Translational Implications of Platelets as Vascular First Responders

Abstract

Platelets play a vital role in normal hemostasis to stem blood loss at sites of vascular injury by tethering and adhering to sites of injury, recruiting other platelets and blood cells to the developing clot, releasing vasoactive small molecules and proteins, and assembling and activating plasma coagulation proteins in a tightly regulated temporal and spatial manner. In synchrony with specific end products of coagulation, primarily cross-linked fibrin, a stable thrombus quickly forms. Far beyond physiological hemostasis and pathological thrombosis, emerging evidence supports platelets playing a pivotal role in vascular homeostasis, inflammation, cellular repair, regeneration, and wide range of autocrine and paracrine functions. In essence, platelets play both structural and functional roles as reporters, messengers, and active transporters surveying the vasculature for cues of environmental or developmental stimuli and participating as first responders.¹ In this review, we will provide a contemporary perspective of platelet physiology, including fundamental, translational, and clinical constructs that apply directly to human health and disease.

Keywords: blood platelets; fibrin; humans; platelet activation; thrombosis.

Figure 1

Schematic representation of contemporary platelet biogenesis and activation. Megakaryocytes derived from myeloid stem cells give rise to platelets. Several factors present or released from endothelial cells, including nitric oxide (NO), prostacyclin, and ADPase, act to keep circulating platelets in a resting state. Platelets can be initially activated by a number of different triggers including (but not limited to) adhesion to collagen via glycoprotein VI (GPVI) and the α2β1 integrin, von Willebrand factor (vWF) binding to GPIβ-IX-V complex, and generation of thrombin at or near the platelet surface that signals through protease-activated receptors (PAR). These pathways elicit downstream activation of phospholipase C (PLC) isoforms to generate second messengers inositol 1,4,5-triphosphate (not shown) and 1,2-diacylglycerol (DAG), which in turn, link to pathways that drive secretion of alpha granule contents including prothrombotic proteins fibrinogen (Fg) and vWF, as well as the secretion of dense granules to release a number of soluble platelet agonists such as ADP and serotonin. Activation is reinforced by secreted ADP acting on the P2Y1 and P2Y12 receptors, as well as the activation of the thromboxane receptor (TP) from thromboxane A2 (TXA2) generated from arachidonic acid (AA) released during the initial wave of platelet activation. Platelet aggregation occurs through Fg mediated integrin αIIbβ3 interactions with adjacent activated platelets.

Figure 2

Role for platelets in inflammation and response to pathogens. At sites of damaged or inflamed endothelium, platelet adhesion occurs through various interactions such as with exposed subendothelium, P-selectin expression on activated endothelium, and release of ultralarge von Willebrand factor (vWF). Adherent platelets, in turn, recruit WBCs which can subsequently transmigrate across the endothelium. Heterotypic cell interactions between platelets and WBCs or RBCs can occur and are associated with increases in systemic inflammation. Activated platelets can trigger the release of Neutrophil extracellular traps (NETs) which contribute to microbial clearance and clot formation. Platelets also interact with viral and bacterial pathogens to contribute to their clearance, as well as respond to gut microbiota that can modulate platelet function.

Figure 3

Platelet participation in neutrophil extracellular trap formation (NETosis). Activated platelets interact with neutrophils via platelet P-selectin and neutrophil PSGL-1, with interactions stabilized by a series of secondary adhesion interactions including ones mediated by platelet GPIb and leukocyte Mac-1 (αMβ2). This interaction can contribute to the trigger the release of neutrophil extracellular traps (NETs), consisting of chromatin containing citrullinated histones complexed with anti-microbial proteases such as elastase and myeloperoxidase, in a process called NETosis. NETs serve to enhance clearance of pathogens. They also contribute to clot formation by forming a mesh with platelets and fibrin and accumulating coagulation factors such as tissue factor (TF).