Von Willebrand Disease
Von Willebrand Disease: Excerpt from The 5-Minute Pediatric Consult
Char Witmer, MDLeslie Raffini, MD (4th Edition)
Von Willebrand Disease - BASICS
Von Willebrand Disease - description
- An inherited bleeding disorder caused by either a quantitative deficiency or dysfunction of von Willebrand protein
- Characterized by mucocutaneous bleeding or bleeding after surgical procedures
Von Willebrand Disease - general prevention
- Most patients with mild type 1 von Willebrand disease (see Pathophysiology) do not need activity restrictions.
- Patients with type 3 disease need to 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.
Von Willebrand Disease - epidemiology
Males and females are equally affected.
Von Willebrand Disease - prevalence
The prevalence of von Willebrand disease in the general pediatric population is estimated to be ~1%.
Von Willebrand Disease - risk factors
Von Willebrand Disease - 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 varies, but in general follows an autosomal-dominant inheritance pattern.
- Type 3 follows an autosomal-recessive or compound heterozygote inheritance pattern.
Von Willebrand Disease - 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 the 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 procedures.
- Von Willebrand disease is an inherited bleeding disorder; however, acquired forms of von Willebrand disease have been described in association with hypothyroidism, Wilms tumor, other neoplasms, cardiovascular disorders with increased shear stress, 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 of von Willebrand factor
- 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 be 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 small multimers are less functional, causing the von Willebrand factor R:Co to be more reduced than the von Willebrand factor Ag (see “Laboratory”).
- Type 2B: An abnormal von Willebrand factor that spontaneously binds to normal platelets resulting in accelerated clearance of these platelets. This results in mild thrombocytopenia. There is a loss of the high-molecular-weight multimers in this subtype.
- Type 2N: The mutant 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 von Willebrand factor fails to bind normally to platelets.
- 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
Von Willebrand Disease - DIAGNOSIS
Von Willebrand Disease - signs & symptoms
Von Willebrand Disease - 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.
- Mucosal bleeding is especially common in von Willebrand disease; patients who have had tooth extraction without bleeding are unlikely to have von Willebrand disease.
- Bruising is common, with increased quantity, and quite frequently, increased size (>5 cm), and often in unusual locations with minimal trauma.
- Recurrent and/or prolonged epistaxis
- Menorrhagia occurs in 50–75% of women with von Willebrand disease.
- Excessive posttraumatic or postsurgical bleeding
Von Willebrand Disease - physical exam
- Bruises: Increased number, size, and/or unusual location
- May be entirely normal
Von Willebrand Disease - tests
Von Willebrand Disease - lab
- Screening tests for bleeding disorder:
- PT is normal in von Willebrand disease.
- Activated partial thromboplastin time (aPTT) may be prolonged if there is a decrease in factor VIII levels.
- 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 in young children)
- Platelet function assay (PFA)-100 is usually prolonged, but may be normal in mild type 1 von Willebrand disease.
- Specific tests for von Willebrand disease include:
- Von Willebrand factor antigen: Quantitation of von Willebrand factor by immunoassay
- Von Willebrand factor activity or ristocetin cofactor (RICo): 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.
Von Willebrand Disease - differencial diagnosis
- Primary hemostatic disorders:
- Platelet function abnormalities, congenital thrombocytopenia
- Mild inherited coagulation factor deficiencies
- Hemophilia (type 3 von Willebrand disease and type 2N are similar to mild and moderate factor VIII deficiency)
- 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
- Osteogenesis imperfecta
- Scurvy
- Prolonged aPTT but no bleeding symptoms:
- Inhibitor
- Factor XII deficiency
- 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.
- A normal laboratory evaluation does not necessarily indicate the absence of disease.
- The laboratory tests may need to be repeated several times before declaring that a patient does not have von Willebrand disease.
- Normal ranges for von Willebrand factor are blood type specific, with lower levels in those with blood type O.
- 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
- Other estrogens
Von Willebrand Disease - TREATMENT
Von Willebrand Disease - 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.
Von Willebrand Disease - 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 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 mcg/kg results in an ~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 and platelet-type von Willebrand disease, not recommended
- DDAVP may not be useful when prolonged hemostasis is required. After 24–48 hours, there may be depletion of stored von Willebrand factor, causing it to be ineffective.
- It is important to remember that DDAVP will also cause fluid retention, and in some cases, hyponatremia. This can be avoided with fluid restriction following treatment.
- 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 most 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
- Aminocaproic acid (Amicar):
- Stabilizes the fibrin clot
- Best for oral mucosal bleeding
- Dose is 100 mg/kg given PO q6h.
Von Willebrand Disease - FOLLOW UP
Von Willebrand Disease - 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.
Von Willebrand Disease - 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.
Von Willebrand Disease - bibliography
- Gill JC. Diagnosis and treatment of von Willebrand disease. Hematol Oncol Clin N Am. 2004;18:1277–1299.
- Mannucci PM. Treatment of von Willebrand’s disease. N Engl J Med. 2004;351:683–694.
- Mohri H. Acquired von Willebrand syndrome: Features and management. Am J Hematol. 2006;81:616–623.
Montgomery RR, Gill JC, Scott JP. Hemophilia and von Willebrand disease. In: Nathan DG, Orkin SH, eds. Hematology of Infancy and Childhood. 5th ed. Philadelphia: WB Saunders; 2003:1559–1576.- Pruthi RK. A practical approach to genetic testing for von Willebrand disease. Mayo Clin Proc. 2006;81:679–691.
Von Willebrand Disease - CODES
Von Willebrand Disease - icd9
286.4 von Willebrand disease
Von Willebrand Disease - FAQ
- Q: How can a child have a bleeding disorder if he or she went through surgery without a problem?
- A: In von Willebrand disease, the von Willebrand factor level can change as a function of stresses. Many conditions will cause the von Willebrand factor level to rise to a normal level. These conditions include infectious illnesses and pregnancy, as well as emotional stress. In surgery, the reason for the surgery itself (e.g., appendicitis) may cause enough stress to raise the factor levels to normal and prevent bleeding.
- Q: Should the other family members be tested?
- A: Yes, even if there is no history of bleeding in family members. Other affected family members may be unaware that they have the disease because von Willebrand disease can be so mild.
- 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, such as football, boxing, or sky diving. Patients with type 3 should avoid activities with even 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.
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Book Source Details
- Book Title: The 5-Minute Pediatric Consult
- Author(s): M. William Schwartz MD; et al.
- Year of Publication: 2008
- Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: The 5-Minute Pediatric Consult
Authors: M. William Schwartz MD; et al.
Publisher: Lippincott Williams & Wilkins
Copyright: 2008
ISBN: 0-7817-7577-9
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