Basics
Description
- An inherited bleeding disorder caused by either a quantitative or qualitative defect of the von Willebrand protein
- Characterized by mucocutaneous bleeding or bleeding after surgical procedures
Epidemiology
Prevalence
The prevalence of von Willebrand disease in the general pediatric population is estimated to be ’ Ό1%.
Risk Factors
Genetics
- The gene for von Willebrand factor is found on chromosome 12.
- Type 1 (see "Pathophysiology ") follows an autosomal dominant inheritance pattern with variable penetrance.
- Type 2 can be autosomal dominant or recessive.
- Type 3 follows an autosomal recessive inheritance pattern.
General Prevention
- Avoid contact sports.
- For patients with recurrent epistaxis, measures should be taken to avoid drying of the mucosa by applying petroleum jelly, humidifying the air, and reducing trauma to the nasal mucosa by keeping the fingernails short and discouraging nose picking.
- It may be advisable for patients to wear an emergency ID bracelet indicating that they have von Willebrand disease in the event they are involved in an accident that renders them unconscious.
- Avoid medications that negatively affect platelet function (i.e., ibuprofen, aspirin).
- Combination oral contraceptive pills are very effective for some patients with menorrhagia.
- Appropriate hemostatic therapy is needed prior to dental or surgical procedures to prevent bleeding.
Pathophysiology
- Von Willebrand factor is a large multimeric protein that allows platelets to adhere to sites of endothelial injury, initiating the primary step in hemostasis " formation of the platelet plug.
- Von Willebrand factor also serves as a carrier for factor VIII in the peripheral circulation, protecting it from degradation. Deficiency of von Willebrand factor results in a shorter factor VIII half-life, causing a lower level of circulating factor VIII.
- When von Willebrand factor is either deficient or defective, primary hemostasis is compromised, resulting in a bleeding diathesis characterized by easy bruising, frequent epistaxis, menorrhagia, and prolonged bleeding following surgical or dental procedures.
- Acquired forms of von Willebrand disease have been described in association with hypothyroidism, Wilms tumor, other neoplasms, cardiovascular disorders with increased shear stress (aortic stenosis), myeloproliferative disorders, uremia, and medications, including ciprofloxacin, griseofulvin, and valproate therapy.
- Classification: There are three major categories of von Willebrand disease:
- Type 1
- Mild to moderate quantitative deficiency
- The most common type, accounting for 70 " 80% of patients
- Generally a mild bleeding disorder
- Type 2
- Qualitative deficiency of von Willebrand factor
- Diagnosed in 15 " 20% of patients
- Tend to have more significant bleeding symptoms than in type 1
- Type 2 von Willebrand disease is further classified into four subtypes.
- Type 2A: loss of the intermediate- and high-molecular-weight multimers. The loss is secondary to either abnormal assembly or secretion of multimers or increased proteolytic degradation. The multimer deficiency results in decreased platelet binding.
- Type 2B: an abnormal von Willebrand factor that spontaneously binds to normal platelets, resulting in accelerated clearance of these platelets and loss of high-molecular-weight multimers. This can result in mild thrombocytopenia.
- Type 2N: The abnormal von Willebrand factor does not bind factor VIII optimally. This decrease in binding results in a shorter plasma half-life of factor VIII, resulting in reduced plasma factor VIII levels. Type 2N can be confused with mild hemophilia.
- Type 2M: The abnormal von Willebrand factor fails to bind normally to platelets. Normal multimers
- Type 3
- Near-complete quantitative deficiency of von Willebrand factor, which also results in a secondary deficiency of factor VIII
- Accounts for <5% of patients and results in a severe bleeding disorder
Diagnosis
History
- A family history of von Willebrand disease or bleeding tendency is an important question in the evaluation for von Willebrand disease. However, be aware that variation in frequency and severity of bleeding symptoms can occur from person to person, even within an affected family.
- Bruising is common, with increased quantity, increased size (>5 cm), and often in unusual locations with minimal trauma.
- Recurrent and/or prolonged epistaxis
- Menorrhagia occurs in 70 " 90% of women with von Willebrand disease.
- Excessive posttraumatic or postsurgical bleeding
Physical Exam
- Bruises: increased number, size, and/or unusual location
- May be entirely normal
Diagnostic Tests & Interpretation
Lab
- Screening tests for a bleeding disorder:
- Prothrombin time (PT) is normal in von Willebrand disease.
- Activated partial thromboplastin time (aPTT) may be prolonged if there is a decrease in factor VIII levels but can be normal.
- Platelet count is normal except in type 2B patients, who may have mild thrombocytopenia.
- Bleeding time is usually prolonged but may be normal in patients with mild type 1 von Willebrand disease (not recommended as a screening test).
- Platelet function assay (PFA)-100 is usually prolonged but may be normal in mild type 1 von Willebrand disease (not recommended as a screening test).
- Specific tests for von Willebrand disease include the following:
- Von Willebrand factor antigen: quantitation of von Willebrand factor by immunoassay
- Von Willebrand factor activity (ristocetin cofactor): assesses the function of von Willebrand factor using the antibiotic ristocetin, which induces platelet aggregation in the presence of von Willebrand factor
- Factor VIII: factor VIII clotting activity
- Von Willebrand factor multimers: multiple molecular forms of von Willebrand factor evaluated on agarose gel
- Multimer analysis is important in delineating the type of von Willebrand disease. Do not send as part of the initial screening for von Willebrand disease.
