Coagulation and fibrinolysis pathway

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Coagulation and Fibrolytic pathways -Note: High resolution version done for printing - click on image to reach

The coagulation and fibrinolysis pathway is a more accurate term than the classic coagulation cascade and describes the network of biological processes involved in fibrin clot manufacture necessary for haemostasis and dissolution. It has been modelled in considerable detail, and while understanding continues to advance, it is by investigation of steadily smaller differences between expected and in vivo observed responses[1]. A model of the extrinsic pathway in 2002 consisted of 34 differential equations with 42 rate constants describing 27 independent equilibrium expressions, which describe the fates of 34 molecules.[2] and the instrinsic pathway . A model orientated towards the intrinsic pathway also exists [3].

An overview is given in the diagram. Thrombin formation from prothrombin is the essential common step that has positive and negative feedbacks throughout the network.

Extrinsic initiation depends upon tissue factor activating factor VII on cell membranes which activates factor X. Tissue factor pathway inhibitor modulates this activation of factor X. Factor IX is also activated. Cell membrane associated activated factor X and factor V on platelets then activate thrombin. Thrombin in turn activates factor V providing the shortest positive feedback loop to its own formation. This explains in the classic model of coagulation the shorter activation time of the extrinsic pathway. Antithrombin inactivates activated factor X and forms thrombin-antithrombin complexs (TATs) which after about 15 minutes irreversibly inhibits thrombin.

Intrinsic activation involves the activation of factor XI although other activation mechanisms exist that are not essential to haemostasis in vivo including binding to glycoprotein Ibalpha in the presence of presence of high molecular weight kininogen and Zn2+ or prothrombin and Ca2+, which then activates factor IX. This and thrombin activated factor VIII on platelet cell membranes provide another means of activating factor X.

Thrombin acts on fibrinogen to produce the fibrin of the clot. Thrombin also activates two feedback mechanisms. One is through thrombomodulin of the cell membrane coat which activates protein C bound to the cell membrane to act on protein S and so enhance the inactivation of activated factor V. The other is via factor XIII which when activated attenuates the turnover of extravascular fibrin by cross-linking with it.


Structure of coagulation proteases

The structures of factors II (prothrombin), VII, IX, X, XI, XII are shown in the diagram. Each protein is secreted by hepatocytes into the blood. A signal peptide on each is removed during transit into the endoplasmic reticulum. About 200 amino acid residues at the C-terminal end of each protein contain the active site Ser, Asp, and His residues of the protease (catalytic domain). The proteins also contain a variety of domains that are homologous to portions of other proteins such as epidermal growth factor (EGF) and fibronectin. These domains appear to be involved in specific interactions between the proteases and their substrates, cofactors, and/or inhibitors.

Therapeutic implications

While haemostasis is key to survival of wounds a correct balance between coagulation and fibrinolysis is essential to both survive and minimise the consequence of many diseases. Thus haemophilia has been treated for many years with preparations that contain the deficient coagulation factors and peripheral thrombosis with anticoagulants such as heparin. It proved possible to intervene early in many cases of stroke and myocardial infarction with fibrinolysis towards the end of the twentieth century and the preventive role of therapeutic anticoagulation in non valvular atrial fibrillation has been defined in the same period. Indeed in the early twenty first century therapeutic advance continued with better definition of risk benefit of antifibrinolytics agents such as tranexamic acid so use became routine in major trauma, while use of aprotinin decreased markedly.

How warfarin and Ca2+works

After removal of the signal peptide, a carboxylase residing in the endoplasmic reticulum or Golgi apparatus binds to the propeptide region of Gla domain containing coagulation factors and converts about ten to tlweve glutamate (Glu) residues to γ-carboxyglutamate (Gla) in the adjacent "Gla domain". The propeptide is removed from the carboxylated polypeptide prior to secretion. The Gla residues bind calcium ions and are necessary for the activity of these coagulation factors. Synthesis of Gla requires vitamin K. During γ-carboxylation, the vitamin K becomes oxidized and must be reduced subsequently in order for the cycle to continue. Warfarin inhibits reduction of vitamin K.

Novel oral anticoagulants

NOACs work at different points of the pathway to warfarin and have more predictable pharmacodynamics. They became a blockbuster industry in the early twenty-first century as the inconvenience of vitamin K antagonists and heparin for many was replaced.