血小板在血栓形成和止血中是第一反应者，但也是炎症中的中心角色。与招募到血栓中的血小板相比，免疫响应性血小板使用不同的效应器功能，包括 Arp2/3 依赖性迁移沿着粘附基底梯度（触觉趋化作用），这可以防止炎症性出血并有助于宿主防御。在这种情况下，血小板迁移在细胞水平上是如何调控的还不完全清楚。在这里，我们使用时间分辨形态动力学分析单个血小板，展示了迁移，与凝血收缩相比，需要血小板后部的异向性肌球蛋白IIa 活性，这在前部极化的肌动蛋白聚合体之前，用于启动和维持迁移。迁移的极化在移动的血小板中由整合蛋白 GPIIb 依赖的外向内信号传导协调，通过 Gα13 触发酪氨酸激酶 c-Src/14-3-3ζ 依赖的鞭毛体形成和功能，独立于可溶性激动剂或趋化信号。这种信号级联的抑制剂包括临床应用的 ABL/c-Src 抑制剂达沙替尼，主要干扰血小板的迁移能力，而不会严重损伤经典血小板功能。在小鼠炎症模型中，这转化为通过 4D 体内显微镜观察到血小板迁移减少，导致急性肺损伤相关出血增加。最后，从容易发生临床相关出血的达沙替尼治疗白血病患者中分离的血小板表现出突出的迁移缺陷，而其他血小板功能仅部分受影响。总之，我们定义了一条不同的信号通路，对迁移至关重要，并提供了解释达沙替尼相关的血小板功能障碍和出血的新机制。Copyright © 2023 American Society of Hematology。

Platelets are first responders in thrombosis and hemostasis, but also central players in inflammation. Compared to platelets recruited to thrombi, immune-responsive platelets use distinct effector functions including Arp2/3-dependent migration along adhesive substrate gradients (haptotaxis), which prevents inflammatory bleeding and contributes to host defense. How platelet migration in this context is regulated on a cellular level is incompletely understood. Here, we use time-resolved morphodynamic profiling of individual platelets to show that migration, in contrast to clot retraction, requires anisotropic myosin IIa-activity at the platelet rear which is preceded by polarized actin polymerization at the front to initiate and maintain migration. Polarization of migrating platelets is coordinated by integrin GPIIb-dependent outside-in signaling via Gα13 to trigger tyrosine kinase c-Src/14-3-3ζ-dependent lamellipodium formation and functions independent of soluble agonists or chemotactic signals. Inhibitors of this signaling cascade, including the clinically employed ABL/c-Src inhibitor dasatinib, interfere predominantly with the migratory capacity of platelets, without major impairment of classical platelet functions. In murine inflammation models, this translates to reduced migration of platelets visualized by 4D intravital microscopy, resulting in increased inflammation-associated hemorrhage in acute lung injury. Finally, platelets isolated from dasatinib-treated leukemia patients prone to clinically relevant hemorrhage exhibit prominent migration defects, while other platelet functions are only partially affected. In summary, we define a distinct signaling pathway essential for migration, and provide novel mechanistic insights explaining dasatinib-related platelet dysfunction and bleeding.Copyright © 2023 American Society of Hematology.