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

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
  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

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. May be used if Demospressin (DDAVP) and Humate (or Alphanate, Wilfact) are not available
      3. Increases VW Protein by 100%
  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
    3. 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

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Ontology: von Willebrand Disease (C0042974)

Definition (MSH) Group of hemorrhagic disorders in which the VON WILLEBRAND FACTOR is either quantitatively or qualitatively abnormal. They are usually inherited as an autosomal dominant trait though rare kindreds are autosomal recessive. Symptoms vary depending on severity and disease type but may include prolonged bleeding time, deficiency of factor VIII, and impaired platelet adhesion.
Definition (SCTSPA) Incluye la enfermedad de von Willebrand verdadera, con mutación en el locus VWF, así como otros trastornos similares con otras mutaciones (seudo-EVW) y síndrome de von Willebrand adquirido
Definition (SNOMEDCT_US) Includes true von Willebrand disease with mutation at the VWF locus, as well as mimicking disorders with other mutations (pseudo VWD) and acquired von Willebrand syndrome
Definition (NCI) Hereditary or acquired coagulation disorder characterized by a qualitative or quantitative deficiency of the von Willebrand factor. The latter plays an important role in platelet adhesion. Signs and symptoms include bruises, nose bleeding, gum bleeding following a dental procedure, heavy menstrual bleeding, and gastrointestinal bleeding.
Definition (CSP) hemophilioid disorder due to deficiency of Von Willebrand factor and thus of Factor VIII complex.
Concepts Disease or Syndrome (T047)
MSH D014842
ICD9 286.4
ICD10 D68.0 , D69.8
SnomedCT 154819009, 11093006, 128105004
LNC LP21217-2
English Pseudohemophilia, Angiohemophilia, Angiohemophilias, Hemophilia, Vascular, Vascular Hemophilias, von Willebrand's Disease, Vascular Hemophilia, Von Willebrand's disease, VON WILLEBRANDS DISEASE, vascular hemophilia, Von Willebrand disease, von Willebrand Disease, VON WILLEBRAND DIS, VON WILLEBRANDS DIS, vascular pseudohemophilia (diagnosis), von Willebrand's disease (diagnosis), vascular pseudohemophilia, Factor VIII Rag deficiency, Von willebrand's disease, von Willebrand's Diseases, von Willebrand Diseases, Vascular pseudohemophilia, von Willebrand, von Willebrand Diseases [Disease/Finding], von willebrands disease, von willebrand disorder, disease von willebrands, von willebrand disease, disease von willebrand, von willebrand's disease, diseases von willebrand's, Pseudohemophilia, Vascular, Vascular Pseudohemophilias, Von Willebrand's Factor Deficiency, Vascular Pseudohemophilia, Disorder, Von Willebrand, Pseudohemophilias, Vascular, Von Willebrand Disorder, von Willebrand's disease (disorder), von Willebrand disease (disorder), von Willebrand-Jürgens disease, Pseudohaemophilia, Von Willebrand's factor deficiency, Vascular hemophilia, von Willebrand's disease, Constitutional thrombopathy, Factor VIII deficiency with vascular defect, Pseudohemophilia type B, von Willebrand-Jurgens disease, vWD - von Willebrand's disease, Vascular haemophilia, Angiohaemophilia, Pseudohaemophilia type B, von Willebrand disease, von Willebrand disorder (disorder), von Willebrand disorder, angiohemophilia, pseudohemophilia, Minot-von Willebrand-Jürgens, constitutional; thrombopathy, Von Willebrand, Willebrand-Jürgens; thrombopathy, Willebrand-Jürgens, hemophilia; vascular, pseudohemophilia; vascular, thrombopathy; Willebrand-Jürgens, thrombopathy; constitutional, vascular; hemophilia, vascular; pseudohemophilia, von Willebrand disease, NOS, von Willebrand-J?rgens disease, Angiohemophilia, A, Angiohemophilia, B, von Willebrand's-Jurgens' disease, Disease;Von Willebrands, Von Willebrands disease
