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Daily Aspirin — Only Half the Answer
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     Polycythemia vera is a chronic clonal hematopoietic–stem-cell disorder of unknown cause characterized by autonomous bone marrow function. Among the long-term consequences of this unregulated hematopoiesis are the extramedullary production of blood, primarily in the spleen and the liver, with painful and debilitating organomegaly and portal hypertension; hyperuricemia with secondary gout and renal stones; often intractable aquagenic pruritus; and hemorrhage, usually mucocutaneous. In a small proportion of cases, clonal succession or evolution, frequently abetted by chemotherapy, leads to myelofibrosis and bone marrow failure or acute leukemia. However, it is a short-term consequence, thrombosis, that causes much of the illness and death associated with the disease. No part of the vascular system is spared, but there is a predilection for peripheral arterioles and cerebral and abdominal vessels. Thrombosis develops in about 40 percent of patients, and almost two thirds of these events occur before or at the time of diagnosis. Rates of fatal thrombosis as high as 40 percent have been recorded. Most arterial thrombi occur in small vessels, where they can cause burning pain and erythema in the feet and hands (erythromelalgia) or ocular migraine. Polycythemia vera is also a leading cause of hepatic-vein thrombosis, a classic and catastrophic initial manifestation of the disease, particularly in young women.

    The mechanism of thrombosis in polycythemia vera and the means for its prevention are matters of controversy. Attempts to control erythrocytosis by phlebotomy often failed to diminish the high rate of thrombosis, and chemotherapy with alkylating agents, although somewhat more successful, was associated with an unacceptable risk of malignant transformation. Phlebotomy was thought to stimulate the marrow and also promote hypercoagulability, but in fact, marrow function is autonomous in polycythemia vera, and phlebotomy restores hemostatic balance by reducing blood viscosity. Although thrombocytosis is an integral feature of polycythemia vera, and a variety of morphologic and functional platelet defects have been identified, none correlate with the risk of thrombosis. Paradoxically, extreme thrombocytosis creates a risk of hemorrhage by reducing large von Willebrand factor multimers in the plasma; this risk is reversible by reducing the platelet count, and active bleeding is controllable with aminocaproic acid.

    The mystery of hypercoagulability in polycythemia vera is more apparent than real, because this disease fulfills Virchow's triad for thrombosis by perturbing the vessel wall, blood flow, and elements of the coagulation system. Erythrocytes, the most plentiful cellular constituents of the blood, are the principal determinants of blood viscosity and hence of blood flow. However, polycythemia vera is unique among the conditions causing erythrocytosis, because in polycythemia vera, an increase in red-cell mass is accompanied not by a reduction in plasma volume, but often by its expansion. For this reason, it is not possible to estimate the red-cell mass on the basis of the hematocrit in patients with polycythemia vera. The failure to recognize that an apparently normal hematocrit may not be normal in patients with this disease, to acknowledge that women are not small men, and consequently to select a safe target hematocrit (<45 percent in men and <42 percent in women) explains the observed failure of phlebotomy to prevent thrombosis in polycythemia vera.

    In addition to promoting stasis, erythrocytosis has other consequences: increased strain on the vessel wall leading to endothelial-cell activation or damage; increased shear stress causing platelet and leukocyte activation and increased cell–cell interaction; and vasoconstriction due to nitric oxide scavenging. The evidence of platelet activation and utilization in polycythemia vera — increased thromboxane production; the up-regulation of P-selectin, thrombospondin, and its receptor; decreased alpha-granule and dense-body content; and a shortened life span — is indisputable. Neutrophils are also activated, increasing the secretion of elastase and myeloperoxidase and the production of adhesive proteins that permit granulocytes to bind to platelets and endothelium. Endothelial-cell activation with increased release of von Willebrand factor provides the final component necessary for the inappropriate initiation of coagulation. Although patients with polycythemia vera are not at greater risk for genetic causes of hypercoagulability, increased nucleic acid metabolism may promote hyperhomocysteinemia, and the xanthine oxidase response to hyperuricemia could generate reactive oxygen species, leading to endothelial damage.

    The coagulopathy of polycythemia vera can therefore be viewed from two perspectives (see Figure). First, there are the microvascular syndromes erythromelalgia and ocular migraine. These disorders are independent of blood viscosity and arise from widespread platelet and endothelial-cell activation, facilitated by the high shear rate in arterioles. Platelet aggregates form on endothelial cells through interactions among P-selectin, glycoprotein Ib, and von Willebrand factor. The inhibition of platelet aggregation with aspirin therapy usually arrests this process; reducing the number of platelets is also effective. Second, there is large-vessel arterial or venous thrombosis. The blood viscosity is paramount in this situation, since it is in large vessels that the negative effect of a high hematocrit on blood flow is most pronounced. But endothelial-cell activation and damage and cell–cell interactions are also important. Until recently, however, the role of the platelet in the macrovascular thrombosis of polycythemia vera and the role of aspirin in preventing this complication were controversial, because a trial of high-dose aspirin demonstrated that this treatment was not effective and resulted in an increased incidence of bleeding.

    Figure. Mechanisms of Thrombosis in Polycythemia Vera.

    Microvascular thrombosis (Panel A) involves the interaction of activated platelets and endothelial cells in arterioles through the adhesive proteins P-selectin, glycoprotein Ib, and von Willebrand factor, which is facilitated by the high shear rate in these vessels, with thrombus formation in the absence of substantial fibrin generation. Macrovascular thrombosis (Panel B) takes place in larger vessels where the effects of an elevated red-cell mass on blood flow are most pronounced. With the expansion of red-cell mass, laminar flow is disturbed, vessel-wall strain is increased, and the interactions of platelets and leukocytes with the endothelium, red cells, and each other are enhanced. Thus, even in a situation in which blood viscosity leads to low shear, platelet adhesion and aggregation are facilitated, and thrombin generation is initiated. Panel C shows the relation between the blood viscosity and the hematocrit. The relation between thrombosis and the hematocrit in polycythemia vera follows a similar curve, underscoring the fact that it is the expansion of the red-cell mass, rather than abnormal platelets or granulocytes, that leads to the coagulopathy associated with this disorder.

    In this issue of the Journal, Landolfi and colleagues (pages 114–124) provide evidence that aspirin is safe and effective in the primary prevention of thrombosis in polycythemia vera. This clinical trial differs from previous trials with respect to its size and its use of low-dose aspirin. The study population was also unusual, because the patients were heavily pretreated with chemotherapy to normalize the platelet count, and the results may therefore not be generally applicable. Moreover, many of the patients should have been excluded, since their hematocrits were above the acceptable level. Thus, one can conclude only that low-dose aspirin is safe and effective in polycythemia vera when the platelet count is normal. At the same time, it can be argued that had phlebotomy been used judiciously, the effect of aspirin therapy might have been negligible. It will remain for future trials to determine whether aspirin has a role in the management of polycythemia vera when phlebotomy is adequate, other than for erythromelalgia, ocular migraine, or identified cardiovascular risk factors.

    Source Information

    From the Division of Hematology, Johns Hopkins University School of Medicine, Baltimore.

    Related Letters:

    Low-Dose Aspirin in Polycythemia Vera

    Alliot C., Dutrillaux F., Maynadié M., Carli P.-M., Denes A. E., Landolfi R., Marchioli R., Barbui T., Spivak J. L.(Jerry Spivak, M.D.)