Thrombosis and platelets: an update

Abstract

Haemostasis and thrombosis are complex, multifactorial processes. There is an evolving understanding of the mechanisms influencing vascular occlusion and the role of inflammation and immunity. Despite major advances in elucidating the mechanistic pathways mediating platelet function and thrombosis, challenges in the treatment of vascular occlusive diseases persist. Pharmacological advances have greatly affected thrombotic outcomes, but this has led to the unwanted side effect of bleeding. Detailed assessment of the impact of non-thrombotic diseases on haemostasis and thrombosis is necessary to better evaluate thrombotic risk and establish optimal treatment. This review will focus on recent advances in understanding the contribution of evolving risk factors to thrombosis.

Keywords: Bleeding; Cardiovascular; Coagulation; Platelets; Thrombosis.

Figure 1

Major differences between arterial and venous thrombosis. (A) Arterial thrombosis occurs under high shear flow when platelet rich thrombi are formed around ruptured atherosclerotic plaques and damaged endothelium. (B) Venous thrombosis occurs under low shear flow and mostly around intact endothelial wall. Venous thrombi are fibrin rich, encapsulating a large amount of red blood cells in addition to activated platelets.

Figure 2

Mechanisms of platelet-mediated thrombosis. (A) Collagen-mediated platelet thrombus formation occurs when subendothelial collagen becomes exposed to the circulation. Platelets, through their glycoproteins, interact with collagen and collagen-deposited vWF, change their shape and adhere to the site of injury. The attachment leads to secretion of ADP, serotonin and thromboxane (TxA2) leading to the recruitment and activation of more platelets. Activated platelets release thrombin (IIa) leading to platelet aggregation and three-dimensional clot formation. In certain instances, damage to the vessel may extend beyond the endothelium into the adventitial layer. In those instances, thrombosis is mediated through (B) Tissue factor (TF). Active TF is expressed by smooth muscle and adventitial cells and is able to generate thrombin (IIa). TF-generated thrombin, in turn, activates platelets, fibrin generation and the coagulation cascade to form a thrombus. Of note, circulating active TF may also be secreted by monocytes and is present in tumor-secreted microparticles. (C) Platelet thrombosis mediated by ultra large vWF multimers (ULvWF). Endothelial cells activated by high shear stress and/or epinephrine secrete large multimers of vWF forming strings that catch and crosslink platelets to the surface of the morphologically intact endothelium. The contact between the ULvWF and GPIb leads to platelet activation. Similarly as in (A). adherent platelets release ADP and TxA2 which lead to activation of more platelets and ultimately three-dimensional clot formation and retraction. (D) Neutrophil extracellular trap (NET)-mediated platelet thrombosis. In the presence of pathogens, platelets and neutrophils collaborate to form NETs that are highly thrombotic and resistant to tissue plasminogen activator-mediated fibrinolysis. Generally, the size of a thrombus formation is regulated by limiting the level of clot propagation. The endothelium plays a major role by expressing certain thrombo-regulators (NO, prostacyclins, and CD39-ectonucleotidase) that prevent the clot from spreading. Clots are resolved by initiation of fibrinolysis through generation of plasmin from plasminogen and breakdown of fibrin. Depending on the vessel in which the clot forms, the thrombus can be platelet-rich (white clots, form in arteries) or fibrin- and red blood cell-rich (red clots, form in veins). Each step in thrombus formation can lead to uncontrolled clot formation that can result in arterial or venous thrombosis, ultimately presenting a risk for MI, stroke or VTE.