Factor VIII (FVIII) is a complex protein that plays a part in the body’s ability to stop bleeding. It acts as a cofactor, accelerating a crucial step in the coagulation cascade that leads to the formation of a blood clot. FVIII is an integral component of the intrinsic pathway, where its activation is required to generate the enzyme thrombin, the final catalyst for clot stabilization. Without functional FVIII, the body cannot form a stable fibrin plug, leading to the prolonged and dangerous bleeding seen in inherited disorders.
The Body’s Primary Manufacturing Location
The vast majority of Factor VIII circulating in the bloodstream is synthesized in the liver. Production occurs not in the main liver cells (hepatocytes), but in a specialized population of cells called Liver Sinusoidal Endothelial Cells (LSECs). LSECs line the extensive network of blood vessels within the liver and translate instructions from the F8 gene into the final protein structure. They then release the protein directly into the circulation.
While LSECs are the major source, endothelial cells in other organs, such as the spleen, kidney, and lungs, also contribute to the total Factor VIII plasma pool. Once synthesized, the protein is immediately secreted into the sinusoidal blood flow, ready to begin its function in the coagulation system.
Stabilization and Circulation with von Willebrand Factor
Upon release, Factor VIII is a highly unstable molecule that would be rapidly broken down and cleared if left unprotected. To overcome this vulnerability, it immediately forms a non-covalent, reversible complex with a much larger glycoprotein called von Willebrand factor (vWF). This binding significantly extends the half-life of Factor VIII in the circulation from an hour or two to approximately 8 to 12 hours.
Von Willebrand factor acts as both a chaperone and a carrier, transporting Factor VIII safely through the bloodstream. The complex remains intact until a blood vessel is damaged, triggering the coagulation process. At the site of injury, the enzyme thrombin is generated, which cleaves and activates the Factor VIII protein. This cleavage causes FVIII to dissociate from its vWF carrier, allowing the now-active protein to participate fully in the cascade to create a stable blood clot.
When Production Fails: Understanding Hemophilia A
When the body fails to produce sufficient amounts of functional Factor VIII, the result is the inherited bleeding disorder known as Hemophilia A. This condition is caused by a genetic mutation in the F8 gene, which provides the instructions for making the protein. Since the F8 gene is located on the X chromosome, Hemophilia A follows an X-linked recessive inheritance pattern, primarily affecting males. The specific mutation determines whether the protein is completely absent, structurally defective, or produced in very low quantities.
The severity of the disorder is directly proportional to the amount of functional Factor VIII protein remaining in the patient’s blood plasma. Patients are classified into three groups based on their circulating Factor VIII activity levels.
Severity Classifications
Severe hemophilia A is diagnosed when a patient has less than 1% of the normal amount of Factor VIII. This often results in spontaneous bleeding into joints and muscles.
Moderate hemophilia is defined by Factor VIII levels between 1% and 5%. Bleeding typically occurs only after minor trauma.
Individuals with mild hemophilia A retain Factor VIII activity between 6% and 40% of normal. They usually experience bleeding only in response to significant injury, surgery, or dental procedures.
Creating Therapeutic Factor VIII
Modern medicine addresses Factor VIII deficiency in Hemophilia A by administering concentrated replacement therapy. Historically, this Factor VIII was derived by purifying the protein from pooled human blood plasma. This method carried inherent risks of transmitting blood-borne viruses, prompting a search for safer alternatives.
Today, the standard treatment involves Recombinant Factor VIII (rFVIII), a product created through advanced genetic engineering techniques. The process begins by isolating the human F8 gene and inserting it into the DNA of specialized host cells, often mammalian cell lines such as Chinese Hamster Ovary (CHO) cells. These cells are then grown in large-scale bioreactors, where they synthesize the human Factor VIII protein.
The rFVIII product is secreted into the surrounding culture medium, collected, and purified through multiple steps. It is then formulated for intravenous infusion, providing a consistently available, high-quality, and pathogen-free therapeutic protein.