Factor VIII is a protein that plays a specific role in the body’s system for stopping bleeding, a process known as hemostasis. Often called Factor 8, its primary job is to help generate a stable blood clot following injury. This protein is a component of the coagulation cascade, the series of biochemical steps that prevent excessive blood loss. Defects or deficiencies in Factor VIII are directly responsible for Hemophilia A, the most common inherited bleeding disorder.
How Factor VIII Works in the Clotting Cascade
Factor VIII performs its function as a cofactor, meaning it must first be activated before it can participate in clot formation. In its inactive form, it circulates in the bloodstream tightly bound to von Willebrand Factor (vWF). This binding protects Factor VIII from premature breakdown. Upon vascular damage, an enzyme known as thrombin cleaves the Factor VIII protein, causing it to dissociate from vWF and become activated Factor VIIIa.
Activated Factor VIIIa then forms a complex with activated Factor IX (Factor IXa) on the surface of activated platelets. This assembly is called the intrinsic tenase complex. The tenase complex dramatically accelerates the activation of Factor X into Factor Xa, ensuring a rapid and robust production. Factor Xa is the final enzyme needed to convert prothrombin into thrombin, which ultimately leads to the creation of a stable fibrin mesh.
Understanding Factor VIII Deficiency (Hemophilia A)
The condition resulting from inadequate or non-functioning Factor VIII is Hemophilia A. This disorder prevents the blood from clotting effectively, leading to prolonged bleeding after injury and, in severe cases, spontaneous bleeding. The severity of Hemophilia A is directly correlated with the concentration of Factor VIII activity in the blood.
Individuals with severe Hemophilia A have Factor VIII activity levels less than 1% of normal. This low level often causes frequent spontaneous bleeding episodes, particularly into joints and muscles. Recurrent bleeding into joints, known as hemarthrosis, is a major concern in severe cases because it causes chronic inflammation and progressive joint damage.
Moderate Hemophilia A is defined by Factor VIII levels between 1% and 5%, resulting in bleeding only after minor injuries or trauma. Mild Hemophilia A applies to those with Factor VIII activity ranging from 6% up to 49% of normal levels, who usually only experience abnormal bleeding in response to major trauma, surgery, or dental procedures.
The Genetic Basis of Factor VIII Production
Factor VIII is a large glycoprotein primarily produced by the sinusoidal cells of the liver and endothelial cells. The instructions for manufacturing this protein are contained within the \(F8\) gene, which is located on the X chromosome. This location determines the inheritance pattern of Hemophilia A, classifying it as an X-linked recessive disorder.
Males have only one X chromosome, so if it carries the mutated \(F8\) gene, they express the condition. Females have two X chromosomes; if they inherit one affected gene, the second healthy copy usually prevents severe symptoms, making them carriers. A male with Hemophilia A cannot pass the condition to his sons, but all his daughters will inherit the affected gene. In about one-third of new cases, the disorder results from a spontaneous gene mutation with no prior family history.
Modern Treatment Approaches
The management of Factor VIII deficiency relies primarily on replacement therapy. This involves infusing concentrated Factor VIII directly into the bloodstream to replace the missing protein. Concentrates are sourced either from human plasma or, more commonly, manufactured using recombinant DNA technology, which produces a highly purified product.
Treatment is administered either on-demand to stop acute bleeding or prophylactically (on a regular schedule) to prevent bleeds. Prophylaxis, typically involving two to three infusions per week, is the standard of care for severe hemophilia, as it significantly reduces spontaneous joint bleeds and long-term damage. For mild or moderate cases, a synthetic hormone called desmopressin can be used, as it stimulates the release of Factor VIII stored in the body’s tissues.
Newer, non-factor therapies are also transforming care. Emicizumab, a bispecific monoclonal antibody, mimics Factor VIII function by bridging Factors IXa and X, bypassing the need for the deficient protein. Administered by subcutaneous injection, it offers an effective alternative to intravenous Factor VIII infusions. Gene therapy has also become a reality, with approved treatments that aim to provide a functional copy of the \(F8\) gene, offering the potential for a long-term cure by allowing the body to produce its own Factor VIII.