AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1926, Erik von Willebrand first reported an autosomally inherited mucocutaneous bleeding disorder in a large family from the Aland Islands off the coast of Finland. The disease was termed von Willebrand disease (vWD), named after this original report. vWD is a common, inherited, genetically and clinically heterogeneous hemorrhagic disorder caused by a deficiency or dysfunction of the protein termed von Willebrand factor (vWF). Consequently, primary hemostasis is impaired because of defective interaction between platelets and the vessel wall.

vWF is a large multimeric glycoprotein that circulates in blood plasma at concentrations of approximately 10 mg/mL. In response to numerous stimuli, vWF is released from storage granules in platelets and endothelial cells. It performs 2 major roles in hemostasis. First, it mediates the adhesion of platelets to sites of vascular injury. Second, it binds and stabilizes the procoagulant protein factor VIII (FVIII).

vWD is divided into 3 major categories: (1) partial quantitative deficiency (type I), (2) qualitative deficiency (type II), and (3) total deficiency (type III). Qualitative vWD type II is further divided into 4 variants, ie, IIA, IIB, IIN, and IIM, based on the characteristics of the dysfunctional vWF. These categories correspond to distinct molecular mechanisms, with corresponding clinical features and therapeutic requirements.

Pathophysiology

The VWF gene is located near the tip of the short arm of chromosome 12. The gene is composed of 52 exons and spans a total of 180 kb of the human genome; therefore, it is similar in size to the FVIII gene. Expression of the VWF gene is restricted to megakaryocytes, endothelial cells, and, possibly, placental syncytiotrophoblasts. A partial nonfunctional duplication (pseudogene) is present on chromosome 22.

vWF exists as a series of multimers, varying in molecular weight between 0.5 (dimer) and 20 million kd (multimer). The building block of multimers is a dimer, held together by disulfide bonds located near the C-terminal end of each subunit.

vWD type I causes a mild-to-moderate quantitative deficiency in vWF (ie, ~20-50% of normal levels).

Type II vWD is due to qualitative abnormalities of vWF and is subdivided into types IIA, IIB, IIN, and IIM. vWD type IIA is the most common qualitative abnormality of vWF and is associated with the selective loss of large- and medium-sized multimers.

vWD type IIB is characterized by the loss of large multimers through a mechanism distinct from that of type IIA. Observations to date have identified a critical region of vWF involved in the binding of vWF to the platelet receptor glycoprotein Ib (GpIb). Each of these single amino acid substitutions is thought to result in a gain of function, leading to spontaneous binding of vWF to platelets. Normally, plasma vWF is inert in its interaction towards platelets until it encounters an exposed subendothelial surface. vWF binding to collagen or other ligands within the injured vessel wall presumably results in a secondary conformational change, which then facilitates binding to the GpIb receptor.

In vWD type IIB, the mutant vWF is capable of spontaneously binding GpIb in the absence of subendothelial contact. The large multimers have the highest affinity for GpIb and are rapidly cleared from the plasma along with the bound platelets, resulting in thrombocytopenia and the characteristic loss of large multimers.

vWD type IIN, sometimes referred to as vWD Normandy (after the province of origin of one of the first families identified with the disease), is characterized by a defect residing within the patient's plasma vWF that interferes with its ability to bind FVIII. This has important implications in the differential diagnosis of hemophilia. vWD type IIM (for multimer) refers to qualitative variants with decreased platelet-dependent function that is not due to the absence of high molecular weight multimers.

Patients with vWD type III, a severe quantitative deficiency associated with very little or no detectable plasma or platelet vWF, have a profound bleeding disorder. vWD type III appears to result from the inheritance of a mutant vWF gene from both parents. In the most straightforward model, vWD type I would simply represent the heterozygous form of type III vWD; however, inheritance patterns indicate greater complexity. vWD type III is much more rare than the predicted frequency of 1 case per 40,000 persons based on this model and is closer to 1 case per 1 million persons. Although few mutations have been identified in families with pure vWD type I, some vWD type I cases have been suggested to be due to a mutant vWF subunit that interferes in a dominant negative way with the normal allele, accounting for the autosomal dominant inheritance.

Frequency

United States

Prevalence is not different from that observed internationally.

International

Clinically significant vWD affects approximately 125 persons per million population, with severe disease affecting approximately 0.5-5 persons per million population. Reports from screening unselected individuals indicate a higher prevalence of vWD abnormalities, ie, close to 1% of the population.

Mortality/Morbidity

For most affected individuals, vWD is a mild manageable bleeding disorder in which clinically severe hemorrhage manifests only in the face of trauma or invasive procedures. However, significant variability of symptomatology exists between family members.

