Factor VIII is a protein essential for blood clotting. The genetic disorder hemophilia A is caused by a defect or deficiency in this protein, leading to prolonged or spontaneous bleeding. To manage this condition, a laboratory-grown version called recombinant Factor VIII (rFVIII) was developed. This bioengineered protein replaces the missing Factor VIII in individuals with hemophilia A, enabling a more normal clotting process.
Manufacturing of Recombinant Factor VIII
The production of recombinant Factor VIII relies on genetic engineering. The process begins by isolating the human gene for Factor VIII and inserting it into the DNA of mammalian host cells, such as Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cells. These modified cells are selected and cultivated, acting as microscopic factories that produce the human Factor VIII protein.
These engineered cells are grown in large quantities within bioreactors, where they secrete the Factor VIII protein into a culture medium. The protein is then separated from the host cells and purified through multiple steps, including nanofiltration, to ensure the final product is safe for medical use.
This manufacturing method contrasts with older techniques that used plasma from human blood donors. Creating the protein in a laboratory eliminates the risk of transmitting blood-borne viruses associated with plasma-derived products. The resulting rFVIII is then freeze-dried into a powder for stable storage before it is reconstituted for patient use.
Clinical Use in Hemophilia A
Managing hemophilia A with recombinant Factor VIII involves administering the protein directly into the bloodstream through intravenous (IV) infusion. After receiving proper training from a specialized hemophilia treatment center, patients or family members can perform these infusions at home. These centers provide comprehensive care and education, helping individuals manage their condition and treat bleeds promptly to reduce long-term complications.
There are two primary strategies for using rFVIII: prophylaxis and on-demand therapy. Prophylaxis is the standard approach for severe hemophilia A and involves regular infusions to maintain a consistent level of Factor VIII in the blood. This preventative method helps stop bleeding episodes before they start, protecting joints from damage.
The alternative is on-demand, or episodic, therapy, where rFVIII is infused only in response to an active bleed. While this method addresses bleeds as they happen, studies have shown that prophylactic treatment is more effective at preventing the progression of joint damage and reducing the overall frequency of bleeding episodes. The specific dose and frequency of infusions are tailored to the individual’s needs.
Immune Response and Inhibitor Development
A complication in treating hemophilia A is the patient’s immune system reacting to the infused rFVIII. The immune system may identify rFVIII as a foreign substance and produce antibodies against it. These antibodies, known as “inhibitors,” bind to the Factor VIII protein and block its function, rendering the treatment ineffective.
Inhibitor development is most common in patients with severe hemophilia A, particularly within the first 50 days of treatment. The presence of inhibitors makes it difficult to control bleeding, leading to increased health risks and more complex treatment. Patients are monitored through blood tests, such as the Bethesda assay, which measures the inhibitor level, or “titer.” A high titer of inhibitors poses a greater risk of severe bleeding.
If inhibitors develop, a treatment known as Immune Tolerance Induction (ITI) may be used. ITI involves administering high doses of Factor VIII regularly over a prolonged period to train the immune system to accept the protein. While ITI can be successful, it is an intensive process, and the risk of inhibitor development remains a serious challenge in managing hemophilia A.
Evolution of Recombinant Therapies
Recombinant Factor VIII products have evolved to improve patient quality of life by reducing the treatment burden. The first generations are known as Standard Half-Life (SHL) products. The term “half-life” refers to the time it takes for half of the infused Factor VIII to be cleared from the bloodstream, which for SHL products is between 8 and 14 hours. This short duration necessitates frequent infusions for effective prophylaxis, often three times per week.
To address this limitation, newer Extended Half-Life (EHL) products were developed to last longer in the body, with a half-life about 1.5 times longer than SHL products. This extension is achieved through techniques like fusing the Factor VIII molecule to another protein or by attaching polyethylene glycol (PEG) molecules. These modifications help protect the Factor VIII from being cleared from circulation too quickly.
The primary benefit of EHL therapies is a reduced frequency of infusions for prophylaxis. Patients may only need to infuse once every three to five days, or in some cases, once a week. This decreased treatment frequency can improve adherence to prophylactic schedules and the daily lives of individuals with hemophilia A.