增强型 von Willebrand 因子从血浆中清除的遗传决定因素。
Genetic determinants of enhanced von Willebrand factor clearance from plasma.
机构信息
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy; Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy.
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.
出版信息
J Thromb Haemost. 2023 May;21(5):1112-1122. doi: 10.1016/j.jtha.2023.01.012. Epub 2023 Jan 20.
BACKGROUND
Enhanced von Willebrand factor (VWF) clearance from plasma is associated with von Willebrand disease (VWD). However, the genetic background of this disease mechanism is not well defined.
OBJECTIVE
To determine VWF variants that are associated with reduced VWF survival.
METHODS
Two hundred fifty-four patients with VWD (type 1 = 50 and type 2 = 204) were investigated, and the results were compared with 120 healthy controls. The patients were comprehensively characterized for phenotypic and genetic features. The ratio of VWF propeptide (VWFpp)/VWF antigen (VWFpp ratio) was used to establish in each patient the VWF clearance state.
RESULTS
Out of 92 variants associated with type 1 (7 were novel) and type 2 VWD, 19 had a VWFpp ratio ranging from 1.7 to 2.2, 24 had a VWFpp ratio between 2.3 and 2.9, and 24 variants had a ratio of ≥3. The VWFpp median ratio in healthy controls was 0.98 (0.55-1.6) so that a cut-off value of >1.6 was considered an indicator of accelerated VWF clearance from plasma. An enhanced VWF clearance was observed in 34% of type 1 cases, 100% of type 1 Vicenza cases, 81% of 2A cases, 77% of 2B cases, 88% of 2M cases, and 36% of 2N cases.
CONCLUSIONS
An accelerated VWF clearance was found in most patients with type 2A, 2B, and 2M VWD, with a lower proportion of type 1 and 2N. Sixty-seven different variants alone or in combination with other variants were associated with an increased VWFpp ratio. The variants with the highest VWFpp ratio were mostly located in the D3-A1 VWF domains.
背景
从血浆中清除增强的血管性血友病因子（VWF）与血管性血友病（VWD）有关。然而，这种疾病机制的遗传背景尚未明确。
目的
确定与 VWF 生存能力降低相关的 VWF 变体。
方法
对 254 例 VWD 患者（1 型= 50 例，2 型= 204 例）进行了研究，并将结果与 120 例健康对照进行了比较。对患者进行了全面的表型和遗传特征分析。使用 VWF 前肽（VWFpp）/VWF 抗原（VWFpp 比值）来确定每位患者的 VWF 清除状态。
结果
在与 1 型（7 种为新发现）和 2 型 VWD 相关的 92 种变体中，有 19 种 VWFpp 比值在 1.7 至 2.2 之间，24 种 VWFpp 比值在 2.3 至 2.9 之间，24 种变体的比值≥3。健康对照组的 VWFpp 中位数比值为 0.98（0.55-1.6），因此将>1.6 视为指示从血浆中加速清除 VWF 的指标。在 34%的 1 型病例、100%的 Vicenza 1 型病例、81%的 2A 病例、77%的 2B 病例、88%的 2M 病例和 36%的 2N 病例中观察到 VWF 清除加速。
结论
在大多数 2A、2B 和 2M VWD 患者中发现了 VWF 清除加速，1 型和 2N 的比例较低。单独或与其他变体结合的 67 种不同变体与 VWFpp 比值增加相关。VWFpp 比值最高的变体大多位于 D3-A1 VWF 结构域。
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