Intrinsic pathway, coagulation

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...

Intrinsic pathway All the protein factors necessary for coagulation are present in circulating blood. Clot formation may take several minutes and is initiated by activation of factor XII. 

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]. 

Extrinsic pathway This pathway has fewer steps than the intrinsic pathway and occurs rapidly, within a matter of seconds if the trauma is severe. It is called the extrinsic pathway because a protein tissue factor, also called thromboplastin or coagulation factor III, takes into the blood stream from outside and initiates the formation of prothrombinase. Tissue factor is released from the surface of the damaged cells. It activates factor VII. Factor VII combines with factor X, activating it. Factor X in the presence of Ca combines with factor V to give active enzyme prothrombinase. 

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. 

Initiation of blood coagulation (clotting) occurs through the contact activation pathway (intrinsic pathway) and the tissue factor (TF) pathway (extrinsic pathway). The contact activation pathway is quantitatively the most important, but is much slower to initiate the TF pathway is considered to be the primary pathway for the initiation of blood coagulation and affords a more rapid response (the so-called thrombin burst), which augments the contact activation pathway. Both pathways share a common pathway that converges at factor X with the production of thrombin (Figure 11.1). 

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