Von Willebrand Disease

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting an estimated 1% of the population by laboratory criteria, though far fewer have clinically significant bleeding. It results from a quantitative deficiency or qualitative dysfunction of von Willebrand factor (VWF), a large multimeric glycoprotein with two distinct hemostatic roles: it mediates platelet adhesion to exposed subendothelial collagen at a site of vascular injury (primary hemostasis), and it binds and stabilizes circulating factor VIII (FVIII) in plasma, protecting it from premature clearance (secondary hemostasis). VWD therefore produces a mixed bleeding phenotype: mucocutaneous bleeding — epistaxis, easy bruising, gum bleeding, and heavy menstrual bleeding — dominates in most patients, while more severe disease, particularly type 3 and type 2N, adds a secondary FVIII deficiency capable of producing hemophilia-like deep muscle and joint bleeding.^[1]

VWD is classified into 3 principal types that directly determine treatment selection rather than merely describing severity: type 1 is a partial quantitative deficiency (roughly 75% of diagnosed cases, generally mild-to-moderate); type 2 is a qualitative dysfunction with 4 distinct subtypes (2A, 2B, 2M, 2N) that behave and are treated differently from one another; and type 3 is a near-complete deficiency (rare, most severe, usually recessively inherited). The single most important management principle is that desmopressin (DDAVP) only works in a patient who has functional VWF for it to release from endothelial Weibel-Palade bodies — it is ineffective in type 3 (there is nothing to release), is actively contraindicated in type 2B (it releases a dysfunctional VWF that binds platelets excessively, worsening thrombocytopenia), and must never be relied on for an individual patient without a documented trial-of-response confirming they actually respond.^[2]

Most patients present with a lifelong history of mucocutaneous bleeding beginning in childhood or adolescence, often with a family history, though up to about a third of confirmed cases have no clear family history at diagnosis (variable penetrance, recessive inheritance in type 3, or a de novo variant). A structured bleeding history — using the ISTH Bleeding Assessment Tool (ISTH-BAT), a standardized questionnaire and scoring system validated across inherited bleeding disorders — is the recommended way to distinguish a genuinely bleeding-disorder-consistent history from ordinary nuisance bruising or an isolated borderline lab value, since patient recall of "easy bruising" alone is notoriously unreliable and over-inclusive.^[3]

• Epistaxis that is frequent, prolonged (over 10 minutes), bilateral, or has required medical attention or cautery.
• Easy or spontaneous bruising, often out of proportion to any identifiable trauma.
• Gum bleeding with tooth-brushing or minor dental work.
• Heavy menstrual bleeding since menarche — frequently the presenting complaint in adolescent girls and young women, and a strong prompt to test for VWD (see Special Populations and the Heavy Menstrual Bleeding chapter).
• Prolonged bleeding after a minor cut, tooth extraction, tonsillectomy, or other surgery.
• Postpartum hemorrhage, including delayed postpartum hemorrhage occurring after initial normal bleeding (see Special Populations).
• Less commonly, gastrointestinal bleeding, particularly with an angiodysplastic lesion in more severe or acquired VWD.

In more severe disease — type 3 in particular, and type 2N, which is often initially mistaken for mild-to-moderate hemophilia A — hemarthrosis and deep muscle bleeding can occur from the associated FVIII deficiency, a pattern that should prompt VWD-specific testing (not just a factor VIII assay) rather than an assumption of hemophilia A, since the inheritance pattern, family screening implications, and correct replacement product differ between the two.

