Platelets and their response to acute changes in blood flow

In world-first research to combine computational models of blood flow with single platelet signalling studies, a Monash collaborative study has found that platelets are able to sense acute changes in blood flow found within diseased vessels or blood-contacting devices through a unique mechano-sensor.

The team includes Australian Centre for Blood Diseases (ACBD) researchers, in collaboration with Alfred Health, University of Melbourne (Engineering & Medicine) and RMIT University (Engineering).

Supraphysiological hemodynamics (blood flow) are a recognized driver of platelet activation and thrombosis at high-grade stenosis and in blood contacting circulatory support devices. However, the way platelets 'sense' turbulence directly in free flow has been poorly understood.

Unlike previous models of platelet activation, this work highlights the ability of platelets to very rapidly respond to changes in blood flow without interacting with blood vessel surfaces.

Senior author, Dr Warwick Nesbitt said, "By combining expertise in engineering and platelet biology, we have identified a key signalling enzyme that controls this mechanosensory mechanism. Further, we have demonstrated that a novel drug is able to target and block this mechano-sensory process.

"We found that platelets are adapted to rapidly respond to extensional strain (stretching forces) in disturbed blood flow due to blood vessel narrowing or within artificial mechanical circulatory support (MCS) systems, where clotting, unfortunately, is common."

In the context of heart attack and MCS, this research, the first to define an adhesion independent mechanosensory mechanism in blood platelets, proposes that 'extensional strain sensing' acts as the very first trigger that activates platelets and drives life threatening thrombosis.

Dr Nesbitt said, “The identification of this mechanosensory mechanism may pave the way for the development of improved drug therapies for the treatment of heart attack and the management of patients on mechanical circulatory support devices.”

The findings of this paper, Dr Nesbitt said, can also be extended to understanding blood clotting complications associated with mechanical circulatory support systems such as coronary bypass and ECMO.

Future work will aim at further understanding this process and focus on further development of potential drug compounds that can ultimately be used to manage clinical thrombosis (clotting) in both heart attack and mechanical circulatory support.

Dr Nesbitt is a 2022 MedTech Actuator Menzies Fellow.

Reference:

Zainal Abidin NA, Poon EKW, Szydzik C, Timofeeva M, Akbaridoust F, Brazilek RJ, Tovar Lopez FJ, Ma X, Lav C, Marusic I, Thompson PE, Mitchell A, Ooi ASH, Hamilton JR, Nesbitt WS. An extensional strain sensing mechanosome drives adhesion-independent platelet activation at supraphysiological hemodynamic gradients. BMC Biol. 2022 Mar 24;20(1):73. doi: 10.1186/s12915-022-01274-7. PMID: 35331224; PMCID: PMC8944166.