The formation of factor Xa is the major site where the intrinsic and extrinsic pathways converge. The intrinsic pathway involves factors XII, XI, IX, VIII, and X, as well as prekallikrein, high-molecular weight (HMW) kininogen, Ca2+, and cell surface exposed phosphatidylserine. This pathway results in the production of factor Xa by the intrinsic tenase complex (see later for com position), in which factor IXa serves as the serine protease and factor VIIIa as the cofactor. As noted earlier, the activation of factor X provides an important link between the intrinsic and extrinsic pathways.

The intrinsic pathway can be initiated by “contact” in which prekallikrein, HMW kininogen, factors XII and XI are exposed to a negatively charged activating surface. In vivo, polymers of phosphates, such as extracellular DNA, RNA, and polyphosphate (macromolecules available only following cell damage) may serve as this negatively charged activating surface. Kaolin, a highly negatively charged hydrated aluminum silicate, can be used for in vitro tests as an initiator of the intrinsic pathway. When the components of the contact phase assemble on the activating surface, factor XII is activated to factor XIIa on proteolysis by kallikrein. This factor XIIa, generated by kallikrein, cleaves prekallikrein to generate more kallikrein, setting up a positive feedback activation loop. Factor XIIa, once formed, activates factor XI to XIa and also releases bradykinin (a peptide with potent vasodilator action) from HMW kininogen.

In the presence of Ca2+, factor XIa activates factor IX (55 kDa, a Gla-containing zymogen), to the serine protease, factor IXa. This, in turn, also cleaves an Arg-Ile bond in fac tor X to produce factor Xa. This latter reaction requires the assembly of components, called the intrinsic tenase complex, composed of Ca2+-factor VIIIa-factor IXa, which forms on procoagulant membrane surfaces expressing phosphatidyl serine, often activated platelets. (Note that this phospholipid is normally on the inner leaflet side of the plasma membrane bilayer of resting, nonactivated platelets.)

Factor VIII (330 kDa), a circulating glycoprotein, is not a protease precursor but a cofactor precursor that, when activated, serves as a receptor on the platelet surface for factors IXa and X. Factor VIII is activated by minute quantities of thrombin to form factor VIIIa, which is in turn inactivated on further cleavage by thrombin-mediated activated protein C.

The role of the initial steps of the intrinsic pathway in initiating coagulation has been called into question because patients with a hereditary deficiency of factor XII, prekallikrein or HMW kininogen do not exhibit bleeding problems. Similarly, patients with a deficiency of factor XI may not have bleeding problems. In thrombosis, deficiencies in the intrinsic pathway are protective. The intrinsic pathway largely serves to amplify factor Xa and ultimately thrombin formation, through feedback mechanisms. The intrinsic path way may also be important in fibrinolysis since kallikrein, and factors XIIa and XIa can cleave plasminogen, and kallikrein can activate single-chain urokinase.

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Biomembranes Contain Three Principal Classes of Lipids

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