What is factor VIII?

Updated: Aug 04, 2021
  • Author: Bishnu Prasad Devkota, MD, MHI, FRCS(Edin), FRCS(Glasg), FACP, FAMIA; Chief Editor: Eric B Staros, MD  more...
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Answer

Answer

Factor VIII (antihemophilic factor) is a key factor of the intrinsic clotting cascade. Normal hemostasis requires at least a quarter (25%) of factor VIII activity.

Symptomatic hemophiliacs usually have levels 5% of normal level. Disease is categorized as severe if the level is less than 1%, moderate if it is 1-5%, and mild if the level is more than 5%.

Factor VIII assays are used to help replacement therapy in patients with hemophilia. [4]

Factor deficiency can be distinguished from factor inhibitor by an inhibitor screen. [5]

Factor VIII is produced in the liver, [6] perhaps not in hepatocytes. [7] Endothelial cells of liver are the major site of biosynthesis. [8] The notion of cure of hemophilia A by liver transplantation in human and canine subjects supports this statement. [9]

Factor VIII circulates with von Willebrand factor (VWF) in a noncovalent complex. VWF is a complex glycoprotein that works as a carrier for factor VIII. When associated with VWF, the half-life of factor VIII is 8-12 hours. The half-life is shortened without VWF. In many patients with a deficiency of VWF, low level of factor VIII has been found. [10] In a mouse model, isolated hepatocyte transplantation did not correct hemophilia A, but transplantation of a cellular fraction enriched in liver endothelial cells did. [7, 11]

The factor VIII gene is located on the X chromosome. Hemophilia A is transmitted as a sex-linked recessive manner due to deficiency of factor VIII. Activated factor X or thrombin activates factor VIII. This activation also results in the release of factor VIIIa from VWF. Factor VIIIa is inactivated by thrombin or activated protein C (APC). [7]

A study by Raffield et al indicated that in African Americans, factor VIII, which tends to be higher in African Americans than in Europeans, raises the likelihood of incident coronary heart disease events and mortality. The investigators also reported higher factor VIII levels to be associated, independent of B-type natriuretic peptide, with incident heart failure in African Americans. [12]

Bleeding episodes in patients with hemophilia A can be managed by replacing factor VIII. [13, 14] Several products are available for use in raising factor VIII. Both cryoprecipitate and fresh-frozen plasma (FFP) contain factor VIII and were the only products available for treatment in the past. A large volume of plasma must be infused to achieve and maintain even the lowest factor VIII levels. The highest factor VIII level achieved with plasma is about 20% of normal, which may not be adequate for hemostasis. [7] Several commercial lyophilized factor VIII concentrates that use cryoprecipitate of pooled normal human plasmas are available. Because of the risk of transmission of viruses, factor VIII concentrates have been sterilized by heating in solution, by superheating to 80° C, and by exposure to organic solvent-detergents that inactivate lipid-enveloped viruses, including HIV, hepatitis B, and hepatitis C viruses.

However, these procedures do not inactivate parvovirus or hepatitis A. [15, 16, 17] As parvovirus is transmitted by cellular elements of the blood, such infection does not occur frequently in patients with hemophilia A. Nonetheless, seroconversion to parvovirus B19 has been found in patients receiving plasma-derived concentrates treated with pasteurization or solvent-detergent extraction. [17]

Currently a dozen or so factor VIII products are available and are regarded as safe from the perspective of transmission of viruses. [17] Factor VIII produced by available recombinant DNA techniques is safe and effective. However, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) study indicated that in children with severe hemophilia A who have previously undergone minimal or no treatment, those who receive therapy with recombinant factor VIII products have twice the chance of developing inhibitors as do those treated with plasma-derived factor VIII, during the first 50 exposure days. [18, 19] A survey by Sande et al of hemophilia providers suggested that the SIPPET results have influenced the choice of factor VIII therapy being used in the United States, with employment of the recombinant agent for patients with minimal or no previous treatment decreasing from 70.5% to 27.8% of the clinicians and utilization of plasma-derived factor VIII rising from 8.2% to 16.7% of the providers. [20]

The severity and site of bleeding determine the frequency and dose of factor VIII infusion. In mildly or moderately affected hemophilia A patients, 1-desamino-8-D-arginine vasopressin (DDAVP; desmopressin) increases factor VIII levels 2-fold to 3-fold above baseline. However, patients with severe hemophilia A do not respond to DDAVP. [22] Mechanism of action of DDAVP in raising factor VIII level remains unknown. As DDAVP is a potent antidiuretic, hyponatremia may result by its use. Tachyphylaxis does occur with repeated administration.


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