• A first-degree relative with VWD or an unexplained bleeding history — though a negative family history does not exclude VWD, particularly type 3 (recessive, both parents may be unaffected carriers) or a de novo variant.
• Consanguinity, which increases the likelihood of type 3 disease specifically.
• Blood group O — independently associated with VWF levels roughly 25-30% lower than non-O blood groups as a normal population variant, not itself pathologic, but relevant when interpreting a borderline VWF level in someone with group O blood.
• Female sex — bleeding symptoms are more often clinically apparent because menstruation and childbirth are recurring hemostatic challenges that a male with the same VWF level may never encounter.
• Concurrent use of a drug that impairs platelet function or coagulation (NSAIDs, antiplatelet agents, anticoagulants), which can unmask or significantly worsen bleeding in previously mild or undiagnosed VWD.
• An underlying condition associated with acquired von Willebrand syndrome — a distinct, later-in-life, non-inherited entity without a personal or family bleeding history, seen with lymphoproliferative or myeloproliferative disorders, marked thrombocytosis (which adsorbs VWF onto platelets), hypothyroidism, or high-shear cardiac conditions such as severe aortic stenosis or a ventricular assist device (Heyde syndrome describes the aortic-stenosis association) — distinguishing acquired from inherited VWD changes both the workup (treat the underlying condition) and the family-screening implications.

History

Take a structured bleeding history using the ISTH-BAT, construct a family pedigree, and take a detailed menstrual, obstetric, surgical, and dental bleeding history alongside a full medication review (NSAIDs, antiplatelets, anticoagulants, and any supplement with antiplatelet activity).^[3]

Initial laboratory panel

• CBC with platelet count and blood smear — a low or borderline-low platelet count raises the possibility of type 2B, and the smear can also reveal a coexisting platelet disorder.
• PT and aPTT — the aPTT may be prolonged if FVIII is sufficiently reduced (type 3, type 2N, or severe type 1); the PT is normal in VWD.
• VWF antigen (VWF:Ag) — the total quantity of VWF protein present.
• VWF activity — traditionally the ristocetin cofactor assay (VWF:RCo), increasingly being replaced by the VWF:GPIbM assay, which measures the same platelet-binding function with better precision and reproducibility; use whichever is available locally.
• FVIII activity (FVIII:C).

Testing caveats

VWF is an acute-phase reactant and its levels are also raised by stress, exercise, pregnancy, and estrogen exposure — any of these can transiently normalize a mild underlying deficiency and produce a false-negative result. Avoid testing during acute illness or inflammation where possible, and repeat testing is often needed before excluding a mild phenotype, particularly when the bleeding history remains clinically convincing despite a first normal result.^[1]

Type classification

Genetic testing is increasingly used to confirm type 2 subtypes (particularly distinguishing 2B from platelet-type VWD) and to counsel families about type 3's recessive inheritance, but is not required to establish an initial diagnosis or treatment plan in most patients.^[1]

A documented desmopressin trial-of-response (see Choose Initial Treatment) is itself part of the diagnostic-to-treatment-planning workup — every patient being considered for desmopressin-based management needs this on record before it is relied on clinically for a bleed or a procedure.^[2]

• Control active bleeding and prevent bleeding matched to the specific clinical situation — spontaneous mucocutaneous bleeding, a planned minor or major procedure, or an emergency.
• Establish and document each patient's desmopressin-responder status (or contraindication) proactively, before it is urgently needed.
• Achieve the specific VWF activity and FVIII:C targets appropriate to the bleeding risk of a planned procedure (minor versus major).
• Manage heavy menstrual bleeding and peripartum bleeding risk specifically in women with VWD, coordinated with the general HMB approach.
• Avoid avoidable iatrogenic bleeding risk — screen for and avoid unnecessary NSAIDs, antiplatelet agents, and anticoagulants.
• Avoid iatrogenic harm from treatment itself — supratherapeutic FVIII levels from repeated VWF concentrate dosing, and thrombosis risk with tranexamic acid in a patient who has other prothrombotic risk factors.
• Support genetic counselling and cascade family screening given the inherited nature of the disease.

