Blood & Lymphoreticular

Von Willebrand disease: workup and management

Clinical Overview and When to Suspect Von Willebrand Disease

— Mediates platelet adhesion to subendothelial collagen at sites of vascular injury

— Serves as the carrier protein for factor VIII, protecting it from proteolysis

— Type 1 (75%): partial quantitative deficiency, autosomal dominant, usually mild

— Type 2 (20%): qualitative defect — subtypes 2A, 2B, 2M, 2N

— Type 3 (<5%): severe quantitative deficiency, autosomal recessive, near-absent VWF and very low factor VIII

— Aortic stenosis (Heyde syndrome), LVADs, hypothyroidism

— Monoclonal gammopathy (MGUS, multiple myeloma, Waldenström)

— Myeloproliferative neoplasms (especially essential thrombocythemia)

— Wilms tumor (pediatric)

— Mucocutaneous bleeding pattern: epistaxis >10 min, gum bleeding, easy bruising

— Heavy menstrual bleeding since menarche, especially with iron deficiency anemia

— Postpartum hemorrhage

— Excessive bleeding after dental work, tonsillectomy, or minor surgery

— Family history of bleeding (though absence does not exclude)

Board pearl: A young woman with menorrhagia since menarche, iron deficiency anemia, and a normal platelet count — even with a normal aPTT — still warrants VWD workup. Mild type 1 disease frequently has normal screening coagulation tests, so clinical suspicion drives testing more than abnormal labs.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting ~1% of the population by lab criteria though symptomatic prevalence is closer to 1 in 1,000.

Pathophysiology centers on von Willebrand factor (VWF), a multimeric glycoprotein that:

Three major hereditary types:

Acquired von Willebrand syndrome (AVWS) is increasingly recognized in adults — associated with:

When to suspect in an adult or adolescent:

Use a validated ISTH Bleeding Assessment Tool (BAT) to quantify: score ≥4 (men), ≥6 (women), or ≥3 (children) suggests pathologic bleeding warranting workup.

Presentation Patterns and Key History

— Epistaxis: recurrent, often bilateral, lasting >10 minutes or requiring packing/cautery

— Gingival bleeding with routine brushing or after dental cleanings

— Easy bruising: bruises >2 cm without remembered trauma, on trunk/non-bony areas

— Heavy menstrual bleeding (HMB): clots >1 inch, soaking through protection hourly, periods >7 days, PBAC score >100

— GI bleeding: especially with angiodysplasia in type 2A or AVWS (Heyde syndrome)

— Postpartum hemorrhage (immediate or delayed up to 4 weeks as VWF levels fall)

— Bleeding after tonsillectomy, adenoidectomy, dental extraction

— Re-operation for bleeding, transfusion requirement after minor surgery

— Type 1 and most type 2: autosomal dominant — expect bleeding in a parent or sibling

— Type 3 and type 2N: autosomal recessive — consanguinity or both parents mildly affected

— Up to 30% lack a clear family history due to variable penetrance

— NSAIDs and antiplatelet use exacerbate bleeding

— SSRIs increase mucocutaneous bleeding risk

— Alcohol use, herbal supplements (ginkgo, garlic, fish oil)

— Pregnancy, estrogen-containing contraceptives, acute stress, exercise, inflammation, hyperthyroidism — VWF is an acute-phase reactant

— Blood group: type O patients have ~25% lower VWF baseline than non-O

Key distinction: Mucocutaneous bleeding (epistaxis, menorrhagia, petechiae-like bruising) suggests a platelet/VWF problem, whereas deep tissue bleeding (hemarthrosis, muscle hematoma) suggests a coagulation factor problem — though severe type 3 VWD blurs this line by also depleting factor VIII.

Mucocutaneous bleeding is the hallmark — reflects defective primary hemostasis (platelet-VWF-collagen axis):

Surgical/procedural bleeding history — high-yield Step 3 clues:

Type 3 VWD mimics moderate hemophilia: hemarthroses, deep muscle hematomas, intracranial bleeding — because factor VIII is severely low.

Family history:

Medication and lifestyle review:

Modifiers that transiently raise VWF (and can mask diagnosis):

Physical Exam Findings and Hemodynamic Assessment

— Pallor and conjunctival rim pallor in chronic iron deficiency from menorrhagia or GI loss

— Tachycardia or orthostasis in acute bleeding episodes

— Glossitis, angular cheilitis, koilonychia — chronic iron deficiency stigmata

— Ecchymoses of varying ages on trunk, thighs, upper arms

— Petechiae are uncommon in VWD (more typical of thrombocytopenia or platelet function disorders) — their presence should prompt CBC review

— Oral cavity: gingival oozing, hemorrhagic blisters on buccal mucosa after minor trauma

— Active epistaxis or recent nasal packing

— Pale conjunctivae, no scleral icterus (helps exclude liver disease as bleeding cause)

— Inspect for telangiectasias on lips, tongue, fingertips — suggests HHT (Osler-Weber-Rendu) as a differential

— Crescendo-decrescendo systolic murmur at RUSB radiating to carotids — aortic stenosis; in an older patient with new GI bleeding and acquired VWD, think Heyde syndrome (AS + angiodysplasia + AVWS from high-shear VWF cleavage)

— Continuous mechanical hum in an LVAD patient with bleeding suggests device-associated AVWS

— Splenomegaly suggests alternative diagnosis (lymphoproliferative disorder, portal hypertension, MPN-associated AVWS)

— Hepatomegaly or stigmata of chronic liver disease point toward coagulopathy of hepatic origin

— Joint swelling, limited ROM, or chronic arthropathy — concerning for type 3 VWD or undiagnosed hemophilia

— Vital signs, orthostatic measurements, capillary refill

— Estimate volume status — initiate IV access (2 large-bore), crystalloid resuscitation, type and screen, baseline CBC/PT/aPTT/fibrinogen before specific VWD therapy

Step 3 management: In an elderly patient with aortic stenosis and recurrent obscure GI bleeds, send VWF multimer analysis and consider aortic valve replacement — AVR often reverses AVWS and stops the bleeding when endoscopy fails to localize a source.

