Pediatric Von Willebrand Disease Workup
- Author: Suchitra S Acharya, MBBS, MD; Chief Editor: Max J Coppes, MD, PhD, MBA more...
Screening tests for von Willebrand disease (VWD) include the following:
CBC count: Assess platelet number and morphology, which should be normal in most patients with von Willebrand disease, except those with type 2B von Willebrand disease who may have thrombocytopenia.
Template bleeding time: Because it is reasonably well standardized, the template bleeding time is used as a screening test for primary hemostasis. The reference range for the bleeding time in children is longer than that of adults. Results of the bleeding time are affected by many technical factors, such as the direction of the incision and the skill of the technician. Although a bleeding time outside of the reference range may suggest a defect in hemostasis, it is not diagnostic. Similarly, a bleeding time within the reference range does not exclude the presence of such a defect. Although neither sensitive nor specific for von Willebrand disease, template-bleeding time is outside of the reference range in about 50% of patients with type 1 von Willebrand disease. Patients with von Willebrand disease types 2A, 2B, 2M, and 3 often have prolonged bleeding times. The template bleeding time has largely been replaced by automatic platelet function analyzers (PFAs) such as the PFA-100.
Prothrombin time (PT) is within reference range in von Willebrand disease.
Activated partial thromboplastin time (aPTT): Approximately 25% of patients with type 1 von Willebrand disease have aPTT results outside of the reference range. These results may be caused by concurrent deficiencies of other clotting factors in addition to, or rather than, factor VIII (FVIII). The aPTT should be outside of the reference range in patients with severe von Willebrand disease or type 2N von Willebrand disease in whom circulating FVIII levels are very low. Because aPTT and the template bleeding time are insensitive tests for von Willebrand disease, add von Willebrand factor (VWF) activity to the screening tests performed for patients with suspected bleeding disorders (see below).
Specific assays include the following:
von Willebrand factor levels: von Willebrand factor levels vary and can be influenced by numerous factors including blood type. Individuals with type O blood have lower values of von Willebrand factor levels on average, whereas those with type AB blood have higher values of von Willebrand factor. Day-to-day variation in von Willebrand factor levels is a normal occurrence in the same individual; therefore, a single level within reference range does not exclude the diagnosis of von Willebrand disease. Also, estrogen levels increase von Willebrand factor and may affect results in adolescent females and women with menorrhagia.
FVIII activity: FVIII activity is variably decreased.
von Willebrand factor activity (ristocetin cofactor): Ristocetin is an antibiotic that causes von Willebrand factor to bind to and, subsequently, to activate platelets. In the ristocetin cofactor assay, platelets from individuals who are healthy, standard concentrations of ristocetin, and varying quantities of patient or control plasma are used. In individuals who are healthy, platelets rapidly agglutinate in response to ristocetin; however, the presence of plasma von Willebrand factor is necessary for the reaction to occur. The degree of platelet agglutination is proportional to the concentration of von Willebrand factor in the plasma. Several variations of this assay have been developed. Because the result of this assay reflects the functional activity of von Willebrand factor, it is usually called the von Willebrand factor activity. It is variably decreased in von Willebrand disease.
von Willebrand factor antigen: The total plasma concentration of von Willebrand factor protein is measured by one of several assays. The Laurell rocket immunoelectrophoresis technique measures the amount of von Willebrand factor protein in the plasma, whereas radioimmunoassays and enzyme-linked immunoabsorbent assays reflect the number of von Willebrand factor–binding sites. These tests determine the total amount of von Willebrand factor antigen in the plasma but do not reflect its molecular structure and, hence, may be normal in von Willebrand disease variants with abnormal multimers. Therefore, von Willebrand factor antigen is variably decreased.
In multimer analysis to determine the physical structure of von Willebrand factor (ie, whether high molecular weight multimers are present), plasma is electrophoresed through agarose gel. The presence or absence of high molecular weight von Willebrand factor is used to classify von Willebrand disease. Absence or decreased levels of high molecular weight von Willebrand factor multimers is consistent with type 2 von Willebrand disease. Further analysis of von Willebrand factor subunits has been performed with sophisticated electrophoretic techniques, resulting in the description of many type 2 variants.
