JAK2 mutation was detected in 55% of patients, of whom 97% were heterozygotes. Among all patients, acute myocardial infarction occurred in 29%, stroke or transient ischemic attack occurred in 22%, peripheral arterial disease occurred in 17%, and venous thrombosis occurred in 32%.

On univariate analysis, the factors at ET diagnosis that were associated with the subsequent development of thrombosis were age 60, history of thrombosis (P=0.02), and leukocyte count higher than the median of 8.7x10⁹/L (P=0.01). When the authors evaluated the interaction between conventional risk factors (older age, previous thrombosis) and WBC counts, they observed that high leukocyte counts predicted thrombotic events best in patients who lacked other risk factors (relative risk, 2.7). In general, patients with both conventional risk factors and elevated leukocyte counts exhibited the greatest probability of adverse vascular events (hazard ratio, 5.0; 95% confidence interval, 2.1–11.9). Leukocyte counts were generally higher in patients with JAK2 mutations, which were associated with higher hemoglobin levels and lower platelet counts; however, a JAK2 mutation was not an independent predictor of thrombosis. In patients who were treated with hydroxyurea, leukocyte counts decreased to about 70% of baseline values and were no longer associated with thrombosis (P=0.06). Aspirin use was also protective.

Comment: The author of an accompanying perspective observes that monocytes and neutrophils in myeloproliferative disorders show signs of activation and expression of tissue factor; that is, they are strongly procoagulant. We know that hydroxyurea therapy downregulates neutrophil tissue-factor expression and the number of neutrophil–platelet complexes, and aspirin also inhibits formation of platelet–neutrophil complexes. These data suggest that ET is not just a disease of the platelets — elevated leukocyte counts contribute to thrombotic complications and are a therapeutic target.

— David Green, MD, PhD

Published in Journal Watch Oncology and Hematology April 9, 2007

Citation(s):

Carobbio A et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: Interaction with treatment, standard risk factors, and Jak2 mutation status. Blood 2007 Mar 15; 109:2310-3.

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• Medline abstract (Free)

Tefferi A. The granulocyte connection in MPD-associated thrombosis. Blood 2007 Mar 15; 109:2270-1.

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