Haemostatic regulation Natural anticoagulants

The prevention of unlimited thrombin generation and, therefore, unchecked thrombosis is catalysed by the important, naturally occurring anti-coagulant proteins. These include:

(1) Anti-thrombin:

Anti-thrombin (AT) is a single-chain glycoprotein synthesised in the liver and the endothelium. AT is the main physiological inhibitor of activated coagulation serine proteases (Figs. 8 and 9). It inactivates thrombin, factor Xa, IXa, and XIa. Its activity is greatly accelerated (1000- to 2000-fold) by therapeutic heparin and, therefore, it is sometimes known as heparin co-factor I.17

(2) Heparin co-factor II:

This is also a single chain glycoprotein and is of liver origin. It complexes with thrombin in a 1:1 ratio, thereby inactivating it. In contrast to AT, heparin co-factor II is specific for thrombin, having no inhibitory activity against the other serine proteases. Its activity is also greatly amplified, 1000-fold, by therapeutic heparin.

Heparan Endothelium sulphate

Key: AT, anti-thrombin; T, thrombin; TM, thrombomodulin; PC, protein C; PS, protein S Fig. 8 Natural anti-coagulant pathways that inhibit thrombin generation.

Heparan Endothelium sulphate

Key: AT, anti-thrombin; T, thrombin; TM, thrombomodulin; PC, protein C; PS, protein S Fig. 8 Natural anti-coagulant pathways that inhibit thrombin generation.

(3) Protein C and Protein S pathway:

Protein C is a vitamin K dependent factor that plays a dual role in haemostasis by inhibiting blood coagulation and stimulating fibrinolysis. Recently, it was shown to have a major antiinflammatory role. Upon activation by thrombin in the presence of its endothelial cofactor, thrombomodulin (TM) and protein C endothelial receptor (EPCR), activated protein C inhibits the coagulation cascade by inactivating activated factors VIII and V.18 This reduces the rate of thrombin generation (Figs. 9 and 11). Protein S is required as a non-enzymatic cofactor for protein C activity (Figs. 8 and 10). Thrombomodulin is present in tight association with vascular endothelium. Complexed thrombin

FVIII-

F IXa

F Xa-AT Complex

AT + heparin

AT + heparin

Fibrinogen Fibrin

T-AT complex

Fig. 9 Anti-thrombin pathway.

Fibrinogen Fibrin

T-AT complex

Fig. 9 Anti-thrombin pathway.

Fibrinogen Fibrin

Fig. 10 PC/PS pathway.

Fibrinogen Fibrin

Fig. 10 PC/PS pathway.

Clot initiating complex

Indirect |_

Direct

Prothrombin ▼ ^ Thrombin

activates protein C several thousand times faster than unbound thrombin, but does not clot fibrinogen, activate factors V and VIII, or aggregate platelets. Thrombomodulin-bound thrombin can still be inhibited by AT.

Protein S is a single chain glycoprotein synthesised in the liver and the endothelium. It is vitamin K dependent, but is not a serine protease. Activated protein C complexes with protein S and calcium ions on platelets and on the endothelial surface. The inhibitory activity of complexed protein C is greatly amplified.18 Protein Z is also a vitamin K dependent factor, but its full function is not as yet known.

The two principle anti-coagulant pathways, known to be important in the regulation of coagulation proteinase activity are schematically represented in Figs. 8 and 9. On the left side of each diagram, is a simplified view of the coagulation cascade with its "procoagulant" feedback loops by which thrombin activates factors V and VIII. To the right, are the "anti-coagulant" pathways by which excessive activation of coagulation is prevented. These pathways involve anti-thrombin (which directly inhibits the coagulation proteins, such as, factor Xa and thrombin) and PC-PS (which inactivates factors Va and VIIIa).18

(4) Tissue factor pathway inhibitor (TFPI):

It is an important inhibitory regulator of in vivo coagulation (Fig. 10). TFPI is synthesised by the endothelial cells and circulates in plasma bound to low-density lipoproteins. It is also present in platelets and bound to heparan sulphate on the endothelial surface. TFPI inhibits coagulation by binding to factor Xa-TF-VIIa complex and, therefore, inhibiting its proteloytic activity.1^

It is the downregulation of tissue factor pathway activity is via a natural plasma component, tissue factor pathway inhibitor (TFPI), which halts continued direct generation of factor Xa. Therefore, continued Xa formation becomes dependent on ongoing activation of factor X by the IXa-VIIIa-phospholipid complex. Neither components of the thrombus initiating complex, TF or VIIa, can be inhibited separately (Fig. 10).15,16

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