Prevention of Blood Clotting in the Normal Vascular System— Intravascular Anticoagulants
Endothelial Surface Factors. Probably the most importantfactors for preventing clotting in the normal vascular system are (1) the smoothness of the endothelial cell surface, which prevents contact activation of the intrin-sic clotting system; (2) a layer of glycocalyx on the endothelium (glycocalyx is a mucopolysaccharide adsorbed to the surfaces of the endothelial cells), which repels clotting factors and platelets, thereby pre-venting activation of clotting; and (3) a protein bound with the endothelial membrane, thrombomodulin, which binds thrombin. Not only does the binding of thrombin with thrombomodulin slow the clotting process by removing thrombin, but the thrombomod-ulin-thrombin complex also activates a plasma protein, protein C, that acts as an anticoagulant by inactivating activated Factors V and VIII.
When the endothelial wall is damaged, its smooth-ness and its glycocalyx-thrombomodulin layer are lost, which activates both Factor XII and the platelets, thus setting off the intrinsic pathway of clotting. If Factor XII and platelets come in contact with the subendothelial collagen, the activation is even more powerful.
Antithrombin Action of Fibrin and Antithrombin III. Amongthe most important anticoagulants in the blood itself are those that remove thrombin from the blood. The most powerful of these are (1) the fibrin fibers that themselves are formed during the process of clotting and (2) an alpha-globulin called antithrombin III or antithrombin-heparin cofactor.
While a clot is forming, about 85 to 90 per cent of the thrombin formed from the prothrombin becomes adsorbed to the fibrin fibers as they develop. This helps prevent the spread of thrombin into the remaining blood and, therefore, prevents excessive spread of the clot.
The thrombin that does not adsorb to the fibrin fibers soon combines with antithrombin III, which further blocks the effect of the thrombin on the fi-brinogen and then also inactivates the thrombin itself during the next 12 to 20 minutes.
Heparin. Heparin is another powerful anticoagulant,but its concentration in the blood is normally low, so that only under special physiologic conditions does it have significant anticoagulant effects. However, heparin is used widely as a pharmacological agent in medical practice in much higher concentrations to prevent intravascular clotting.
The heparin molecule is a highly negatively charged conjugated polysaccharide. By itself, it has little or no anticoagulant properties, but when it combines with antithrombin III, the effectiveness of antithrombin III for removing thrombin increases by a hundredfold to a thousandfold, and thus it acts as an anticoagulant. Therefore, in the presence of excess heparin, removal of free thrombin from the circulating blood by antithrombin III is almost instantaneous.
The complex of heparin and antithrombin III removes several other activated coagulation factors in addition to thrombin, further enhancing the effective-ness of anticoagulation. The others include activated Factors XII, XI, X, and IX.
Heparin is produced by many different cells of the body, but especially large quantities are formed by the basophilic mast cells located in the pericapillary con-nective tissue throughout the body. These cells contin-ually secrete small quantities of heparin that diffuse into the circulatory system. The basophil cells of the blood, which are functionally almost identical to the mast cells, release small quantities of heparin into the plasma.
Mast cells are abundant in tissue surrounding the capillaries of the lungs and to a lesser extent capillar-ies of the liver. It is easy to understand why large quan-tities of heparin might be needed in these areas because the capillaries of the lungs and liver receive many embolic clots formed in slowly flowing venous blood; sufficient formation of heparin prevents further growth of the clots.