Upon vascular injury, the coagulation system is activated: thrombocytes and fibrin molecules coalesce into a "plug" (p. 148) that seals the defect and halts bleeding (hemostasis). Unnecessary formation of an intravascular clot - a thrombosis - can be life-threatening. If the clot forms on an atheromatous plaque in a coronary artery, myocardial infarction is imminent; a thrombus in a deep leg vein can be dislodged, carried into a lung artery, and cause complete or partial interruption of pulmonary blood flow (pulmonary embolism).
Drugs that decrease the coagulability of blood, such as coumarins and hep-arin (A), are employed for the prophylaxis of thromboses. In addition, attempts are directed at inhibiting the aggregation of blood platelets, which are prominently involved in intra-arterial thrombogenesis (p. 148). For the therapy of thrombosis, drugs are used that dissolve the fibrin meshwork^fibrino-lytics (p. 146).
An overview of the coagulation cascade and sites of action for coumar-ins and heparin is shown in A. There are two ways to initiate the cascade (B): 1) conversion of factor XII into its active form (XIIa, intrinsic system) at intravascular sites denuded of endothelium; 2) conversion of factor VII into VIIa (extrinsic system) under the influence of a tissue-derived lipoprotein (tissue throm-boplastin). Both mechanisms converge via factor X into a common final pathway.
The clotting factors are protein molecules. "Activation" mostly means proteolysis (cleavage of protein fragments) and, with the exception of fibrin, conversion into protein-hydrolyzing enzymes (proteases). Some activated factors require the presence of phos-pholipids (PL) and Ca2+ for their proteolytic activity. Conceivably, Ca2+ ions cause the adhesion of factor to a phos-pholipid surface, as depicted in C. Phos-pholipids are contained in platelet factor 3 (PF3), which is released from ag-Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
gregated platelets, and in tissue throm-boplastin (B). The sequential activation of several enzymes allows the aforementioned reactions to "snowball", culminating in massive production of fibrin (p. 148).
Progression of the coagulation cascade can be inhibited as follows:
1) coumarin derivatives decrease the blood concentrations of inactive factors II, VII, IX, and X, by inhibiting their synthesis; 2) the complex consisting of heparin and antithrombin III neutralizes the protease activity of activated factors; 3) Ca2+ chelators prevent the enzymatic activity of Ca2+-dependent factors; they contain COO-groups that bind Ca2+ ions (C): citrate and EDTA (ethy-lenediaminetetraacetic acid) form soluble complexes with Ca2+; oxalate precipitates Ca2+ as insoluble calcium oxalate. Chelation of Ca2+ cannot be used for therapeutic purposes because Ca2+ concentrations would have to be lowered to a level incompatible with life (hypocalcemic tetany). These compounds (sodium salts) are, therefore, used only for rendering blood incoagulable outside the body.
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