Von Willebrand Disease (vWD)

Pathophysiology and overview

• Most common inherited bleeding disorder (about 1% of the population).
• vWF biology: a protein that helps form clots to stop bleeding; a 270 kD monomer assembling into multimers of 600 to 20,000 kD (the most active are the high-molecular-weight, HMW, multimers). Synthesized by endothelium and megakaryocytes.
• Two main functions: (1) facilitates platelet binding to subendothelial collagen (via GPIb and GPIIb/IIIa) and platelet-platelet interactions; (2) is the carrier for FVIII, extending its half-life (from minutes to hours). Other roles include wound healing and angiogenesis.
• Synthesis starts in the endoplasmic reticulum, undergoes post-translational modification, and is multimerized in the Golgi and stored in intracellular endothelial Weibel-Palade bodies for regulated secretion (these bodies do not attach to the endothelium).
• ADAMTS13 has a binding site on the endothelium and cleaves vWF into smaller multimers. ADAMTS13 deficiency (autoimmune or congenital) leads to accumulation of ultra-large vWF multimers and a thrombotic state (TTP, a different disease).
• Inheritance: all types are autosomal dominant except types 2N and 3, which are autosomal recessive.

Subtypes

• Type 1 (about 75%): partial quantitative deficiency with preserved ratios (ratio about 1) between VWF antigen, activity and FVIII; normal multimer distribution. Autosomal dominant, variable penetrance; mild-to-moderate bleeding. If VWF:Act and Ag are 10 to 30, FVIII is usually proportionally reduced (roughly similar to VWF); disproportionately low FVIII should prompt evaluation for type 2N or hemophilia A.
• Type 1C: quantitative decrease with preserved ratios but increased clearance of VWF. The VWFpp:VWF:Ag ratio is often elevated (>3) but can be normal (the propeptide is not cleared as quickly as VWF). On DDAVP challenge the level rises at 1 hour then falls by >30% by 4 hours.
• Type 2 (qualitative defects): VWF:activity/VWF:Ag ratio <0.7 in 2A, 2B, 2M; type 2N has a preserved ratio (≥0.7) with a low FVIII:C/VWF:Ag ratio:
  • 2A: loss of HMW multimers (synthesis or proteolysis defect; increased ADAMTS13 cleavage); decreased platelet-dependent activity; low ristocetin response; absent/abnormal multimers.
  • 2B: gain-of-function, increased binding of vWF to platelet GPIb-alpha → clearance of HMW multimers and thrombocytopenia. Increased response to low-dose RIPA; abnormal multimers. Exon 28 pathogenic variant. Avoid DDAVP (worsens thrombocytopenia). Severe bleeding phenotype: treat with weekly VWF prophylaxis.
  • 2M: defective platelet binding with normal multimers (mnemonic: 2M = normal Multimers); low ristocetin response; decreased platelet-dependent activity.
  • 2N (Normandy): defective FVIII binding; looks like hemophilia A (low FVIII with normal VWF:Ag/activity). Autosomal recessive. FVIII activity 5 to 15% because vWF cannot bind and protect FVIII from protein C degradation.
• Type 3 (about 5%): severe quantitative deficiency (absent or near-absent vWF, usually <3%; FVIII often 1 to 10%). Recessive. Severe bleeding including hemarthroses; treat like severe hemophilia A. No response to RIPA; no DDAVP.
• Platelet-type VWD: a GPIb mutation (functional defect in platelet GPIb-alpha) causing excessive platelet-vWF binding with thrombocytopenia and loss of HMW multimers. Increased low-dose RIPA with loss of HMW multimers; mimics type 2B (distinguish by genetics: a gain-of-function VWF A1-domain variant = 2B, a GP1BA variant = platelet-type VWD; exon 28 location alone is not diagnostic).

Subtype criteria table

Clinical features

• Mucocutaneous bleeding: epistaxis, gingival bleeding, easy bruising, menorrhagia, postoperative/post-procedural bleeding. Hemarthrosis is uncommon (except type 3 with FVIII <10%).
• Family history often present (autosomal dominant or, for 2N and 3, recessive).

