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Overview of the Coagulation System
Hemostasis means stopping blood loss or bleeding. Hemostasis is an orchestrated, balanced, and tightly regulated process. Hemostasis can be subdivided into three sequential processes: primary hemostasis, secondary hemostasis and tertiary hemostasis. In primary hemostasis the interaction of the injured endothelium with von Willebrand factor (VWF) and platelets is crucial for the formation of a platelet plug at the injury site. In secondary hemostasis, the coagulation factors are activated on the surface of injured endothelium and activated platelets which ultimately form a fibrin mesh that stabilizes the platelet plug to allow wound healing. And last, in tertiary hemostasis, fibrinolysis is activated to dissolve the platelet plug and return the normal architecture of the endothelium, smooth endothelial lining and normal lumen size.
Primary Hemostasis
During injury or damage to a blood vessel, the first response to prevent blood loss is vasoconstriction, leading to activation of endothelial cells (ECs). Activated EC secrete VWF, which major role is to recruit platelets to the wounded endothelium. VWF first binds to exposed collagen in the injured endothelium and recruits circulating platelets by recognizing glycoprotein Ib-V-IX (GPIb) on platelets. The binding of VWF to platelets is the first step in the platelet adhesion process. The role of VWF in hemostasis is discussed in details in Chapter 109 .
Platelets are essential for normal hemostasis, and their functions can be summarized with the triple A mnemonic: adhesion, activation, and aggregation ( Fig. 91.1 ).
Platelet Adhesion
VWF plays a major role in platelet adhesion by recruiting platelets to the injured endothelium and subendothelial matrix, which is abundant in collagens and other extracellular matrix proteins. Under high shear conditions, the A3 domain of VWF first bind to subendothelial collagen. This process induces uncoiling of VWF and exposes the A1 domain of VWF, which in turns bind to platelet-GPIb-V-IX receptor (GP1b). Binding of the platelet glycoprotein GPIb to collagen-bound VWF anchors the platelets at the site of injury. In turn, platelets have other glycoproteins that directly bind collagens, including glycoprotein Ia/IIa and glycoprotein VI. Signaling via these glycoproteins, adhesion proteins and soluble ligands induce activation from the intracellular compartment to the extracellular compartment, a process called “inside-out” activation. A very important protein that undergoes “inside-out” activation is glycoprotein IIb/IIIa, wherein phosphorylation of its cytoplasmic domain induces changes in the extracellular domain resulting in increased affinity for VWF and fibrinogen. These changes induced by adhesion and signaling initiate the activation of platelets.
Platelet Activation
Platelet activation results from a series of events that are orchestrated to happen in sequence and sometimes in synchrony leading to synergism. One of the first steps during activation is the shape change. Platelets are discoid in shape when resting, but during activation their cytoplasm expands and flattens and the cytoskeleton rearranges to develop fingerlike extensions called lamellipodia and filopodia. The adhesion receptors are redistributed in the lipid rafts and concentrate to the filopodia ends (sticky ends). These shape change is essential to make platelets more adherent to the injured endothelium and to other activated platelets thus increasing the surface area of platelets protecting the injured endothelium and physically preventing further blood loss.
Another important step during platelet activation is the redistribution of phospholipids to the outer membrane. Platelets use flippases, floppases, and scramblases to move phospholipids to the outer membrane. This process is very important for the recruitment and activation of coagulation factors on the surface of activated platelets, which is crucial for the initiation of secondary hemostasis.
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