Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence
Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence
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DOI：
10.3324/haematol.2018.206250
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发表时间：
2019-12-01
期刊：
影响因子：
10.1
通讯作者：
Kauskot, Alexandre
中科院分区：
文献类型：
--
作者：
Dupont, Annabelle;Soukaseum, Christelle;Kauskot, Alexandre
2B 型冯·维勒布兰德病 (vWD)（由冯·维勒布兰德因子编码基因的功能获得性突变引起）患者会出现不同程度的出血，在某些情况下还会出现血小板减少症。 2B 型 vWD 血小板减少症有多种根本原因。最近有人提出，去唾液酸化介导的血小板清除会导致这种疾病中的血小板减少。然而，这一假设尚未在体内得到检验。在 36 名 2B 型冯维勒布兰德病（p.R1306Q、p.R1341Q 和 p.V1316M 突变）患者和携带严重 p.V1316M 突变的小鼠模型（2B 小鼠）中探讨了血小板去唾液酸化与血小板计数之间的关系。我们观察到 p.V1316M 突变患者和 2B 小鼠的血小板脱唾液酸化水平异常升高。在体外，我们证明 2B p.V1316M/von Willebrand 因子比野生型 von Willebrand 因子诱导更多的正常血小板去唾液酸化。此外，我们发现 N-聚糖被去唾液酸化，并且我们确定 α IIb 和 β 3 作为去唾液酸化目标。用唾液酸酶抑制剂（纠正血小板去唾液酸化）治疗 2B 小鼠与恢复正常血小板计数无关。最后，我们证明了在体内诱导血小板减少症需要一个关键的血小板去唾液酸阈值（在 2B 患者或 2B 小鼠中均未达到）。总之，在 2B 型 vWD 中，血小板去唾液酸化作用较小，不足以介导血小板减少。
Patients with type 2B von Willebrand disease (vWD) (caused by gain-of-function mutations in the gene coding for von Willebrand factor) display bleeding to a variable extent and, in some cases, thrombocytopenia. There are several underlying causes of thrombocytopenia in type 2B vWD. It was recently suggested that desialylation-mediated platelet clearance leads to thrombocytopenia in this disease. However, this hypothesis has not been tested in vivo. The relationship between platelet desialylation and the platelet count was probed in 36 patients with type 2B von Willebrand disease (p.R1306Q, p.R1341Q, and p.V1316M mutations) and in a mouse model carrying the severe p.V1316M mutation (the 2B mouse). We observed abnormally high elevated levels of platelet desialylation in both patients with the p.V1316M mutation and the 2B mice. In vitro, we demonstrated that 2B p.V1316M/von Willebrand factor induced more desialylation of normal platelets than wild-type von Willebrand factor did. Furthermore, we found that N-glycans were desialylated and we identified alpha IIb and beta 3 as desialylation targets. Treatment of 2B mice with sialidase inhibitors (which correct platelet desialylation) was not associated with the recovery of a normal platelet count. Lastly, we demonstrated that a critical platelet desialylation threshold (not achieved in either 2B patients or 2B mice) was required to induce thrombocytopenia in vivo. In conclusion, in type 2B vWD, platelet desialylation has a minor role and is not sufficient to mediate thrombocytopenia.