What does low factor VIII (8) activity mean in a patient with a family history of bleeding disorders?

What Does Low Factor VIII Activity Mean?

Low factor VIII activity indicates either hemophilia A (an inherited or acquired bleeding disorder) or von Willebrand disease, both of which impair blood clotting and increase bleeding risk. 1, 2

Primary Diagnostic Implications

Factor VIII deficiency represents one of two distinct conditions:

• Hemophilia A occurs when factor VIII protein itself is deficient or dysfunctional, affecting approximately 1 in 5,000 males as an X-linked inherited disorder 3
• Von Willebrand disease (VWD) causes secondary factor VIII deficiency because von Willebrand factor normally stabilizes and carries factor VIII in circulation 3, 4

Severity Classification Based on Factor VIII Levels

The American Society of Hematology classifies hemophilia A severity by factor VIII activity levels: 2

• Severe: <1% of normal activity
• Moderate: 1-5% of normal activity
• Mild: >5% to <40% of normal activity

Patients with factor VIII levels ≥10-15% typically do not experience significant bleeding problems, while those below this threshold face progressively higher bleeding risk. 5

Clinical Bleeding Manifestations

The bleeding pattern depends on severity: 3

• Severe deficiency (<1%): Spontaneous bleeding into joints (hemarthroses), muscles, and potential intracranial hemorrhage (5-12% risk of ICH)
• Moderate deficiency (1-5%): Bleeding with minor trauma or after procedures
• Mild deficiency (>5%): Bleeding primarily after significant trauma or surgery, may go undiagnosed until challenged

Mucosal bleeding (nosebleeds, gum bleeding, heavy menstrual periods) is common across all severity levels. 5

Critical Diagnostic Considerations With Family History

When a patient has low factor VIII activity AND a family history of bleeding disorders, the probability of true hemophilia A or VWD increases substantially: 3

• X-linked inheritance pattern suggests hemophilia A (affects males, carried by females)
• Autosomal dominant pattern suggests type 1 or 2 VWD
• Consanguinity or autosomal recessive pattern may suggest rare combined factor deficiencies

Distinguishing Hemophilia A from Von Willebrand Disease

To differentiate these conditions, measure von Willebrand factor alongside factor VIII: 6

• Hemophilia A: Isolated low factor VIII with normal VWF:RCo (ristocetin cofactor) and VWF:Ag (antigen)
• Von Willebrand disease: Low factor VIII accompanied by low VWF:RCo and/or VWF:Ag 3
• VWF:RCo/VWF:Ag ratio <0.5-0.7 suggests type 2 VWD variants rather than type 1 3

Important Testing Pitfalls to Avoid

Several factors can cause falsely low or misleadingly normal factor VIII results: 1, 6

• Mild hemophilia may be missed if only aPTT is checked without specific factor VIII measurement—always order factor VIII activity when clinical suspicion exists 1
• Von Willebrand factor is an acute phase reactant that rises with stress, inflammation, pregnancy, or recent exercise, potentially masking mild VWD by normalizing factor VIII levels 3, 6
• Repeat testing up to 3 times may be necessary for reliable VWD diagnosis due to this variability 3
• Lupus anticoagulant can artifactually lower factor VIII measurements in laboratory assays; if present, request testing at higher dilutions 6

Clinical Significance for Bleeding Risk

The probability of serious bleeding complications correlates with factor VIII levels: 3

• Intracranial hemorrhage risk: 5-12% in severe factor VIII deficiency, particularly after even mild head trauma
• Joint bleeding (hemarthroses): Common in severe deficiency, leading to chronic arthropathy without treatment
• Surgical bleeding: Significant risk without factor replacement, even in mild deficiency

However, factor VIII deficiency causing spontaneous intracranial hemorrhage without trauma is relatively rare (probability 1 in 50,000 males in the general population). 3

Immediate Clinical Actions Required

When low factor VIII activity is identified in a patient with bleeding history or family history: 1, 2

• Consult pediatric or adult hematology for definitive diagnosis and management planning
• Perform mixing studies to exclude acquired hemophilia (factor VIII inhibitor) if bleeding is recent-onset or severe 1, 6
• Measure Bethesda assay to quantify inhibitor titer if mixing study suggests inhibitor presence 1, 2
• Complete VWD workup with VWF:RCo, VWF:Ag, and potentially VWF multimer analysis 3, 6
• Avoid aspirin, NSAIDs, and antiplatelet agents that further impair hemostasis 4