Hematology & Internal Medicine & Family Medicine
Von Willebrand disease
Von Willebrand disease (VWD) is the most common inherited coagulopathy—affecting approximately 1 in 3,000 of the global population in its mild form—although the prevalence of clinically significant forms requiring treatment is estimated to be 1 in 1,000 to 1 in 10,000, depending on the diagnostic criteria used. It is caused by a quantitative or qualitative deficiency of von Willebrand factor (VWF)—a large multimeric glycoprotein synthesized by endothelial cells and megakaryocytes—which plays a dual essential role in primary hemostasis: on the one hand + as a platelet adhesion protein to the injured vascular subendothelium (via binding to collagen and the platelet GPIb receptor) + enabling the formation of the platelet plug under high shear stress (arteries and arterioles), and on the other hand, as a chaperone protein for coagulation factor VIII (FVIII), protecting it from premature degradation in plasma, which explains why a VWF deficiency secondarily leads to a reduction in FVIII (hence the prolonged APTT in certain types of von Willebrand disease). Von Willebrand disease (VWD) was first described in 1926 by the Finnish physician Erik Adolf von Willebrand, who described a familial hemorrhagic diathesis affecting a family on the Åland Islands, presenting with recurrent mucosal bleeding (epistaxis + menorrhagia + gingival bleeding + easy bruising)—distinct from classic hemophilia (muscle and joint bleeding) due to its mucosal involvement and autosomal inheritance (dominant for types 1 and 2 + recessive for severe type 3). The wide phenotypic variability + overlap with low-normal values in type 1 + and the influence of ABO blood groups on VWF levels (group O → VWF naturally 20–25% lower than other groups) sometimes make diagnosis difficult and often require multiple repeated assays and specialized functional tests.
Classification of von Willebrand disease types
| Type | Deficit | Frequency | VWF:Ag | VWF:RCo | FVIII | Transmission |
|---|---|---|---|---|---|---|
| Type 1 (most frequent) | Partial quantitative — proportional reduction of all multimeric forms of vWF | 70–80 % of MvW | Baseline (20–50 IU/dL) | Proportionately | Slightly low or normal | Autosomal dominant with variable penetrance |
| Type 2A | Qualitative — loss of large multimers (the most active) → platelet adhesion defect | 10–15 % of the MvW | Normal or slightly low | Very low (RCo/Ag ratio <0.6) | Normal | Autosomal dominant |
| Type 2B | Qualitative—gain-of-function → abnormal VWF with increased affinity for GPIb → spontaneous platelet aggregation → consumption of large multimers + thrombocytopenia | 5 % of the MvW | Normal or low | Very low | Normal | Autosomal dominant + DDAVP contraindicated (worsens thrombocytopenia) |
| Type 2 meters | Qualitative - Collagen or GPIb binding defect without loss of large multimers | Rare | Normal | Very low | Normal | Autosomal dominant |
| Type 2N (Normandy) | Qualitative — FVIII binding defect → rapid FVIII degradation → picture resembling mild hemophilia A | Rare | Normal | Normal | Very low (5–40 %) | Autosomal recessive — can mimic hemophilia A → VWF-FVIII binding test |
| Type 3 (most severe) | Comprehensive quantitative — near-total absence of vWF | 1–5 % of the MvW | Undetectable or <3 UI/dL | Undetectable | Very low (1–10 %) | Autosomal recessive — severe mucosal, joint, and muscle bleeding |
Clinical presentation
- Mucosal bleeding (characteristic of vWD): recurrent epistaxis + menorrhagia (often inaugural in women - very heavy first menstruation) + gingival bleeding + easy bruising + prolonged post-dental extraction bleeding + digestive bleeding (telangiectasias + intestinal angiodysplasias in severe forms)
- Heavy menstrual bleeding affect 32–100 women aged 1–3 years with MvW + often unrecognized and mistakenly attributed to an irregular cycle + PBAC (Pictorial Blood Assessment Chart) score >100 = significant menorrhagia
- Post-operative bleeding After surgery + childbirth + dental extractions → mandatory hematologic planning before any invasive procedure
- Severe Type 3: can resemble hemophilia with muscle and joint bleeding (hemarthrosis) plus mucosal bleeding
- Hemorrhagic score (BAT — Bleeding Assessment Tool ISTH) : standardized tool to quantify bleeding severity + score ≥ 3 (male) or ≥ 5 (female) = significant hemorrhagic diathesis → mandatory investigation
Diagnostic biological assessment
- Initial assessment: NFS + platelets (thrombocytopenia in type 2B) + PT + aPTT (prolonged if FVIII is low - type 2N + type 3) + bleeding time or PFA-100 (prolonged occlusion time)
- Specialized assessment (hematology): VWF:Ag (VWF antigen — quantitative) + VWF:RCo (ristocetin cofactor activity — functional) + FVIII:C (coagulant) + multimeric analysis by electrophoresis + VWF-FVIII binding test (type 2N) + RIPA (ristocetin-induced platelet aggregation — type 2B)
- VWF:RCo / VWF:Ag ratio ratio <0.6 = qualitative defect (type 2) → points towards types 2A + 2B + 2M
- Repeat the dosages: VWF is an acute phase protein that increases during inflammation, stress, pregnancy, exercise, and estrogen therapy. Doses can be falsely normal in these contexts. Repeat at a distance from confounding factors.
