Coagulation Factor VIII (FVIII) is a large glycoprotein that plays a necessary role in hemostasis, the mechanism that stops bleeding after injury. It functions as an accelerator in the chain reaction leading to the formation of a stable blood clot. Without sufficient levels of this protein, the clotting process is significantly impaired, leading to prolonged and often dangerous bleeding.
The Role of Coagulation Factor VIII in Hemostasis
Factor VIII circulates in the bloodstream in an inactive form, tightly bound to a larger carrier protein called von Willebrand factor (VWF). This association with VWF protects FVIII from being prematurely degraded and rapidly cleared from the circulation, thereby stabilizing its plasma levels. When a blood vessel wall is damaged, the coagulation cascade is triggered, and a small amount of the enzyme thrombin is generated.
Thrombin cleaves the inactive FVIII molecule, causing it to dissociate from VWF and become activated into Factor VIIIa (FVIIIa). FVIIIa does not possess enzymatic activity itself but functions as a cofactor to accelerate the next step in the cascade. FVIIIa binds to activated Factor IX (Factor IXa) on the surface of activated platelets at the site of injury.
This assembly forms the “tenase complex,” a highly efficient molecular machine. The tenase complex converts Factor X into its active form, Factor Xa, an action accelerated approximately 50-fold by FVIIIa. This amplification step is essential for generating a large burst of thrombin. Thrombin converts the soluble protein fibrinogen into the insoluble fibrin mesh that forms a durable clot.
Hemophilia A: Cause and Symptoms of Deficiency
A deficiency or malfunction of Factor VIII leads directly to the inherited bleeding disorder Hemophilia A, also called classic hemophilia. This condition is an X-linked recessive genetic disorder; the responsible gene, F8, is located on the X chromosome. Because males have only one X chromosome, they are predominantly affected, while females are typically carriers.
The severity of Hemophilia A is classified based on the residual FVIII activity level in the blood (normal levels range from 50% to 150%). Individuals with severe form have less than 1% of normal FVIII activity and experience frequent spontaneous bleeding episodes. Moderate hemophilia is defined by FVIII levels between 1% and 5%, with bleeding episodes typically occurring after minor injuries.
People with mild hemophilia have FVIII levels ranging from 6% up to 49% and usually only experience bleeding following significant trauma, surgery, or dental procedures. The most common symptoms are internal bleeds, especially into the joints, a condition called hemarthrosis. Recurrent joint bleeding causes chronic inflammation and progressive joint damage, leading to debilitating hemophilic arthropathy. Other serious concerns include muscle hematomas and bleeds into the central nervous system.
Standard Treatment: Factor VIII Replacement
The primary management strategy for Hemophilia A involves Factor VIII replacement therapy, which restores the missing clotting protein to the blood. This therapy can be administered in two main ways: prophylaxis or on-demand treatment. Prophylaxis is the standard of care for severe hemophilia, involving routine infusions of FVIII concentrate to maintain a protective factor level and prevent bleeding from occurring.
Prophylactic regimens are typically started early in childhood to protect against long-term joint damage and disability. On-demand treatment involves administering FVIII only after a bleeding episode has begun to stop the hemorrhage. While effective for acute bleeds, the on-demand approach does not offer the same protection as prophylaxis and is generally not recommended for severe disease.
Replacement FVIII products come from two main sources: plasma-derived concentrates (purified from human blood) and recombinant FVIII products (manufactured using biotechnology). Recent advances have introduced extended half-life (EHL) products, which are modified to remain in the bloodstream longer. EHL products reduce the frequency of required intravenous infusions, improving adherence and quality of life for patients.
Beyond direct replacement, non-factor therapies have emerged, such as the bispecific antibody emicizumab, which functionally mimics FVIIIa. This agent bridges Factor IXa and Factor X to form the tenase complex, bypassing the need for FVIII. These non-replacement options offer simplified subcutaneous administration and are beneficial for patients who have developed complications with traditional FVIII therapy.
Immune Response to Treatment: Inhibitor Development
The most significant complication of FVIII replacement therapy is the development of “inhibitors,” which are neutralizing antibodies against the infused FVIII protein. The body recognizes the replacement factor as foreign and mounts an immune response, rendering the treatment ineffective. This complication occurs in approximately 30% of people with severe Hemophilia A, typically early in life during the first treatment exposures.
When inhibitors are present, the infused FVIII is rapidly neutralized, meaning the factor level cannot be raised high enough to control bleeding. This makes managing bleeding episodes extremely difficult and puts patients at high risk for severe complications and joint damage. The current method to address this is Immune Tolerance Induction (ITI). ITI involves giving high doses of FVIII frequently over an extended period to train the immune system to accept the protein. ITI is the only established approach to successfully eradicate the inhibitor and allow a return to standard FVIII replacement therapy.