在与 - 相关疾病的小鼠模型中,血小板力降低是止血功能受损的基础。
Reduced platelet forces underlie impaired hemostasis in mouse models of -related disease.
作者信息
Baumann Juliane, Sachs Laura, Otto Oliver, Schoen Ingmar, Nestler Peter, Zaninetti Carlo, Kenny Martin, Kranz Ruth, von Eysmondt Hendrik, Rodriguez Johanna, Schäffer Tilman E, Nagy Zoltan, Greinacher Andreas, Palankar Raghavendra, Bender Markus
机构信息
Institute of Experimental Biomedicine-Chair I, University Hospital and Rudolf Virchow Center, Würzburg, Germany.
Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
出版信息
Sci Adv. 2022 May 20;8(20):eabn2627. doi: 10.1126/sciadv.abn2627. Epub 2022 May 18.
-related disease patients with mutations in the contractile protein nonmuscle myosin heavy chain IIA display, among others, macrothrombocytopenia and a mild-to-moderate bleeding tendency. In this study, we used three mouse lines, each with one point mutation in the gene at positions 702, 1424, or 1841, to investigate mechanisms underlying the increased bleeding risk. Agonist-induced activation of mutant platelets was comparable to controls. However, myosin light chain phosphorylation after activation was reduced in mutant platelets, which displayed altered biophysical characteristics and generated lower adhesion, interaction, and traction forces. Treatment with tranexamic acid restored clot retraction in the presence of tPA and reduced bleeding. We verified our findings from the mutant mice with platelets from patients with the respective mutation. These data suggest that reduced platelet forces lead to an increased bleeding tendency in patients with -related disease, and treatment with tranexamic acid can improve the hemostatic function.
与收缩蛋白非肌肉肌球蛋白重链IIA突变相关的疾病患者,除其他症状外,还表现出大血小板减少症和轻度至中度出血倾向。在本研究中,我们使用了三种小鼠品系,每个品系在基因的702、1424或1841位置有一个点突变,以研究出血风险增加的潜在机制。激动剂诱导的突变血小板活化与对照相当。然而,突变血小板活化后的肌球蛋白轻链磷酸化减少,表现出改变的生物物理特性,并产生较低的粘附、相互作用和牵引力。在纤溶酶原激活物存在的情况下,用氨甲环酸治疗可恢复血块回缩并减少出血。我们用具有相应突变的患者的血小板验证了来自突变小鼠的研究结果。这些数据表明,血小板力降低导致与相关疾病患者的出血倾向增加,而氨甲环酸治疗可改善止血功能。
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