What is Factor VIII?
Factor VIII is an essential glycoprotein cofactor within the intrinsic pathway of the blood coagulation cascade. It is synthesized primarily in the liver by sinusoidal endothelial cells. Once in circulation, the inactive form of factor VIII forms a stable, non-covalent complex with another protein called von Willebrand factor (VWF). This partnership is crucial for two reasons: VWF protects factor VIII from being rapidly degraded and also helps to transport it to the site of an injury.
When a blood vessel is damaged, the coagulation cascade is activated. An enzyme called thrombin cleaves factor VIII, causing it to detach from VWF and become its active form, factor VIIIa. Factor VIIIa then works as a cofactor with activated factor IX (factor IXa) to accelerate the activation of factor X, a crucial step in forming a fibrin clot.
The Normal Range of Factor VIII Concentration
The concentration of factor VIII in plasma can be described in two ways: by its mass concentration (e.g., in mg/L) and by its activity level (e.g., in IU/dL or as a percentage of normal). The reason for this dual metric is that the protein's function is as important as its presence.
From a mass perspective, factor VIII is a trace protein. Its concentration is very low, typically cited as approximately 0.2 mg/L or 100–200 ng/mL. To put this into perspective, its molar concentration is around 1 nM.
In clinical and laboratory settings, however, factor VIII activity is the more relevant measurement. Activity levels are compared to the level found in a pool of normal human plasma, which is defined as 100%. The typical normal range is between 50% and 150%. Newer studies, however, suggest that the reference range may be wider, sometimes observed as 82.2–218.0 IU/dL.
Implications of Abnormal Factor VIII Levels
Abnormal concentrations or activity of factor VIII can lead to serious health conditions. Understanding the severity and cause of the abnormality is critical for proper diagnosis and treatment.
Low Factor VIII: Hemophilia A
Congenital deficiency or dysfunction of factor VIII is the cause of hemophilia A, also known as classic hemophilia. This is an X-linked genetic disorder, affecting primarily males, though females can be carriers or, in some cases, exhibit symptoms. The severity of hemophilia A is categorized based on the patient's factor VIII activity level:
- Severe Hemophilia A: Factor VIII activity is less than 1% of normal. Individuals with severe hemophilia experience frequent, spontaneous bleeding into muscles and joints.
- Moderate Hemophilia A: Factor VIII activity is between 1% and 5% of normal. These individuals have less frequent spontaneous bleeding but may experience prolonged or delayed bleeding after minor trauma.
- Mild Hemophilia A: Factor VIII activity is above 5% but below the normal range. These individuals may only have excessive bleeding after major injury or surgery.
High Factor VIII: Thrombosis Risk
Conversely, persistently elevated factor VIII levels can also pose a health risk. Levels of factor VIII that are consistently above 150% of normal are associated with a fivefold increased risk for venous thrombosis, such as deep vein thrombosis (DVT) or pulmonary embolism. The precise cause is not fully understood, but it is believed that a higher level of this procoagulant factor shifts the balance of the hemostatic system toward excessive clotting.
How Laboratory Tests Measure Factor VIII
Because of the dual nature of factor VIII (concentration and activity), different laboratory tests are used to get a complete picture. The measurement of factor VIII activity is standard for diagnosing and managing hemophilia.
- One-Stage Clotting Assay: This is the most common test used in clinical laboratories. It measures how effectively the patient's plasma corrects the clotting time of factor VIII-deficient plasma. The result is expressed as a percentage of normal activity.
- Chromogenic Assay: A more specific test that directly measures the ability of factor VIII to accelerate the activation of factor X. It can sometimes yield different results than the one-stage assay, particularly with certain newer, extended half-life products.
- Immunologic Assays: These tests measure the actual amount of factor VIII protein (antigen) present, regardless of its function. They are less common for routine diagnosis but can be useful for differentiating between low protein levels and dysfunctional protein.
The Importance of Von Willebrand Factor
As mentioned, VWF is the carrier protein for factor VIII, and its status is critical for interpreting factor VIII levels. Individuals with von Willebrand disease (VWD), a common hereditary bleeding disorder, often have decreased factor VIII levels because the VWF that stabilizes it is deficient or defective. Conversely, some cases of VWD show normal VWF antigen but low factor VIII, indicating a defect in the VWF's ability to bind to factor VIII.
Factor VIII and its Role in Hemostasis
The importance of factor VIII cannot be overstated. It acts as a bridge between the intrinsic and common pathways of the coagulation cascade, ensuring a robust and stable clot is formed when needed. Without sufficient functional factor VIII, this critical amplification step is compromised, leading to the bleeding phenotype characteristic of hemophilia A. The precise regulation of its concentration is therefore a key element of maintaining overall hemostatic balance.
| Feature | Normal Plasma | Severe Hemophilia A | Elevated Factor VIII |
|---|---|---|---|
| Factor VIII Activity | 50–150% | < 1% | > 150% |
| Bleeding Risk | Normal | High risk of spontaneous bleeding | Normal, but increased risk of thrombosis |
| Associated Condition | None | Hemophilia A | Venous thromboembolism risk |
| Symptoms | No unusual bleeding | Frequent, spontaneous joint and muscle bleeds | Usually asymptomatic for bleeding |
| Diagnosis | Normal coagulation study | Prolonged aPTT, low factor VIII activity | Normal coagulation study, elevated factor VIII activity |
Conclusion
The concentration of factor VIII in plasma is remarkably low by mass, highlighting its potent catalytic activity within the coagulation cascade. Clinically, its function, measured as activity, is the more critical parameter, with normal levels ranging roughly from 50% to 150%. Deviations from this normal range are central to significant health conditions, from the severe bleeding disorder hemophilia A caused by low levels to an increased risk of venous thrombosis associated with high levels. The intricate relationship with von Willebrand factor and the importance of precise measurement underscore its vital role in maintaining hemostatic balance. Advancements in measuring and managing factor VIII levels continue to improve outcomes for those with clotting disorders.
An excellent resource for learning more about hemophilia and other bleeding disorders is the National Bleeding Disorders Foundation (formerly the National Hemophilia Foundation) at https://www.bleeding.org/.
