Tissue thromboplastin

Extrinsic Pathway. Coagulation is initiated when tissue extracts with Hpid—protein properties are released from the membranes of endothehal cells following injury or insult. These substances, collectively designated tissue thromboplastin, complex with circulating Factor VII and in the presence of calcium ions subsequentiy activate Factor X (Fig. 1). In vitro evidence suggests that Factor X can be activated less rapidly through the interaction of kaUikrein [9001-01-8] with Factor VII. 

The extrinsic mechanism of blood coagulation begins when a blood vessel is ruptured and the surrounding tissues are damaged. The traumatized tissue releases a complex of substances referred to as tissue thromboplastin. The tissue thromboplastin further complexes with factor VII and Ca++ ions to activate factor X directly. 

An overview of the coagulation cascade and sites of action for coumarins and heparin is shown in A. There are two ways to initiate the cascade (B) 1) conversion of factor XII into its active form (Xlla, intrinsic system) at intravascular sites denuded of endothelium 2) conversion of factor VII into Vila (extrinsic system) under the influence of a tissue-derived lipoprotein (tissue thromboplastin). Both mechanisms converge via factor X into a common final pathway. 

In the extravascular pathway (right), tissue thromboplastin (factor 111), a membrane protein in the deeper layers of the vascular wall, activates coagulation factor Vll. The activated form of this (Vila) autocatalytically promotes its own synthesis and also generates the active factors IXa and Xa from their precursors. With the aid of factor Villa, PL, and Ca factor IXa produces additional Xa, which finally— with the support of Va, PL, and Ca ""—releases active thrombin. 

Extrinsic pathway Coagulation is activated by release of tissue thromboplastin, a factor not found in circulating blood. Clotting occurs in seconds because factor III bypasses the early reactions. 

Tissue thromboplastin (III), Stuart factor (X), proconvertin (VII), and calcium (IV)... 

Lindahl AK, Abildgaard U, Larsen ML, Aamodt LM, Nordfang O, Beck TC. Extrinsic pathway inhibitor (EPI) and the postheparin anticoagulant effect in tissue thromboplastin induced coagulation. Thromb Res 1991 (suppl 14) 39—48. 

I 10 Day KC, Hoffman LC, Palmier MO, et al, Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit. Blood 1990 76 1538-1545. 

The mechanism by which heparinized surfaces maintain their non-thrombogenicity has been investigated by a number of experimental techniques. The evidence indicates that the absence of clotting in in vitro experiments is not caused by heparin release into the blood because normal clotting occurred in heparinized vessels to which either tissue thromboplastin or an activating surface such as kaolin was added. In addition, a number of surfaces which contained large amounts of heparin caused clotting in contacted blood. These surfaces presumably did not... 

The procedure used for determination of clotting time is a modification of a Lee-White Clotting Test. Before each test was undertaken, the surface of each sample was thoroughly washed with distilled water and oven dried. Blood used in these tests was obtained from a normal human volunteer and was used as drawn without citration. The twenty cc. of blood used for each test were drawn from an antecubital vein. In order to ensure that the blood which was used in each test was of a low tissue thromboplastin concentration, a two syringe technique was used and only the last 6 cc. of blood taken were used in the test the first 14 cc. were discarded. Time measurement was started as soon as the blood entered the tube and stopped upon the onset of clot formation. Occasionally, when the sample was observed not to have clotted within thirty minutes, a portion of the blood was removed from the tube and placed on a piece of gauze and carefully examined for slight evidence of clot formation. The samples which were used for the above test were as follows ... 

Physiological coagulation (the extrinsic pathway) begins when tissue factor (TF, tissue thromboplastin), exposed by vascular injury, activates and complexes with factor VII to activate factors IX and X which complex with Villa and Va respectively on membrane surfaces (which provide phospholipid, PL). The Xa/Va complex converts prothrombin to thrombin which converts fibrinogen to fibrin and also activates factors XI, VIII, V and XIII, both accelerating coagulation and cross-linking fibrin (-F-F-F-). 