General appearance:

Skin and mucous membranes — the highest-yield exam region:

HEENT:

Cardiopulmonary:

Abdomen:

Musculoskeletal:

Hemodynamic assessment in acute bleeding:

Diagnostic Workup — Initial Labs

— CBC with platelet count: usually normal; thrombocytopenia in type 2B (high-affinity VWF binds and clears platelets); microcytic anemia from chronic iron loss

— PT: normal in VWD — use to exclude liver disease/vitamin K issues

— aPTT: may be prolonged if factor VIII is reduced (severe type 1, type 2N, type 3); often normal in mild disease

— Fibrinogen: normal — abnormal suggests DIC or liver disease

— Peripheral smear: rule out thrombocytopenia, schistocytes, platelet clumps

— VWF antigen (VWF:Ag) — quantitative measure of total VWF protein

— VWF activity — measured by VWF:GPIbM (preferred, recombinant) or ristocetin cofactor assay (VWF:RCo, older, more variable)

— Factor VIII activity (FVIII:C) — VWF carries and stabilizes FVIII

— VWF:Ag and/or activity <30 IU/dL: diagnostic of VWD regardless of bleeding

— VWF level 30–50 IU/dL with bleeding phenotype: "low VWF" — clinical diagnosis, treat as VWD perioperatively

— Normal VWF >50 IU/dL: VWD largely excluded (consider platelet function disorders next)

— Recent stress, exercise, illness, pregnancy, estrogen exposure transiently elevate VWF

— Repeat testing on 2–3 separate occasions before excluding VWD if clinical suspicion is high

— Blood group O affects reference range — labs typically report population norms

Board pearl: A normal aPTT does not rule out VWD. Most type 1 patients have aPTT in the reference range because factor VIII is only mildly reduced. Send specific VWF testing whenever the clinical picture fits, regardless of screening coags.

First-tier screening labs when VWD is suspected:

Specific VWD initial panel ("VWD initial testing") — all three together:

Interpretation thresholds (2021 ASH/ISTH/NHF/WFH guidelines):

Bleeding time is no longer recommended — replaced by PFA-100/PFA-200 closure times in some centers, but neither is required to diagnose VWD.

Iron studies, ferritin, reticulocyte count in any patient with menorrhagia or GI bleeding to identify and treat iron deficiency, which itself worsens bleeding symptoms.

Preanalytic pitfalls that cause false-normal results:

Diagnostic Workup — Confirmatory and Subtyping Studies

— Ratio >0.7: quantitative defect → type 1 (mild-moderate decrease) or type 3 (near-absent)

— Ratio <0.7: qualitative defect → type 2A, 2B, or 2M (functional defect)

— Disproportionately low FVIII (FVIII:C/VWF:Ag <0.7) → type 2N ("Normandy") — VWF cannot bind/protect FVIII; mimics mild hemophilia A but inherited autosomal recessive, affects both sexes

— Loss of high-molecular-weight (HMW) multimers: type 2A, 2B, and acquired VWS

— Normal multimer distribution despite low activity: type 2M

— Normal multimers with low FVIII binding: type 2N

— Absent all multimers: type 3

— Increased aggregation at low ristocetin concentrations → type 2B (gain-of-function VWF binds platelets spontaneously, causing thrombocytopenia)

— Critical to distinguish 2B from platelet-type (pseudo) VWD (mutation in platelet GPIbα) — managed differently; mixing studies and genetic testing resolve this

— SPEP/UPEP and serum free light chains (monoclonal gammopathy)

— Echocardiogram (aortic stenosis, LVAD shear)

— TSH (hypothyroidism)

— CBC and JAK2 (myeloproliferative neoplasms)

— Imaging for Wilms tumor in pediatrics

Key distinction: Type 2B VWD and platelet-type VWD both show enhanced ristocetin response and thrombocytopenia, but DDAVP is contraindicated in type 2B (worsens thrombocytopenia by releasing more abnormal VWF), whereas platelet-type requires platelet transfusion rather than VWF replacement.

Once VWF:Ag, VWF activity, and FVIII confirm VWD, subtype to guide therapy:

VWF activity-to-antigen ratio (VWF:Act/VWF:Ag):

FVIII-to-VWF:Ag ratio:

VWF multimer analysis (gel electrophoresis):

Low-dose ristocetin-induced platelet aggregation (LD-RIPA):

VWF:FVIII binding assay (VWF:FVIIIB): confirms type 2N

VWF propeptide-to-antigen ratio: elevated in AVWS and conditions of increased VWF clearance (Vicenza variant)

Genetic testing of the VWF gene (chromosome 12): useful for type 2 subtyping, type 3 confirmation, prenatal counseling, and distinguishing 2B from platelet-type VWD.