- ABO Blood Group: Group O is associated with lower VWF 20–25 % levels than the other groups → take this into account when interpreting the reference ranges
Treatment
- Desmopressin (DDAVP — Minirin® or Octostim®) — treatment of choice for type 1: Synthetic vasopressin analogue → release of endothelial von Willebrand factor (vWF) stores (Weibel-Palade bodies) → transient increase in vWF and Factor VIII (FVIII) by 3 to 5 times for 4–6 hours → IV + SC + or intranasal administration (Octostim® nasal spray) + mandatory prior therapeutic test to verify individual response + tachyphylaxis after 2–3 consecutive doses (depletion of stores) + contraindicated in type 2B (worsens thrombocytopenia) + adverse effects: hyponatremia (mandatory fluid restriction × 24 h) + flush + headaches
- VWF Concentrates (Haemate P® + Voncento® + Wilate®): indicated in type 2 + type 3 + DDAVP non-responsive type 1 + and during major surgeries + childbirths + or severe bleeding → provide vWF and FVIII → management by a specialized hemophilia center
- Tranexamic acid (Cyklokapron®): antifibrinolytic + inhibits plasmin → reduces mucosal bleeding (nosebleeds + menorrhagia + mouth bleeds) → 1 g × 3–4/d PO + or IV → often used alone or in combination with DDAVP + particularly effective for mucous membranes
- Hormone Therapy (Women): combined oral contraceptives → raise vWF + reduce menorrhagia + first-line gynecological treatment for menorrhagia related to vWD + levonorgestrel IUD (Mirena®) → effectively reduces menstrual flow
- Before any invasive procedure (surgery + childbirth + tooth extraction): Mandatory preoperative hematological consultation + individualized hemostatic management plan according to the type and level of vWF and the type of procedure
ℙ️
Type 1 von Willebrand disease is often underdiagnosed in women, with menorrhagia since menarche wrongly attributed to «heavy normal cycles» for years. In cases of severe initial menorrhagia (very heavy first period + anemia + need for transfusion) OR significant postpartum bleeding OR any family history of bleeding diathesis, a coagulation workup including VWF levels should be performed. vWD is the most common cause of coagulopathy in women with unexplained menorrhagia.
Medical consultation recommended
Consult a doctor or hematologist if recurrent nosebleeds, heavy menstrual bleeding since menarche, prolonged bleeding after a tooth extraction or minor surgery, or multiple bruises without trauma are present. These signs may suggest von Willebrand disease, which requires specialized coagulation testing. Any patient known to have vWD must consult a hematologist before any invasive procedure. For coagulation testing and referral to hematology, Clinique Omicron offers consultations at its service points in Quebec and via telemedicine. To make an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron's physicians and nurse practitioners (NPs) consider a diagnosis of von Willebrand disease in cases of recurrent mucosal bleeding + menorrhagia since menarche + or a high BAT bleeding score. They order an initial coagulation workup (CBC + PT + aPTT + PFA-100) and specialized VWF:Ag + VWF:RCo + FVIII assays, refer to a hemophilia center for diagnostic confirmation and treatment planning, prescribe tranexamic acid for mucosal bleeding, and coordinate preoperative management. Consultations are available at several service locations in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not replace the advice of a doctor or a hematologist specializing in coagulopathies. DDAVP is contraindicated in von Willebrand disease type 2B - it worsens thrombocytopenia. Any patient with known vWD must consult a hemophilia center before any surgical procedure to establish an individualized hemostatic plan.
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