Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease

Summary

We performed a nation-wide cross-sectional study to evaluate determinants of bleeding symptoms in a large unselected cohort of adults with von Willebrand disease (VWD). VWD patients were included (n=664), based on lowest historically measured VWF:Ag and VWF:Act levels ≤30 U/dl. Menorrhagia (85%), cutaneous bleeding (77%), bleeding from minor wounds (77%) and oral-cavity bleeding (62%) occurred most frequently. Higher age was associated with a higher bleeding score (BS), determined according to Tosetto, in females. A 10 year increase in age was associated with 0.8 point (95% confidence interval [CI] 0.4–1.1) higher BS. Females had higher BS than males (median 12 vs. 10, p=0.012). BS differed significantly between VWD type 1, 2 and 3: median 9 (-2–31), 13 (-1–33) and 19.5 (1–35), respectively (p<0.001). BS was strongly associated with VWF and FVIII levels: individuals with VWF:Ag levels ≤10 IU/dl, VWF:Act ≤10 IU/dl and FVIII:C ≤10 IU/dl had, respectively, 5.3 point (95%CI 3.2–7.3), 4.3 point (95%CI 2.9–5.8) and 9.6 point (95%CI 6.5–12.7) higher BS, than those with levels >30 IU/dl. In type 3 patients 1 IU/dl FVIII:C decrease was associated with 0.6 point (95% CI 0.1–1.1) BS increase (p=0.021). In conclusion, in VWD patients the bleeding phenotype is strongly associated with type of VWD and VWF and FVIII levels.

Keywords

Bleeding - bleeding phenotype - von Willebrand disease - von Willebrand factor

• References

• 1 Rodeghiero F. et al. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987; 69: 454-459.
• 2 Ruggeri ZM. Structure of von Willebrand factor and its function in platelet adhesion and thrombus formation. Best Pract Res Clin Haematol 2001; 14: 257-279.
• 3 James AH. More than menorrhagia: a review of the obstetric and gynaecological manifestations of von Willebrand disease. Thromb Res 2007; 120 (Suppl. 01) S17-20.
• 4 Kadir RA, Chi C. Women and von Willebrand disease: controversies in diagnosis and management. Semin Thromb Hemost 2006; 32: 605-615.
• 5 Kouides PA. Current understanding of von Willebrand's disease in women - some answers, more questions. Haemophilia 2006; 12 (Suppl. 03) 143-151.
• 6 Sadler JE. 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; 04: 2103-2114.
• 7 Tosetto A. et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost 2006; 04: 766-773.
• 8 Bowman M. et al. Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost 2008; 06: 2062-2066.
• 9 Gill JC. et al. The Zimmerman Program Investigators. Bleeding Scores in Von Willebrand Disease (VWD) Re-Visited: Analysis of the TS Zimmerman Program for the Molecular and Clinical Biology of VWD. ASH Annual Meeting Abstracts. Blood 2008; 112: 425 abstract.
• 10 Federici AB. et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood 2009; 113: 526-534.
• 11 Nichols WL. 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; 14: 171-232.
• 12 de Wee EM. et al. Health-related quality of life among adult patients with moderate and severe von Willebrand disease. J Thromb Haemost 2010; 08: 1492-1499.
• 13 de Wee EM. et al. Impact of von Willebrand disease on health related quality of life in a pediatric population. J Thromb Haemost 2010; 09: 502-509.
• 14 Tosetto A. et al. Bleeding scores in inherited bleeding disorders: clinical or research tools?. Haemophilia 2008; 14: 415-422.
• 15 Salem RO, Van Cott EM. A new automated screening assay for the diagnosis of von Willebrand disease. Am J Clin Pathol 2007; 127: 730-735.
• 16 Smith DR, Murphy D. Capillary blotting of agarose gels. Methods Mol Biol 1996; 58: 23-25.
• 17 Budde U. et al. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD). J Thromb Haemost 2008; 06: 762-771.
• 18 Landsteiner K. On agglutination of normal human blood. Transfusion 1961; 01: 5-8.
• 19 Castaman G. et al. Different bleeding risk in type 2A and 2M von Willebrand disease: a 2-year prospective study in 107 patients. J Thromb Haemost 2012; 10: 632-638.
• 20 Mathew P. et al. Type 2B vWD: the varied clinical manifestations in two kindreds. Haemophilia 2003; 09: 137-144.
• 21 Casonato A. et al. A novel von Willebrand factor mutation (I1372S) associated with type 2B-like von Willebrand disease: an elusive phenotype and a difficult diagnosis. Thromb Haemost 2007; 98: 1182-1187.
• 22 Roland K. et al. The value of genetic testing for type 2B Von Willebrand disease. Clin Lab Haematol 2006; 28: 17-21.
• 23 Federici AB. Prophylaxis of bleeding episodes in patients with von Willebrand's disease. Blood Transfus 2008; 06 (Suppl. 02) s26-32.
• 24 Makris M. Gastrointestinal bleeding in von Willebrand disease. Thromb Res 2006; 118 (Suppl. 01) S13-17.
• 25 Metjian AD. et al. Bleeding symptoms and laboratory correlation in patients with severe von Willebrand disease. Haemophilia 2009; 15: 918-925.
• 26 Lak M. et al. Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease. Br J Haematol 2000; 111: 1236-1239.
• 27 Rodeghiero F. et al. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study. J Thromb Haemost 2005; 03: 2619-2626.
• 28 Astrup K. et al. Menstrual bleeding patterns in pre- and perimenopausal women: a population-based prospective diary study. Acta Obstet Gynecol Scand 2004; 83: 197-202.
• 29 Duckitt K. Managing perimenopausal menorrhagia. Maturitas 2010; 66: 251-256.
• 30 De Wee EM. et al. Gynaecological and obstetric bleeding in moderate and severe von Willebrand disease. Thromb Haemost 2011; 106: 885-892.
• 31 Jenkins PV, O'Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all?. Transfusion 2006; 46: 1836-1844.
• 32 Gallinaro L. et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 2008; 111: 3540-3545.
• 33 Goodeve A. et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood 2007; 109: 112-121.
• 34 James PD. et al. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood 2007; 109: 145-154.
• 35 Cumming A. et al. An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease. Thromb Haemost 2006; 96: 630-641.
• 36 Collins PW. et al. Type 1 von Willebrand disease: application of emerging data to clinical practice. Haemophilia 2008; 14: 685-696.
• 37 Klarmann D. et al. Association of ABO(H) and I blood group system development with von Willebrand factor and Factor VIII plasma levels in children and adolescents. Transfusion 2010; 50: 1571-1580.
• 38 Favaloro EJ. et al. Reassessment of ABO blood group, sex, and age on laboratory parameters used to diagnose von Willebrand disorder: potential influence on the diagnosis vs the potential association with risk of thrombosis. Am J Clin Pathol 2005; 124: 910-917.
• 39 Boren MT, Ramey J. Thinking aloud: Reconciling theory and practice. IEEE Transact Prof Commun 2000; 43: 261-278.
• 40 de Wee EM. et al. Diagnosis and management of Von Willebrand Disease in the Netherlands. Semin Thromb Hemost 2011; 37: 480-487.