Workup for acquired VWS when no family history and adult onset:

Risk Stratification and First-Line Management Logic

— Minor: epistaxis, simple dental extraction, skin biopsy, IUD insertion — target VWF activity ≥50 IU/dL

— Major surgery/major bleeding (intracranial, GI, major orthopedic, neurosurgery): target VWF activity and FVIII ≥100 IU/dL preoperatively, maintain ≥50 IU/dL for 7–14 days

— Childbirth/postpartum: maintain VWF and FVIII ≥50 IU/dL for at least 3 days after vaginal delivery, 5 days after cesarean

— Give IV or intranasal DDAVP and measure VWF:Ag, VWF activity, FVIII at baseline, 1 hour, and 4 hours

— Responder: 2–4× rise in VWF and FVIII, peak >50 IU/dL, sustained at 4 hours

— Most type 1 patients respond; type 2A and 2M variable; type 2B contraindicated; type 2N and type 3 generally non-responders (no storage to release or no VWF to stabilize FVIII)

— Minor mucosal bleeding/menorrhagia: tranexamic acid ± hormonal therapy ± DDAVP

— Procedural prophylaxis in DDAVP responder, minor procedure: DDAVP + antifibrinolytic

— Major surgery, type 2/3, or DDAVP nonresponder: VWF/FVIII concentrate (plasma-derived Humate-P, Wilate, Alphanate; or recombinant vonicog alfa — Vonvendi)

— Acquired VWS: treat the underlying cause; for acute bleeding use IVIG (especially MGUS-associated), VWF concentrate, or recombinant FVIIa for refractory cases

Step 3 management: Always document a DDAVP trial in stable outpatients before they need it — discovering a patient is a nonresponder during active hemorrhage or in the OR is a preventable adverse event and a frequent test scenario.

Management decisions hinge on three variables: VWD subtype, severity of bleeding/procedure, and patient-specific responsiveness to DDAVP.

Bleeding/procedural risk tiers:

DDAVP responsiveness trial — cornerstone risk stratification:

Tachyphylaxis: repeat DDAVP doses every 12–24 hours show diminishing returns after 2–3 doses as Weibel-Palade body stores deplete — for prolonged coverage, switch to VWF concentrate.

General first-line approach by setting:

Pharmacotherapy — First-Line Drug Regimen

— IV/SC dose: 0.3 mcg/kg in 50 mL NS over 30 minutes (max 20 mcg)

— Intranasal (Stimate, 1.5 mg/mL): 150 mcg one nostril if <50 kg; 300 mcg (one spray each nostril) if ≥50 kg — distinct from the much lower-dose nasal DDAVP for diabetes insipidus

— Onset 30–60 min, peaks at 1–2 hr, lasts 6–12 hr

— Repeat every 12–24 hr; expect tachyphylaxis after 2–3 doses

— Adverse effects: hyponatremia (free water retention — restrict fluids to maintenance, monitor sodium especially in children, elderly, postoperative patients), facial flushing, headache, tachycardia, hypotension

— Contraindications/cautions: type 2B (thrombocytopenia worsens), type 3 (no response), children <2 (seizure risk from hyponatremia), active cardiovascular disease, uncontrolled hypertension

— Tranexamic acid (TXA): 1300 mg PO TID (or 10 mg/kg IV q8h) during menses, dental procedures, epistaxis; topical mouthwash 5% TID after dental work

— Aminocaproic acid: alternative, longer dosing schedule

— Avoid in upper urinary tract bleeding (clot in collecting system → obstruction)

— Plasma-derived: Humate-P, Wilate, Alphanate (contain both VWF and FVIII)

— Recombinant VWF (vonicog alfa, Vonvendi): pure VWF; pair with recombinant FVIII for the first dose if FVIII is very low, then VWF alone (endogenous FVIII rises within hours)

— Dosing in VWF:RCo IU/kg; typical loading 40–60 IU/kg, then 20–40 IU/kg q12–24h, titrated to trough levels >50 IU/dL

Board pearl: Cryoprecipitate is no longer recommended for routine VWD management in the US — it is not virally inactivated. Use factor concentrates instead. Cryoprecipitate is acceptable only when VWF concentrates are unavailable and bleeding is life-threatening.

Desmopressin (DDAVP) — synthetic vasopressin analog that releases stored VWF and FVIII from endothelial Weibel-Palade bodies:

Antifibrinolytics — adjunctive for mucosal sites where local fibrinolysis is high:

VWF/FVIII concentrates — for type 2B, type 3, nonresponders, and major bleeding/surgery:

Hormonal therapy for menorrhagia: combined OCPs or levonorgestrel IUD (highly effective, often first-line for HMB in VWD).

Procedural and Perioperative Management

— Confirm subtype, DDAVP responsiveness, baseline VWF/FVIII levels

— Hematology consultation; coordinate with surgeon, anesthesia, blood bank, pharmacy

— Hold antiplatelets and NSAIDs ≥7 days; avoid neuraxial anesthesia if levels <50

— Minor procedures (dental extraction, skin biopsy, endoscopy without biopsy): VWF activity ≥30–50 IU/dL for 1–3 days; TXA mouthwash + single DDAVP dose often sufficient

— Major surgery: VWF activity and FVIII ≥100 IU/dL preoperatively, trough ≥50 IU/dL through postoperative day 7–14

— Neurosurgery, cardiac surgery: maintain ≥100 IU/dL trough for 7–10 days, then ≥50 IU/dL through day 14

— Daily VWF:Act, FVIII:C, CBC

— Watch for postoperative thrombosis — supraphysiologic FVIII levels from repeated dosing increase VTE risk; consider mechanical prophylaxis and cautious dose adjustment when FVIII >150 IU/dL

— Single DDAVP dose (if responder) 30 min before procedure

— TXA 1 g PO 1 hr pre-procedure + 1 g TID × 5–7 days

— Topical TXA rinse; local hemostatic measures (sutures, oxidized cellulose)

— Check VWF and FVIII at 34–36 weeks; pregnancy raises these (especially type 1), so many achieve hemostatic levels

— If VWF or FVIII <50 IU/dL near term, give factor concentrate or DDAVP (post-cord clamp for DDAVP)

— Neuraxial anesthesia generally safe if VWF activity and FVIII ≥50 IU/dL

— Maintain levels ≥50 IU/dL for ≥3 days post-vaginal, ≥5 days post-cesarean

— Active management of third stage; have TXA available

CCS pearl: In CCS, when admitting a VWD patient for surgery, order "VWF:Ag, VWF activity, FVIII" preop, give Humate-P 40–60 IU/kg IV prior to incision, schedule q12h dosing with trough levels, add DVT mechanical prophylaxis, and consult hematology — advancing the clock without these steps generates penalty points.