• Genetic counselling and cascade testing of first-degree relatives given the inherited nature of VWD.
• Ensure every patient carries medical alert identification stating their VWD type and desmopressin-responder status, and an individualized bleeding action plan — particularly important when travelling.
• Avoid intramuscular injections where an alternative route is feasible (hematoma risk); when an IM injection genuinely cannot be avoided (for example, a required vaccine), apply firm, extended direct pressure to the injection site afterward.
• Local hemostatic measures for minor bleeding or dental work: direct pressure, ice, nasal packing for epistaxis, topical thrombin or a fibrin sealant, and an antifibrinolytic mouthwash before and after dental procedures.
• Individualize activity counselling — avoid contact sports and other high bleeding-risk activities in more severe disease, while encouraging normal activity in mild, well-controlled VWD.
• Treat iron-deficiency anemia directly with iron repletion in anyone with chronic blood loss (heavy menstrual bleeding, recurrent epistaxis) rather than assuming it will resolve once bleeding is controlled.
• Arrange the hemostatic plan for any planned surgery or dental extraction well in advance of the appointment, not on the day of the procedure.
• Hepatitis A and B vaccination is recommended for anyone who may receive plasma-derived blood products, consistent with standard comprehensive bleeding-disorder care.

Pregnancy

Neonates and pediatrics

Check cord blood or neonatal FVIII and VWF levels when type 3 or type 2N is suspected antenatally. Apply firm, extended pressure after any intramuscular injection (including routine vitamin K) in a newborn with suspected severe VWD. A structured bleeding history can be harder to elicit in young children with a limited bleeding-exposure history; desmopressin is generally avoided or used with particular caution under 2 years of age given a materially higher risk of hyponatremic seizures from free-water retention — strict fluid restriction is essential whenever it is used in this age group. VWF concentrate is dosed on the same weight-based (IU/kg) principle as in adults.

Renal impairment

Desmopressin's antidiuretic effect and hyponatremia risk are more pronounced with reduced renal clearance — use particular caution and closer sodium monitoring. Tranexamic acid requires dose reduction in renal impairment (see Drug Tables for the specific serum-creatinine-based adjustment).

Cardiovascular disease

Desmopressin causes a transient blood pressure change and fluid retention — use caution in cardiovascular disease or uncontrolled hypertension, and always infuse the IV dose slowly (15-30 minutes) rather than as a rapid push. Tranexamic acid is contraindicated in active thromboembolic disease or a significant thrombosis risk.

Repeated dosing / tachyphylaxis

Repeated desmopressin dosing over several days shows a diminishing response after about 3-4 doses as endothelial VWF stores are depleted — space repeated doses at least 24-48 hours apart, and switch to VWF concentrate if hemostatic coverage is needed over a longer multi-day course.^[2]

Confirm bleeding has actually stopped or that a procedure achieved adequate hemostasis clinically, not from a single reassuring lab value alone. With desmopressin, monitor serum sodium, fluid balance, and blood pressure — hyponatremia risk rises with repeated dosing, in young children, and if fluid restriction is not followed. With VWF concentrate, particularly for major surgery, monitor VWF activity and FVIII:C at the interval specified in the treatment plan (commonly every 12 hours on the day of surgery, then every 24 hours) to stay within the target range — avoid supratherapeutic FVIII levels, since FVIII can continue rising for days after VWF replacement (VWF's own stabilizing effect on endogenous and infused FVIII) and materially elevated levels carry a real thrombosis risk, particularly with a higher-VWF:FVIII-ratio product and repeated dosing.^[2] For women with VWD and heavy menstrual bleeding, track bleeding pattern and quality-of-life impact and recheck CBC/ferritin as in the Heavy Menstrual Bleeding chapter. A documented type and desmopressin-responder status does not need re-testing on a routine schedule once established, but should be reconfirmed if the clinical bleeding pattern changes unexpectedly. Arrange annual comprehensive-care review at a hemophilia treatment centre or hematology clinic, as for other inherited bleeding disorders, and screen for inhibitor development — rare, seen mainly in type 3 patients with repeated VWF concentrate exposure — if response to concentrate becomes unexpectedly inadequate.

