VON WILLEBRAND DISEASE

Von Willebrand Disease — the most common inherited bleeding disorder, affecting up to 1% of the population, where most cases remain undiagnosed and treatment depends entirely on which of 6 subtypes the patient carries.

Whole genome sequencing reads the complete VWF gene — one of the largest in the genome at 178kb — distinguishing all 6 subtypes and identifying the specific variant that determines whether desmopressin, factor concentrate, or platelet transfusion is the correct treatment.

About this condition

Von Willebrand Disease

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in von Willebrand factor (VWF), a large multimeric glycoprotein essential for platelet adhesion and as a carrier for coagulation factor VIII. VWD affects up to 1% of the population by laboratory criteria, though clinically significant disease requiring treatment is estimated at 1 in 1,000 to 1 in 10,000. VWD is classified into three major types: type 1 (partial VWF deficiency, ~70-80% of cases), type 2 (qualitative VWF defects, subdivided into 2A, 2B, 2M, and 2N), and type 3 (complete VWF deficiency, severe and rare).

Clinical presentation ranges from mild mucocutaneous bleeding — easy bruising, prolonged bleeding from cuts, menorrhagia (heavy menstrual bleeding), excessive bleeding after dental procedures — to life-threatening hemorrhage in type 3 VWD. VWD is one of the most commonly missed diagnoses in hematology: many patients are dismissed with 'easy bruising,' women with menorrhagia undergo years of investigation without VWD being considered, and surgical bleeding complications occur without prior genetic identification. Standard coagulation tests (PT, aPTT) are often normal in type 1 and some type 2 variants.

Treatment depends entirely on VWD subtype. Desmopressin (DDAVP) — which releases stored VWF from endothelial cells — is effective in most type 1 patients but is contraindicated in type 2B (it worsens thrombocytopenia by releasing dysfunctional VWF that causes platelet agglutination). Type 2N and type 3 require VWF-containing factor VIII concentrate. Type 2A may or may not respond to DDAVP depending on the specific variant. This treatment-critical distinction between subtypes requires molecular VWF genotyping — phenotypic laboratory tests (VWF antigen, VWF activity, multimer analysis) can be ambiguous or fluctuating.

Type 2B VWD is worsened by desmopressin (DDAVP) — the standard first-line VWD treatment — because the gain-of-function VWF variant causes spontaneous platelet binding. Administering DDAVP to a type 2B patient causes acute thrombocytopenia. Subtype identification before treatment is essential.

Gene locus: VWF (12p13.31)

VWF laboratory phenotyping is notoriously variable — VWF levels fluctuate with stress, blood type, hormonal status, and acute illness. Molecular genotyping provides a permanent, unambiguous diagnosis that does not change with the patient's clinical state.

VWF levels fluctuate — a normal lab result does not exclude VWD, and the genotype provides a permanent answer

VWF is an acute-phase reactant — levels rise with stress, surgery, pregnancy, oral contraceptive use, and acute illness. Patients with type 1 VWD can have VWF levels that test within the normal range during acute illness or pregnancy, leading to false-negative laboratory results and missed diagnoses. The reverse also occurs: repeat testing during non-stressed states may produce abnormal results. This variability creates diagnostic uncertainty that is resolved permanently by molecular VWF genotyping. A confirmed VWF pathogenic variant establishes the diagnosis regardless of laboratory fluctuations and enables immediate subtype-specific treatment planning.

Women with undiagnosed VWD experience years of untreated menorrhagia and postpartum hemorrhage risk

Menorrhagia (heavy menstrual bleeding) is the most common presenting symptom of VWD in women. Studies estimate that 5-20% of women evaluated for menorrhagia have underlying VWD that was never investigated. These women undergo years of gynecological evaluation, iron supplementation, and sometimes hysterectomy without the underlying bleeding disorder being identified. During pregnancy, VWF levels rise physiologically — often normalizing by delivery — then drop rapidly postpartum, creating a high-risk window for postpartum hemorrhage. Genetic diagnosis before pregnancy enables prophylactic VWF replacement during delivery and the postpartum period.

Von Willebrand Disease — the most common inherited bleeding disorder, affecting up to 1% of the population, where most cases remain undiagnosed and treatment depends entirely on which of 6 subtypes the patient carries.