2.1. GENERAL CONCEPTS The components of coagulation include the blood vessels, platelets, coagulation factors and cofactors, and the fibrinolytic proteins. As a result, hemostasis is a delicate balance between surface proteins on vessels/suben-dothelium, surface glycoproteins on platelets, procoagulant and anticoagulant proteins, and fibrinolytic proteins (3). The interaction among these components results in both fibrin clot formation and dissolution at the site of injury. Hereditary or acquired defects in any of these components can result in bleeding or thrombosis.
Hemostasis is generally viewed as two linked processes: primary and secondary hemostasis (4). Primary hemostasis, through platelet adhesion, activation, and aggregation, represents the platelet response to damaged endothelium and, at the same time, provides a template for the coagulation cascade. The coagulation cascade of proenzymes and cofactors is, in turn, referred to as secondary hemostasis. Together, these two processes form the basis of clot formation.
2.2. PRIMARY HEMOSTASIS With damage to a blood vessel, the exposed collagen binds circulating Von Willebrand factor (VWF), which, in turn, functions as a "glue" between the subendothelium and the circulating platelets (5). Platelets adhere to the damaged vessel through the platelet receptor for VWF, glycoprotein Ib (GpIb), followed by platelet activation with release of ADP and serotonin, among others, from their storage granules. Platelet activation also results in expression of the surface receptor glycoprotein IIb/IIIa (GpIIb/IIIa), which, together with fibrinogen and other proteins, allows for platelet aggregation. Meanwhile, the presence of phospha-ditylserine on the surface of the platelet plug provides a negatively charged phospholipid surface, necessary for the subsequent formation of the fibrin clot (4).
2.3. SECONDARY HEMOSTASIS Secondary hemostasis is characterized by the formation of a fibrin meshwork, which serves to reinforce the platelet plug. The system is comprised of a coagulation cascade of proenzymes and it's activated forms, along with cofactors and calcium (4). The procoagulants include the contact system proteins (factors XII and XI, high-molecular-weight kallikrein and kininogen), the vitamin K-dependent proteins (factors II, VII, IX, X), fibrinogen, the cofactors V and VIII, and factor XIII.
In vitro observations led to the traditional concept of two separate pathways involved in the generation of thrombin and the subsequent fibrin clot: the intrinsic and extrinsic pathways (3). In the intrinsic pathway, the components are found "inside the blood," best demonstrated when whole blood in a glass tube is left to clot by itself. In contrast, in the extrinsic pathway, clotting is initiated by tissue factor, which might originate from one of several sources located "outside the blood." The extrinsic pathway is generally considered the physiologic pathway in vivo while the intrinsic pathway provides a reinforcing mechanism (6).
The coagulation cascade is initiated when tissue factor binds to the small amount of circulating activated factor VII and this complex, in turn, activates both factors IX and X (3). Of note, the in vivo activation of factor IX by factor VII has replaced the traditional view of distinct intrinsic and extrinsic pathways. In the presence of cofactor VIII, activated factor IX will further activate factor X. Likewise, activated factor X, in the presence of cofactor Va, will subsequently convert prothrombin to thrombin, followed by the conversion of fibrinogen to fibrin.
Thrombin plays a central role in procoagulation: activating platelets, converting fibrinogen to fibrin, and providing positive feedback for further activation of cofactors V and VIII and factor XI. At the same time, thrombin also acts as an anticoagulant by activating the protein C system. Thrombin loses its procoagulant activity by binding to thrombomodulin present in most endothelial cell surfaces, followed by activation of the natural anticoagulant, protein C (6).
2.4. THE NATURAL ANTICOAGULANT SYSTEMS Physiologic anticoagulant system(s) help keep thrombin formation in check, thus avoiding abnormal clot propagation. Tissue factor pathway inhibitor (TFPI), serine protease inhibitors (so-called serpins), the protein C system, and the fib-rinolytic system are all necessary for the regulation of thrombin and fibrin formation (4).
The protein C system, through protein C, protein S, and thrombomodulin, plays a major anticoagulant role by inactiva-tion of cofactors V and VIII (7). Activated protein C, in the presence of phospholipid and the cofactor protein S, degrades specific peptide bonds at positions Arg 506 and Arg 306 in the B-domain of the factor V heavy chain.
The fibrinolytic system includes plasminogen, plasminogen activators and activator inhibitors, plasmin, and a2-antiplasmin (8). Plasminogen is activated mainly by tissue plasminogen activator (tPA) to form plasmin, which then degrades the clot. Plasminogen activation is confined to the fibrin clot, limiting the overall effect of fibrinolysis to the clot itself.
In sum, the physiologic balance of procoagulation and anticoagulation results in controlled thrombin formation limited to the site of vascular injury. A number of mutations and polymorphisms in the genes coding for these various proteins might result in increase risk of bleeding or thrombosis. A few of these genetic defects are now evaluable through molecular testing.
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