Preoperative planning is a Step 3 favorite — start coordination 2–4 weeks before elective surgery:

Target levels by procedure:

Monitoring intraoperatively and postoperatively:

Dental procedures specifically:

Childbirth and labor management:

Emergency surgery: empirically give VWF/FVIII concentrate 40–60 IU/kg, draw levels, and treat presumptively; consult hematology urgently.

Special Populations — Elderly and Renal/Hepatic Impairment

— A genuinely new bleeding diathesis after age 50 is much more likely acquired VWS than newly recognized inherited VWD

— Workup must include SPEP/free light chains, echocardiogram, TSH, and CBC with smear (MPN)

— Heyde syndrome: severe aortic stenosis → high-shear cleavage of HMW VWF multimers by ADAMTS13 → AVWS + colonic angiodysplasia → recurrent obscure GI bleeding; aortic valve replacement is definitive therapy and often curative

— Hyponatremia: age-related decline in free water excretion; restrict fluids to 1 L/day for 24 h post-dose; check sodium at 24 h

— Volume overload and CHF exacerbation: avoid in decompensated heart failure

— Coronary events: DDAVP causes tachycardia and increases von Willebrand-mediated platelet adhesion — relative contraindication in unstable CAD; use VWF concentrate instead

— Consider a reduced dose (0.2 mcg/kg) and slower infusion in patients >70

— Uremia itself causes acquired platelet dysfunction with prolonged bleeding time — distinct from VWD but managed similarly with DDAVP, conjugated estrogens, and dialysis optimization

— Drug dosing: TXA requires renal adjustment (reduce dose in CrCl <50, contraindicated in severe AKI per some protocols)

— VWF concentrates do not require renal dose adjustment

— Liver disease causes complex coagulopathy with elevated VWF (acute-phase reactant and reduced clearance) but reduced ADAMTS13 — adds confounding when interpreting labs

— Bleeding in cirrhotic patients is multifactorial; do not anchor on VWD without specific evidence

— Avoid TXA in those with active intravascular thrombosis

— Discontinue or minimize antiplatelets, anticoagulants, NSAIDs, SSRIs where feasible

— Counsel against herbal supplements with antiplatelet effects

— Address iron deficiency aggressively — oral iron, or IV iron (ferric carboxymaltose, ferric derisomaltose) for malabsorption or intolerance

Step 3 management: An 80-year-old with aortic stenosis and recurrent GI bleeding with negative endoscopies — order VWF multimer analysis, refer for TAVR or SAVR evaluation, and avoid empirically labeling as "diverticular bleeding."

Older adults with new-onset bleeding:

DDAVP in elderly carries amplified risks:

Renal impairment:

Hepatic impairment:

Polypharmacy review:

Special Populations — Pregnancy and Pediatrics

— Multidisciplinary care: maternal-fetal medicine, hematology, anesthesia, planned delivery center

— VWF and FVIII rise progressively in pregnancy (peak third trimester), often normalizing in type 1

— Check VWF:Ag, activity, FVIII at booking, 28 weeks, and 34–36 weeks

— Type 2B may worsen thrombocytopenia; type 3 sees no rise

— Neuraxial anesthesia: acceptable if VWF activity AND FVIII ≥50 IU/dL at the time

— Aim VWF activity ≥50 IU/dL at delivery and for ≥3 days postpartum (vaginal) or ≥5 days (cesarean)

— If levels inadequate: VWF/FVIII concentrate; DDAVP only after cord clamping (fetal hyponatremia/seizure risk)

— Active third-stage management with oxytocin; TXA available

— Postpartum hemorrhage can be delayed up to 4 weeks as VWF returns to baseline — counsel patients on warning signs and arrange early postpartum follow-up

— Offer genetic counseling for type 2 and type 3

— Avoid fetal scalp electrodes, vacuum extraction, and rotational forceps in affected fetuses

— Cord blood VWF testing limited utility (neonatal VWF is physiologically elevated)

— Often presents with epistaxis, easy bruising, post-tonsillectomy bleeding, menarche menorrhagia

— Avoid DDAVP in children <2 years — high seizure risk from hyponatremia

— Use weight-based VWF concentrate preferentially for young children

— Counsel on activity: avoid contact sports in severe type 3; helmet and protective gear for moderate disease

— School: emergency action plan, no aspirin/NSAIDs, ID bracelet

— VWF testing should be routine in adolescents with HMB severe enough to cause anemia or interfere with school

— Levonorgestrel IUD is highly effective and often first-line; combined OCPs second-line; TXA during menses

— Iron supplementation — most have iron deficiency anemia

Board pearl: A teenager with menorrhagia since menarche, IDA, and a negative pelvic ultrasound — send VWF panel before labeling as "dysfunctional uterine bleeding." Up to 20% of adolescents with HMB requiring evaluation have an underlying bleeding disorder, most commonly VWD.