1. Confirm the documented type and desmopressin-responder status are genuinely based on an actual trial-of-response for this patient, not assumed from a family member's status or a single untested level.
2. For an inadequate desmopressin response: confirm correct dose, route, and timing, and specifically check whether the 1-hour level was adequate but the 4-hour level had already fallen (type 1C, accelerated clearance) — move to VWF concentrate rather than repeating the same desmopressin dose.
3. For an inadequate response to VWF concentrate despite an apparently adequate dose: check for an inhibitor (rare, seen mainly in type 3 with repeated exposure, occasionally with an anaphylactoid reaction) — involve hematology urgently for inhibitor testing and alternative strategies.
4. For persistent heavy menstrual bleeding despite VWD-directed therapy: reassess for a coexisting structural cause using the PALM-COEIN workup in the Heavy Menstrual Bleeding chapter rather than assuming VWD alone explains ongoing bleeding.
5. For unexpected or recurrent bleeding despite correct, type-appropriate therapy: screen for a newly started interacting drug (an NSAID, antiplatelet agent, or anticoagulant), another acquired coagulopathy, or a second, previously unrecognized bleeding disorder.
6. Escalate any genuine treatment-failure pattern to a hemophilia treatment centre or hematology rather than empirically repeating or increasing the same therapy.

• Giving desmopressin without ever having documented an actual trial-of-response for that specific patient.
• Giving desmopressin to a patient with type 2B, or with unconfirmed/unclassified VWD and thrombocytopenia.
• Relying on desmopressin instead of VWF concentrate for major surgery, even in a documented responder.^[2]
• Treating type 2N as hemophilia A (an FVIII-only product) based on an isolated low FVIII:C, without confirming the diagnosis with a VWF:FVIII binding assay.
• Missing VWD in a woman with heavy menstrual bleeding since menarche because the workup stopped at a gynecologic explanation without a bleeding-disorder history and VWF panel.
• Giving an intramuscular injection without extended direct pressure afterward, or without considering an alternative route.
• Repeating desmopressin doses too close together, risking both tachyphylaxis (diminishing hemostatic response) and hyponatremia.
• Not fluid-restricting or not monitoring serum sodium after desmopressin, especially in young children.
• Missing the postpartum window when physiologically elevated VWF/FVIII levels fall after delivery, leading to a missed delayed postpartum hemorrhage risk.
• Starting an NSAID, antiplatelet agent, or anticoagulant in a known VWD patient without specialist input.
• Confusing type 2B with platelet-type VWD on a markedly increased low-dose RIPA response — the two need different products (VWF concentrate versus platelet concentrate) and are distinguished by genetic/mixing studies, not RIPA alone.

How to use this table: doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment and a documented desmopressin trial-of-response before clinical use. Select any linked drug name to open its complete Pharmasist Drug Database page.

Desmopressin (DDAVP) — for a documented responder only

Works by releasing endogenous VWF from endothelial Weibel-Palade bodies -- effective in type 1 and most desmopressin-responsive type 2A/2M/2N; ineffective in type 3 (nothing to release); contraindicated in type 2B (releases a dysfunctional VWF that worsens thrombocytopenia). Not used for major surgery even in a documented responder -- use VWF concentrate instead. Named as text only in this chapter: the Drug Database's only "desmopressin" page is the low-dose oral melt tablet dosed for diabetes insipidus/nocturnal enuresis, a different formulation, concentration, and dose entirely from the hemostatic products below.

Concentrated hemostatic desmopressin dosing above is cross-checked against the current Health Canada product monograph.^[4]

Von Willebrand factor / factor VIII replacement concentrates

Required for type 3, type 2B, confirmed desmopressin non-responders, and every major surgery regardless of desmopressin-responder status. Dosed by VWF activity (VWF:RCo or VWF:GPIbM) in international units per kg -- choice between products is generally based on institutional protocol and availability rather than a clinically meaningful efficacy difference.

Dosing for both plasma-derived VWF/FVIII concentrates above is cross-checked against the current ASH/ISTH/NHF/WFH international guideline and their current Health Canada product monographs.^[2][5][6]

Antifibrinolytic

Effective as monotherapy for minor mucosal bleeding, and as an adjunct to desmopressin or VWF concentrate around a larger bleed or procedure, including dental extractions.

Evidence note: drug inventory, dosing, adverse effects, and comments reflect standard practice cross-checked against the current ASH/ISTH/NHF/WFH international guideline and current Health Canada product monographs.^[2][7]