Platelets Drive Thrombus Propagation in a Hematocrit and Glycoprotein VI–Dependent Manner in an In Vitro Venous Thrombosis Model

Abstract

A 3-step process regulated by hemodynamics was necessary for robust thrombus propagation: First, immobilized tissue factor initiates coagulation and fibrin deposition within a low flow niche defined by a secondary vortex in the pocket of a model venous valve. Second, a primary vortex delivers platelets to the fibrin interface in a red blood cell-dependent manner. Third, platelets adhere to fibrin, activate through glycoprotein VI, express phosphatidylserine, and subsequently promote thrombus growth beyond the valve sinus and into the bulk flow.

Functional significance of the platelet immune receptors GPVI and CLEC-2

“…The binding site for fibrin(ogen) resides in the D-region, with D-dimer inhibiting platelet activation by collagen at concentrations that lie at the upper end of those reached in vivo (36,40). The buildup of a fibrin monolayer in a microfluidic model of human venous valve disease was shown to initiate thrombus formation through a pathway that is inhibited by D-dimer (41).…”

Thrombotic Regulation From the Endothelial Cell Perspectives

“…5 Despite these differences, platelet adhesion/activation, and fibrin deposition as the result of coagulation constitute the fundamental processes of thrombus formation. 6,7 Platelet activation occurs when they interact with activated ECs (with increased VWF release and selectin expression) via glycoprotein Ib-V-IX complex binding to VWF, or when they expose to subendothelial extracellular matrix components, such as collagen (via glycoprotein VI receptor), in the cases of endothelial injury or plaques rupture. 1,8 Coagulation cascade is triggered by coagulation factor VII binding to tissue factor (TF; extrinsic pathway) or by contact system activation via factor XII (FXII; intrinsic pathway), followed by a common pathway that leads to fibrin formation through intricate enzymatic actions of different coagulation factors (Figure).…”

Fibrinogen and factor XIII: newly recognized roles in venous thrombus formation and composition

“…For example, RBCs with abnormal deformability as in sickle cell disease or spherocytosis may lead to increased retention in thrombi and therefore, result in formation of larger, more occlusive thrombi. (49) RBCs can also induce platelet accumulation and activation within clots in the presence of flow(4), and RBC compaction within contracted thrombi can decrease thrombus permeability and accessibility of fibrinolytic enzymes. (6) Thus, the relative impact of altering RBC presence in thrombi warrants careful evaluation.…”

“…Together, these activated leukocytes and endothelial cells initiate the coagulation cascade, which is propagated by blood flow- and red blood cell (RBC)-mediated accumulation of platelets within the venous valve pocket. (4) These processes produce a burst of thrombin, culminating in conversion of fibrinogen to fibrin, which traps resident proteins and blood cells within the growing and contracting thrombus. Cumulatively, this process results in the formation of an intravascular mass that occludes blood flow.…”