Von Willebrand Disease

Aka: Von Willebrand Disease, Von Willebrand's Disease, Von Willebrand Deficiency, Von Willebrand Disorder, Von Willebrand Syndrome, VWF Deficiency

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II. Epidemiology

  1. Prevalence estimated at 1.3%
    1. However only 0.01% is diagnosed with lab testing
    2. Most common inherited Bleeding Disorder
  2. Mild Bleeding Disorder (often undiagnosed)
  3. Autosomal Dominant disorder

III. Pathophysiology

  1. See Von Willebrand Factor (VWF)

IV. Types

  1. Acquired Von Willebrand Syndrome
    1. See Von Willebrand Factor (VWF) for causes
  2. Type 1: Partial quantitative VWF Deficiency
    1. Most common form (89% of VWF Deficiency)
    2. VWF decreased (as well as possibly Factor VIII)
    3. However the VWF that is present functions normally
    4. Associated with mild bleeding symptoms (e.g. Menorrhagia, prolonged Epistaxis)
    5. Responds to Desmopressin (DDAVP)
  3. Type 2: Quantitative VWF Deficiency (subtypes are Phenotype mutations)
    1. Manifestations: Typically more severe bleeding than for Type I
    2. VWF is a deformed Protein that functions poorly in Type II(in contrast to Type I where the VWF Protein is simply reduced)
    3. Unresponsive to DDAVP (except in Type 2N and in 10% of Type 2A)
      1. Use Humate-P instead
    4. Type 2A
      1. Decreased large functional VWF monimers
      2. Decreased VWF-dependent Platelet adhesion
    5. Type 2B
      1. Decreased large functional VWF monimers (due to increased gpIIb binding)
      2. Circulating Platelets are coated with non-functional VWF which prevents Platelet binding to injury site
    6. Type 2M
      1. Normal number of large functional VWF monimers
      2. Decreased VWF-dependent Platelet adhesion
    7. Type 2N
      1. Impaired VWF binding to Factor VIII (lowers Factor VIII levels)
      2. May be misdiagnosed as Autosomal RecessiveHemophilia A
  4. Type 3: Virtually Complete VWF Deficiency
    1. Rare form of VWF
    2. VWF levels are are typically undetectable
    3. Factor VIII levels are very low
    4. Unresponsive to DDAVP (use Humate-P instead)
  5. Pseudo-Von Willebrand (Platelet-Type)
    1. Abnormal gpIIb results in lower levels of high molecular weight multimers

V. Symptoms

  1. Skin Bruising
  2. Rectal Bleeding not explained by a known source (Peptic Ulcer, Colon Polyp, Hemorrhoid)
  3. Severe Anemia requiring transfusion
  4. Recurrent or persistent Epistaxis
    1. Bleeding lasting longer than 10 minutes or required medical attention
  5. Excessive bleeding with minor procedures (e.g. dental work) or Trauma
    1. Bleeding lasting longer than 15 minutes
    2. Wound bleeding recurred spontaneously within 7 days from onset
  6. Excessive uterine bleeding
    1. Postpartum Hemorrhage several days after delivery
    2. Severe Menorrhagia (common presentation in women)
      1. Blood clots >1 inch diameter
      2. Bleeding requiring frequent change in pad or tampon (hourly)
      3. Anemia with persistently or recurrently low Hemoglobin or Ferritin

VI. Evaluation

  1. Indications
    1. Personal or Family History of significant bleeding (see symptoms as above) and
      1. Planned for surgical procedure with moderate to high risk of bleeding or
      2. Current bleeding symptoms or abnormal lab results
  2. Complete history and examination
    1. See Bleeding Disorder
    2. Symptoms suggestive of Bleeding Diathesis as listed above
    3. Medication causes of Bleeding Disorder (e.g. Plavix, Aspirin, NSAIDs, Warfarin)
    4. Liver, Kidney or Bone Marrow disorders

VII. Labs

  1. Initial (Lab results vary over time in each patient)
    1. Partial Thromboplastin Time (PTT) prolonged
      1. Corrects on 1:1 mixing study
    2. Fibrinogen Level
  2. Von Willebrand specific assays
    1. Von Willebrand Factor Antigen (VWF:Ag)
    2. Von Willebrand Factor Ristocetin Cofactor Activity (VWF:RCo)
    3. Factor VIII
      1. Often associated with Factor VIII:C deficiency
  3. Labs that are no longer recommended for Von Willebrand diagnosis
    1. Bleeding Time prolonged
    2. Platelet Function Closure Time (PFCT) or Platelet Function Analyzer-100