• In individuals with types II and III, bleeding episodes may be severe and potentially life threatening.
• Individuals with type III disease who have correspondingly low FVIII levels may develop arthropathies, as is more common in patients with FVIII deficiency, with comparable FVIII levels.

Race

• No racial predilection exists for vWD.

Sex

• Males and females are affected equally; however, the phenotype may be more pronounced in females because of menorrhagia and the visibility of easy bruising.
• During pregnancy, the vWF level increases in most patients with non–type III disease. Thus, in patients with functionally normal vWF, labor and delivery usually proceed normally. However, patients with type II disease may experience hemorrhagic problems. In particular, patients with type IIB may experience thrombocytopenia due to the increased plasma levels associated with abnormal vWF. All patients should be monitored for excessive bleeding, particularly during the first week postpartum.

Age

• This is an inherited condition. Bleeding-related symptoms may occur at a young age, even just after or during birth.
• Females often present with heavy periods at menarche.
• Some reports suggest a decreased bleeding tendency as patients age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The most common symptoms include nosebleeds, skin bruises, and hematomas. Prolonged bleeding from trivial wounds, oral cavity bleeding, and excessive menstrual bleeding are common. Gastrointestinal bleeding is rare.

• A common but nonspecific symptom is easy bruising.
• Prolonged bleeding after minor trauma to skin or mucous membranes is characteristic of vWD.
• Severe hemorrhage after major surgery is less common, but delayed bleeding may occur up to several weeks after surgery.
• Heavy bleeding is common after tooth extraction or other oral surgery, such as tonsillectomy and adenoidectomy.
• Menorrhagia is a common presenting complaint in women.
• Bleeding symptoms are often exacerbated by the ingestion of aspirin and are ameliorated by the use of oral contraceptives.

Physical

Physical examination findings are usually normal. However, patients may have physical sequelae, such as bleeding or bruises.

Causes

See Pathophysiology for a discussion of the inherited nature of the condition (congenital vWD). A rare acquired form of vWD exists and is due to antibodies to vWF (acquired vWD).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Hemophilia A
Hemophilia B
Bernard-Soulier syndrome
Platelet function defects
Antiplatelet drug ingestion
Fibrinolytic defects
Platelet-type pseudo vWD
Acquired vWD

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• General laboratory workup for vWD
• • Laboratory studies are directed towards documenting a vWF deficiency. vWF levels vary with physiologic stress. In particular, plasma levels increase with estrogens, vasopressin, growth hormone, and adrenergic stimuli. Thus, vWF levels may be normal intermittently in patients with vWD, and measurements should be repeated to confirm abnormal results. Repeating tests at intervals of more than 2 weeks is advisable to confirm or definitively exclude the diagnosis, optimally at a time remote from hemorrhagic events, pregnancy, infections, and strenuous exercise.
  • Screening tests typically include prothrombin time (PT), activated partial thromboplastin time (aPTT), FVIII level, ristocetin cofactor (RCoF) activity, and vWF antigen (vWF:Ag).
  • vWF levels correlate with ABO blood type. Individuals with type O blood normally have the lowest levels of vWF, ie, approximately 50-75% of the vWF levels found in persons with other blood types. vWF levels should be compared to an ABO blood group type-specific range from the laboratory where the test is performed.
  • vWF levels are evaluated using the following:
    • Ristocetin activity: The test for RCoF activity is good for evaluating vWF function, although results are difficult to standardize and the test is difficult to perform. Thus, the validity of test results should be verified when the test is performed at centers with personnel who are not accustomed to performing this test. Ristocetin is added to a suspension of washed formalin- or paraformaldehyde-fixed platelets in the presence of the patient's plasma (as a source of vWF). The rate of aggregation is then measured using an aggregometer, a device specifically designed to monitor this activity.

    • vWF:Ag: This assay is usually performed (with the use of rabbit antibody to vWF) using either a quantitative immunoassay or an enzyme-linked immunosorbent assay. A discrepancy between the vWF:Ag value and RCoF activity suggests a qualitative defect that should be further investigated by characterization of the vWF multimeric distribution.
  • PT and aPTT are also measured as part of the workup, as follows:
    • The aPTT is mildly prolonged in approximately 50% of patients with vWD. The prolongation is secondary to low levels of FVIII because one of the normal functions of vWF is to protect FVIII from degradation.

    • The PT should be within reference ranges. Prolongations of both the PT and the aPTT signal a problem with acquisition of a proper specimen or a disorder other than or in addition to vWD.
  • Bleeding time is discussed as follows:
    • Historically, the template bleeding time is a test used to help diagnose vWD. This test is subject to wide variation and, with the availability of tests that provide more specific results, is not currently essential for making the diagnosis of vWD.

    • A prolonged bleeding time is not specific for vWD and does not help predict whether patients without a bleeding disorder will have problematic bleeding during surgery. The test is difficult to perform, and results are difficult to confirm (ie, reproducibility); results frequently are normal in patients with vWD type I.