Differential Diagnosis
- Primary hemostatic disorders
- Platelet function abnormalities, congenital thrombocytopenia
- Mild inherited coagulation factor deficiencies
- Hemophilia A
- Acquired and secondary hemostatic disorders
- Liver disease
- Uremia
- Acquired thrombocytopenia
- Drugs that affect platelet function
- Acquired factor inhibitors (extremely rare in children)
- Connective tissue disorders
- Ehlers-Danlos syndrome
- Scurvy
- Prolonged aPTT but no bleeding symptoms
- Inhibitor
- Factor XII deficiency
Alert
- The diagnosis of von Willebrand disease is not always straightforward.
- Because of normal physiologic variation in plasma levels of von Willebrand factor, repeated measurements over time may be necessary to establish the diagnosis.
- Conditions that may increase von Willebrand factor levels:
- The newborn period
- Surgery
- Liver disease
- Hyperthyroidism
- High-stress states
- Pregnancy
- Inflammatory or infectious disease
- Steroids
- Oral contraceptives (high dose)
- Other estrogens
Treatment
General Measures
- There are several options for the management of bleeding in patients with von Willebrand disease. Superficial bleeding can usually be stopped by applying local pressure, ice, or topical thrombin, particularly in type 1.
- There are two main approaches to systemic therapy in von Willebrand disease: increasing the release of endogenous von Willebrand factor or exogenous replacement of von Willebrand factor. The appropriate therapy depends on the type of von Willebrand disease and the clinical scenario.
Medication
- Desmopressin (DDAVP) is a synthetic analog of vasopressin that stimulates endothelial cell release of von Willebrand factor. It is effective in patients who have a functional von Willebrand factor, as in type 1 von Willebrand disease. It may be used for some patients with type 2 von Willebrand disease but is ineffective in type 3:
- Available in intravenous and intranasal formulations
- An infusion of 0.3 Όg/kg results in a 3 " 5-fold increase in von Willebrand factor and factor VIII; nasal administration is slightly less effective.
- Side effects include facial flushing, light-headedness, or nausea.
- Prior to use in a surgical setting, patients should have a trial to demonstrate an appropriate response (10% of patients do not respond).
- May worsen thrombocytopenia in type 2B; it is not recommended
- DDAVP may not be useful when prolonged hemostasis is required. After 24 " 48 hours, there is depletion of stored von Willebrand factor, causing it to be ineffective (tachyphylaxis).
- It is important to remember that DDAVP will also cause fluid retention and, in some cases, hyponatremia. This can be avoided with fluid restriction for 24 hours following treatment.
- Factor concentrates
- Humate-P or alphanate
- Plasma-derived, intermediate-purity factor VIII concentrate products with adequate levels (especially large multimers) of von Willebrand factor
- Therapy of choice for some patients with type 2 von Willebrand disease and all patients with type 3 von Willebrand disease
- Useful in type 1 von Willebrand disease when prolonged hemostasis is necessary
- Antifibrinolytics: aminocaproic acid or tranexamic acid
- Stabilize the fibrin clot by inhibiting the physiologic process of clot lysis
- Best for oral mucosal bleeding
Ongoing Care
Prognosis
- Von Willebrand disease type 1 is often a very mild bleeding disorder and may go undetected.
- Most patients with von Willebrand disease have a normal life expectancy and, with proper education and treatment, minimal risk for permanent disability.
- Type 3 von Willebrand disease is a severe bleeding disorder, and life-threatening hemorrhage can occur.
Complications
- Significant perioperative bleeding can occur, especially with tonsillectomy, but the most common complications are recurrent epistaxis, prolonged bleeding with cuts and abrasions, and menorrhagia.
- Patients with type 3 von Willebrand disease have a more severe bleeding disorder and can have bleeding complications similar to those seen in hemophilia such as hemarthroses and intracranial hemorrhage.
Additional Reading
- Cox Gill J. Diagnosis and treatment of von Willebrand disease. Hematol Oncol Clin North Am. 2004;18(6):1277 " 1299. [View Abstract]
- Mannucci PM. Treatment of von Willebrand 's Disease. N Engl J Med. 2004;351(7):683 " 694. [View Abstract]
- Mohri H. Acquired von Willebrand syndrome: features and management. Am J Hematol. 2006;81(8):616 " 623. [View Abstract]
- Pruthi RK. A practical approach to genetic testing for von Willebrand disease. Mayo Clin Proc. 2006;81(5):679 " 691. [View Abstract]
- Robertson J, Lillicrap D, James PD. Von Willebrand disease. Pediatr Clin North Am. 2008;55(2):377 " 392. [View Abstract]
Codes
ICD09
- 286.4 Von Willebrand 's disease
ICD10
- D68.0 Von Willebrand 's disease
SNOMED
- 128105004 von Willebrand disorder (disorder)
- 128106003 von Willebrand disease type 1 (disorder)
- 128107007 von Willebrand disease type 2 (disorder)
- 128108002 von Willebrand disease type 3 (disorder)
FAQ
- Q: What sports activities can a person with von Willebrand disease participate in safely?
- A: People with type 1 von Willebrand disease can participate in most activities, although it is usually advised to avoid situations in which significant trauma takes place, like contact sports such as football or boxing. Patients with type 3 von Willebrand disease should avoid activities with moderate trauma. For type 2 patients, the risk of bleeding varies.
- Q: Is life expectancy lower in people with von Willebrand disease?
- A: For most patients with von Willebrand disease, their life expectancy and quality of life will be normal.
- Q: Are there any medications contraindicated in a patient with von Willebrand disease?
- A: Aspirin should not be given, as it interferes with platelet function. Nonsteroidal anti-inflammatory agents cause a milder effect on platelets and should also be avoided when possible. Patients should use acetaminophen for fever or pain.