Italian Malattia di von Willebrand, Deficit di RAG correlato al Fattore VIII, Deficit di fattore di Von Willebrand, Pseudoemofilia, Emofilia vascolare, Angioemofilia, VWD, Malattie di von Willebrand
Dutch angiohemofilie, pseudo-hemofilie, vasculaire hemofilie, factor VIII Rag deficiëntie, Von Willebrand-factor-deficiëntie, Willebrand-Jürgens; trombopathie, constitutioneel; trombopathie, hemofilie; vasculair, pseudohemofilie; vasculair, trombopathie; Willebrand-Jürgens, trombopathie; constitutioneel, vasculair; hemofilie, vasculair; pseudohemofilie, Ziekte van Willebrand, ziekte van Von Willebrand, Angiohemofilie, Hemofilie, vasculaire, Ziekte van Von Willebrand
French Pseudohémophilie, Déficit en facteur VIII RAg, Carence en facteur de Von Willebrand, Maladies de von Willebrand, Angiohémophilies, Maladie de von Willebrand, Maladie de Von Willebrand, Maladie Von Willebrand, Angiohémophilie, Hémophilie vasculaire, Maladie de Willebrand
German Angiohaemophilie, Pseudohaemophilie, vaskulaere Haemophilie, Faktor VIII RAG-Defizienz, Von Willebrand-Faktormangel, Willebrand-Juergens-Syndrom, von Willebrand-Juergens' Syndrom, Von-Willebrand-Krankheit, Von-Willebrand-Syndrom, Angiohämophilie, Hämophilie, vaskuläre, Willebrand-Jürgens-Syndrom
Portuguese Angiemofilia, Hemofilia vascular, Carência de factor VIII Rag, Pseudo-hemofilia, Carência de factor de von Willebrand, Doenças de von Willebrand, Doença de von Willebrand, Doença von Willebrand, Doenças von Willebrand, Angiohemofilia, Hemofilia Vascular
Spanish Hemofilia vascular, Seudohemofilia, Deficiencia del factor de Von Willebrand, Déficit de factor VIIIR, Enfermedades de von Willebrand, Enfermedad de von Willebrand, enfermedad de von Willebrand - Jurgens, deficiencia de factor VIII con defecto vascular, hemofilia vascular, angiohemofilia, enfermedad de von Willebrand (concepto no activo), enfermedad de von Willebrand - Jürgens, pseudohemofilia tipo B, enfermedad de von Willebrand, trombopatía generalizada, trastorno de von Willebrand (trastorno), trastorno de von Willebrand, Enfermedad de Von Willebrand, Angiohemofilia, Hemofilia Vascular
Japanese フォンウィルブランド因子欠乏, 偽性血友病, 第VIII因子関連抗原欠乏症, ケッカンケツユウビョウ, ギセイケツユウビョウ, ダイ8インシカンレンコウゲンケツボウショウ, ケッカンセイケツユウビョウ, フォンウィルブランドビョウ, フォンウィルブランドインシケツボウ, フォン・ウィルブランド病, von Willebrand病, フォン・ビルブラント病, フォン・ウィルブラント病, フォン・ウィレブランド病, フォンウィルブランド病, ウィルブランド病, 偽血友病, 血管性血友病, ウィレブランド病, フォン-ウィルブランド病, フォン-ウィレブランド病, 血友病-血管性, 血管血友病
Finnish von Willebrandin tauti
Czech Deficit faktoru VIII Rag, Angiohemofilie, Pseudohemofilie, Von Willebrandova choroba, Vaskulární hemofilie, Deficit Von Willebrandova faktoru, von Willebrandovy nemoci, von Willebrandova nemoc, Willebrandova nemoc, angiohemofilie, vaskulární hemofilie, von Willebrandova choroba
Korean 폰 빌레브란트 병
Swedish von Willebrands sjukdomar
Polish Choroba von Willebranda
Hungarian Vascularis haemophilia, Faktor VIII Rag hiánya, Angiohaemophilia, Pseudohemophilia, Pseudohaemophilia, Von Willebrand-betegség, Ér eredetű vérzékenység, Von Willebrand faktor hiánya, Angiohemophilia
Norwegian Willebrands sykdom, Von Willebrands sykdom, von Willebrands sykdommer, Vaskulær hemofili, Angiohemofili