In this issue, Shibata and colleagues (page 4416) have studied a transgenic mouse with extreme polycythemia (erythrocytosis) due to constitutive overexpression of erythropoietin. They expected this to be a useful model for thrombotic complications that are a major cause of mortality and morbidity of individuals with polycythemia vera (PV). But this was not observed. At first glance, their results might be surprising, since a widely quoted paper by Pearson et al (Lancet. 1978;2:1219-1221) suggested that the risk of thrombosis in PV was proportional to the elevation in hematocrit, and a recent PV review (Spivak, Blood. 2002;100:4272-4290) also considered the hematocrit to be the principal measure of risk of thrombosis. It is becoming widely practiced to keep the hematocrit in PV below 45 despite the fact that there are no rigorous data backing this recommendation. Although it may be argued that mice are not people and that high and low erythropoietin states may have different extraerythroid effects (Sokol and Prchal, N Engl J Med. 2002;346:1584-1586), there are other arguments against an elevated hematocrit being the sole risk factor of thrombosis. There are other conditions associated with elevated hematocrit such as polycythemia of high altitude, erythropoietin receptor mutations, Chuvash polycythemia, hemoglobin mutants with high oxygen affinity, and 2,3-BPG deficiency, in which rates of thrombotic complications are far below those seen in patients with PV. These observations suggest that the thrombotic complications of PV may be induced, at least in part, by other unique features of PV, such as quantitative and qualitative defects of platelets and neutrophils; these myeloid cells are, after all, the progeny of the same mutated hematopoietic stem cell as the red cells. It might even be speculated that PV is a disease of endothelial cells that are derived from an even more primitive progenitor such as the hemangioblast that also gives rise to the pluripotent stem cells sustaining hematopoiesis, but this has not yet been studied.
Only rigorously conducted clinical studies will decisively answer the thrombo-genic role of elevated hematocrit in PV and the optimal level that should be maintained when managing the disease. The European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study, which included 1638 patients from 12 participating countries and 94 centers, was completed recently. Its main findings, currently submitted for publication, should make a valuable, if not definitive, contribution to our knowledge regarding the risk of thrombosis associated with elevated hematocrit, as well as on the efficacy and safety of aspirin in the prevention of thrombotic complications.