Bleeding assessment tools (BATs)

• Structured questionnaires to quantify bleeding history: Condensed MCMDM-1 (2008, about 10 minutes), Pediatric Bleeding Questionnaire (PBQ) (2009, about 20 minutes), ISTH-BAT (2010, about 20 minutes), and Self-BAT (2015, about 10 minutes).
• Normal bleeding-score ranges (higher in females, who have more bleeding exposures over life):
  • 0 to 3 in adult males.
  • 0 to 5 in adult females.
  • 0 to 2 in male and female children.
• BATs are useful in the primary care setting to document severity. If a patient is referred to hematology for bleeding, check levels and activity (VWF:Ag and VWF:GPIbM) directly.

Diagnostic approach

• Diagnostic thresholds:
  • VWF:Ag (quantity of vWF): VWD if <30 IU/dL regardless of bleeding, or 30 to 50 IU/dL with bleeding. If <50 IU/dL with bleeding, do additional definitive testing.
  • VWF:activity: VWD if <30% regardless of bleeding, or 30 to 50% with bleeding. If <50% with bleeding, do additional definitive testing.
• Measuring vWF function (ability to bind GPIb, collagen, or FVIII):
  • VWF:RCo (ristocetin cofactor assay): ability of vWF to bind GPIb when ristocetin is added. About 60% of African-American and about 20% of white individuals have a VWF polymorphism (p.D1472H) that lowers measured VWF:RCo without true dysfunction or increased bleeding (separate from the assay's inherently high coefficient of variation).
  • VWF:GPIbR: binding to recombinant GPIb-alpha on latex beads; more sensitive than VWF:RCo.
  • VWF:GPIbM: binding to a recombinant mutant (gain-of-function) GPIb-alpha, so ristocetin is not needed. This is the best available test to assess vWF activity.
  • VWF:CB: collagen-binding assay (type I or III collagen).
• FVIII:C (factor VIII clotting activity) and the VWF:FVIII binding assay.
• RIPA (ristocetin-induced platelet aggregation): measures the affinity of vWF for platelet GPIb; low-dose RIPA is increased in type 2B and platelet-type VWD.
• VWF multimer analysis, and clearance assessment for type 1C.
• VWF clearance assessment (type 1C):
  • DDAVP challenge: measure VWF activity and level at 1 h and 4 h. DDAVP is short acting; levels rise at 1 h and fall by >30% by 4 h in type 1C.
  • VWFpp (propeptide, a marker of newly synthesized vWF): if vWF has a shorter half-life than the propeptide (increased clearance), the VWFpp:VWF:Ag ratio is elevated (>3). There is no good literature cutoff (the ratio can be normal in 1C), so guidelines recommend the DDAVP test instead.
• Ratio algorithm (VWF:activity / VWF:Ag = activity divided by level):
  • <0.7 → type 2A, 2B or 2M (dysfunctional vWF, low numerator). Then check multimers (or collagen-binding VWF:CB/Ag). Normal multimers = 2M. Abnormal multimers (loss of HMW) = 2A or 2B, so do genetic testing: a gain-of-function A1-domain variant (increased GPIb binding) is diagnostic of 2B (A1 lies within exon 28, but 2A and 2M variants also occur in exon 28). If genetics for 2B are negative, do RIPA: a negative (normal) RIPA = 2A; an increased RIPA with negative 2B genetics suggests platelet-type VWD. (In Bernard-Soulier syndrome, RIPA is absent due to a GPIb variant on the platelet.) Do not use RIPA upfront.
  • ≥0.7 → type 1, 1C, 3 or 2N (low vWF level, low denominator). If the VWF level is <30 (or 30 to 50 with bleeding), do a DDAVP challenge: type 1 rises and stays stable at 4 h; type 1C rises at 1 h then falls >30% by 4 h; type 3 has near-absent vWF, typically <3 IU/dL (not simply <10). If the FVIII:C/VWF:Ag ratio is low (<0.7), check the VWF:FVIII binding assay: if low, the diagnosis is 2N.
• Pearls:
  • vWF and FVIII are acute-phase reactants: they rise 2 to 5× with exercise, stress and inflammation, and with pregnancy (about 2 to 3× by the third trimester); modern low-dose combined OCPs have little effect and need not be stopped for testing. Re-test if borderline.
  • vWF levels fall in hypothyroidism.
  • Levels are affected by age, ethnicity (lower in whites), and ABO type: blood type O has about 25% lower average baseline vWF, but most remain within the normal range; do not use ABO-adjusted reference ranges, apply the standard diagnostic thresholds.
  • Do not use a lower cutoff (e.g. <0.5) for the activity/Ag ratio: it reduces false positives but misses type 2. It is better to mislabel a few type 1 patients as type 2, because type 2 treatment also works for type 1.

