Intrinsic Pathway

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The intrinsic pathway of blood clotting is a cascade reaction resulting in the formation of a fibrin clot through a process that does not require the participation of substances extrinsic to the blood. It works on the basis of protein-clotting factors acting in pairs where one behaves like an enzyme and the other like a substrate. Each of these protein-clotting factors are converted to factors with enzymatic properties eventually bringing about the conversion of prothombin to thrombin.

The intrinsic pathway is suggested to be a cascade reaction, which is supported by the investigations that have been, carried out on the pathway this far. It is important to note that each of the protein clotting factors are present in the blood in their inactive form and when clotting is started, each clotting factor except fibrinogen is converted to an active enzyme. This mechanism is initiated by contact with abnormal surfaces produced by injury. For example when you graze your knee the contact with the gravel initiates this mechanism.

The first step in this cascade is the conversion of Hageman factor to activated Hageman factor. The exact molecular events that occur during this process are unclear but we are able to assume that some rearrangement of the protein occurs to unveil of form anactive enzyme site. The activated Hageman factor then converts plasma thromboplastin antecedent (PTA) to an activated form.

The next step is the activation of Christmas factor by activated PTA. Activated PTA acts as an enzyme and this process has requirements of divalent metal ions and an optimum pH of 8.0. This step has many inhibitors, which prevent the clotting of blood. For example, citrate, oxalate and ethylenediaminetetraacetrate have a high affinity for binding with calcium; the most effective metal ion that plays a part in the activation of Christmas factor.

Another important inhibitor is Heparin. Heparin forms a complex with activated PTA making it inactive. Heparin plays an import role in surgery. It is regularly used when performing open-heart surgery, bypass surgery, kidney dialysis and blood transfusions to prevent blood clotting. The effects of heparin are reversed by protamine sulphate or hexadimethrine bromide. Protamine is used at the end of surgery so that when the operation is finished the blood can clot as usual.
Heparin also interferes with the activation of antihemophilic factor (AHF) and the formation of the thrombin fibrinogen complex but the major site of interference is blocking the Christmas factor activation.

The activation of AHF by Christmas factor requires calcium ions and phospholipids, a mixture containing phosphatidyl serine and phosphatidyl choline in equal measures is most effective. Subsequently, activated AHF interacts to form activated Stuart factor.

One of the final steps is the interaction between activated Stuart factor and proaccelerin to form activated proaccelerin. This reaction also requires phospholids.
Activated proaccelerin converts prothrombin to thrombin. Thrombin consequently converts fibrinogen to fibrin by cleaving 2 specific peptides from the N-terminal end of fibrinogen in a process called proteolysis. In the presence of calcium ions and activated fibrin stabilizing factor, a carbohydrate component and ammonia are released, N-terminal glycine residues disappear and fibrin monomerspolymerize and from cross linked bonds to give an insoluble fibrin network. The production of thrombin starts as a positive feedback reaction as thrombin activates FVIII (antihemophilic factor) and FV that produces thrombin. The thrombin can then bind with thrombomodulin (TM) to form TM-thrombin complexes that activate protein C. Activated protein C breaks down FVIII and FV therefore working as a negative feedback reaction as well.

The intrinsic system is likely to overlap with the extrinsic system at the point of the Stuart factor. In the extrinsic system, tissue thromboplastin and factor VII probably are responsible for activation of Stuart factor. Therefor the AHF, Christmas factor, PTA and Hageman factor would be missed out [1][2][3].

References

  1. Earl E. Davie and Oscar D. Ratnoff (29th June 1964) “Waterfall Sequence for Intrinsic Blood Clotting” http://www.sciencemag.org/content/145/3638/1310.long
  2. Jeremy M. Berg, John L.Tymoczko and Lubert Stryer, 7th edition Biochemistry page 318
  3. Jovan P. Antovic and Margareta Blombäck, “Essential Guide to Blood Coagulation” (2010)
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