Platelet‐Derived Factor V Is a Critical Mediator of Arterial Thrombosis

Abstract

BackgroundCoagulation factor V (FV) plays a key role in hemostasis, is present in plasma and platelets, and has both pro‐ and anticoagulant properties; however, the contribution of platelet‐derived FV to arterial thrombosis remains undetermined.Methods and ResultsUsing transgenic mice with various levels of FV gene expression that was restricted to the plasma or platelets, the roles of platelet FV were evaluated in the regulation of arterial thrombosis and platelet activation. Mice with higher levels of platelet FV exhibited faster thrombotic occlusion of the carotid artery after injury compared with mice with lower platelet FV levels. Infusion of platelets with higher levels of FV into transgenic mice with undetectable levels of platelet FV reduced the time to carotid artery occlusion. In contrast, infusion of purified recombinant plasma FV into mice with undetectable platelet FV levels failed to reduce the carotid occlusion times following injury. Evaluation of isolated platelets revealed that platelet‐derived FV was critical for the regulation of platelet activation. These effects were associated with an increased level of expression of P‐selectin and increased cGMP in platelets.ConclusionsWe established that platelet‐derived FV is a critical mediator of arterial thrombosis that involves platelet activation.

Platelet-Derived Factor V Is an Important Determinant of the Metastatic Potential of Circulating Tumor Cells

“…In addition, the authors found that the addition of normal platelets reduced the time required to initiate clotting, suggesting an important role for platelet FV release in initiating thrombin generation. As shown in our previous study, mice with lower platelet FV levels exhibit slower thrombotic occlusion of the carotid artery after injury (18). However, based on our current findings, mice with lower platelet FV develop more lung metastases due to increased adhesion of tumor cells to endothelial cells.…”

“…However, researchers have not yet determined whether the levels of FV are associated with tumor progression and metastasis. Using transgenic mice that express different levels of the FV gene in either plasma or platelets (17), we recently identified a critical role for platelet-derived FV in the regulation of arterial thrombosis through platelet activation (18). In the current study, we evaluated the role of FV from different sources in metastasis.…”

Antithrombotic Therapy: Prevention and Treatment of Atherosclerosis and Atherothrombosis

“…Platelet-derived factor V may be an important determinant of local prothrombinase formation, driving atherogenesis (Ren et al 2017). Additional factors that are secreted by platelets are tissue factor (TF) (the origin still somewhat controversial) and protein disulfide-isomerase (PDI) that acts to de-encrypt TF in an active conformation.…”

Latent opportunities for the prevention of ischemic stroke in patients with atherosclerosis-related diseases: additional analysis of randomized trials on rivaroxaban

“…Результаты экспериментального исследования на трансгенных мышах позволяют предположить, что V фактор свертывания тромбоцитарного происхождения представляет собой ключевой медиатор развития артериального тромбоза in vivo, способствующий активации тромбоцитов и повышению свертываемости крови [27]. Такой фактор участвует в соединении протромбиназного комплекса с Ха фактором в месте разрыва атеросклеротической бляшки.…”

“…В результате образуется большое количество тромбина на поверхности активированного тромбоцита и по механизму обратной связи отмечается ранняя активация свертывающего каскада. Считается, что прямые ингибиторы тромбина, в частности дабигатран, могут не приводить к такому же уменьшению образования тромбина, которое вызывают ингибиторы Ха фактора [27,28]. Такую концепцию подтверждают данные о том, что V фактор свертывания крови человека высвобождается из α-гранул активированных тромбоцитов при их частично активированном состоянии, а Ха фактор оказывает в 50-100 раз большее влияние на активацию выделяемого тромбоцитами V фактора по сравнению с тромбином.…”