Mechanobiological Insights into Thrombosis Using Advanced Biophysical Techniques

Abstract

Thrombosis, the formation of a blood clot within a vessel, disrupts circulation and underlies serious conditions such as stroke and myocardial infarction. This thesis employs advanced biophysical approaches, including the biomembrane force probe (BFP) and microfluidic blood perfusion assays, to investigate the cellular and molecular mechanisms underlying thrombotic events and to identify novel therapeutic strategies.

Using BFP, the role of endoplasmic reticulum protein 72 (ERp72) in activating Mac-1 (integrin αMβ2) on neutrophils is elucidated, linking redox-regulated integrin activation to vascular inflammation and thrombosis. In parallel, the thesis identifies a novel peptide-based mechanomedicine, Lp, which selectively inhibits the mechanosensitive interaction between von Willebrand factor (VWF) and glycoprotein Ibα (GPIbα). BFP and flow-based assays reveal that Lp preferentially disrupts VWF–GPIbα interactions under shear, offering a targeted antithrombotic approach that avoids the bleeding risks of conventional agents.

Furthermore, this work provides mechanistic insights into how the ChAdOx1 nCoV-19 vaccine protein (ChAdOx1) interacts directly with platelet integrin αIIbβ3 under arterial shear, promoting platelet aggregation through a GPIb-independent biophysics mechanism. Unlike known pathways such as VITT or VWF-mediated thrombosis, this shear-sensitive integrin-mediated mechanism represents a distinct, previously uncharacterized form of vaccine-related platelet activation.

The findings significantly advance the understanding of thrombosis from a mechanobiological perspective, emphasizing the need to integrate biomechanical insights into diagnostics, therapies, and preventive strategies. The research contributes profoundly to thrombosis studies and demonstrates the potential of biophysical approaches to impact clinical practices and improve patient outcomes, underscoring the transformative nature of the work in clinical and therapeutic settings.