Mechanisms of thrombogenesis in polycythemia vera

Abstract

Thrombotic and cardiovascular events are among the leading causes of death for patients with polycythemia vera (PV), and thrombosis history is a key criterion for patient risk stratification and treatment strategy. Little is known, however, about mechanisms of thrombogenesis in patients with PV. This report provides an overview of thrombogenesis pathophysiology in patients with PV and elucidates the roles of conventional and nonconventional thrombotic risk factors. In addition to several conventional risk factors for thrombosis, clinical data have implicated increased hematocrit and red blood cell adhesiveness, activated platelets, leukocytosis, and elevated JAK2(V617F) allele burden in patients with PV. Furthermore, PV-related inflammation may exacerbate thrombogenesis through varied mechanisms, including endothelial damage, inhibition of natural anticoagulant pathways, and secretion of procoagulant factors. These findings suggest a direct link between myeloproliferation and thrombogenesis in PV, which is likely to provide new opportunities for targeted antithrombotic interventions aimed at decreasing PV-related morbidity and mortality.

Keywords: Janus kinase 2; Polycythemia vera; Thrombosis.

Figure 1

Proposed Mechanism of Thrombogenesis in Patients With PV. Thrombogenesis in patients with PV is a complex process that involves many components. Future research will be necessary to confirm and refine this proposed mechanism; however, several drivers of thrombogenesis are depicted in this figure that may be unique to patients with PV. (1) Under high hematocrit conditions common in patients with PV, platelets are pushed centrifugally and are more likely to adhere to vessel wall collagen and vWF, thus initiating thrombus formation. (2) High shear conditions resulting from vascular damage and elevated blood cell counts directly enhance platelet adhesion and activation, and thereby promote leukocyte-platelet interactions. These interactions, which are principally mediated by platelet CD62P binding to leukocyte CD11b, result in neutrophil and monocyte activation. Neutrophil activation amplifies platelet activation through the release of cathepsin G, and monocyte activation results in its expression of tissue factor, leading to the activation of the soluble coagulation system. JAK2 mutations also promote the direct activation of leukocytes and platelets. Activated platelets and leukocytes bind to and activate ECs, and activated leukocytes, platelets, and ECs secrete procoagulant microparticles that contribute to formation of the fibrin clot. (3) PV-related blood cell and EC activation, as well as PV-related inflammation, results in endothelial injury. EC injury results in a prothrombotic state through the inhibition of EC-derived natural anticoagulant pathways, and the stimulation of several EC-derived procoagulant factors, particularly tissue factor and vWF. EC=endothelial cell; PV=polycythemia vera; vWF=von Willebrand factor.