Background: von Willebrand disease (VWD) is the commonest inherited bleeding disorder caused by reduced levels or reduced function of von Willebrand factor (VWF). With increasing age, VWD patients undergo changes with regard to VWF levels, FVIII levels and bleeding symptoms. As the number of elderly VWD patients is increasing, the pathophysiology of aging in VWD has become clinically relevant. In this two-center cohort study we re-evaluated patients previously diagnosed with VWD with respect to their bleeding phenotype and VWF levels based on age-and blood group (BG)-dependent reference values.1
Methods: Since February 2012 in the study center Lübeck and Kiel 969 consecutively admitted patients presenting with hemorrhagic diathesis (HD) one year before laboratory work-up/re-classification were enrolled. Reclassification was performed on the basis of age- and BG-dependent reference values with respect to the presence or absence of VWD (1). 174 of 504 patients aged 1 to 86 years (median 35) suffering from non-acquired and non-VWD-associated clinically relevant HD (Rodeghiero ISTH bleeding score) were diagnosed with VWD type 1 (n=154), type 2 (n=17) or 3 (n=3) within the last two decades prior re-classification based on VWF levels, multimeric pattern and/or genotyping. Laboratory cut-off values for re-classification (VWF:ac & VWF:ag; < 10th percentiles) derived from healthy population-based blood donors (n=1010) were as follows: < 60% (BG non-0: 72%) until the age of 49, < 100% (BG non-0: 120%) patients aged 50 to 59 years, and < 113% (BG non-0: 135%) in subjects > 60 years of age.
Results: In the present patient follow-up visits in patients aged 20 to < 49 years 42 of 230 individuals (18,3%) compared to 55 of 131 older patients aged 50 to 86 years (median 66: 42%) the formerly classification of VWD type 1 would have been missed (p<0,001) without using age- and BG-dependent cut-off values. In patients < 20 years of age previous diagnosis were confirmed in all cases (n=39). Of note, inclusion of the variable blood group "0" versus "non-0" in our model has improved the detection rate of previously diagnosed VWD by 5%. Interestingly, although the bleeding phenotype in women with VWD type 1 switched over the aging process from epistaxis (prior puberty) to menorrhagia back to epistaxis and non-vaginal mucosal bleeding the severity of bleeding documented via ISTH score did not mitigate during the aging process.
Conclusion: Based on the model of "developmental hemostasis" including not only the youngest but also elderly patients classification of inherited HD especially of VWD by using age- and BG-dependent reference values is suggested in order not to miss patients prone to possible bleeding episodes during emergency or elective interventions
Nowak Goettl: Octapharma: Research Funding. Kenet: Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Opko biologics: Consultancy, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees.
Asterisk with author names denotes non-ASH members.