In vivo versus in vitro coagulation The role of factor VIItissue factor complex TFVII

Current evidence indicates that the dominant pathway for blood coagulation is via factor VII and TF, and that the contact system activation plays a little role, if any, in vivo coagulation. Mainly, factor VII causes activation of factor IX.11,12 Factor XI in vivo is activated directly by thrombin and is important only at sites of major trauma

11_13

or operation.11 13

Therefore, the classical waterfall hypothesis described above, fails to represent accurately in vivo haemostasis. This is may be demonstrated by considering the following issues. First, although patients with congenital deficiency of factor XII, prekallikrein, or HMWK have extremely prolonged aPTTs, they do not have any clinical bleeding manifestations. This clinical observation indicates that these proteins are probably not important components of blood coagulation in vivo. Similarly, factor XI deficiency is not always associated with bleeding and, therefore, its role is unclear. Patients with factor VII deficiency, however, bleed abnormally, although the intrinsic pathway is largely intact. Third, factor VII-tissue factor is known to activate not only factor X, but also factor IX. In the classical pathway this activation is not required. Tissue factor is a natural constituent of many non-vascular cells. Tissue factor on such cells is able to initiate blood coagulation, supporting a more central role for the TF-VII complex.14

The revised hypothesis of coagulation

Based on the findings of the direct activation of factor IX by factor Vll-tissue factor the coagulation cascade was revised, with factor VII-TF and factor X central to the model. This model also takes into account the newly discovered feedback inhibition of factor Vila-tissue factor produced by tissue factor pathway inhibitor (TFPI).14,15

The role of vitamin K in blood coagulation

In addition to protein C, protein S, and protein Z coagulation factors II, VII, IX, and X are dependent on vitamin K for their biological activation and, therefore, normal function. These are synthesised in the liver in inactive forms that cannot bind calcium ions. This ability is conferred by a post-translational modification that involves gamma carboxylation of glutamic acid residues. Vitamin K in vivo continuously cycles between three forms: vitamin K quinone, vitamin K hydroquinone, and vitamin K epoxide. The gamma carboxylation reaction is coupled to the conversion of vitamin K hydroquinone to the epoxide form. Therefore, in vitamin K deficiency, gamma carboxylation fails and non-carboxylated forms of factors II, VII, IX, X and protein C, protein S, and protein Z are released into the circulation. Although they are immunologically identical to the normal proteins, these proteins induced by vitamin K absence or antagonism (PIVKAs) cannot bind calcium ions. They are non-biologically competent as they cannot bind to phospholipid surfaces.16

Fibrinolysis

Like coagulation, fibrinolysis is a normal haemostatic response to vascular injury. The deposition of fibrin is coupled by activation of the fibrinolytic pathway (Fig. 7). Fibrinogen and fibrin are substrates for the proteolytic action of plasmin. Unlike the highly specific action of thrombin on fibrinogen, which results in the cleavage of only two pairs of small fibrinopeptides, A and B, plasmin cleaves fibrinogen and fibrin at multiple sites. This produces a variety of split (degradation) products. Plasmin is normally present in its inactive zymogen form, plasminogen, in blood, urine, and tissue fluids. Major activation of the fibrinolytic system follows the release

Endothelium Liver

Other Cells Clearance

Endothelium Liver

Other Cells Clearance

Degradation Products

Fig. 7 Fibrinolysis.

Degradation Products

Fig. 7 Fibrinolysis.

of tissue plasminogen activator (t-PA) from endothelial cells. t-PA is a serine protease that binds to fibrin. This enhances its capacity to convert thrombus-bound plasminogen into plasmin. This fibrin dependence of t-PA action strongly localises plasmin generation by t-PA, to the fibrin clot. Release of t-PA occurs after stimuli, such as, trauma, exercise, or emotional stress. Activated protein C stimulates fibrinolysis by destroying plasmin inhibitors of t-PA. Therapeutic t-PA and urokinase are produced by recombinant DNA technology, while the fibrinolytic agent, streptokinase, is a peptide produced by haemolytic streptococci. It forms a complex with plasminogen, which converts other plasminogen molecules to plasmin. Plasmin has a wider range of activity than thrombin, hydrolysing both arginine and lysine peptide bonds in a wider range of substrates. Tissue plasminogen activator is inactivated by plasminogen activator inhibitor-1 (PAI-1). Circulating plasmin is inactivated by potent inhibitors a2-antiplasmin and a2-macroglobulin. This prevents widespread destruction of fibrinogen and other coagulation factors.11 In addition, thrombin activatable fibrinolysis inhibitor (TAFI) plays a role in limiting the fibrinolytic activity locally. Activated protein C stimulates the release of TAFI.12

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