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von Willebrand Disease, Emergency Medicine

Basics

Description

- Coagulopathy caused by deficiency or dysfunction of von Willebrand factor (vWF) - vWF functions: - Mediates platelet " “endothelial cell adhesion - Carrier protein for factor VIII

- Type 2 " ”qualitative defect of vWF: - 10 " “15% of cases - Divided into types 2A, 2B, 2M, 2N " ”all are autosomal dominant except 2N which is autosomal recessive. - Decrease in intermediate and high molecular-weight multimer - 2N " ”decreased binding to factor VIII - Leads to decreased levels of VIII and thus more serious coagulopathy

- In addition to genetic causes, acquired forms exist. - Multiple mechanisms: - vWF antibody production - Decreased synthesis - Proteolysis - Increased clearance from binding to tumor cells

- Immunologic: - Systematic lupus erythematosus - Rheumatoid arthritis

- Medication induced: - Valproic acid - Ciprofloxacin - Hetastarch - Griseofulvin

- Symptoms vary depending on type of disease. - Many type 1 and some type 2 are asymptomatic, severe type 2 and type 3 are symptomatic: - Easy bruising - Menorrhagia - Recurrent epistaxis - Gum bleeding - GI bleeding - Soft-tissue bleeds and hemarthroses - Prolonged or excessive procedural bleeding - Postoperative hemorrhage

- Desmopressin acetate (DDAVP): - Promotes release of vWF from endothelial cells, increases factor VIII levels - Maximal levels obtained at 30 " “60 min, with duration of 6 " “8 hr - Effective for type 1; variable effectiveness for type 2; not indicated for type 3 - Patients may use intranasal spray at home before menses or minor procedures

- vWF replacement therapy: - Humate-P factor VIII concentrate with vWF: - Treated to reduce virus transmission risks - Indicated for type 3 vWD and severe bleeding in all types - Doses, length of treatment depend on severity of bleeding - Cryoprecipitate is no longer a treatment of choice as it carries risk of virus transmission. If no other treatments are available and patient having life-threatening hemorrhage, it can be used

- Topical agents " ”applied directly to bleeding site: - Gelfoam or Surgicel soaked in thrombin - Micronized collagen - Fibrin sealant

  • Coagulopathy caused by deficiency or dysfunction of von Willebrand factor (vWF)
  • vWF functions:Mediates platelet " “endothelial cell adhesionCarrier protein for factor VIII
  • Prevalence as high as 1 " “2% in the general population
  • Genetics:Most cases inherited " ”multiple genetic defects identifiedType 1 " ”quantitative defect of vWF:70% of casesAutosomal dominantvWF deficiency results from decreased synthesis and increased clearance of protein.Manifestation ranges from asymptomatic to moderate bleeding.Type 2 " ”qualitative defect of vWF:10 " “15% of casesDivided into types 2A, 2B, 2M, 2N " ”all are autosomal dominant except 2N which is autosomal recessive.Decrease in intermediate and high molecular-weight multimer2N " ”decreased binding to factor VIIILeads to decreased levels of VIII and thus more serious coagulopathyType 3 " ”absent or severe deficiency in amount of vWF:Rare disease " ”1 per million casesAutosomal recessiveSevere coagulopathyvWD genetically associated with sickle cell disease, hemophilia A, factor XII deficiency, hereditary hemorrhagic telangiectasia, and thrombocytopenia

Etiology

  • In addition to genetic causes, acquired forms exist.
  • Multiple mechanisms:vWF antibody productionDecreased synthesisProteolysisIncreased clearance from binding to tumor cells
  • Seen in association with the following:Malignancy:Wilms tumorMultiple myelomaChronic lymphocytic leukemiaNon-Hodgkin lymphomaChronic myelogenous leukemiaWaldenstrom macroglobulinemiaMonoclonal gammopathy of uncertain significanceImmunologic:Systematic lupus erythematosusRheumatoid arthritisMedication induced:Valproic acidCiprofloxacinHetastarchGriseofulvinMiscellaneous:HypothyroidismUremiaHemoglobinopathiesCirrhosisCongenital heart diseaseDisseminated intravascular coagulation

Diagnosis

Signs and Symptoms

  • Symptoms vary depending on type of disease.
  • Many type 1 and some type 2 are asymptomatic, severe type 2 and type 3 are symptomatic:Easy bruisingMenorrhagiaRecurrent epistaxisGum bleedingGI bleedingSoft-tissue bleeds and hemarthrosesProlonged or excessive procedural bleedingPostoperative hemorrhage

History

  • Most often diagnosed in pediatric and adolescent populations
  • Family history
  • Minor/moderate recurrent mucosal bleeding most common historical clue
  • Heavy menses

Physical Exam

  • Most will have normal exam
  • Multiple large bruises
  • Deep-tissue hematomas, hemarthroses
  • Pregnancy causes increased vWF levels in patients with types 1 and 2 disease
  • Pregnancy, labor, and delivery are usually uncomplicated
  • vWF levels fall quickly after delivery:Patients may suffer postpartum bleeding 10 " “28 days after delivery

Always consider nonaccidental trauma in an infant or child presenting with bruising or bleeding of unknown cause ‚

Essential Workup

  • Screen and refer for testing if historical concerns or consistent physical findings
  • For type 1 diagnosis, patient must have significant mucocutaneous bleeding, lab confirmation, and family history of type 1 disease

Diagnosis Tests & Interpretation

Lab

  • CBC: Normal platelet count and morphology
  • PT: Normal
  • PTT:Mildly prolonged in 50%Due to low factor VIII levels or coexistent factor deficiency
  • Measurement of vWF level and activity:vWF ristocetin cofactor activity (vWF:RCo):Uses platelet agglutination to determine vWF functionvWF antigen " ”tests for vWF level in serum using rabbit antibodies
  • Bleeding time:May be normal in type 1 (50%); prolonged in types 2 and 3Not specific and hard to reproduce; has fallen out of favor for diagnosis