Pregnancy in known VWD:

Delivery planning:

Fetal considerations:

Pediatric VWD:

Adolescent menorrhagia workup:

Complications and Adverse Outcomes

— Iron deficiency anemia: most common chronic complication, primarily from menorrhagia and recurrent epistaxis; left untreated worsens fatigue, work/school absenteeism, restless legs, pica

— GI bleeding from angiodysplasia: especially type 2A, type 3, and AVWS — loss of HMW multimers impairs vascular remodeling, predisposing to AVMs; often requires repeated endoscopy and may need long-term VWF prophylaxis or bevacizumab in refractory cases

— Intracranial hemorrhage: rare except in type 3; head trauma in type 3 mandates immediate factor replacement before imaging

— Hemarthroses and target joints: type 3 patients can develop hemophilic arthropathy

— Postpartum hemorrhage: occurs in up to 20% of pregnancies in type 1, higher in type 2/3; may be delayed

— Quality of life: chronic bleeding, missed work/school, anxiety, restricted activities

— DDAVP:

— Hyponatremic seizures (especially children, postoperative patients with hypotonic fluids) — restrict free water, monitor sodium

— Tachyphylaxis after 2–3 doses

— Flushing, headache, hypotension, MI/stroke (rare, in patients with vascular disease)

— VWF/FVIII concentrates:

— Thrombosis risk with cumulative supraphysiologic FVIII levels — keep trough FVIII <150 IU/dL when feasible; add mechanical or pharmacologic VTE prophylaxis postoperatively

— Alloantibody (anti-VWF) formation: rare but serious complication in type 3 VWD after repeated exposures, presenting as loss of therapeutic response and potentially anaphylaxis; manage with recombinant FVIIa or activated PCC for bleeding

— Transfusion transmission risk (extremely low with current viral inactivation)

— TXA:

— Thrombosis risk (avoid in active VTE)

— Seizures at high doses or rapid infusion

— Avoid in upper urinary tract bleeding (ureteral clot obstruction)

— Hormonal therapy:

— VTE risk with combined OCPs (caution if comorbid thrombophilia)

— Breakthrough bleeding with progestin-only options

Key distinction: A type 3 VWD patient who suddenly stops responding to concentrate has developed an inhibitor until proven otherwise — send an inhibitor assay; treatment shifts to recombinant FVIIa while immunotolerance options are considered. This parallels hemophilia A inhibitor management.

Disease-related complications:

Treatment-related complications:

When to Escalate — ICU, Consultation, and Inpatient Triage

— Initial subtyping and DDAVP trial

— Any planned surgery or invasive procedure

— Pregnancy preconception and antepartum

— Suspected acquired VWS

— Refractory or escalating bleeding

— Suspected inhibitor in type 3

— Active bleeding requiring factor replacement

— Hemoglobin <7 g/dL or symptomatic anemia requiring transfusion

— Postoperative monitoring after major surgery (typically 3–7 days)

— Pregnancy at term in type 2 or type 3 — admit for planned delivery

— Suspected ICH, GI bleed with hemodynamic instability, or compartment syndrome

— Hemodynamic instability despite resuscitation

— Intracranial hemorrhage

— Airway compromise (oropharyngeal hematoma, post-tonsillar bleed)

— Massive transfusion protocol activation

— Compartment syndrome from deep muscle bleed (type 3)

— Severe hyponatremia with seizures from DDAVP

— Two large-bore IVs; type and cross; CBC, PT/aPTT, fibrinogen, VWF panel, FVIII level

— Empiric VWF/FVIII concentrate 40–80 IU/kg IV — do not wait for level results

— TXA 1 g IV (avoid in upper urinary tract bleeding)

— pRBCs to maintain Hgb >7 (>8 if cardiac comorbidity); platelets if <50 in type 2B

— Reverse any concurrent anticoagulant

— Imaging directed by site (CT head, EGD/colonoscopy, CT abdomen)

— Consult hematology, surgery, GI as indicated; admit to ICU if unstable

— Recheck factor levels at 1 hour; target trough VWF activity ≥50–100 IU/dL

— Discharge with written bleeding action plan, MedicAlert ID, hematologist follow-up within 1–2 weeks

— Provide home supply of intranasal DDAVP (Stimate) and TXA for responders

— Coordinate with PCP for iron repletion monitoring

CCS pearl: In a CCS case of trauma in a known VWD patient, order factor concentrate before CT scan — waiting on imaging to confirm bleeding location while withholding factor will lower your score. Treat the bleeding disorder empirically, image concurrently.

Indications for hematology consultation (essentially all confirmed VWD at diagnosis):

Inpatient admission criteria:

ICU-level care:

Emergency management algorithm for active major bleeding:

Transitions of care (a Step 3 emphasis):

Key Differentials — Same-Category Causes (Other Bleeding Disorders)

— X-linked recessive — affected males, carrier females

— Deep bleeding: hemarthroses, muscle hematomas, ICH

— Prolonged aPTT, normal PT, normal VWF:Ag and activity, low FVIII, normal platelet count

— VWD type 2N and type 3 can mimic hemophilia A — order VWF panel in any "atypical hemophilia A" (female, recessive pattern, or low VWF too)

— X-linked, indistinguishable from hemophilia A clinically; differentiated by specific factor assays

— Glanzmann thrombasthenia (GPIIb/IIIa defect): mucocutaneous bleeding, normal VWF, abnormal aggregation to all agonists except ristocetin

— Bernard-Soulier syndrome (GPIb defect): large platelets, thrombocytopenia, abnormal ristocetin aggregation — can mimic type 2B VWD; platelet GPIb genetic testing distinguishes

— Storage pool disease: dense granule deficiency, abnormal aggregation curves

— Aspirin/NSAID effect: most common acquired platelet dysfunction

— Isolated thrombocytopenia, mucocutaneous bleeding with petechiae (uncommon in VWD), normal VWF

Key distinction: Type 2B VWD vs platelet-type VWD — both have enhanced ristocetin-induced aggregation and thrombocytopenia. Mixing studies: in type 2B, patient plasma + normal platelets aggregate; in platelet-type, normal plasma + patient platelets aggregate. Misclassification leads to ineffective therapy.

