Clinical Infectious Disease Research Center, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
PLoS Pathog. 2019 Mar 8;15(3):e1007500. doi: 10.1371/journal.ppat.1007500. eCollection 2019 Mar.
Thrombocytopenia and platelet dysfunction are commonly observed in patients with dengue virus (DENV) infection and may contribute to complications such as bleeding and plasma leakage. The etiology of dengue-associated thrombocytopenia is multifactorial and includes increased platelet clearance. The binding of the coagulation protein von Willebrand factor (VWF) to the platelet membrane and removal of sialic acid (desialylation) are two well-known mechanisms of platelet clearance, but whether these conditions also contribute to thrombocytopenia in dengue infection is unknown. In two observational cohort studies in Bandung and Jepara, Indonesia, we show that adult patients with dengue not only had higher plasma concentrations of plasma VWF antigen and active VWF, but that circulating platelets had also bound more VWF to their membrane. The amount of platelet-VWF binding correlated well with platelet count. Furthermore, sialic acid levels in dengue patients were significantly reduced as assessed by the binding of Sambucus nigra lectin (SNA) and Maackia amurensis lectin II (MAL-II) to platelets. Sialic acid on the platelet membrane is neuraminidase-labile, but dengue virus has no known neuraminidase activity. Indeed, no detectable activity of neuraminidase was present in plasma of dengue patients and no desialylation was found of plasma transferrin. Platelet sialylation was also not altered by in vitro exposure of platelets to DENV nonstructural protein 1 or cultured DENV. In contrast, induction of binding of VWF to glycoprotein 1b on platelets using the VWF-activating protein ristocetin resulted in the removal of platelet sialic acid by translocation of platelet neuraminidase to the platelet surface. The neuraminidase inhibitor oseltamivir reduced VWF-induced platelet desialylation. Our data demonstrate that excessive binding of VWF to platelets in dengue results in neuraminidase-mediated platelet desialylation and platelet clearance. Oseltamivir might be a novel treatment option for severe thrombocytopenia in dengue infection.
血小板减少症和血小板功能障碍在登革病毒（DENV）感染患者中很常见，可能导致出血和血浆渗漏等并发症。登革热相关血小板减少症的病因是多因素的，包括血小板清除增加。凝血蛋白血管性血友病因子（VWF）与血小板膜的结合和唾液酸（去唾液酸化）的去除是两种众所周知的血小板清除机制，但这些情况是否也会导致登革热感染中的血小板减少症尚不清楚。在印度尼西亚万隆和杰帕拉的两项观察性队列研究中，我们表明登革热的成年患者不仅具有更高的血浆血管性血友病因子抗原和活性 VWF 浓度，而且循环血小板与它们的膜结合了更多的 VWF。血小板-VWF 结合量与血小板计数呈良好相关性。此外，通过 Sambucus nigra 凝集素（SNA）和 Maackia amurensis 凝集素 II（MAL-II）与血小板的结合评估，登革热患者的唾液酸水平显著降低。血小板膜上的唾液酸是神经氨酸酶不稳定的，但登革病毒没有已知的神经氨酸酶活性。事实上，在登革热患者的血浆中未检测到神经氨酸酶的活性，也未发现血浆转铁蛋白的去唾液酸化。体外暴露于 DENV 非结构蛋白 1 或培养的 DENV 也不会改变血小板的唾液酸化。相比之下，使用 VWF 激活蛋白瑞斯托霉素诱导 VWF 与血小板糖蛋白 1b 的结合会导致血小板神经氨酸酶通过易位到血小板表面来去除血小板的唾液酸。神经氨酸酶抑制剂奥司他韦可减少 VWF 诱导的血小板去唾液酸化。我们的数据表明，登革热中 VWF 与血小板的过度结合导致神经氨酸酶介导的血小板去唾液酸化和血小板清除。奥司他韦可能是登革热感染中严重血小板减少症的一种新的治疗选择。
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