• vWD type I
• • vWD type I can be diagnosed in a patient with significant mucocutaneous bleeding, laboratory test results compatible with vWD type I, and a positive family history for vWD type I. These criteria may be impossible to satisfy in many patients for various reasons. Therefore, physicians must acknowledge this diagnostic uncertainty and should not deny patients treatment, especially when patients' laboratory test results are compatible with vWD type I and they have either a significant history of mucocutaneous bleeding or a positive family history for vWD type I.
  • A less common problem is the misdiagnosis of vWD type I in patients who actually have a qualitative defect. The results of screening tests recommended for patients with vWD type I often show proportionally decreased RCoF activity and vWF:Ag in patients with vWD type IIB, although classic teaching is that a discrepancy should exist between the two. In this scenario, ristocetin-induced platelet aggregation test results should demonstrate an exaggerated affinity of the mutant vWF for platelets in the presence of ristocetin.

• vWD type II
• • Disproportionately low RCoF activity relative to vWF:Ag may reflect a decreased affinity of vWF for platelets. The most common cause of such loss of function is the absence of hemostatically effective large vWF multimers, characteristic of vWD type IIA. This subtype is diagnosed based on the combination of markedly reduced RCoF activity and compatible multimer gel analysis results.
  • In type IIB, brisk platelet agglutination occurs at low concentrations of ristocetin that have little or no effect on platelet-rich plasma from normal controls. Positive results from this test are found in only one other extremely rare disease, platelet-type or pseudo vWD, in which mutations in platelet GpIb cause a phenotype similar to that of vWD type IIB.
  • vWD type IIM (M for multimer) includes variants in which binding to platelets is impaired but the vWF multimer distribution is normal. Screening laboratory test findings are similar to those found in vWD type IIA, but multimer gel analysis results show that large multimers are present.
  • In vWD type IIN (N for Normandy), the platelet-dependent functions of vWF are preserved, but FVIII levels are low (often <10%). This condition is an autosomal mimic of hemophilia A, and a careful family history helps distinguish the two.
  • Multimeric examination of the vWF is particularly important in the diagnosis of type II vWD. Results from this laboratory test reveal the multimeric distribution of vWF, thus allowing classification of type II disease depending on the specific absence of large multimers (type IIB) or both intermediate and large (type IIA) multimers.

• vWD type III
• • This is a recessive disorder in which vWF protein is virtually undetectable. The absence of vWF causes a secondary deficiency of FVIII and a subsequent severe combined defect in blood clotting and platelet adhesion.

  • Results from screening assays show absent RCoF activity and vWF:Ag and a prolonged aPTT.

• Testing for therapeutic options
• • A laboratory evaluation of a patient's response to administrations of desmopressin (DDAVP) is commonly performed to assess whether or not a patient can receive this product either therapeutically or prophylactically before surgery.

  • Rule out whether the patient has type IIB prior to testing, particularly in patients with risk factors for thrombotic complications, because case reports suggest that this drug may be contraindicated in this setting.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The 2 main treatment options for patients with vWD are DDAVP and transfusion therapy.

• Desmopressin
• • Type 1 vWD
    • DDAVP is the treatment of choice for individuals with vWD type I. DDAVP is a synthetic analogue of the antidiuretic hormone vasopressin; it has enhanced antidiuretic activity and no pressor activity related to vasopressin. The infusion of DDAVP into healthy individuals and individuals with vWD type I results in a rapid increase in circulating levels of vWF:Ag and FVIII and RCoF activity.

    • Typically, a maximal rise of vWF and FVIII is observed in 30-60 minutes. The typical maximal rise is 2- to 4-fold for vWF and 3- to 6-fold for FVIII. Additionally, hemostatic levels of both factors are usually maintained for at least 6 hours. DDAVP can also be administered via a highly concentrated nasal spray; 300 mcg intranasally produces levels comparable to those observed with an intravenous infusion. Intranasal therapy is particularly useful for home therapy of menorrhagia and recurrent epistaxis.
  • Type III vWD
    • Individuals with vWD type III have a virtually complete deficiency of vWF; thus, the fact that DDAVP, an agent that causes release of stored vWF, has no effect in patients with vWD type III is not surprising.

    • The treatment of choice for patients with vWD type III (and other vWD types unresponsive to DDAVP) is virus-inactivated, vWF-containing FVIII concentrates that contain a near-normal complement of high molecular weight vWF multimers. Most experience reported in the literature has been with the use of Humate-P, a plasma-derived product of intermediate purity. Two other FVIII concentrates, Alphanate and Koate-HP, have been reported to be efficacious in the treatment of vWD. Too little vWF is present in monoclonally purified FVIII concentrates and recombinant FVIII concentrates to allow their use in the treatment of vWD.

