eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

von Willebrand Disease: Differential Diagnoses & Workup

Author: Eleanor S Pollak, MD, Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania
Contributor Information and Disclosures

Updated: Aug 13, 2009

Differential Diagnoses

Factor X
Factor XI Deficiency
Hemophilia, Overview

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

Laboratory 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.

More on von Willebrand Disease

Overview: von Willebrand Disease
Differential Diagnoses & Workup: von Willebrand Disease
Treatment & Medication: von Willebrand Disease
Follow-up: von Willebrand Disease
References
[ CLOSE WINDOW ]

References

  1. 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].

  2. Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood. Oct 1 1997;90(7):2515-21. [Medline].

  3. Mannucci PM. Hemostatic drugs. N Engl J Med. Jul 23 1998;339(4):245-53. [Medline].

  4. Mannucci PM. How I treat patients with von Willebrand disease. Blood. Apr 1 2001;97(7):1915-9. [Medline].

  5. Nichols WL, Hultin MB, James AH, et al, and the NHLBI von Willebrand Disease Expert Panel. The Diagnosis, Evaluation, and Management of von Willebrand Disease. Bethesda, Md: National Heart, Lung, and Blood Institute. NIH publication no. 08-5832. December 2007. Available at http://www.nhlbi.nih.gov/guidelines/vwd/index.htm. Accessed September 30, 2008.

  6. Sadler JE, for the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. A revised classification of von Willebrand disease. Thromb Haemost. Apr 1994;71(4):520-5. [Medline].

  7. 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.

  8. 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].

  9. 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].

  10. Rodeghiero F, Castaman G, Tosetto A. How I treat von Willebrand disease. Blood. Aug 6 2009;114(6):1158-65. [Medline]. [Full Text].

  11. Franchini M, Targher G, Montagnana M, Lippi G. Antithrombotic prophylaxis in patients with von Willebrand disease undergoing major surgery: when is it necessary?. J Thromb Thrombolysis. Aug 2009;28(2):215-9. [Medline].

  12. Udvardy ML, Szekeres-Csiki K, Hársfalvi J. Novel evaluation method for densitometric curves of von Willebrand Factor multimers and a new parameter (M(MW)) to describe the degree of multimersation. Thromb Haemost. Aug 2009;102(2):412-7. [Medline].

  13. Sutherland MS, Cumming AM, Bowman M, et al. A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3. Blood. Jul 30 2009;114(5):1091-8. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

von Willebrand disease, von Willebrand's disease, vWD, VWD, hemophilia, von Willebrand factor, VWF, vWF, angiohemophilia, vascular hemophilia, mucocutaneous bleeding disorder, primary hemostasis impairment, bleeding disorder, hemorrhagic disorder, hematological disorder, partial quantitative deficiency, qualitative deficiency, total deficiency, inherited blood coagulation disorder, coagulation protein disorder, blood platelet disorder

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Eleanor S Pollak, MD, Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania
Eleanor S Pollak, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

Medical Editor

Koyamangalath Krishnan, MD, FRCP, FACP, Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University
Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group
Disclosure: No financial interests None None

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.