Hemophilia A (factor VIII deficiency):

Hemophilia B (factor IX deficiency):

Platelet function disorders:

Immune thrombocytopenia (ITP):

Rare factor deficiencies: factor XI (Ashkenazi Jewish), factor VII, fibrinogen disorders, factor XIII (delayed wound bleeding, normal PT/aPTT)

Acquired VWS (already detailed): consider in adult-onset, no family history, contextual triggers

Platelet-type (pseudo) VWD: gain-of-function GPIbα mutation; clinically resembles type 2B but managed with platelet transfusion, not DDAVP/VWF; LD-RIPA with patient platelets vs normal platelets distinguishes

Key Differentials — Other-Category Causes of Bleeding

— Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu): autosomal dominant, recurrent epistaxis, mucocutaneous telangiectasias, AVMs (pulmonary, hepatic, cerebral); normal coagulation studies

— Ehlers-Danlos syndrome (vascular type): easy bruising, hyperextensible skin, joint hypermobility, arterial rupture risk; normal coags

— Scurvy (vitamin C deficiency): perifollicular hemorrhage, gingival bleeding, corkscrew hairs — dietary history key

— Senile purpura, steroid-induced purpura: dermal atrophy, normal coags

— Liver disease: decreased factor synthesis (II, V, VII, IX, X, XI), thrombocytopenia, dysfibrinogenemia — prolonged PT > aPTT initially, elevated VWF (paradoxical)

— Vitamin K deficiency / warfarin: elevated PT and INR, normal VWF

— DIC: thrombocytopenia, low fibrinogen, elevated D-dimer, schistocytes, prolonged PT/aPTT — VWF may be elevated as acute-phase reactant

— Anticoagulant effect: heparin (elevated aPTT), DOACs (variable), warfarin

— Massive transfusion dilutional coagulopathy

— Hypothyroidism: reduces VWF synthesis and can cause mild acquired VWS — replace thyroid hormone, recheck VWF

— Cushing syndrome: vascular fragility, easy bruising; normal coags but skin findings prominent

— Antiplatelets (aspirin, clopidogrel, ticagrelor)

— SSRIs (impair platelet serotonin uptake)

— Herbals (ginkgo, garlic, ginger, fish oil)

— Chemotherapy (thrombocytopenia)

Board pearl: In a child with unexplained bruising, screening labs must include CBC, PT, aPTT, VWF:Ag, VWF activity, and FVIII before raising concerns about non-accidental trauma. Missed VWD diagnoses in this scenario are both a medical and medicolegal disaster.

Vascular and connective tissue disorders:

Acquired coagulopathies:

Endocrine causes affecting VWF:

Drug-induced bleeding:

Nonaccidental trauma / abuse: in children, pattern bruising, posterior locations, retinal hemorrhage — but always send coag workup including VWF before concluding abuse to avoid misdiagnosis of a bleeding disorder

Secondary Prevention and Long-Term Plan

— Wear MedicAlert identification noting VWD type and severity

— Avoid aspirin, NSAIDs, and herbal antiplatelet supplements; acetaminophen is preferred analgesic

— Maintain dental hygiene to minimize gingival bleeding; gentle brushing, regular cleanings with prophylactic TXA rinse

— Activity counseling: contact sports generally avoided in severe type 2 and type 3; helmet use; swimming and cycling encouraged

— Smoking cessation and limit alcohol (impairs platelet function)

— Intranasal DDAVP (Stimate 1.5 mg/mL) — explicitly note this is different from the diabetes insipidus formulation

— Oral TXA tablets for menses, dental work, or minor bleeding

— Written bleeding action plan with thresholds for ED visit

— First-line: levonorgestrel-releasing IUD — reduces blood loss 70–95%, well tolerated

— Alternatives: combined OCPs (continuous or cyclic), oral progestins, GnRH analogs (short term)

— Adjunct: TXA 1300 mg PO TID days 1–5 of menses

— Iron repletion: oral ferrous sulfate or IV iron (carboxymaltose, derisomaltose) if intolerant or refractory

— Severe type 3 with frequent bleeding (twice weekly to daily VWF concentrate)

— Recurrent angiodysplastic GI bleeding

— Pediatric patients with target joints

— Routine vaccines via subcutaneous route when possible to reduce muscle hematoma; if IM required, use smallest gauge needle, apply firm pressure ≥5 minutes

— Hepatitis A and B vaccination in any patient receiving plasma-derived concentrates

— Annual influenza, COVID-19, age-appropriate pneumococcal

— Offer first-degree relatives VWF panel testing

— Prenatal counseling for type 2 and type 3 couples; preimplantation genetic testing available

Step 3 management: At every visit, screen for iron deficiency (CBC, ferritin) in menstruating VWD patients — chronic undertreated iron deficiency is the most common preventable comorbidity and contributes substantially to symptom burden and quality of life impairment.

Lifestyle and self-management:

Home medication kit for responders:

Menstrual management (a chronic care cornerstone):

Prophylactic factor replacement — indicated in:

Immunizations:

Genetic counseling and family screening:

Follow-Up, Monitoring, and Counseling

— Stable type 1: hematology visit annually

— Type 2: every 6–12 months

— Type 3: every 3–6 months, more if on prophylaxis

— PCP visits in between for general care and iron monitoring

— Annual CBC, ferritin, iron studies

— Repeat VWF:Ag, activity, and FVIII at baseline, before any major procedure, during pregnancy, and when clinical pattern changes

— Type 3 on prophylaxis: trough levels, inhibitor screen periodically

— Liver and renal panels annually (concentrate exposure, comorbidities)

— Hepatitis serologies if receiving plasma-derived concentrates

— Patient should call hematology before any dental work, elective surgery, pregnancy attempt, or new anticoagulant/antiplatelet prescription