Exogenous activation is initiated by tissue thromboplastin (= tissue factor) and the activated form of factor XII in the plasma. This complex is enlarged by ionic calcium and platelet factor 3. As a result, the activation of factors IX to IXa and X to Xa is triggered, thus forming a cross-connection between the endogenous and the exogenous system, (s. fig. 19.1)... 

Thrombotic microangiopathy results from a massive activation of the clotting cascade. The major initiating factors are the release or expression of tissue factor, usually involving entry of tissue thromboplastins into the circulation, extensive injury to vascular endothe-... 

Disorders of fibrinogen also occur in the liver. For example, dysfibrinogenemia may be seen in both acute and chronic liver disease and leads to prolongation of the partial thromboplastin time, Disseminated intravascular coagulation occurs with acute hepatic necrosis, presumably as a result of the release of tissue thromboplastin and defective clearance of inhibitors such as antithrombin and protein C. Thrombocytopenia may contribute to ineffective intravascular coagulation. Although commonly attributed to splenic sequestration (hypersplenism), there is evidence of antibody-mediated platelet destruction, as occurs in... 

Factor VII is the only coagulation foctor in the circulating blood which has enzymatic activity in its native form (03). While Factor VII has esterase activity, it must interact with tissue thromboplastin to form a potent activator of Factor IX or Factor X (05). An assay which could detect the presence of Factor Vila in the circulation could help to screen for those patients at a high risk for cardiovascular disease. 

The first phase of the multiphased sequence has the production of the prothrombin-converting factor as its ultimate purpose. The synthesis of the activated form of factor X begins with the activation of factor XII (the contact factor) to XI, then IX followed by VIII. This represents the intrinsic pathway. An extrinsic pathway to activated factor X also exists. It depends on the release of thromboplastin (factor III) into the blood from the damaged blood vessel wall (or other tissue). This tissue thromboplastin, in the presence of Ca2+ and activated factor VII, is also activated to factor X. The two pathways are essential. They operate at very different rates. 

The components of the intrinsic system are all present in the plasma or platelets. They are stimulated by contact with a foreign surface, especially collagen. The components of the extrinsic system require additional components for activation. In particular, a factor called tissue factor or tissue thromboplastin is released after damage to the walls of blood vessels and triggers the extrinsic system. 

Pharmacokinetics generation, neutralizes tissue thromboplastin blocking the action of vitamin K... 

When blood is lost or clotting is initiated in some other way, a complex cascade of biochemical reactions is set in motion, which ends in the formation of a network or clot of insoluble protein threads enmeshing the blood cells. These threads are produced by the polymerisation of the molecules of fibrinogen (a soluble protein present in the plasma) into threads of insoluble fibrin. The penultimate step in the chain of reactions requires the presence of an enzyme, thrombin, which is produced from its precursor prothrombin, already present in the plasma. This is initiated by factor lit (tissue thromboplastin), and subsequently involves various factors including activated factor Vn, DC, X, XI and XII, and is inhibited by antithrombin in. Platelets are also involved in the coagulation process. Fibrinolysis is the mechanism of dissolution of fibrin clots, which can be promoted with thrombolytics. For further information on platelet aggregation and clot dissolution, see Antiplatelet drugs and thrombolytics , (p.697). 

The prothrombin time test (PT, Pro-Time, tissue factor induced coagulation time) is the most eommon method employed in clinical situations. It measures the time taken for a fibrin elot to form in a citrated plasma sample eontaining ealeium ions and tissue thromboplastin. The PT is usually reported as the International Normalised Ratio (INR). 

Fibrinogen Prothrombin Tissue thromboplastin Calcium ions Proaccelerin Not assigned Proconvertin Antihemophilic factor Christmas factor Stuart factor... 

Expression of tissue thromboplastin and urokinase-type plasminogen activator (EC 3.4.21.73) receptor were stimulated in monocyte-like U-937 cells treated with 5 ng 12-0-tetradecanoylphorbol-13-acetate per ml (Haase et al. 1993). 

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