Blood clotting is an essential mechanism in body that prevents the loss of the blood. In the blood vessels the blood remains in the liquid state but thickens or coagulates once it leaves the vessels. This process requires a combined action of many clotting factors, enzymes, calcium ions and platelets and damaged tissues. This is known a coagulation cascade which restores the homeostasis (Ware, Corken, & Khetpal, 2013). There are 13 clotting factors (please refer concept map). The most important plasma clotting factor is factor VIII. The paper deals with the deficiency of factor VIII which results in Haemophilia and disturbance of the haemostasis.
The complete process of blood clotting is divided into three stages. It includes vascular phase, secondary phase or primary haemostasis and coagulation phase or secondary haemostasis (Hoffman & Pawlinski, 2014). The process is initiated by the formation of prothrombinase, thrombin, and fibrin. Prothrombinase is formed by (prothrombinase activator) intrinsic and extrinsic system. Both the systems interact with the coagulation factor. The intrinsic pathway is mediated by the contact of the foreign substance with the liquid blood or its exposure to collagen. The extrinsic pathway is initiated by interaction between liquid blood and the damaged vascular or extravascular tissue (Refer concept map).
Figure: Extrinsic and intrinsic pathway
(Source: www.haemophilia .ca)
Haemophilia is the genetic disorder due to deficiency of factor VIII. Factor VIII has high affinity for VON WILLEBRAND FACTOR or vWF complex that prevents its premature binding to factor X–activating complex (Bladel et al., 2014). In haemophilia this binding is prevented and factor VIII is not stabilised. Further factor VIII markedly enhances the proteolytic activity of the factor IXa in the factor X–activating complex which is also inhibited in the haemophilic condition. In the tenase complex, the cofactor to factor of F IXa is F VIII (Gouw et al., 2013). Therefore, deficiency of this factor decreases the generation of thrombin. In the normal individuals the photolysis of factor VIII activates its cofactor activity. In the haemophilia individual both these enzymes fail to cleave factor VIII (at heavy and light chains, at Arg site) and thus factor IXa activity is not enhanced.
Figure: Activation of FVIII by vWF
It is due to genetic mutation the amino acids (Arg, Ser,) at the cleavage sites are replaced (Bladel et al., 2014). Consequently, the factor VIII–vWF complex upon treatment with the thrombin fails to dissociate. This inhibits factor X–activating complex and activation of factor X. Formation of this assembly, is required only after the coagulation cascade is initiated. Conclusively, the hemostatic balance is disturbed due to deficicncy in factor VIII (Shahverdi et al., 2016).
Figure: clotting cascade
Given below is the concept map illustrating the mechanism by which factor VIII deficiency disturbs Haemostasis.
Bladel, E. R., Tuinenburg, A., Roest, M., Groot, P. G., & Schutgens, R. E. (2014). Factor VIII concentrate infusion in patients with haemophilia results in decreased von Willebrand factor and ADAMTS?13 activity. Haemophilia, 20(1), 92-98.
Gouw, S. C., Van Der Bom, J. G., Ljung, R., Escuriola, C., Cid, A. R., Claeyssens-Donadel, S., ... & Muntean, W. (2013). Factor VIII products and inhibitor development in severe hemophilia A. New England Journal of Medicine, 368(3), 231-239.
Hoffman, M., & Pawlinski, R. (2014). Hemostasis: old system, new players, new directions. Thrombosis research, 133, S1-S2.
Shahverdi, E., Abolghasemi, H., Dolatimehr, F., Beheshtian, S., Chaeichi, S. M., & Masoumi, A. (2016). Combined Factor V and Factor VIII Deficiency: A Case Report. Galen Medical Journal, 5(1), 42-44.
Ware, J., Corken, A., & Khetpal, R. (2013). Platelet function beyond hemostasis and thrombosis. Current opinion in hematology, 20(5).