— Update bleeding action plan annually; reassess DDAVP responsiveness every few years (response can drift)

— Disease basics, inheritance pattern, expected bleeding triggers

— How to recognize emergencies: severe headache (ICH), abdominal pain with anemia (GI bleed), joint pain with swelling (hemarthrosis in type 3)

— Demonstration of nasal DDAVP technique with return demonstration

— TXA dosing instructions; signs of thrombosis to report

— When to use ED vs urgent care vs phone advice

— Travel: carry letter from hematologist, supply of medications, identify hemophilia treatment centers at destination

— 504 plan for affected children: bathroom access during menses, gym class modifications, school nurse access to TXA/DDAVP per protocol

— Workplace ergonomics for jobs with bleeding risk

— Screen for anxiety/depression related to chronic disease and procedural fears

— Support groups (National Bleeding Disorders Foundation)

— Care at a Hemophilia Treatment Center for type 3 and complex type 2 — multidisciplinary care improves outcomes

Board pearl: Reassess DDAVP responsiveness periodically and document peak response in the chart — emergency teams will rely on this information when the patient cannot speak for themselves, and demonstrated responsiveness from years ago may not match current physiology.

Routine outpatient follow-up cadence:

Lab monitoring:

Procedural and life-event planning:

Patient and family education:

School and workplace accommodation:

Psychosocial care:

Ethical, Legal, and Patient Safety Considerations

— Discuss treatment alternatives including DDAVP vs concentrate, plasma-derived vs recombinant, with their respective risks (anaphylaxis, thrombosis, infection)

— Document discussion of hyponatremia and thrombosis risks for repeated dosing

— In pregnancy, counsel on neuraxial anesthesia eligibility based on real-time labs, and on delayed PPH

— Engage adolescents in their own care planning; assent for contraceptive/hormonal management of menorrhagia

— Confidentiality concerns around hormonal therapy in minors — know state laws on reproductive health confidentiality

— In suspected nonaccidental trauma evaluations, always send bleeding workup first — falsely accusing caregivers when a child has undiagnosed VWD causes irreparable harm; failing to recognize true abuse equally so

— Type 2 and type 3 carry meaningful reproductive implications — offer formal genetic counseling

— Patient autonomy in disclosing diagnosis to relatives; physician may encourage but not compel disclosure

— Document offer of cascade family screening

— Highest-risk moments: ED handoffs, postoperative discharge, pregnancy intrapartum-to-postpartum, transfer between hospitals

— Use standardized handoff tools (I-PASS) mentioning VWD type, factor level targets, last factor dose, DDAVP responsiveness

— Reconcile medications carefully — avoid inadvertent NSAID or anticoagulant prescriptions in EHR alerts

— Provide structured discharge summary including bleeding action plan; ensure hematology follow-up appointment is scheduled before discharge, not "patient to call"

— Adverse drug reactions to factor concentrates reported to FDA MedWatch

— Suspected non-accidental injury reported per state law after medical workup is complete

— Document discussions of activity restrictions, school accommodations

— Women historically underdiagnosed — heavy menses normalized as "just bad periods"; deliberately ask about bleeding history in every woman with anemia

— Insurance authorization barriers for recombinant VWF and IV iron — engage social work and prior authorization staff early

— Hemophilia Treatment Center referral may require insurance navigation; HTC services often available regardless of payer

Step 3 management: When discharging a VWD patient after major surgery, the transition-of-care checklist must include: factor product name and lot, taper plan, VTE prophylaxis decisions, hematology follow-up date/time, written bleeding action plan, and reconciled medication list — missing any of these is a documented patient safety lapse.

Informed consent and shared decision-making:

Pediatric assent and parental decision-making:

Genetic counseling and disclosure:

Patient safety — transitions of care:

Mandatory reporting and documentation:

Health equity considerations:

High-Yield Associations and Rapid-Fire Facts

Board pearl: When a question stem mentions a young woman with menorrhagia since menarche + iron deficiency anemia + normal aPTT, the answer is VWF panel — not "endometrial biopsy" and not "pelvic ultrasound only."

Most common inherited bleeding disorder — ~1% lab prevalence, ~0.1% clinically significant

Most common subtype: type 1 (~75%); most severe: type 3

Inheritance: type 1, 2A, 2B, 2M — autosomal dominant; type 2N, type 3 — autosomal recessive

Blood group O patients have ~25% lower baseline VWF

VWF gene is on chromosome 12

Weibel-Palade bodies in endothelium and alpha granules in platelets store VWF

ADAMTS13 cleaves ultralarge VWF multimers — deficiency causes TTP (the flip side: too much VWF activity)

High-shear states (severe AS, LVAD, HCM, ECMO) cleave HMW multimers → AVWS

Heyde syndrome: aortic stenosis + colonic angiodysplasia + AVWS → GI bleeding cured by AVR

DDAVP = desmopressin = synthetic vasopressin analog → V2 receptor → releases VWF from endothelium

DDAVP contraindicated in type 2B (worsens thrombocytopenia), ineffective in type 3, caution children <2 (hyponatremic seizures)

Stimate intranasal (1.5 mg/mL) is the bleeding-disorder formulation — distinct from low-dose nasal DDAVP for diabetes insipidus

TXA is gold-standard adjunct for mucosal bleeding; avoid in upper urinary tract bleeding

Cryoprecipitate is no longer first-line — use VWF/FVIII concentrate (Humate-P, Wilate, Alphanate) or recombinant VWF (Vonvendi)

Type 2N mimics mild hemophilia A but is autosomal recessive and affects females equally — order VWF panel in any atypical hemophilia A

Type 3 inhibitors develop in ~10% with repeated exposure → treat bleeding with recombinant FVIIa

AVWS causes: aortic stenosis, LVAD, MGUS/myeloma/Waldenström, MPNs, hypothyroidism, Wilms tumor

ISTH-BAT score ≥4 (men), ≥6 (women), ≥3 (children) → warrants workup

Bleeding time is obsolete — do not order

Pregnancy normalizes VWF in most type 1; postpartum hemorrhage can be delayed up to 4 weeks

Levonorgestrel IUD is the most effective single intervention for menorrhagia in VWD

Iron deficiency is the most common comorbidity — treat aggressively

Board Question Stem Patterns

— 16-year-old with heavy menses since menarche, soaks through pads, Hgb 9.5 g/dL, MCV 72, ferritin 8, platelets 240, PT and aPTT normal. Next best step?