In some laboratories, platelet von Willebrand factor analysis is performed. Gene analysis can also be performed for diagnosis.
Schneppenheim R. The pathophysiology of von Willebrand disease: therapeutic implications. Thromb Res. 2011. 128 Suppl 1:S3-7. [Medline].
Grabowski EF, Curran MA, Van Cott EM. Assessment of a cohort of primarily pediatric patients with a presumptive diagnosis of type 1 von Willebrand disease with a novel high shear rate, non-citrated blood flow device. Thromb Res. 2012 Apr. 129(4):e18-24. [Medline].
Akin M. Laboratory diagnostic approach of the parents-children relationship in differentiating low-level von Willebrand factor from mild type 1 von Willebrand disease. Blood Coagul Fibrinolysis. 2012 Jun. 23(4):351-3. [Medline].
Lindsay H, Bergstrom K, Srivaths L. Co-inheritance of mild hemophilia A and heterozygosity for type 2N von Willebrand disease: a diagnostic and therapeutic challenge. Pediatr Blood Cancer. 2014 Oct. 61(10):1888-90. [Medline].
Bowman M, Hopman WM, Rapson D, Lillicrap D, Silva M, James P. A prospective evaluation of the prevalence of symptomatic von Willebrand disease (VWD) in a pediatric primary care population. Pediatr Blood Cancer. 2010 Mar 8. [Medline].
Tosetto A, Castaman G, Rodeghiero F. Evidence-based diagnosis of type 1 von Willebrand disease: a Bayes theorem approach. Blood. 2008 Apr 15. 111(8):3998-4003. [Medline].
Sidonio RF Jr, Gunawardena S, Shaw PH, Ragni M. Predictors of von Willebrand disease in children. Pediatr Blood Cancer. 2012 May. 58(5):736-40. [Medline].
Rodriguez KD, Sun GH, Pike F, et al. Post-tonsillectomy bleeding in children with von Willebrand disease: a single-institution experience. Otolaryngol Head Neck Surg. 2010 May. 142(5):715-21. [Medline].
Loeffelbein F, Funk D, Nakamura L, Zieger B, Grohmann J, Siepe M, et al. Shear-stress induced acquired von Willebrand syndrome in children with congenital heart disease. Interact Cardiovasc Thorac Surg. 2014 Sep 16. [Medline].
[Guideline] Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008 Mar. 14(2):171-232. [Medline].
[Guideline] Nichols WL, Rick ME, Ortel TL, et al. Clinical and laboratory diagnosis of von Willebrand disease: A synopsis of the 2008 NHLBI/NIH guidelines. Am J Hematol. 2009 Mar 16. [Medline].
Batlle J, Torea J, Rendal E, Fernandez MF. The problem of diagnosing von Willebrand's disease. J Intern Med Suppl. 1997. 740:121-8. [Medline].
Carcao MD, Blanchette VS, Dean JA, et al. The Platelet Function Analyzer (PFA-100): a novel in-vitro system for evaluation of primary haemostasis in children. Br J Haematol. 1998 Apr. 101(1):70-3. [Medline].
Federici AB, Mannucci PM. Management of inherited von Willebrand disease in 2007. Ann Med. 2007. 39(5):346-58. [Medline].
[Guideline] Lee CA, Brettler DB. Guidelines for the diagnosis and management of von Willebrand disease. Haemophilia. 1997. 3:1-25.
Nichols WC, Ginsburg D. von Willebrand disease. Medicine (Baltimore). 1997 Jan. 76(1):1-20. [Medline].
Sadler JE, Budde U, Eikenboom JC, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006 Oct. 4(10):2103-14. [Medline].
Werner EJ. von Willebrand disease in children and adolescents. Pediatr Clin North Am. 1996 Jun. 43(3):683-707. [Medline].
Zhang Z, Blomback M, Anvret M. Understanding von Willebrand's disease from gene defects to the patients. J Intern Med Suppl. 1997. 740:115-9. [Medline].