Platelets and Their Role in Hemostasis and Thrombosis-From Physiology to Pathophysiology and Therapeutic Implications

Abstract

Hemostasis is a physiological process critical for survival. Meanwhile, thrombosis is amongst the leading causes of death worldwide, making antithrombotic therapy one of the most crucial aspects of modern medicine. Although antithrombotic therapy has progressed tremendously over the years, it remains far from ideal, and this is mainly due to the incomplete understanding of the exceptionally complex structural and functional properties of platelets. However, advances in biochemistry, molecular biology, and the advent of 'omics' continue to provide crucial information for our understanding of the complex structure and function of platelets, their interactions with the coagulation system, and their role in hemostasis and thrombosis. In this review, we provide a comprehensive view of the complex role that platelets play in hemostasis and thrombosis, and we discuss the major clinical implications of these fundamental blood components, with a focus on hemostatic platelet-related disorders and existing and emerging antithrombotic therapies. We also emphasize a number of questions that remain to be answered, and we identify hotspots for future research.

Keywords: anticoagulants; antiplatelet agents; hemostasis; platelets; thrombosis.

Figure 1

Schematic image of the hemostatic process. (A) Classic view of hemostasis as a three-step process involving vasoconstriction and primary and secondary hemostasis as independent and sequential events. (B) Current view of hemostasis as a complex process in which the vessel wall, the platelets, and the coagulation system collaborate and continuously influence one another.

Figure 2

Schematic image of platelets. Resting platelets have asymmetrical distribution of phospholipids: the anionic phospholipids phosphatidylserine and phosphatidylethanolamine, responsible for binding many of the blood coagulation proteins, are sequestered in the inner leaflet of the membrane lipid bilayer facing the cytosol, whereas the electrically neutral phosphatidylcholine and sphingomyelin are exposed on the outer membrane leaflet. This arrangement prevents the membranes of resting platelets from supporting coagulation. When platelets become activated, the function of the phospholipid transporters is altered, leading to transfer of anionic phospholipids on the outer membrane leaflet. Loss of this asymmetry provides a procoagulant surface for sequential activation of coagulation enzymes. The outer surface of resting circulating platelets is covered by a prominent glycocalyx that prevents spontaneous platelet aggregation. Platelets possess a plasma membrane-based open canalicular system connected with the extracellular space through a multitude of small pores that increases the platelet membrane’s surface area. A second platelet canalicular system that is not connected to the platelet’s exterior—the dense tubular system—serves as a store for calcium and for various enzymes involved in platelet activation. Platelet alpha and dense granules contain a large number of substances critical for hemostasis, as well as for vasomotor function and immunity.

Figure 3

Main receptors and ligands involved in platelets’ adhesion, activation, and aggregation. The boxes indicate some examples of existing or emerging antiplatelet therapies. ADP—adenosine diphosphate; COX-1—cyclooxygenase-1; GP—glycoprotein; PAR—protease-activated receptors; TP—thromboxane receptor; TxA2—thromboxane A2; vWF—von Willebrand factor.

Figure 4

Macroscopic appearance of a (A) white thrombus in a patient with carotid artery occlusion and of a (B) red thrombus in a patient with deep vein thrombosis.