Von Willebrand Disease

Clinical Background

von Willebrand disease (vWD) is the most common congenital bleeding disorder in humans.

Epidemiology

Incidence
- 1/100 in the general population
- Occurrence of types
  - Type 1 - 70%
  - Type 2 - 15-30%
  - Type 3 - rare
Gender - F>M
Ethnicity - Caucasians have highest risk

Genetics

Type 1 - autosomal dominant with incomplete penetrance (60%)
Type 2
- 2A - autosomal dominant with strong penetrance
- 2B - autosomal dominant with strong penetrance
- 2M - X-linked recessive
- 2N - autosomal dominant with strong penetrance
Type 3 - autosomal recessive

Pathophysiology

von Willebrand factor antigen (vWF:Ag)
- An immunologic measure of vWF
- Decreased in patients with vWD
- Normal in patients with hemophilia A and in carriers of hemophilia A
Defective synthesis or function of the von Willebrand factor (vWF) causes von Willebrand disease
- von Willebrand ristocetin cofactor (vWD:RCo)
  - Essential for the formation of the hemostatic plug
  - Primarily involved in the adhesion of platelets to the injured vessel wall
  - Acts to stabilize factor VIII
Characterized by type of defect
- Quantitative - types 1, 3
- Qualitative - type 2

Clinical Presentation

Mucocutaneous bleeding (mild to moderate)
- Epistaxis
- Hematomas
- Menorrhagia
- Gingival bleeding
Acquired vWD - associated with same symptoms as congenital
- Rare - associated with lymphoproliferative disease, myeloproliferative disorders and immunologic disorders

Treatment

Desmopressin - mild to moderate cases of types 1 and 2 disease
Replacement therapy with concentrates (vWF and factor VIII) - type 3 disease and only severe cases of types 1 and 2 disease
In acquired vWD - treat underlying disorder

Refer to vonWillebrand Disease topic at www.arupconsult.com for a Flowchart Proposed for the Diagnosis of Different von Willebrand Disease Types

See Also

Functional Platelet Disorders

Hemophilia - Factor VIII Carrier

Diagnosis

Three main criteria
- Positive history of bleeding since childhood
- Reduced levels of vWF activity
- Autosomal dominant or recessive inheritance patterns
Laboratory testing
- Screening tests - platelet count, bleeding time, PT/PTT
- von Willebrand panel testing
  - von Willebrand factor antigen decreased
  - Factor VIII activity is somewhat decreased (mild)
  - Ristocetin cofactor activity decreased
- Identification of vWD type (see table below for laboratory diagnostic testing parameters)

vWD Types	Laboratory Diagnostic Testing Parameters
Type 1	Mild to moderately reduced level of vWF Frequently reduced factor VIII activity No functional abnormalities Levels of factor VIII, vWf:AG and vWF:RCo are often decreased to the same relative degree
Type 2	Abnormality in the vWF molecule resulting in abnormal structure and function (qualitative defects)
Type 2A	Decreased platelet dependent function due to the absence of high molecular weight multimers of vWF The vWF:RCo result is often disproportionately low compared to the vWF:Ag (low vWD:RCo to vWF:Ag ratio)
Type 2B	Increased affinity for platelet glycoprotein GPIb Demonstrated by an enhanced platelet response to ristocetin and the absence of large vWF multimers vWF:AG, vWF:RCo and factor VIII are variable and may be within normal limits Some patients with this defect have chronic thrombocytopenia and circulating platelet aggregates due to spontaneous aggregation
Type 2M	Decreased vWF-dependent platelet function is not caused by the absence of high molecular weight multimers The vWF:RCo level may be disproportionately low compared to the vWF:Ag level
Type 2N	Abnormally low affinity of vWF for factor VIII Most patients described have both type 1 vWD and the factor VIII binding defect resulting in decreased vWF:Ag and vWF:RCo, normal multimers and a disproportionately low factor VIII level compared to the vWF level Patients with the type 2N defect alone may resemble patients with hemophilia
Type 3	Severe form of vWD in which levels of vWF are severely reduced or absent, factor VIII is markedly decreased and all multimers are absent

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: von Willebrand Panel

ARUP #: 0030125

Methodology: Clotting/Platelet Agglutination/Microlatex Particle-Mediated Immunoassay

Use:

Order for patients with life-long bleeding disorder and family history of bleeding to determine if due to von Willebrand disease (vWD)

The 3 tests contained in panel (vWD antigen, ristocetin cofactor activity and factor VIII activity), when combined, increase the probability of identifying the various forms of von Willebrand disease

Limitations:

Normal values do not exclude vWD

Female patients with vWD on oral contraceptives or who are pregnant may have normal values

In type 1, normal levels of vWF:ag are significantly different in the population based on ABO blood group with type O having the lowest normal concentration

Follow-up:

Test name: von Willebrand Multimeric Panel

ARUP #: 0030002

Methodology: Electrophoresis/Western Blot/Clotting/Microlatex Particle-Mediated Immunoassay/Platelet Agglutination

