Comorbidities associated with higher von Willebrand factor (VWF) levels may explain the age-related increase of VWF in von Willebrand disease

Ferdows Atiq, Karina Meijer, Jeroen Eikenboom, Karin Fijnvandraat, Eveline P Mauser-Bunschoten, Karin P M van Galen, Marten R Nijziel, Paula F Ypma, Joke de Meris, Britta A P Laros-van Gorkom, Johanna G van der Bom, Moniek P de Maat, Marjon H Cnossen, Frank W G Leebeek, WiN study group, Ferdows Atiq, Karina Meijer, Jeroen Eikenboom, Karin Fijnvandraat, Eveline P Mauser-Bunschoten, Karin P M van Galen, Marten R Nijziel, Paula F Ypma, Joke de Meris, Britta A P Laros-van Gorkom, Johanna G van der Bom, Moniek P de Maat, Marjon H Cnossen, Frank W G Leebeek, WiN study group

Abstract

Some comorbidities, such as hypertension, are associated with higher von Willebrand factor (VWF) levels in the general population. No studies have been conducted to assess this association in patients with von Willebrand disease (VWD). Therefore, we studied this association in patients with type 1 (n = 333) and type 2 (n = 203) VWD from the 'WiN" study. VWF antigen (VWF:Ag) was higher in type 1 VWD patients with hypertension [difference: 0·23 iu/ml, 95% confidence interval (CI): 0·11-0·35], diabetes mellitus (0·11 iu/ml, 95% CI: -0·02 to 0·23), cancer (0·14 iu/ml, 95% CI: 0·03-0·25) and thyroid dysfunction (0·14 iu/ml, 95% CI: 0·03-0·26) than in patients without these comorbidities (all corrected for age, sex and blood group). Similar results were observed for VWF collagen binding capacity (VWF:CB), VWF activity as measured by the VWF monoclonal antibody assay (VWF:Ab) and factor VIII (FVIII) coagulant activity (FVIII:C). In type 1 VWD, age was associated with higher VWF:Ag (0·03 iu/ml; 95% CI: 0·01-0·04), VWF:CB (0·02 iu/ml; 95% CI: 0·00-0·04), VWF:Ab (0·04 iu/ml; 95% CI: 0·02-0·06) and FVIII:C (0·03 iu/ml; 95% CI: 0·01-0·06) per decade increase. After adjustment for relevant comorbidities, these associations were no longer significant. Despite the higher VWF and FVIII levels, type 1 VWD patients with comorbidities had more bleeding episodes, particularly during surgery. There was no association between comorbidities and VWF/FVIII levels or bleeding phenotype in type 2 VWD patients. In conclusion, comorbidities are associated with higher VWF and FVIII levels in type 1 VWD and may explain the age-related increase of VWF and FVIII levels.

Keywords: VWD; VWF; cancer; diabetes; elderly.

