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Coagulation Factor VIII

 

Overview:

Human factor VIII, also called anti-hemophilic factor, is a plasma glycoprotein that performs a substantial role in blood-clotting (Pratt, 1999). By being found in the blood plasma, factor VIII is able to get to any part of the body that may be bleeding. Without being localized in the blood, this factor would have to be expressed in every cell of the body to ensure bleeding could be stopped anywhere it started. Human factor VIII's amino acid sequence is 216aa long. This amino acid sequence is derived from an mRNA sequence containing 2536bp (NCBI, 2003). However, the coding sequence for the protein is only 651bp long. This protein is not only found in humans though. Many other creatures, dogs and mice included, also use a form of factor VIII in blood-clotting. In these other organisms the amino acid sequence is conserved, but the cDNA and mRNA varies slightly.

 

Blood Coagulation in mammals:

Blood clotting in mammals results from the conversion of a soluble plasma protein, into an insoluble matrix of fibers (Fig. 1). Fibrinogen or factor I is the soluble plasma protein that is eventually converted into fibrin, the insoluble matrix (Ratnoff, 1978). The change of fibrinogen into fibrin requires many other components that all play a role in the change.One protein that acts on the fibrinogen is thrombin.

Fig. 1. The formation of fibrin in human plasma (Ratnoff, 1973)

 

However, thrombin is not found in normal circulating blood. Thrombin is generated from its precursor, prothrombin (factor II), by what has been described as a waterfall or cascade with each product triggering the activation of the next (Ratnoff, 1978). In order for thrombin to be made, one factor, factor VIII, is required along with calcium and without factor VIII, thrombin cannot be made. Figure 2 displays the waterfall diagram of how thrombin is made with factor VIII interacting in the reaction sequence.

Fig. 2. The mechanisms of normal coagulation. Factor VIII shown interacting to help form thrombin(Ratnoff, 1978).

In order for factor VIII to form a functional protein, it must be activated by Christmas factor on the surface of phospholipids, along with calcium ions being present. However, Factor VIII circulates through the blood not as a solitary unit, but as a complex paired with von Willebrand factor (Pratt, 1999). As shown in Fig. 2., after factor VII is cleaved by thrombin, it binds with factor IX at either the surface of activated platelets or endothelial cells. Factor IX is then able to activate factor X, which in turn converts prothrombin to thrombin in the presence of factor V. With calcium present, the waterfall activation sequence is able to continue, however, without it, activated factor VIII is not produced. Without the activation of factor VIII, prothrombin is never changed into thrombin and clotting will not function properly (Pratt, 1999).

 

Disorders related to Factor VII:

The main disorder that is related to factor VII is Hemophilia A. Hemophilia A is a blood disorder that affects many people through-out the world. In the United States alone this disorder affects more than 20,000 people, along with about 400 babies being born with the disorder (MSN Encarta, 2003). Hemophilia A is known to cause, among other things, hemorrhaging into joints and muscles, easy bruising, and prolonged bleeding from wounds. Hemophilia A is a X-linked recessive disorder caused by a deficiency in the blood-clotting protein coagulation factor VIII (OMIM, 2003). This disorder has been traced to heterogeneous mutations in the factor VIII gene, located at Xq28(OMIM, 2003). The severity of the disorder has been shown to be inversely related to the "amount of residual factor VIII (<1%, severe; 2-5%, moderate; and 5-30%, mild)" (OMIM, 2003). Hemophilia can also lead to further ailments, including swelling, pain, decreased function, and degenerative arthritis in the joints of the ankles, hips and knees (OMIM, 2003). Muscle hemorrhage, another secondary ailment due to Hemophilia A, can also cause necrosis, contractures, and neuropathy (OMIM, 2003).

The origin of Hemophilia A may be in the original binding of factor VIII to von Willebrand factor. In order for prothrombin to be changed into thrombin, the entire cascade of activations is dependent on factor VIII binding to the von Willebrand factor. This binding has been shown to be dependent upon the C2 region of factor VIII, shown in figure 3 (Pratt, 1999). Structurally destabilizing mutations in this area of the the protein could cause factor VIII to become unable to bind with von Willebrand factor and lead to the bleeding disorders of Hemophilia A (Pratt, 1999).

To view an in-depth video on Hemophilia click here

Fig. 3. Ribbon diagram of the C2 domain of Factor VIII.

 

 

 

Resources

MSN Encarta. 2003. Hemophilia. <http://www.nhlbi.nih.gov/health/public/blood/other/hemophel.htm>. Accessed 2003 Mar 11.

NCBI. 2003. Hemophilia A. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=nucleotide&list_uids=18490689&dopt=GenBank>. Accessed 2003 Mar 11.

OMIM. 2003. Hemophilia A. <http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=306700>. Accessed 2003 Mar 11.

Pratt, K.P., Shen, B.W., Takeshima, K., Davie, E.W., Fujikawa, K., and Stoddard, B.L. 1999. Structure of the C2 domain of human factor VIII at 1.5 Å resolution. Nature. 402:439-441.

Ratnoff, O.D., and Bennett, B., 1973. The Genetics of Hereditary Disorders of Blood Coagulation. Science. 179:1291-1298.