Coagulation cascade intrinsic pathway

Figure 51-1. The pathways of blood coagulation. The intrinsic and extrinsic pathways are indicated. The events depicted below factor Xa are designated the final common pathway, culminating in the formation of cross-linked fibrin. New observations (dotted arrow) include the finding that complexes of tissue factor and factor Vila activate not only factor X (in the classic extrinsic pathway) but also factor IX in the intrinsic pathway, in addition, thrombin and factor Xa feedback-activate at the two sites indicated (dashed arrows). (PK, prekallikrein HK, HMW kininogen PL, phospholipids.) (Reproduced, with permission, from Roberts HR, Lozier JN New perspectives on the coagulation cascade. Hosp Pract [Off Ed] 1992Jan 27 97.)...

The pathophysiology of hemophilia is based on the factor VIII or IX deficiency resulting in inadequate thrombin generation and an impaired intrinsic-pathway coagulation cascade (see... 

Figure 12.2 The steps unique to the intrinsic coagulation pathway. Factor Xlla can also convert prekal-likrein to kallikrein by proteolysis, but this is omitted for the sake of clarity. Full details are given in the main text. The final steps of the coagulation cascade, which are shared by both extrinsic and intrinsic pathways, are outlined in Figure 12.3...

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. 

From a series of sulfated bis-aldonic acid amides with different alkyl spacer length, compound 34 was chosen for further evaluation as an antithrombotic. This compound was synthetically available in four steps from lactobionic acid (Scheme 7). Compound 34 had relatively high APTT values (42 U/mg) and antithrombotic activity, both of which decreased gradually when the number of methylene groups in the spacer was increased. It was thought to act via HCII and multiple sites in the intrinsic pathway of the coagulation cascade [64]. 

Hemostasis begins with the formation of the platelet plug, followed by activation of the clotting cascade, and propagation of the clot. One of the major multicomponent complexes in the coagulation cascade consists of activated factor IX (factor IXa) as the protease, activated factor VIII (factor Villa), calcium, and phospholipids as the cofactors, and factor X as the substrate. Factor IXa can be generated by either factor Xa activation of the intrinsic pathway or by the tissue factor/factor Vila complex. 

Traditionally, the coagulation cascade has been divided into three distinct parts the intrinsic, extrinsic, and common pathways " (see Fig. 19-4). This artificial division is somewhat misleading because there are numerous interactions among the three pathways. The extrinsic pathway, sometimes referred to as the tissue factor pathway, appears to be the principal mechanism that triggers the coagulation... 

Measurements of the coagulation proteins are generally the responsibility of the hematology laboratory and are usually confined to prothrombin time and activated partial thromboplastin time measurements, or some alternative measures of the performance of the intrinsic and extrinsic coagulation cascade pathways (Theus and Zbinden 1984). The coagulation proteins synthesized by the liver also can be used as markers of hepatotoxicity (Pritchard et al. 1987). 

Activation of the blood coagulation cascade is triggered by the reaction of plasma proteins with the subendothelium at the same time that platelets are adhering to the subendothelial layer. Historically, two different pathways were discovered, one dependent on external stimuli (such as blunt trauma, which initiates the extrinsic pathway) and one using internal stimuli (the intrinsic pathway). As our understanding of blood clotting has expanded, it has become obvious that these distinctions are no longer correct, because there is overlap between the pathways, but the terms have persisted in the description of the pathways. 

Blood coagulation occurs as a "cascade" of proteolytic factors are activated. Each factor is proteolyzed into an active protease. The newly-formed protease in turn proteolyzes the next factor into an active protease. The cascade produces fibrin, which forms an insoluble network that entangles blood cells and platelets. The clotting cascade can be activated by factors that reside only in the bloodstream (intrinsic pathway) or by tissue factors that are not present in blood (extrinsic pathway). 

Stuart-Factor, Stuart Prower-Factor, Thrombokinase, Factor X, a serine protease and constituent of the blood coagulation cascade. It is either be activated by factor IX (intrinsic pathway) or by Factor Vila (extrinsic pathway). In complex with Factor V as the cofactor it cleaves prothrombin at Arg-Thr and Arg-Ile to give active thrombin. 

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