VWF-level bleeding-risk bands (likelihood ratios)

• Interpretation: a likelihood ratio (LR) >10 highly predicts disease; LR of 1 means no change; LR <1 lowers the probability of disease (the smaller the value, the stronger the exclusion); LR = 1 is uninformative.

• Guidelines: ASH/ISTH/NHF/WFH 2021 guidelines on the diagnosis and on the management of von Willebrand disease (Blood Advances 2021).

Treatment

• Therapies to increase vWF: desmopressin (IV, SC, intranasal); VWF concentrate (plasma-derived or recombinant); estrogen.
• Adjunctive therapies: antifibrinolytics (TXA, aminocaproic acid); topical therapies (fibrin sealant, topical thrombin); recombinant FVIIa.

Desmopressin (DDAVP)

• Releases stored vWF/FVIII from endothelial Weibel-Palade bodies. Use only in known responders (in adults with type 1 VWD and baseline VWF >30 can presume responsive (confirming the response is still reasonable); do not assume in children or type 2; if <30, do a DDAVP trial and confirm the level remains >50 at 4 h). Mainly used in type 1.
• Contraindicated in type 2B (worsens thrombocytopenia) and type 3 (lack of efficacy); generally ineffective across type 2/3. Also contraindicated with active cardiovascular disease (CAD, CVA, PAD), seizure disorder, age <2 years, type 1C in the surgical setting, and preeclampsia.
• Tachyphylaxis after 2 to 3 doses (depletion of the vWF storage pool): may repeat after 8 to 12 h then once daily if needed (tachyphylaxis limits response) and for no more than 2 to 3 consecutive days.
• Hyponatremia risk (free water retention): limit fluid intake for 24 hours after use; can also cause thrombosis.
• Dosing: IV 0.3 mcg/kg (max 20 to 30 mcg) in 50 mL saline over 20 minutes; nasal spray >50 kg 300 mcg (1 spray each nostril), <50 kg 150 mcg (1 spray in 1 nostril).

VWF/FVIII concentrates

• For major bleeding, surgery, type 3, type 2B, and DDAVP non-responders. Plasma-derived options include Humate-P, Wilate and Alphanate. Recombinant vWF (Vonvendi) has been available since 2015; it is FVIII-free and can be given alone or with rFVIII (if the FVIII level is <40%, add rFVIII with the first dose).
• For most major bleeding or surgery VWF concentrate is appropriate, but not universally: platelet-type VWD may need platelet transfusion, and type 3 with anti-VWF alloantibodies may have ineffective, reaction-prone replacement.

Antifibrinolytics

• Aminocaproic acid 25 to 50 mg/kg per dose orally (max 5 g) 4 times/day; tranexamic acid 25 mg/kg per dose orally every 6 to 8 hours, or 10 mg/kg IV 3 times/day.
• Used alone or with other therapies (use caution when combined with DDAVP); especially useful for mucosal bleeding and dental procedures. Reduce the dose in impaired kidney function.

Heavy menstrual bleeding

• Hormonal therapy (combined hormonal contraceptive or a levonorgestrel-releasing IUD) if not trying to conceive; tranexamic acid (preferred) and desmopressin.

