Tissue Plasminogen Acfcivn-fcor" -from damaged tissues sentially a male disorder, and classic hemophilia affects about one in 10,000 males in the U.S. Males with one hemophilia gene develop hemophilia, whereas females with one hemophilia gene are carriers.
3) Calcium (Factor IV) is important to the clotting process, but does not decrease enough to present a clinical clotting problem. However, substances are commonly added to collected blood samples to remove calcium from the blood and prevent the blood from clotting in the tube (e.g. citrate or oxalate ions)
4) Severe liver disease, such as cirrhosis and hepatitis, can cause clotting problems, since most of the clotting factors are produced by the liver (e.g. prothrombin, fibrinogen, etc.).
5) Deficiency of vitamin K may cause bleeding problems, because vitamin K is important in the formation of prothrombin and factors VII, IX, and X. Normally, we get plenty of vitamin K in the diet, and it is also produced by bacteria in the gut, but in conditions of fat malabsorption (vitamin K is a fat-soluble vitamin), vitamin K deficiency may occur.
The body normally has a number of negative feedback mechanisms that prevent clotting from proceeding excessively:
1) Fibrin in the clot absorbs excess thrombin.
2) A globulin in the clot area called anti-thrombin III inactivates excess thrombin.
3) Heparin, a powerful anticoagulant produced by mast cells and basophils, enhances the activity of anti-thrombin III. Heparin is commonly used clinically as an anticoagulant. It has immediate anticoagulant effects. It is administered intravenously. Coumarin is another clinically used anticoagulant, which acts by a different mechanism. It competes with vitamin K and inhibits the production in the liver of prothrombin and other clotting factors. It is given orally, but requires one or more days to take effect, since one must wait for the existing prothrombin to be depleted.
4) Plasma contains a protein called plasminogen (profibrinolysin), which, when activated, becomes plasmin (fibrinolysin). Fibrinolysin lyses fibrin and helps remove the clot. The process of plasminogen activation is relatively slow, occurring at least a day after the clot has formed to allow time for the initation of wound healing. It is activated by tissue plasminogen activator, which is released by the damaged tissues.
Tests for the integrity of the coagulation mechanism are based on whether one wishes to test the intrinsic or extrinsic pathway, or platelet function, as follows:
1) Tests of the intrinsic pathway: The whole blood clotting time test measures the time taken for blood to clot in a glass test tube (normally about 9-15 minutes). This tests the intrinsic pathway, which is activated by contact with a foreign surface. If any component of the intrinsic pathway is defective, the clotting time will be prolonged over normal controls. One can then identify the particular component that is defective by assaying for particular clotting factors.
The partial thromboplastin time (PTT), like the whole blood clotting time, tests for the integrity of the intrinsic pathway. Clotting in a test tube is initially prevented by citrating the plasma to remove calcium. The PTT measures the time taken for recalcified citrated plasma to clot in the test tube.
2) Tests of the extrinsic pathway: The one step prothrombin time (PT) is the time needed for recalcified citrated plasma to clot in the presence of tissue thromboplastin. Thus, the "protime" adds the critical tissue ingredient (tissue thromboplastin) that is necessary to start off the relatively fast extrinsic pathway. The normal protime is about 11-15 seconds. If the protime is prolonged, in relation to controls, this suggests a problem somewhere in the extrinsic pathway. Mnemonic: PTT (the test for the intrinsic path) has more letters than PT (the test for the extrinsic path), corresponding to the intrinsic path having more steps than the extrinsic path.
3) Tests of platelet function. Platelet function may be diminished either because of decreased numbers of platelets or because of a deficiency in the functioning of existing platelets.
A platelet count is, of course, useful in assessing the number of platelets. Bleeding may occur with low platelet counts. The bleeding time assesses platelet function. A small cut is placed on the patient's forearm, with a blood pressure cuff kept on the arm at 40mm I lg to resist venous flow. Normal bleeding time (depending on method) may be 2-7 min. Bleeding time tends to be normal in coagulation disorders of the extrinsic and intrinsic pathways, because the platelet plug operates independently of these pathways and is sufficient in itself to close up such small wounds. If the bleeding time is prolonged, this usually suggests a defect in platelet function.
The examination of both PTT and PT tests is useful to distinguish extrinsic from intrinsic coagulation disorders:
Intrinsic path defect Normal Abnormal
Extrinsic path defect Abnormal Normal Liver failure, vitamin Abnormal Abnormal K deficiency, coumarin or heparin therapy
Neither the intrinsic nor extrinsic pathway can cause clotting if there is a defect at the end steps of prothrombin to thrombin or fibrinogen to fibrin. Therefore, both the prothrombin time and PTT will be abnormal in severe liver disease (the liver manufactures prothrombin, fibrinogen and other clotting factors), vitamin K defi ciency, (vitamin K is necessary for formation of prothrombin and other factors), coumarin therapy (coumarin interferes with the formation of prothrombin and other clotting factors), and heparin administration (heparin indirectly inactivates thrombin).
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