Elsevier

Blood Reviews

Volume 25, Issue 4, July 2011, Pages 155-167
Blood Reviews

REVIEW
Platelets at work in primary hemostasis

https://doi.org/10.1016/j.blre.2011.03.002Get rights and content

Abstract

When platelet numbers are low or when their function is disabled, the risk of bleeding is high, which on the one hand indicates that in normal life vascular damage is a rather common event and that hence the role of platelets in maintaining a normal hemostasis is a continuously ongoing physiological process. Upon vascular injury, platelets instantly adhere to the exposed extracellular matrix resulting in platelet activation and aggregation to form a hemostatic plug. This self-amplifying mechanism nevertheless requires a tight control to prevent uncontrolled platelet aggregate formation that eventually would occlude the vessel. Therefore endothelial cells produce inhibitory compounds such as prostacyclin and nitric oxide that limit the growth of the platelet thrombus to the damaged area. With this review, we intend to give an integrated survey of the platelet response to vascular injury in normal hemostasis.

Introduction

Platelets are involved in many processes ranging from fighting microbial infection and triggering inflammation to promoting tumor angiogenesis and metastasis1. Nevertheless, the main function of platelets still is stopping hemorrhage following vascular injury. In normal circumstances platelets do not interact with the intact vessel wall. However, upon tissue trauma platelets adhere to the extracellular matrix in a process that involves the coordinated action of different platelet receptors, leading to initial tethering and rolling of platelets over the damaged vessel wall, eventually resulting in firm adhesion. Platelet adhesion triggers a signaling cascade mediated by tyrosine kinases and G-protein coupled receptors, which guide full activation of the platelet and concomitant granule release, in turn resulting in recruitment and activation of additional platelets. Platelet adhesion and activation leads to platelet aggregation and the presentation of a procoagulant surface promoting formation of a fibrin-rich hemostatic plug at the injured site. Platelet activation, in addition, also triggers endothelial cells to synthesize and secrete molecules which tightly control and limit thrombus formation.

This review summarizes our current understanding of the basic platelet reactions upon vascular injury.

Section snippets

Platelet adhesion to the vessel wall

In normal circulation within intact vasculature, most platelets never undergo significant interaction with the endothelial surface during their entire lifetime. However, at sites of vascular injury, the subendothelial extracellular matrix is exposed to the blood, to which platelets promptly adhere in order to limit hemorrhage and promote tissue healing. This matrix contains several adhesive macromolecules such as collagen, von Willebrand factor (VWF), laminin, fibronectin and thrombospondin,

Signal transduction via tyrosine kinase activation

As with other cells, platelets can be activated by different signal transduction pathways, one of which is through the activation of a cascade of tyrosine kinases. Evidence is available that such signals are generated upon occupancy of GPIb by VWF62, of the FcRγII receptor by antibody complexes, of the receptors Tyro3, Axl and Mer by GAS663, of GPVI-FcRγ by collagen64 and of CLEC2 by podoplanin (Fig. 2), that equally results in platelet aggregation65, which is essential in vivo for the

Amplification of the signal transduction

Following platelet binding to the injured vessel wall and subsequent signaling to the platelet cytoplasm, a controlled release reaction takes place. Platelet granules fuse with the outer membrane, emptying their content and enriching the local environment with a multitude of bio-active molecules. Their para- and autocrine nature causes preliminary signals to quickly feedback into the process by increasing activation of nearby platelets in both number and magnitude thereby evoking secondary

Platelet aggregation

Platelet adhesion and activation is followed by platelet aggregation leading to the formation of a fibrinogen-rich thrombus at the site of injury. It is clear that platelet aggregation is a complex and dynamic process involving many ligands (such as fibrinogen, fibronectin, and VWF), receptors (such as GPIbα and αIIbβ3) and platelets in different activation states[143], [144], [145].

Recent insights in the platelet aggregation process led to the identification of three distinct mechanisms that

Signals that limit platelet activation and aggregation

Spontaneous or sustained platelet clumping should be limited at all times to prevent vessel clogging with downstream ischemia. There are strong inhibitory signals that prevent platelets from undesired activation and equally limit thrombus size to the site of vascular injury. Nitric oxide (NO) and prostacyclin (PGI2) and PGD2 are strong negative regulators able to interfere with platelet adhesion, activation, aggregation, secretion and shape change.

Like TxA2, PGs are produced through the

Perspectives

We here wanted to provide a comprehensive overview of what is currently known about platelet function in hemostasis. It is however anticipated that knowledge on platelet signaling will explode in coming years as recent advanced proteomic studies identified a multitude of novel platelet proteins with currently unknown function. Representing the contact interface with the external environment and first line to intracellular signaling, numerous studies are being performed to identify the function

Conflict of interest

The authors state no conflict of interest.

Role of funding source

HBF and SFD are fellows of the Research Foundation Flanders (Fonds voor wetenschappelijk Onderzoek, Vlaanderen (FWO)). This work was supported by a KU Leuven Campus Impulse Financing (CIF/07/02) and Concerted Research Action (GOA09/013) grant. The study sponsors had no involvement in the writing of the manuscript.

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