Pregnancy, labor and postpartum

• vWF rises 2 to 3× in the third trimester; most type 1 patients normalize by delivery. Type 3 and most type 2 require concentrate at delivery, guided by third-trimester VWF activity and FVIII (some type 2, e.g. 2N, may normalize) and postpartum monitoring (vWF drops 1 to 2 weeks postpartum).
• Neuraxial anesthesia: target VWF activity 0.50 to 1.50 IU/mL with VWF concentrate (do not exceed 1.50 IU/mL). Do a third-trimester visit and check FVIII and VWF; keep VWF activity >0.50 IU/mL while the epidural is in place and for at least 6 hours after removal. Suitability of neuraxial anesthesia is a multidisciplinary decision.
• Postpartum: use tranexamic acid in type 1 or low-VWF women (and it may apply to type 2/3); it reduces secondary and possibly primary postpartum hemorrhage and is safe in breastfeeding. Oral dose 25 mg/kg (typically 1000 to 1300 mg) 3 times/day for 10 to 14 days or longer if blood loss remains heavy.

Surgery and prophylaxis

• Major surgery: target both FVIII and VWF activity ≥0.50 IU/mL for at least 3 days after surgery (duration and trough levels vary by surgery type).
• Minor surgery: raise VWF activity to ≥0.50 IU/mL with VWF concentrate or desmopressin, plus tranexamic acid. In type 3 and type 2B use VWF concentrate (no DDAVP); selected other type 2 (e.g. 2M) may use DDAVP if a durable response is proven, plus TXA. TXA alone (without targeting VWF levels) can be used for minor mucosal procedures in type 1 with VWF >0.30 IU/mL and a mild bleeding phenotype. Dental proceduralists may use local hemostatic measures (gelatin sponges, fibrin glue, tranexamic acid rinse).
• Long-term prophylaxis with VWF concentrate for a history of severe and frequent bleeds (uncommon but underused).

Acquired von Willebrand syndrome (AVWS)

• Five mechanisms:
  • Decreased production of vWF (e.g. hypothyroidism).
  • Autoantibodies against vWF and immune-complex formation (e.g. SLE, Hashimoto thyroiditis).
  • Adsorption of vWF to tumor cells (e.g. Wilms tumor, lymphoproliferative disorders).
  • Drug-associated AVWS (e.g. ciprofloxacin, valproate, hydroxyethyl starch): mechanisms are heterogeneous, not uniformly HMW-multimer proteolysis.
  • Increased proteolysis of HMW multimers under high-shear conditions (congenital heart disease, aortic stenosis [Heyde syndrome], ECMO, mechanical valves, HOCM, LVAD/VAD, mitral regurgitation).
• Most forms lose HMW multimers with impaired function, but VWF:Ag may be normal or elevated (high-shear states) and multimers can be preserved (hypothyroidism). Also seen in Waldenstrom macroglobulinemia (20 to 30%), MGUS, MM, CLL, and MPNs (ET/PV with extreme thrombocytosis >1 million; large platelets adsorb vWF).
• Treatment: treat the underlying cause. For acute bleeding: DDAVP, vWF concentrate, or IVIG for IgG-MGUS-related AVWS (response within about 24 to 48 h, lasting about 2 to 3 weeks, by reducing immune-mediated VWF clearance, not antibody depletion; usually ineffective in IgM-MGUS). Give VWF concentrate or DDAVP for acute bleeding while awaiting IVIG.

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• vWD is the most common inherited bleeding disorder.
• Type 2N (Normandy) looks like hemophilia A but is autosomal recessive; a FVIII-binding defect on vWF.
• Type 2B + DDAVP = thrombocytopenia. Avoid.
• vWF rises in pregnancy; most type 1 patients normalize. Re-check postpartum.
• Heyde syndrome: aortic stenosis + AVWS + GI angiodysplasia bleeding; valve replacement may resolve it.
• AVWS in IgG-MGUS: IVIG restores vWF for about 2 to 3 weeks (usually ineffective in IgM-MGUS).
• Blood type O has lower baseline vWF.
• Vonvendi (recombinant vWF) can be given alone or with rFVIII; add rFVIII only when FVIII is insufficient (on-demand: FVIII <40% or unknown).