Use:

Order only if von Willebrand panel results are abnormal

Use to classify type of von Willebrand disease

Limitations:

Normal values do not exclude vWD

Female patients with vWD on oral contraceptives or who are pregnant may have normal values

In type 1, normal levels of vWF:ag are significantly different in the population based on ABO blood group with type O having the lowest normal concentration

Follow-up:

Test name: Immunohistochemistry Stain Offering

ARUP #: arup005

Methodology: Immunohistochemistry

Use:

For fixed tissue samples, consultative services as well as immunohistochemical staining for Factor VIII are available

Additional Tests Available

Test name: von Willebrand Factor Activity (Ristocetin Cofactor)

ARUP #: 0030250

Methodology: Platelet Agglutination

Comments:

Test name: von Willebrand Factor Antigen

ARUP #: 0030285

Methodology: Microlatex Particle-Mediated Immunoassay

Comments:

Test name: Factor VIII, Activity

ARUP #: 0030095

Methodology: Clotting

Comments:

Test name: von Willebrand Modified Panel

ARUP #: 0030284

Methodology: Platelet Agglutination/Microlatex Particle-Mediated Immunoassay (LIA)

Comments:

Additional Information

If initial testing is negative but high suspicion of vWD still exists, repeat testing

In patients with mild disease, test may be falsely-negative

For accurate test interpretation, the same sample must be used for von Willebrand panel tests and von Willebrand Multimeric test

References

Guidelines

The Diagnosis, Evaluation, and Management of von Willebrand Disease. Bethesda, MD, National Heart Lung and Blood Institute. National Institutes of Health, December 2007 (Link to Resource)

Cited References

Federici AB, Mannucci PM. Management of inherited von Willebrand disease in 2007. Ann Med. 2007;39(5):346-358.

General References

Cox Gill J. Diagnosis and treatment of von Willebrand disease. Hematol Oncol Clin North Am. 2004;18(6):1277-99, viii.

Dietrich JE. Von Willebrand's disease. J Pediatr Adolesc Gynecol. 2007;20(3):153-155.

Favaloro EJ. Laboratory identification of von Willebrand disease: technical and scientific perspectives. Semin Thromb Hemost. 2006;32(5):456-471.

Federici AB, Mannucci PM. Management of inherited von Willebrand disease in 2007. Ann Med. 2007;39(5):346-358.

Federici AB. Clinical diagnosis of von Willebrand disease. Haemophilia. 2004;10 Suppl 4:169-176.

Federici AB. Diagnosis of inherited von Willebrand disease: a clinical perspective. Semin Thromb Hemost. 2006;32(6):555-565.

Federici AB. Management of inherited von Willebrand disease in 2006. Semin Thromb Hemost. 2006;32(6):616-620.

Franchini M. Advances in the diagnosis and management of von Willebrand disease. Hematology. 2006;11(4):219-225.

Hemophilia Treatment Center, Orthopaedic Hospital. Von Willebrand Disease 2008. (Accessed June 7, 2008)

Kujovich JL. von Willebrand disease and pregnancy. J Thromb Haemost. 2005;3(2):246-253.

Lillicrap D, Nair SC, Srivastava A, Rodeghiero F, Pabinger I, Federici AB. Laboratory issues in bleeding disorders. Haemophilia. 2006;12 Suppl 3:68-75.

Lillicrap D. Von Willebrand disease - phenotype versus genotype: deficiency versus disease. Thromb Res. 2007;120 Suppl 1:S11-S16.

Mohri H. Acquired von Willebrand syndrome: features and management. Am J Hematol. 2006;81(8):616-623.

NIH National Heart, Lung and Blood Institute: The Diagnosis, Evaluation and Management of von Willebrand Disease. December 2007 (Accessed 29 Feb 2008)

Peake I, Goodeve A. Type 1 von Willebrand disease. J Thromb Haemost. 2007;5 Suppl 1:7-11.

Pruthi RK. A practical approach to genetic testing for von Willebrand disease. Mayo Clin Proc. 2006;81(5):679-691.

Schneppenheim R, Budde U. Phenotypic and genotypic diagnosis of von Willebrand disease: a 2004 update. Semin Hematol. 2005;42(1):15-28.

Schneppenheim R. The evolving classification of von Willebrand disease. Blood Coagul Fibrinolysis. 2005;16 Suppl 1:S3-S10.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

Flanders MM, Crist RA, Roberts WL, Rodgers GM. Pediatric reference intervals for seven common coagulation assays. Clin Chem. 2005;51(9):1738-1742.

Medical Reviewers

Rodgers, George M. III, M.D., Ph.D. Medical Director, Hemostasis/Thrombosis at ARUP Laboratories; Professor, Medicine, Adjunct Professor, Pathology, University of Utah

Comprehensive Review: March 2008
Last Update: March 2008