Thrombocytosis drives alteration of primary hemostasis and acquired von willebrand syndrome occurrence in myeloproliferative neoplasms

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Abstract Introduction Acquired von Willebrand syndrome (AvWS) is a rare condition that results in biological alterations of primary hemostasis and related bleeding manifestations closed to hereditary von Willebrand syndrome. Few data reported incidence of AvWS in hematological malignancies. Myeloproliferative neoplasms (MPN)-associated AvWS (M-AvWS) account for a part of AvWS but precise pathogenesis is not yet fully understood. In this retrospective study, we aimed to evaluate acquired von Willebrand syndrome incidence and its characteristics by systematically assessing Willebrand parameters and bleeding manifestations in patients with MPN-related thrombocytosis. Patients and Methods Patients with confirmed MPN according to WHO 2022 and thrombocytosis (defined as platelets ≥ 450 G/L) were eligible. At time of diagnosis and/or first thrombocytosis observation, patients were explored for hemostasis assays focused on vWF axis (FVIII coagulant activity (FVIII:C), von Willebrand factor antigen (vWF:Ag) and activity (vWF:GpIbR), collagen binding assay (vWF:CB) and neutralizing anti-vWF antibody detection (vWF:n). Thrombotic and bleeding history was also recorded at baseline and during follow-up. For some patients, sequential biological parameters were evaluated during their follow-up. Results Between 2020 and 2025, 169 patients presenting with MPN related thrombocytosis at Hospital Lyon Sud Hematology Department were included in this study. The median age was 60 years (range 15-98), 106 patients were females (62.7%), 111 (65.7%) patients presented ET, 26 (15.4%) PV, 16 (9.5%) chronic myeloid leukemia (CML), 8 (4.7%) primary myeloid fibrosis (PMF), 3 myelodysplastic-MPN, 4 MPN unclassifiable and 1 MPN with SH2B3 mutation. The mean platelet level was 798 G/L (range 457-4117). Low (<0.7) vWF:GpIbR/vWF:Ag ratio was found in 156 patients (92.3 %) and low (<0.7) vWF:CB/vWF:Ag ratio in 105 patients (62.1%). Thirty-one patients with low vWF:GpIbR/Ag ratio were screened for vWF:n and 11 were found positive. Interestingly, all 169 patients (100%) presented normal or increased vWF:Ag levels. The overall prevalence of AvWS was observed in 11.2% of patients (19/169). This corresponds to 13/111 (11.7%) ETs, 4/26 (15.4%) PVs, 1/8 (12.5%) PMFs, and the single case of SH2B3 MPN. Bleeding events included 12 (63.2%) Grade 1, 4 (21.0%) Grade 2 and 3 (15.8%) Grade 3 . At the time of hemorrhage 14 patients (73.7%) had antiplatelet treatment and 1 (5.3%) had selective serotonin reuptake inhibitor treatment. Among them all 19 (100%) patients had high platelet level at the time of hemorrhage, 18 (94.7%) and 10 (52.6%) had low vWF:GpIbR/Ag and vWF:CB/Ag ratio respectively and 3 (15.8%) were positive for vWF:n screening . In comparison with the 150 patients without bleeding, AvWS patients had significantly lower FVIII:C (mean 87.3 vs 109.6 UI/L, p=0.003). There was no significant difference in terms of platelet level, MPN subtype, driver mutation identified nor vWF parameters . Thrombotic events occurred in 2 (10.5%) of the AvWS patients and in 19 (12.7%) of the other participants (p=1.00), with 2 (100%) and 15 (78.9%) arterial events respectively. Fifty -two patients (30.8%) had further biological testing during their follow-up, 33 of them (63.5%) received cytoreductive therapy (mostly hydroxyurea). Paired analysis on patients who experienced platelet counts normalization showed a significant increase in vWF:GpIbR/Ag (mean 0.68 Standard deviation -SD 0.28 vs 0.30 SD 0.19, p<0.0001) and vWF:CB/Ag ratios (mean 1.01 SD 0.42 vs mean 0.63 SD 0.15p= 0.017), resulting in 8 (42.1%) vs 0 patients with normal vWF:GpIbR/Ag ratio and 18 (94.7%) vs 7 patients (36.8%) with normal vWF:CB/Ag ratio. Conclusions In this retrospective analysis of patients with MPN-related thrombocytosis we showed that abnormal vWF parameters were frequently observed but bleeding diathesis was only reported in 11% of MPN patients with thrombocytosis. Heterogenous mechanisms are involved in MPN-aVWS (decreased vWF activity, loss of high molecular weight multimers and neutralizing antibody) but no quantitative defect was observed in this study. Finally, platelet counts normalization through MPN cytoreductive therapy was associated with a substantial improvement in vWF:GpIbR/Ag and vWF:CB/Ag ratios (0.68 vs 0.3 and 1.01 vs 0.42 respectively), with a concomitant normalization of vWF parameters in 42% and 58% of patients, respectively.

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