© 2018 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Consort diagram illustrating patient inclusion in the study. VWD, von Willebrand disease.
Figure 2
Figure 2
The association between hypertension and VWF and FVIII. Number of patients with and without hypertension are respectively in type 1: n = 75 vs. n = 255, type 2: n = 42 vs. n = 160. Multiple regression outcomes in type 1 VWD corrected for; age, sex, blood group and anti‐hypertensive treatment. VWF:Ab and FVIII:C additionally corrected for diabetes. Multiple regression outcomes in type 2 VWD corrected for; age, sex, blood group and anti‐hypertensive treatment. VWF:Ag, VWF:CB and FVIII:C additionally corrected for hypercholesterolaemia. Moreover, FVIII:C also corrected for arterial thrombotic events. The association between hypertension and VWF levels was only adjusted for other comorbidities when the other comorbidities were relevant confounders (see methods). Data presented as boxplots with median and interquartile ranges, and 5–95 percentiles. *P < 0·05. **P < 0·01. ***P < 0·001. FVIII:C, factor VIII coagulant activity; ns, not significant; VWD, von Willebrand disease; VWF:Ab, von Willebrand factor activity as measured by a monoclonal antibody assay; VWF:Ag; von Willebrand factor antigen; VWF:CB, von Willebrand factor collagen binding capacity.
Figure 3
Figure 3
The association between diabetes mellitus and VWF and FVIII. Number of patients with and without diabetes are respectively in type 1: n = 14 vs. n = 319, type 2: n = 6 vs. n = 197. Multiple regression outcomes in type 1 VWD corrected for; age, sex and blood group. VWF:Ag. VWF:CB and VWF:Ab additionally corrected for hypertension. Moreover, VWF:Ag also corrected for hypercholesterolaemia. Multiple regression outcomes in type 2 VWD corrected for; age, sex and blood group. VWF:Ag, VWF:Ab and FVIII:C additionally corrected for hypertension. Moreover, VWF:Ag, VWF:CB and FVIII:C for hypercholesterolaemia and FVIII:C for arterial thrombotic events. The association between diabetes and VWF levels was only adjusted for other comorbidities when the other comorbidities were relevant confounders (see methods). Data presented as boxplots with median and interquartile ranges, and 5–95 percentiles. *P < 0·05. **P < 0·01. FVIII:C, factor VIII coagulant activity; ns, not significant; VWD, von Willebrand disease; VWF:Ab, von Willebrand factor activity as measured by a monoclonal antibody assay; VWF:Ag; von Willebrand factor antigen; VWF:CB, von Willebrand factor collagen binding capacity.
Figure 4
Figure 4
The association between cancer and VWF and FVIII. Number of patients with and without cancer are respectively in type 1: n = 15 vs. n = 318, type 2: n = 8 vs. n = 195. Multiple regression outcomes corrected for age, sex and blood group. Data presented as boxplots with median and interquartile ranges, and 5–95 percentiles. *P < 0·05. FVIII:C, factor VIII coagulant activity; ns, not significant; VWD, von Willebrand disease; VWF:Ab, von Willebrand factor activity as measured by a monoclonal antibody assay; VWF:Ag; von Willebrand factor antigen; VWF:CB, von Willebrand factor collagen binding capacity.
Figure 5
Figure 5
The association between thyroid dysfunction and VWF and FVIII. Number of patients with and without hyperthyroidism are respectively n = 5 vs n = 327. Number of patients with and without hypothyroidism are respectively n = 10 vs. n = 322. Multiple regression outcomes corrected for; age, sex, blood group and hypo‐ or hyperthyroidism. Data presented as boxplots with median and interquartile ranges, and 5–95 percentiles. *P < 0·05. FVIII:C, factor VIII coagulant activity; ns, not significant; VWD, von Willebrand disease; VWF:Ab, von Willebrand factor activity as measured by a monoclonal antibody assay; VWF:Ag; von Willebrand factor antigen; VWF:CB, von Willebrand factor collagen binding capacity.
Figure 6
Figure 6
The number of comorbidities and VWF and FVIII levels in type 1 VWD. There were 236 patients with 0 relevant comorbidities, 77 patients with 1 relevant comorbidity and 18 patients with two relevant comorbidities. Only 2 patients had three relevant comorbidities and are excluded from the figure. Data presented as boxplots with median and interquartile ranges, and 5–95 percentiles. *P < 0·001, Multiple regression outcomes corrected for age, sex and blood group. FVIII:C, factor VIII coagulant activity; VWD, von Willebrand disease; VWF:Ab, von Willebrand factor activity as measured by a monoclonal antibody assay; VWF:Ag, von Willebrand factor antigen; VWF:CB, von Willebrand factor collagen binding capacity.
Figure 7
Figure 7
The effect of comorbidities on the age‐related increase of VWF and FVIII levels in type 1 VWD. FVIII:C, factor VIII coagulant activity; VWD, von Willebrand disease; VWF:Ab, von Willebrand factor activity as measured by a monoclonal antibody assay; VWF:Ag, von Willebrand factor antigen; VWF:CB, von Willebrand factor collagen binding capacity.

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