Disruption of the normal tissue architecture with transection of blood vessels following injury, results in the exposure of blood elements to subendothelial collagen. This initiates coagulation by surface activation of Hageman factor, the release of tissue procoagulants from damaged cells and the exposure of phospholipids on activated platelets and endothelial cells (
1: Pravachol ). The key element that initiates the cascade is the surface absorption of coagulation proenzyme, which protects it from protease inhibitors and allows rapid amplification of the coagulation cascade leading to clot formation.
fibrin
The extent of clot formation is also regulated at the microvascular level by several factors, including production of prostacyclin, which inhibits platelet aggregation (2: Pravachol); antithrombin III, which inhibits the activity of thrombin (3); protein C, which degrades coagulation factors V and VIII (4); and the release of plasminogen activator, which converts plasminogen to plasmin and initiates clot lysis (5). Plasminogen activator and plasmin are capable of degrading a large number of extracellular matrix proteins. Their activity is confined to cell surface microenvironment by the presence of plasminogen inhibitor bound to extracellular matrix protein (6: Pravachol ).
Once hemostasis has been established, a second major function of this primary hemostatic plug is to act as a provisional matrix, or a scaffold, for the recruitment of cells to the site of injury. Fibrin is a 340-kd hexamer composed of three fibrinogen chains that are coded on three different genes.
Fibrinogen is synthesized in the liver and circulates in the blood. At the site of injury, thrombin cleaves the fibrinogen, which yields fibrin chains that polymerize with other fibrin molecules forming a fibrin polymer. The provisional network at this stage is unstable. Stability is achieved by the actions of plasma transglutaminases (factor XIIIa:
Pravachol ), which cause the formation of covalent intermolecular bonds by linking amino acid residues between adjacent fibrin chains resulting in a highly stable structure. This intricate network serves as a preliminary matrix that can bind and release cytokines and fibronectin. It also acts as a scaffold for migrating cells such as infiltrating monocytes, keratinocytes, endothelial cells, and fibroblasts (
7: Pravachol ). These migrating cells express integrins that bind to complimentary ligands on fibrin and fibronectin in the primary hemostatic plug (
8). Fibronectin is composed of two 250-kd polypeptide chains linked by disulfide bonds. It expresses several domains that bind various macromolecules such as fibrin, collagen, heparin, and integrins expressed on migrating cells, which results in increased cell adhesion in the hemostatic plug.
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Pravachol,
Scientific Principles,
Wound Healing: Cellular and Molecular Mechanisms
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