Differential Diagnosis

  • Hemophilia A, B
  • Platelet defects
  • Use of antiplatelet drugs " ”NSAIDs
  • Platelet-type pseudo vWD
  • Bernard " “Soulier syndrome

Treatment

Pre-Hospital

Direct pressure for control of hemorrhage ‚

Initial Stabilization/Therapy

Resuscitation with crystalloid and packed RBCs as needed ‚

Ed Treatment/Procedures

  • As with all significant bleeding, apply direct pressure to site of bleeding
  • 3 treatment strategies:Increase endogenous vWFReplacement of vWFAgents that generally promote hemostasis but do not alter levels of vWF
  • Desmopressin acetate (DDAVP):Promotes release of vWF from endothelial cells, increases factor VIII levelsMaximal levels obtained at 30 " “60 min, with duration of 6 " “8 hrEffective for type 1; variable effectiveness for type 2; not indicated for type 3Patients may use intranasal spray at home before menses or minor procedures
  • vWF replacement therapy:Humate-P factor VIII concentrate with vWF:Treated to reduce virus transmission risksIndicated for type 3 vWD and severe bleeding in all typesDoses, length of treatment depend on severity of bleedingCryoprecipitate is no longer a treatment of choice as it carries risk of virus transmission. If no other treatments are available and patient having life-threatening hemorrhage, it can be used
  • Antifibrinolytic therapy:Aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron)Block plasmin formation to prevent clot degradation
  • Topical agents " ”applied directly to bleeding site:Gelfoam or Surgicel soaked in thrombinMicronized collagenFibrin sealant
  • Avoid antiplatelet agents

First Line

  • Minor bleeding (epistaxis, oropharyngeal, soft tissue):IV or intranasal desmopressin
  • Major bleeding (intracranial, retroperitoneal):Replace vWF and factor VIII so activity level is at least 100 IU/dL

Second Line

  • Minor bleeding:vWF concentrate:Given if desmopressin is ineffectiveShould be given in consultation with a hematologistAminocaproic acid or tranexamic acid:For mild mucocutaneous bleeding

Medication

  • Aminocaproic acid: 50 " “60 mg/kg PO/IV q4 " “q6h
  • Cryoprecipitate: 10 " “12 U initial dose or 2 " “4 bags/10 kg
  • Desmopressin (DDAVP):0.3 ˇ ¼g/kg IV, max. 20 ˇ ¼g0.3 ˇ ¼g/kg SQ, max. 20 ˇ ¼g300 ˇ ¼g (1 spray each nostril) intranasalPeds: <50 kg " ”150 ˇ ¼g (1 spray in each nostril) intranasal
  • Antihemophilic factor/vWF complex, human (Humate-P): 20 " “40 U/kg IV
  • Tranexamic acid: 20 " “25 mg/kg PO, IV q8h
  • Fresh frozen plasma (FFP) " ”10 " “20 mL/kg IV

Follow-Up

Disposition

Admission Criteria

  • Patients with significant bleeding requiring further IV medical management
  • Observation after major trauma for types 2 and 3 vWD
  • Consider transferring patients with major bleeding events to a center with round-the-clock lab capability, and a care team that includes a hematologist and a surgeon skilled in management of bleeding disorders

Discharge Criteria

  • Control of hemorrhage
  • Adequate follow-up and access to medical therapy

Followup Recommendations

Hematology: ‚

  • Severe, difficult-to-manage bleeding
  • Prior to elective/semielective procedures
  • Definitive workup of suspected cases

Pearls and Pitfalls

Patients may not know their type of hemophilia: ‚

  • Consider FFP for the patient with unknown type of hemophilia in the setting of trauma or bleeding

Additional Reading

  • Mannucci ‚ P. Treatment of von Willebrand disease. N Engl J Med. 2004;351:683 " “694.
  • Nichols ‚ WL, Hultin ‚ MB, James ‚ AH, et al. von Willebrand disease (vWD): Evidence-based diagnosis and management guidelines, the National Heart, Lung and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008;14:171 " “232.
  • Pacheco ‚ L, Costantine ‚ M, Saade ‚ G, et al. von Willebrand disease and pregnancy: A practical approach for the diagnosis and treatment. Am J Obstet Gynecol. 2010;203(3):194 " “200.
  • Robertson ‚ J, Lillicrap ‚ D, James ‚ P. Von Willebrand disease. Pediatr Clin North Am. 2008;55(2):377 " “392.
  • The Diagnosis, Evaluation and Management of von Willebrand Disease. National Heart, Lung and Blood Institute. Available at http://www.nhlbi.nih.gov/guidelines/vwd./ Accessed January 14, 2013.

See Also (Topic, Algorithm, Electronic Media Element)

Hemophilia ‚

Codes

ICD9

286.4 Von Willebrands disease ‚

ICD10

D68.0 Von Willebrands disease ‚

SNOMED

  • 128105004 von Willebrand disorder (disorder)
  • 234446004 Congenital von Willebrands disease (disorder)
  • 128106003 von Willebrand disease type 1 (disorder)
  • 128107007 von Willebrand disease type 2 (disorder)
  • 128108002 von Willebrand disease type 3 (disorder)
  • 359711001 hereditary von Willebrand disease type 2A (disorder)
  • 359717002 hereditary von Willebrand disease type 2B (disorder)
  • 359725000 Hereditary von Willebrand disease type 2M (disorder)