— Answer: VWF:Ag, VWF activity, FVIII (and start iron repletion)

— 30-year-old woman with prolonged bleeding after wisdom tooth extraction; reports lifelong epistaxis; family history of "easy bruising." Labs: normal CBC, PT, aPTT.

— Answer: Order VWD panel; normal aPTT does not exclude

— 78-year-old with severe aortic stenosis and recurrent obscure GI bleeding; colonoscopy shows angiodysplasia; multiple endoscopic interventions fail.

— Answer: Heyde syndrome — refer for aortic valve replacement; check VWF multimers

— Known type 1 VWD patient scheduled for laparoscopic cholecystectomy. Best preop management?

— Answer: DDAVP trial; if responder, IV DDAVP + TXA before surgery; target VWF activity ≥50–100 IU/dL

— 4-year-old given DDAVP for epistaxis develops seizure 12 hours later, Na 121.

— Answer: DDAVP-induced hyponatremia; restrict free water, hypertonic saline if seizing; avoid DDAVP in <2 years and limit fluids in all

— Patient with thrombocytopenia, mucocutaneous bleeding, increased ristocetin-induced aggregation at low doses given DDAVP — platelets drop further.

— Answer: Type 2B; DDAVP contraindicated; use VWF concentrate

— 65-year-old with new mucocutaneous bleeding, monoclonal IgG spike, low VWF multimers.

— Answer: Acquired VWS associated with MGUS; consider IVIG, treat underlying plasma cell disorder

— Type 1 VWD patient at 36 weeks, VWF activity 65 IU/dL, FVIII 70 IU/dL. Neuraxial OK?

— Answer: Yes, both ≥50 IU/dL; recheck at delivery

— Woman with low FVIII (25 IU/dL), normal VWF:Ag — labeled "hemophilia A carrier." Bleeding doesn't fit X-linked pattern.

— Answer: Send VWF:FVIII binding assay — suspect type 2N

— Type 3 patient suddenly stops responding to Humate-P after years of use.

— Answer: Anti-VWF inhibitor; treat acute bleeding with recombinant FVIIa

Key distinction: Stems emphasizing mucocutaneous bleeding with normal screening coags in a young woman or child point to VWD; stems with deep tissue bleeding and elevated aPTT in a male point to hemophilia — but remember type 2N and type 3 VWD blur this line.

Stem 1 — Classic adolescent presentation:

Stem 2 — Postoperative bleeding:

Stem 3 — Elderly GI bleeding:

Stem 4 — Perioperative planning:

Stem 5 — DDAVP complication:

Stem 6 — Wrong DDAVP in type 2B:

Stem 7 — Acquired VWS:

Stem 8 — Pregnancy management:

Stem 9 — Type 2N misdiagnosis:

Stem 10 — Inhibitor in type 3:

One-Line Recap

— Diagnose: mucocutaneous bleeding + ISTH-BAT score elevated → send VWF:Ag, VWF activity, FVIII; ratio activity/antigen distinguishes quantitative from qualitative; multimers and LD-RIPA subtype further; bleeding time obsolete, normal aPTT does not exclude VWD

— Treat: DDAVP (responders, type 1) + TXA for minor/mucosal bleeding; VWF/FVIII concentrate (Humate-P, Wilate, Vonvendi) for type 2/3, nonresponders, major surgery; levonorgestrel IUD is best chronic menorrhagia therapy; treat iron deficiency aggressively

— Avoid: DDAVP in type 2B (worsens thrombocytopenia), type 3 (ineffective), children <2 (hyponatremic seizures); NSAIDs/aspirin in all VWD; cryoprecipitate when concentrate available; TXA in upper urinary tract bleeding

— Special scenarios: pregnancy — recheck at 34–36 weeks, neuraxial if VWF and FVIII both ≥50; postpartum hemorrhage can be delayed up to 4 weeks; Heyde syndrome (AS + GI angiodysplasia + AVWS) cured by AVR; new adult-onset bleeding → think acquired VWS (MGUS, MPN, AS, LVAD, hypothyroidism)

Step 3 management: Establish VWD diagnosis and subtype, document DDAVP responsiveness, build a written bleeding action plan, ensure annual iron status review, coordinate hematology + PCP + OB-GYN longitudinal care, plan procedures ≥2 weeks in advance with factor level targets, and treat transitions of care as the highest-risk safety moments — these are the recurrent Step 3 management touchpoints across every VWD vignette you will encounter.

One-line recap: Von Willebrand disease is the most common inherited bleeding disorder, presenting with mucocutaneous bleeding and normal screening coags, diagnosed by VWF:Ag, VWF activity, and FVIII (with subtyping by multimers, ratios, and RIPA), and managed with DDAVP (for responders, not type 2B or 3), tranexamic acid, hormonal therapy for menorrhagia, and VWF/FVIII concentrate for major bleeding, surgery, or nonresponders — with vigilant attention to iron deficiency, perioperative planning, and acquired VWS in older adults.

High-yield bullet recaps: