Age Regulates Desmopressin Responses in Patients with Low Von Willebrand Factor and Type 1 Von Willebrand Disease in the Lovic and Win Studies

Introduction Desmopressin is the treatment of choice in many patients with Low VWF and type 1 VWD. However, not all patients respond well to desmopressin. Moreover, desmopressin is contra-indicated in patients > 60 years in some countries. Interestingly however, previous studies have demonstrated that increases in plasma VWF levels seen with ageing are attributable to enhanced VWF biosynthesis coupled with reduced VWF clearance. Therefore, we investigated the hypothesis that Weibel-Palade body stores of VWF and clearance of VWF, and hence desmopressin responses, may vary with ageing. Methods We investigated datasets collected through the previously described Low VWF in Ireland Cohort (LoVIC) and Willebrand in the Netherlands (WiN) studies. All patients included in the LoVIC study had a personal bleeding history and VWF levels in the 30-50 IU/dL range. Conversely, WiN patients had either a personal bleeding history or positive family history, combined with VWF levels ≤ 30 IU/dL. Desmopressin was administered intravenously at a dosage of 0.3 μg/kg (maximum dose capped at 28 μg/kg) or intranasally at a total dosage of 300 μg. Complete desmopressin response was defined according to the 2021 ASH/ISTH/NHF/WFH guideline (i.e. increase of 2 times the baseline and sustained VWF and FVIII activity > 50 IU/dL for at least 4 hours). Results In total, 261 patients were included (178 WiN patients with type 1 VWD and 83 LoVIC patients with Low VWF). Based upon levels at inclusion in the WiN study versus original diagnosis, type 1 VWD patients were categorized into three groups - (i) 69 patients with persistent VWF levels < 30 IU/dL; (ii) 55 patients with partial correction in VWF levels into the 30-50 IU/dL range; and (iii) 54 patients with normalization of VWF levels > 50 IU/dL. Importantly, a complete response to desmopressin was observed in only 58% of WiN patients with persistent VWF levels < 30 IU/dL, whereas 100% of WiN patients with partially corrected or normalized levels and 100% of LoVIC patients had a complete response to desmopressin (p<0.001). Type 1 patients with persistent VWF levels < 30 IU/dL had significantly lower VWF:Ag at all time points after desmopressin compared to the other groups (Fig 1, p<0.001). Unexpectedly, VWF:Ag at 1, 4 and 24 hours after desmopressin was significantly higher in WiN normalized compared to LoVIC patients (Fig 1, p<0.001). Importantly however, the WiN normalized cohort was significantly older at the time of their desmopressin trial than the LoVIC group (41.9 ±13.8 years versus 32.9 ±10.7 years, p=0.002). Therefore, we hypothesized that the difference in VWF responses might be age-dependent. To investigate this concept, desmopressin responses for different age groups were assessed in LoVIC patients and WiN partially corrected and WiN normalized patients. Interestingly, an age-dependent effect on VWF responses at 1, 4 and 24 hours after desmopressin administration was observed (Fig 2). Older patients had both a significantly better initial desmopressin response at 1 hour after desmopressin (Fig 2, p=0.018), and a significantly prolonged half-life of VWF at 4 hours after desmopressin (Fig 2, p=0.004). Together, these data suggest that aging leads to both increased VWF synthesis/secretion and reduced clearance of VWF. Finally, we performed a retrospective cohort study to investigate whether desmopressin response could be utilized to predict which type 1 VWD patients would normalize their plasma VWF levels with aging. We included 94 LoVIC and 185 type 1 WiN patients with a mean follow-up of 9.7 ±3.9 years and 16.9 ±7.4 years respectively. We demonstrate that desmopressin response predicted the normalization of VWF levels with aging with a 100% accuracy (p<0.001). None of the patients with an incomplete response to desmopressin normalized during follow-up, whereas the median time of normalization was 13 years [7-26] in patients with complete response to desmopressin (p<0.001). Conclusion Cumulatively, we demonstrate that desmopressin responses increase significantly in VWD patients and Low VWF patients as they get older. Given our findings, future studies assessing the clinical efficacy and safety of using attenuated desmopressin doses in older patients should be considered. Alternatively, developing additional therapies that can be safely used to trigger secretion of enhanced Weibel-Palade body stores of VWF in older patients may provide novel treatment opportunities.

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