Bleeding Patterns in Type I VWD in Effect of VWF Levels: An Individual Participant Data Meta-Analysis of Three Cohorts

Type I von Willebrand disease (VWD) is the most frequent bleeding disorder, with a prevalence of 10-50 cases per 10,000 persons. VWD usually shows an autosomal dominant inheritance pattern, at least in families having VWF:Ag levels below 30 IU/dL. There is considerable uncertainty whether patients having only mildly reduced VWF levels (in the range 30-50 IU/dL) should be diagnosed as having VWD or if they should be considered as a separate clinical entity, broadly referred to as "reduced VWF patients." We hypothesize that these patients may have a clinically distinct bleeding pattern, in terms of presenting symptoms at diagnosis, bleeding severity, and possibly even clinical.

We pooled data from three cohorts of patients. The MCMDM-1 VWD Study is a multicenter survey on type 1 VWD that recruited 154 type 1 VWD families from nine European countries. The Kingston cohort recruited consecutive patients with type 1 VWD diagnosed in Kingston, Canada and includes patients screened because of bleeding symptoms or family history of VWD over a 10 year period. The Zimmerman Program for the Molecular and Clinical Biology of VWD is a multicenter study that enrolled VWD patients mostly from US clinical centres, primarily carrying a diagnosis of type 1 VWD (315 families) but also including type 2 and type 3 subjects. For the present study, only patients with a confirmed diagnosis of type 1 VWD were retained. From the three cohorts, demographic, laboratory and clinical data were abstracted, including severity of bleeding symptoms classified according to the MCMDM-1 study criteria. Only data from index cases and affected family members were retained for the present analysis. Bleeding symptoms receiving a score >=2 (and therefore requiring some type of medical intervention) were classified as "clinically relevant". VWF:Ag and VWF:RCo were measured centrally by the reference core lab of each of the three studies, against the WHO International Standard. For this purpose of the present study, Type 1 VWD is defined as VWF:Ag levels (or VWF:RCo for the Zimmerman Program) below 30 IU/dL; affected family members and index cases with VWF:Ag levels equal or above 30 IU/dL were classified as "low-VWF" patients.

Pooled data from the three studies resulted in 1411 patients. At multivariate analysis, blood group O females with lower bleeding scores were the characteristics associated with the "low-VWF" patients; interestingly, the number of clinically relevant bleeding symptoms was associated with the phenotype independently from the total bleeding score. For all considered bleeding symptoms, VWD patients had a higher prevalence of relevant bleeding, with the notable exception of menorrhagia. Particularly in index cases, menorrhagia but also post-surgical bleeding was increased in patients having the "low-VWF" phenotype, although only for menorrhagia the difference was statistically significant (p=0.022).

Unsupervised cluster analysis of symptom distribution disclosed three subgroups of patients. The first two were composed by males (first group) or females (second group), both having few or none bleeding symptoms. The third identified by unsupervised cluster analysis group was composed of highly symptomatic patients, predominantly women. In these patients, mucous ("wet") bleeding (epistaxis and menorrhagia) was common together with post-surgical or extraction bleeding. This pattern was not correlated with mean VWF:Ag level or "low-VWF" or Type 1 VWD phenotype. We conclude that "low-VWF" patients are more frequently blood group O, older females, with lower average bleeding scores and number of symptoms and possibly selected because of menorrhagia. A group of "severe bleeders" may be identified (n=270, 19%), having a similar distribution of "low VWF" and "VWD" phenotypes.