Anatomy And Physiology

Blood Coagulation



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Your body has many ways of maintaining its integrity when injury occurs. The formation of blood clots is necessary when you get a cut or damage a blood vessel, so that you stop bleeding. Stoppage of bleeding is called hemostasis. When there is an unwanted blood clot, it is called thrombosis, and can lead to heart attacks or embolisms.

When you injure a blood vessel, three interrelated events occur. First, platelets, small blood cells, stick to the site of injury and become activated. Platelet activation causes them to release different factors so that they stick to each other (aggregate), forming a platelet plug. The membranes of the activated platelets also turn inside out.

Second, blood vessels constrict at the site of injury, limiting blood flow. This constriction is caused by serotonin, another factor released by activated platelets.

Third, a series of enzymatic reactions causes soluble proteins in the blood to form an insoluble sticky blood clot. Thus, a blood clot is a mixture of activated, aggregated platelets and a sticky insoluble blood protein called fibrin.

Fibrin is formed by cutting off pieces of a soluble protein called fibrinogen. The enzyme that cuts fibrinogen is called thrombin. The pieces of fibrinogen that are cut off consist of water-soluble amino acids, whereas the rest of the molecule is less water soluble and very sticky. Thus, once the pieces are cut off, fibrin is very sticky and polymerizes into strands that trap platelets and other cells and proteins. Fibrin is further stabilized (cross-linked) by an enzyme called Factor XIIIa.

Thrombin is formed by cutting a precursor protein called prothrombin, by a series of enzymatic reactions of eleven other enzymes or proteins in the blood by two different pathways. These enzymes and other proteins are named using Roman numerals or common names. Conversions (or activations) are accomplished by enzymatic activity called proteolysis, which breaks specific chemical bonds between amino acids of the blood coagulation factors (all proteins).

The reaction of converting prothrombin to thrombin is catalyzed by an enzyme called Factor Xa (where the lower case a stands for activated factor). Factor Xa is not alone when it converts prothrombin to thrombin. It needs another factor, Factor Va, calcium ion, and phospholipids (from the inside out platelet membrane) to perform its function. Factor Va is converted from Factor V by thrombin.

Factor Xa is in turn converted from Factor X by either of two different pathways. One pathway is called the extrinsic pathway, where tissue damage releases tissue factor and Factor VIIa, which when combined directly converts Factor X to Factor Xa.

The second pathway to converting Factor X to Factor Xa is called the intrinsic pathway. In this pathway, the tissues under the cells lining the blood vessel are exposed and activate Factor XII to Factor XIIa. This step also requires another protein called high molecular weight kininogen (HMWK). Factor XIIa in turn activates Factor XI to Factor XIa, and Factor XIa activates Factor IX to Factor IXa. The latter two steps require calcium ion as cofactor.

Finally, Factor IXa converts Factor X to Factor Xa. Factor IXa requires other cofactors, including Factor VIIIa and phospholipids from the activated platelet membrane. Also calcium ion is required for this step. Factor VIIIa is activated from Factor VIII by thrombin. Genetic deficiency of Factor VIII (also called antihemophilic factor) is the cause of hemophilia, the most common genetic blood clotting disease.

The separation of extrinsic and intrinsic pathways is not clear, since people with genetic deficiency of Factors XII and XI do not have coagulation problems. Also, people with hemophilia, a deficiency of a protein in the intrinsic pathway, have bleeding problems when they are cut (an extrinsic pathway). Thus, there is a connection between the extrinsic and intrinsic pathway. The discovery of an inhibitor of the extrinsic pathway (tissue factor pathway inhibitor, or TFPI) showed that the Factor VIIa-tissue factor combination can activate Factor IX of the intrinsic pathway. This may be the normal pathway. Apparently, only when there is extensive tissue damage does the activation of Factor X take place by the extrinsic pathway.

The blood clotting pathways are regulated by specific inhibitors in the blood. One is called antithrombin, an inhibitor of the enzymatic activity of Factor Xa and thrombin. Antithrombin is regulated by a complex polysaccharide called heparin, which activates the activity of antithrombin by 2000-fold.

Many of the blood clotting factors require vitamin K for their biosynthesis. Vitamin K is involved in the modification of a certain amino acid to make the factor functional. Vitamin K antagonists (such as Coumadin) are used to inhibit blood clotting by inhibiting their biosynthesis.

In clinical situations, heparin works immediately, but cannot be given orally; whereas Coumadin requires more time to begin to work as an anti-clotting agent and can be given orally. Thus, hyper-coagulating patients are started on heparin in the hospital and released on Coumadin at home.

After healing begins, the fibrin clot is dissolved by another proteolytic enzyme called plasmin, which breaks down the fibrin clot. Plasmin is activated from plasminogen by one of three different plasminogen activators: tissue-type plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) or streptokinase. The activators t-PA and u-PA are made by human cells, whereas streptokinase is made by bacteria. These activators are effective in dissolving unwanted blood clots in heart attack patients if given within a few hours of the first symptoms.

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