Platelet transfusions can fail to prevent bleeding in patients with inherited platelet function disorders (IPDs), such as Glanzmann’s thrombasthenia (GT; integrin αIIbβ3 dysfunction), Bernard-Soulier syndrome [BSS; glycoprotein (GP) Ib/V/IX dysfunction], and the more recently identified nonsyndromic RASGRP2 variants. Here, we used IPD mouse models and real-time imaging of hemostatic plug formation to investigate whether dysfunctional platelets impair the hemostatic function of healthy donor [wild-type (WT)] platelets. In Rasgrp2^−/− mice or mice with platelet-specific deficiency in the integrin adaptor protein TALIN1 (“GT-like”), WT platelet transfusion was ineffective unless the ratio between mutant and WT platelets was ~2:1. In contrast, thrombocytopenic mice or mice lacking the extracellular domain of GPIbα (“BSS-like”) required very few transfused WT platelets to normalize hemostasis. Both Rasgrp2^−/− and GT-like, but not BSS-like, platelets effectively localized to the injury site. Mechanistic studies identified at least two mechanisms of interference by dysfunctional platelets in IPDs: (i) delayed adhesion of WT donor platelets due to reduced access to GPIbα ligands exposed at sites of vascular injury and (ii) impaired consolidation of the hemostatic plug. We also investigated the hemostatic activity of transfused platelets in the setting of dual antiplatelet therapy (DAPT), an acquired platelet function disorder (APD). “DAPT” platelets did not prolong the time to initial hemostasis, but plugs were unstable and frequent rebleeding was observed. Thus, we propose that the endogenous platelet count and the ratio of transfused versus endogenous platelets should be considered when treating select IPD and APD patients with platelet transfusions.

血小板输注可能无法预防遗传性血小板功能障碍 (IPD) 患者的出血，例如格兰兹曼血小板无力症（GT；整合素 αIIbβ3 功能障碍）、Bernard-Soulier 综合征 [BSS；糖蛋白 (GP) Ib/V/IX 功能障碍]，以及最近发现的非综合征性RASGRP2变异。在这里，我们使用 IPD 小鼠模型和止血栓形成的实时成像来研究功能障碍的血小板是否损害健康供体 [野生型 (WT)] 血小板的止血功能。在Rasgrp2 ^−/−小鼠或整合素接头蛋白 TALIN1（“GT 样”）中血小板特异性缺陷的小鼠中，WT 血小板输注无效，除非突变型血小板与 WT 血小板之间的比例约为 2:1。相比之下，血小板减少症小鼠或缺乏 GPIbα 胞外结构域（“BSS 样”）的小鼠只需输注很少的 WT 血小板即可使止血正常化。 Rasgrp2 ^−/−和 GT 样（但不是 BSS 样）血小板均有效地定位于损伤部位。机制研究确定了 IPD 中功能障碍血小板的干扰至少有两种机制：(i) 由于接触血管损伤部位暴露的 GPIbα 配体的机会减少，导致 WT 供体血小板的粘附延迟；(ii) 止血塞的巩固受损。我们还研究了双重抗血小板治疗（DAPT）（一种获得性血小板功能障碍（APD））中输注血小板的止血活性。 “DAPT”血小板不会延长初始止血时间，但栓塞不稳定并且观察到频繁的再出血。 因此，我们建议，在用血小板输注治疗特定的 IPD 和 APD 患者时，应考虑内源性血小板计数以及输注血小板与内源性血小板的比率。