Von Willebrand Disease

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

1. See Also
   1. Von Willebrand Factor (VWF)
2. Epidemiology
   1. Prevalance 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
3. Physiology
   1. See Von Willebrand Factor (VWF)
4. Types
   1. Acquired Von Willebrand Syndrome
      1. See Von Willebrand Factor (VWF) for causes
   2. Type 1: Partial quantitative VWF Deficiency
      1. VWF decreased (as well as possibly factor VIII)
      2. However the VWF that is present functions normally
      3. Associated with mild bleeding symptoms (e.g. Menorrhagia, prolonged Epistaxis)
   3. Type 2: Quantitative VWF Deficiency (subtypes are phenotype mutations)
      1. Manifestations: Typically more severe bleeding than for Type I
      2. Type 2A
         1. Decreased large functional VWF monimers
         2. Decreased VWF-dependent platelet adhesion
      3. Type 2B
         1. Decreased large functional VWF monimers
         2. Circulating platelets are coated with non-functional VWF which prevents platelet binding to injury site
      4. Type 2M
         1. Normal number of large functional VWF monimers
         2. Decreased VWF-dependent platelet adhesion
      5. Type 2N
         1. Impaired VWF binding to Factor VIII (lowers factor VIII levels)
         2. May be misdiagnosed as autosomal recessive Hemophilia A
   4. Type 3: Virtually Complete VWF Deficiency
      1. VWF levels are are typically undetectable
      2. Factor VIII levels are very low
5. 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
6. 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
7. 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
      3. Bleeding Time prolonged
      4. Platelet Function Closure Time (PFCT) or Platelet Function Analyzer-100
         1. Replaces Bleeding Time
   2. Von Willebrand specific assays
      1. Von Willebrand Factor Antigen (VWF:Ag)
      2. Von Willebrand Factor Ristocetin Cofactor Activity (VWF:RCo)
      3. Factor VIII
8. Differential Diagnosis
   1. Bleeding Disorder
9. Management
   1. Referral to hematology or Hemophilia center
   2. Specific Agents
      1. Synthetic hormone arginine vasopressin (Desmopressin, DDAAVP, synthetic vasopressin)
         1. Indicated for Type I and in some Type II cases prior to surgery and in cases of trauma
         2. Do not repeat more often than every 24 to 48 hours due to Hyponatremia risk (as well as tachyphylaxis)
      2. Von Willebrand Factor and Factor VIII Replacement
         1. Preparations: Humate P, Alphanate
         2. Cryoprecipitate is no longer recommended for Von Willebrand Factor (or Factor VIII)
      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
   3. Specific conditions
      1. Menorrhagia
         1. Oral Contraceptives
         2. Mirena IUD
      2. 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
10. References
    1. Federici (2006) Semin Thromb Hemost 32(6): 616-20
    2. Nichols (2008) Haemophilia 14(2): 171-232
    3. Sadler (2000) Thromb Haemost 84(2): 160-74
    4. Yawn (2009) Am Fam Physician 80(11): 1261-70