    • Alloantibody formation occurs in 10-15% of patients with type III disease. Therefore, the possibility of this complication must be managed appropriately because patients are at increased risk for life-endangering anaphylactic reactions to vWF-FVIII preparations. With hemostatic stress in emergency situations, infusion of FVIII preparations devoid of vWF, while adjusting for the markedly decreased FVIII half-life, may be necessary.
  • Type II vWD
    • Responses to DDAVP are variable in patients with type II disease. A trial infusion may be performed to evaluate the potential efficacy for a particular patient.

    • Many individuals with vWD type IIA have a response to DDAVP, with peak vWF and FVIII levels at 30-60 minutes. This is similar to responses observed in patients with vWD type I; however, rapid loss of vWF, FVIII, and, particularly, RCoF activity, occurs as the high molecular weight multimers are degraded, with return to baseline levels at 4 hours postinfusion. Although the response is transient, it may be adequate therapy in certain clinical situations.

    • For prophylaxis in major surgery or for treatment of serious bleeding episodes, vWF-containing FVIII concentrates are the treatment of choice.

    • DDAVP trials may be contraindicated in patients with type IIB because of thrombocytopenia and possible thrombotic complications.

    • DDAVP is probably not effective in patients with type IIM and is rarely effective in patients with type IIN.

• Platelet transfusions
• • These may be helpful in some patients with vWD whose disease is refractory to other therapies.

  • Cryoprecipitate and fresh frozen plasma contain functional vWF but should be avoided whenever possible because of the potential transmission of viral disease. An additional drawback of fresh frozen plasma is the large infusion volume required.

Surgical Care

Particular attention to hemostasis is advised once the hemostatic defect has been corrected medically.

Consultations

Seek the opinion of a hematologist experienced in the management of bleeding disorders prior to all surgical/dental procedures.

Diet

No special diet is necessary in the treatment of patients with vWD.

Activity

Patients should be wary of any physical activity associated with an increased risk of hemorrhage.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The 2 principal drug categories include nontransfusional compounds (eg, DDAVP, antifibrinolytics) and transfusional compounds. Whenever possible, avoid transfusions.

Drug Category: Synthetic hormones

Improve platelet function in qualitative disorders.

Drug Category: Antihemorrhagics

For use in patients with blood-product deficiencies. Platelets may be valuable option in treatment of patients with type III disease.

Drug Category: Antifibrinolytics

May be used to prevent breakdown of formed blood clots to temper hemorrhage. Block formation of plasmin. May be used to manage mucosal bleeding, particularly in the nasopharynx and in the GI and GU tracts. Most often used concomitantly with other medications for dental extractions and oral surgery.

Drug Category: Estrogens

May be helpful in reducing menorrhagia. Even in type III disease in which case vWF and FVIII levels are not necessarily increased, may mediate changes in endometrium, which lessen menstrual bleeding severity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Because of the effects of stress on the expression of vWF, laboratory testing should be repeated in patients with newly diagnosed vWD.

In/Out Patient Meds

• Medications should be recommended as necessary for prophylactic and therapeutic treatment of vWD.

Deterrence/Prevention

• Advise patients to avoid aspirin-containing compounds.

Patient Education

• Patients should be instructed about their coagulation disorder and should be aware of the conditions in which they will require prophylactic therapy.
• For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Bruises.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to obtain a consultation with a hematologist prior to surgical procedures and dental extractions in patients with vWD


• Failure to obtain a bleeding history in patients undergoing surgical procedures or dental extractions


• Failure to test older patients who received cryoprecipitate or plasma in the past for HIV1 and viral hepatitis infections

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Conti M, Mari D, Conti E, et al. Pregnancy in women with different types of von Willebrand disease. Obstet Gynecol. Aug 1986;68(2):282-5. [Medline].
• Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood. Oct 1 1997;90(7):2515-21. [Medline].
• Mannucci PM. Hemostatic drugs. N Engl J Med. Jul 23 1998;339(4):245-53. [Medline].
• Mannucci PM. How I treat patients with von Willebrand disease. Blood. Apr 1 2001;97(7):1915-9. [Medline].
• Sadler JE. A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. Apr 1994;71(4):520-5. [Medline].
• Sadler JE. Von Willebrand Disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY: McGraw-Hill; 2001:. 4415-31.
• Sadler JE, Mannucci PM, Berntorp E, et al. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost. Aug 2000;84(2):160-74. [Medline].
• Tout H, Obert B, Houllier A, et al. Mapping and functional studies of two alloantibodies developed in patients with type 3 von Willebrand disease. Thromb Haemost. Feb 2000;83(2):274-81. [Medline].

Article Last Updated: Jul 5, 2006