VIII. Differential Diagnosis

  1. See Bleeding Disorder

IX. Management

  1. Referral to hematology or Hemophilia center
  2. Specific Agents
    1. Synthetic Hormone Arginine Vasopressin (Desmopressin, DDAVP, Synthetic Vasopressin)
      1. Indicated for Type I (and in Type 2N) cases prior to surgery and in cases of Trauma
      2. Other forms of Type 2, Type 3 and pseudo-VWF will not respond to DDAVP (and may have paradoxical lowering of VWF)
      3. Increases release of VWF Protein (stored in Weibel-Palade bodies)
      4. Onset of action within 30-60 minutes with duration of 6-12 hours
      5. Do not repeat more often than every 24 to 48 hours due to Hyponatremia risk (as well as tachyphylaxis)
    2. Von Willebrand FactorProtein and Factor VIII Replacement (Humate-P or Alphanate in U.S., Wilfact internationally)
    3. Oral Antifibronolytics (Epsilon-aminocaproic acid or Amicar)
      1. Indicated for mucous membrane bleeding during oral or dental procedures
    4. Topical Thrombin or Fibrin sealants
      1. May be applied to minor bleeding sites
    5. Cryoprecipitate
      1. No longer recommended for Von Willebrand Factor (or Factor VIII)
      2. Requires many transfused units for adequate replacement (each unit contains only a small amount of factor)
      3. May be used if Demospressin (DDAVP) and Humate (or Alphanate, Wilfact) are not available
      4. Increases VW Protein by 100%
  3. Specific conditions
    1. Minor bleeding
      1. Synthetic Hormone Arginine Vasopressin (Desmopressin, DDAVP)
    2. Major bleeding
      1. Von Willebrand FactorProtein and Factor VIII Replacement (Humate-P or Alphanate in U.S., Wilfact internationally)
    3. Menorrhagia
      1. Oral Contraceptives
      2. Mirena IUD
    4. Pregnancy
      1. Genetic Counseling
      2. Obtain Factor VIII and VWF:RCo assays
        1. Refer to perinatal center with Hemophilia center access if levels are <50 IU/dl
      3. Avoid Desmopressin (DDAAVP) during labor due to interaction with Pitocin and risk of hypnatremia and Seizures
      4. Risk of delayed Postpartum Hemorrhage at 21 to 28 days after delivery
    5. Peri-operative management
      1. Desmopressin Responsive VWF (Type 1, Type 2N)
        1. Desmopressin (DDAVP) 0.3 mcg/kg infusion ending 45 minutes prior to procedure
        2. May repeat every 24 hours to keep trough Factor VIII levels >80% in major procedures (high bleeding risk)
      2. Desmopressin Unresponsive VWF (Type 2 except 2N, Type 3, Pseudo-VWF)
        1. Humate-P
          1. Titrate Factor VIII Level peak to over 120% and trough over 80%
          2. Factor VIII Level trough <30%
            1. Humate-P 40-50 IU/kg initially, followed by 20 IU/kg every 12 hours
          3. Factor VIII Level trough >30%
            1. Humate-P 20-40 IU/kg every 12 hours

X. Management: Acute Bleeding (Emergency Department)

  1. Indications for acute treatment
    1. Major Trauma
    2. Recent surgery and suspicion for uncontrolled bleeding
    3. Uncontrolled Epistaxis
  2. Unknown Von Willebrand Disease Type
    1. Humate-P 3500 von willebrand units or per specific dosing protocol
      1. Alphanate or Wilfact (non-US) are alternative products
      2. Cryoprecipitate may be used if other agents (e.g. Humate-P) are not available
  3. Type 1 and Type 2N (Desmopressin Responsive)
    1. Desmopressin (DDAVP) 0.3 mcg/kg IV, SQ or intranasal
    2. Patients may have a potent form of DDAVP nasal spray (Stimate) for home management of bleeding (and preoperative use)
  4. Type 2 (except Type 2N) and Type 3 (Desmopressin Unresponsive)
    1. Humate-P 3500 von willebrand units or per specific dosing protocol
  5. Pseudo-Von Willebrands (Platelet-type)
    1. Platelets
    2. Humate-P 3500 von willebrand units or per specific dosing protocol
    3. Recombinant Factor VIIa

XI. References

  1. Deloughery and Orman in Majoewsky (2013) EM:Rap 13(9): 1-4
  2. Federici (2006) Semin Thromb Hemost 32(6): 616-20 [PubMed]
  3. Nichols (2008) Haemophilia 14(2): 171-232 [PubMed]
  4. Sadler (2000) Thromb Haemost 84(2): 160-74 [PubMed]
  5. Yawn (2009) Am Fam Physician 80(11): 1261-70 [PubMed]

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