Din Misbahud, Paul Souvik, Ullah Sana, Yang Haoyi, Xu Rong-Guang, Abidin Nurul Aisha Zainal, Sun Allan, Chen Yiyao Catherine, Gao Rui, Chowdhury Bari, Zhou Fangyuan, Rogers Stephenie, Miller Mariel, Biswas Atreyee, Hu Liang, Fan Zhichao, Zahner Christopher, Fan Jing, Chen Zi, Berman Megan, Xue Lingzhou, Ju Lining Arnold, Chen Yunfeng
Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas 77555, USA.
Department of Pathology, The University of Texas Medical Branch, Galveston, Texas 77555, USA.
bioRxiv. 2024 Aug 22:2024.06.11.598290. doi: 10.1101/2024.06.11.598290.
Arterial thrombosis, which represents a critical complication of cardiovascular diseases, is a leading cause of death and disability worldwide with no effective bioassay for clinical prediction. As a symbolic feature of arterial thrombosis, severe stenosis in the blood vessel creates a high-shear, high-gradient flow environment that effectively facilitates platelet aggregation towards vessel occlusion even with platelet amplification loops inhibited. However, no approach is currently available to comprehensively characterize the size, composition and platelet activation status of thrombi forming under this biorheological condition. Here, we present a thrombus profiling assay that monitors the multi-dimensional attributes of thrombi forming in conditions mimicking the physiological scenario of arterial thrombosis. Using this platform, we demonstrate that different receptor-ligand interactions contribute distinctively to the composition and activation status of the thrombus. Our investigation into hypertensive and older individuals reveals intensified biomechanical thrombogenesis and multi-dimensional thrombus profile abnormalities, demonstrating a direct contribution of mechanobiology to arterial thrombosis and endorsing the diagnostic potential of the assay. Furthermore, we identify the hyperactivity of GPIbα-integrin αβ mechanosensing axis as a molecular mechanism that contributes to hypertension-associated arterial thrombosis. By studying the interactions between anti-thrombotic inhibitors and hypertension, and the inter-individual variability in personal thrombus profiles, our work reveals a critical need for personalized anti-thrombotic drug selection that accommodates each patient's pathological profile.
动脉血栓形成是心血管疾病的一种关键并发症，是全球范围内死亡和残疾的主要原因，目前尚无有效的临床预测生物检测方法。作为动脉血栓形成的标志性特征，血管严重狭窄会形成高剪切力、高梯度的血流环境，即使血小板扩增环受到抑制，也能有效地促进血小板聚集，导致血管闭塞。然而，目前尚无方法能够全面表征在这种生物流变学条件下形成的血栓的大小、组成和血小板活化状态。在此，我们提出了一种血栓剖析检测方法，可监测在模拟动脉血栓形成生理场景的条件下形成的血栓的多维属性。利用该平台，我们证明不同的受体-配体相互作用对血栓的组成和活化状态有显著贡献。我们对高血压患者和老年人的研究揭示了生物力学血栓形成的加剧和多维血栓剖析异常，证明了机械生物学对动脉血栓形成的直接影响，并认可了该检测方法的诊断潜力。此外，我们确定GPIbα-整合素αβ机械传感轴的过度活跃是导致高血压相关动脉血栓形成的分子机制。通过研究抗血栓抑制剂与高血压之间的相互作用以及个体间血栓剖析的差异，我们的工作揭示了迫切需要根据每位患者的病理特征进行个性化抗血栓药物选择。
