What is the difference between von Willebrand disease and Hemophilia A (factor VIII deficiency)?

Key Differences Between Von Willebrand Disease and Hemophilia A

Von Willebrand disease (VWD) and Hemophilia A are fundamentally distinct disorders despite both involving factor VIII deficiency: VWD is an autosomal disorder affecting males and females equally with primary deficiency of von Willebrand factor (VWF) leading to secondary factor VIII reduction, while Hemophilia A is an X-linked disorder affecting predominantly males with primary deficiency of factor VIII itself. 1, 2

Genetic Inheritance Pattern

• Hemophilia A is X-linked recessive, caused by pathogenic variants in the F8 gene, affecting approximately 1 in 4,000 males with an estimated prevalence of 24.6 cases per 100,000 males at birth 1
• VWD follows autosomal inheritance (both dominant and recessive patterns), affecting males and females equally, making maternal transmission a key diagnostic clue 2
• The inheritance pattern alone distinguishes these conditions: a maternal history of bleeding disorder strongly suggests VWD rather than hemophilia A 2

Primary Protein Deficiency

• Hemophilia A results from primary deficiency of functional coagulation factor VIII, which acts as a cofactor to accelerate factor X activation by activated factor IX in the coagulation cascade 1, 3
• VWD results from primary deficiency or dysfunction of von Willebrand factor, a multiadhesive protein with dual hemostatic functions: promoting platelet adhesion to injured vessel walls and serving as the carrier protein that stabilizes factor VIII in circulation 4, 3
• In VWD, factor VIII deficiency is secondary to VWF deficiency because VWF carries and stabilizes factor VIII in plasma; loss of this carrier function leads to accelerated factor VIII clearance 2, 4

Clinical Bleeding Patterns

• Hemophilia A predominantly causes deep tissue bleeding including hemarthroses (joint bleeding), intramuscular hematomas, and life-threatening bleeding in the brain and internal organs, particularly in severe forms 1
• VWD characteristically causes mucocutaneous bleeding including easy bruising, heavy menstrual bleeding, nosebleeds, bleeding after dental procedures, and post-procedural bleeding 2, 5
• This distinction reflects the underlying pathophysiology: VWD impairs platelet adhesion (causing mucocutaneous bleeding), while hemophilia A impairs secondary hemostasis (causing deep tissue bleeding) 2, 4

Laboratory Findings

Hemophilia A:

• Factor VIII coagulant activity is markedly reduced (<1 IU/dL in severe, 1-5 IU/dL in moderate, >5-40 IU/dL in mild forms) 1
• VWF antigen (VWF:Ag) and VWF activity (VWF:RCo) are normal 1
• Prolonged aPTT with normal PT 2
• Normal bleeding time 5

Von Willebrand Disease:

• VWF:RCo (activity) and VWF:Ag are reduced (typically <30 IU/dL for definite diagnosis of Type 1) 1
• Factor VIII is mildly to moderately reduced (often 30-64% in Type 1 VWD) as a secondary consequence of VWF deficiency 1, 2
• Prolonged bleeding time and decreased ristocetin-induced platelet aggregation 5
• VWF:RCo/VWF:Ag ratio <0.5-0.7 suggests Type 2 variants 1

Critical diagnostic distinction: In hemophilia A, VWF levels are normal; in VWD, VWF is the primary deficiency with secondary factor VIII reduction 1, 2

Treatment Approaches

Hemophilia A:

• Prophylactic or episodic replacement with factor VIII concentrates (plasma-derived or recombinant, including extended half-life products) 1
• Emicizumab (FVIII-mimetic bispecific antibody) for prophylaxis in severe hemophilia A with or without inhibitors 1
• Bypassing agents (recombinant FVIIa, activated prothrombin complex concentrate) for patients with inhibitors 1
• Desmopressin is indicated only for mild hemophilia A with factor VIII levels >5%, not for severe forms 6

Von Willebrand Disease:

• Desmopressin 0.3 μg/kg IV is first-line therapy for Type 1 VWD, raising endogenous VWF and factor VIII levels 3-6 fold within 30-90 minutes 2, 6
• VWF-containing concentrates (with or without factor VIII) are used when desmopressin is ineffective or contraindicated, particularly in Type 2 and Type 3 VWD 4, 3
• Desmopressin is ineffective for severe Type 3 VWD and contraindicated in Type 2B VWD 6, 4

Severity Classification Differences

• Hemophilia A severity is classified strictly by factor VIII levels: severe (<1 IU/dL), moderate (1-5 IU/dL), mild (>5-40 IU/dL) 1
• VWD has six subtypes based on mechanism: Type 1 (partial quantitative deficiency, ~75% of cases), Type 2A/2B/2M/2N (qualitative defects), and Type 3 (virtually complete deficiency) 1, 2
• Type 2N VWD can mimic hemophilia A because it specifically affects VWF binding to factor VIII, causing disproportionate factor VIII reduction (factor VIII 10-40 IU/dL) with normal VWF:RCo/VWF:Ag ratio (>0.5-0.7) 1

Common Pitfall: Type 2N VWD Mimicking Hemophilia A

Type 2N VWD represents a critical diagnostic challenge because markedly decreased VWF binding affinity for factor VIII causes disproportionate factor VIII deficiency (often <10 IU/dL) with relatively preserved VWF levels (30-200 IU/dL), potentially mimicking mild hemophilia A 1, 7. The key distinguishing feature is the VWF:RCo/VWF:Ag ratio >0.5-0.7 in Type 2N VWD versus normal VWF levels in true hemophilia A 1. This distinction has profound therapeutic implications, as Type 2N VWD requires VWF-containing concentrates rather than isolated factor VIII replacement 7.