Appendix D

Hemostasis

Whenever damage occurs to a blood vessel, a variety of processes are evoked that are aimed at preventing or stopping blood from exiting the vascular space. The 3 primary processes are summarized in the following list:

1. Platelet aggregation and plug formation: Occur as a result of the following steps:

   1. Vessel injury with endothelial damage and collagen exposure.

   2. Platelet adherence to collagen (mediated by the plasma protein, von Willebrand factor).

   3. Platelet shape change (from disks to spiny spheres) and degranulation with release of the following:

      1. Adenosine diphosphate, which causes platelet aggregation and “plugs” the hole.

      2. Thromboxane, which causes vasoconstriction and potentiates platelet adhesion and aggregation.

2. Local vasoconstriction: Mediated largely by thromboxane but may also be induced by local release of other chemical signals that constrict local vessels and reduce blood flow.

3. Blood clotting: The formation of a solid gel made up of the protein, fibrin, platelets, and trapped blood cells.

   The critical step in blood clotting is the formation of thrombin from prothrombin, which then catalyzes the conversion of fibrinogen to fibrin. The final clot is stabilized by covalent cross-linkages between fibrin strands catalyzed by factor XIIIa (the formation of which is catalyzed by thrombin).

   

   The cascade of reactions that leads from vessel injury to the formation of thrombin is shown in the figure below and is described as follows:

   1. Vessel injury or tissue damage with blood exposure to subendothelial cells that release thromboplastin (“tissue factor”).

   2. The plasma protein factor VII binds to the tissue factor, which converts it to an activated form, factor VIIa.

   3. VIIa catalyzes the conversion of both factors IX and X to activated forms IXa and Xa, respectively.

   4. IXa also helps convert factor X to Xa (Stuart factor).

   5. Xa converts prothrombin to thrombin.

   6. Thrombin.

      1. Activates platelets (makes them sticky, induces degranulation, and promotes attachment of various factors that participate in clotting).

      2. Converts fibrinogen to fibrin.

      3. Recruits the “intrinsic pathway,” which amplifies further formation of factor Xa and facilitates the conversion of prothrombin to thrombin by promoting the following reactions:

         1. Conversion of factor XI to its activated form, XIa, which then converts factor IX to IXa, which then attaches to activated platelets and converts factor X to Xa.

         2. Conversion of factor VIII (missing in hemophiliacs) to its activated form, VIIIa, which attaches to activated platelets and accelerates conversion of factor X to Xa.

         3. Conversion of factor V to its activated form, Va, which attaches to activated platelets and accelerates conversion of prothrombin to thrombin.

Several agents clinically used as anticoagulants interfere with various steps in this clotting process. Aspirin and other cyclooxygenase inhibitors are anticoagulants because they prevent the formation of thromboxane. Dicoumarol and coumadin block the activity of vitamin K, which is necessary for synthesis of many of the clotting factors by the liver. Specific inhibitors of the actions of various clotting factors are also now available. Heparin activates a plasma protein called antithrombin III, which, in turn, ...