Journal of thrombosis and haemostasis : JTH · 2025
Confining thrombus morphospace through targeted inhibition of platelet mechanosensory signaling.
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Larsson Pia, McGovern Abigail, Tarlac Volga, Setiabakti Natasha M, Parker Louis, Cody Stephen H, Nunez-Iglesias Juan, Faxälv Lars, Prahl Wittberg Lisa, Hamilton Justin R, Boknäs Niklas
Аннотация
BACKGROUND: While current antiplatelets protect against thrombosis, their clinical utility is limited by an elevated risk of bleeding.
OBJECTIVES: To understand how structure-function relations in the hemostatic system may be leveraged into improve risk/benefit ratios of antiplatelet therapies.
METHODS: We developed a deep learning-based framework to track the activities of large numbers of platelets in vivo, enabling a detailed comparative assessment of the effects of therapeutic interventions on the evolving structural hierarchy of the hemostatic response.
RESULTS: Unlike conventional antiplatelets targeting paracrine signaling, selective pharmaceutical inhibition of platelet mechanosensory signaling via PI3KC2α preserved the initial build-up of thrombi following vascular injury to high-flow mesenteric veins. However, as this burst of hemostatic activity subsided, inhibition of platelet mechanosensory signaling caused localized reductions of platelet intracellular calcium ion levels ([Ca2+]i) in shear-exposed peripheral thrombus subregions, inhibiting the formation of platelet clusters capable of withstanding the drag forces of the blood flow. As a consequence, platelets in these subregions detached, became elongated, and/or slid along the thrombus surface. On a macrostructural level, this selective destabilization prevented sustained physical expansion of thrombi outside the perimeters of vascular injuries while preserving platelet packing density in thrombus subregions close to vascular injuries.
CONCLUSION: Collectively, our results highlight platelet mechanosensory signaling as a significant driver of sustained platelet population growth after the initial agonist-driven phase of thrombus expansion. We show that pharmaceutical targeting of this pathway enforced the convergence of thrombus growth trajectories toward a rheologically favorable setpoint without compromising the structural integrity of thrombus subregions that are critical for hemostasis.
OBJECTIVES: To understand how structure-function relations in the hemostatic system may be leveraged into improve risk/benefit ratios of antiplatelet therapies.
METHODS: We developed a deep learning-based framework to track the activities of large numbers of platelets in vivo, enabling a detailed comparative assessment of the effects of therapeutic interventions on the evolving structural hierarchy of the hemostatic response.
RESULTS: Unlike conventional antiplatelets targeting paracrine signaling, selective pharmaceutical inhibition of platelet mechanosensory signaling via PI3KC2α preserved the initial build-up of thrombi following vascular injury to high-flow mesenteric veins. However, as this burst of hemostatic activity subsided, inhibition of platelet mechanosensory signaling caused localized reductions of platelet intracellular calcium ion levels ([Ca2+]i) in shear-exposed peripheral thrombus subregions, inhibiting the formation of platelet clusters capable of withstanding the drag forces of the blood flow. As a consequence, platelets in these subregions detached, became elongated, and/or slid along the thrombus surface. On a macrostructural level, this selective destabilization prevented sustained physical expansion of thrombi outside the perimeters of vascular injuries while preserving platelet packing density in thrombus subregions close to vascular injuries.
CONCLUSION: Collectively, our results highlight platelet mechanosensory signaling as a significant driver of sustained platelet population growth after the initial agonist-driven phase of thrombus expansion. We show that pharmaceutical targeting of this pathway enforced the convergence of thrombus growth trajectories toward a rheologically favorable setpoint without compromising the structural integrity of thrombus subregions that are critical for hemostasis.