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
- Prevalence as high as 1 " “2% in the general population
- Genetics:
- Most cases inherited " ”multiple genetic defects identified
- Type 1 " ”quantitative defect of vWF:
- 70% of cases
- Autosomal dominant
- vWF 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 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
- Type 3 " ”absent or severe deficiency in amount of vWF:
- Rare disease " ”1 per million cases
- Autosomal recessive
- Severe coagulopathy
- vWD 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 production
- Decreased synthesis
- Proteolysis
- Increased clearance from binding to tumor cells
- Seen in association with the following:
- Malignancy:
- Wilms tumor
- Multiple myeloma
- Chronic lymphocytic leukemia
- Non-Hodgkin lymphoma
- Chronic myelogenous leukemia
- Waldenstrom macroglobulinemia
- Monoclonal gammopathy of uncertain significance
- Immunologic:
- Systematic lupus erythematosus
- Rheumatoid arthritis
- Medication induced:
- Valproic acid
- Ciprofloxacin
- Hetastarch
- Griseofulvin
- Miscellaneous:
- Hypothyroidism
- Uremia
- Hemoglobinopathies
- Cirrhosis
- Congenital heart disease
- Disseminated 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 bruising
- Menorrhagia
- Recurrent epistaxis
- Gum bleeding
- GI bleeding
- Soft-tissue bleeds and hemarthroses
- Prolonged or excessive procedural bleeding
- Postoperative 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 function
- vWF antigen " ”tests for vWF level in serum using rabbit antibodies
- Bleeding time:
- May be normal in type 1 (50%); prolonged in types 2 and 3
- Not 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 vWF
- Replacement of vWF
- Agents that generally promote hemostasis but do not alter levels of vWF
- 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
- 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 thrombin
- Micronized collagen
- Fibrin 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 ineffective
- Should be given in consultation with a hematologist
- Aminocaproic 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 ¼g
- 0.3 ˇ ¼g/kg SQ, max. 20 ˇ ¼g
- 300 ˇ ¼g (1 spray each nostril) intranasal
- Peds: <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)