Lab Spotlight – Personalized Platelet Therapy Laboratory

The Laboratory

The personalized platelet therapy laboratory is led by Dr. Marie Lordkipanidzé, Canada Research Chair in Platelets as biomarkers and vectors.  The lab is active since 2013, and is based in the research center of the Montreal Heart Institute affiliated with the Faculté de pharmacie of the Université de Montréal, in Montréal, Canada. Ongoing projects cover the R&D spectrum, from preclinical studies on cells and animals to clinical trials. The work is supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Canadian Foundation for Innovation, and the Montreal Heart Institute Foundation.

There are two main programmes within the lab. First, our focus on understanding the biological function of neurotrophins and their receptors in platelets, megakaryocytes, and haemostasis, and the use of platelet neurotrophins as biomarkers in neurological disorders, attempts to bridge the gap between cardiovascular and neurodegenerative disorders. In this sphere, projects explore in in vitro studies the mechanisms of neurotrophins in cardiovascular diseases, and explore clinical consequences in larger epidemiological studies.  Second, personalization of antiplatelet therapy, based on the understanding of platelet mechanisms making each individual unique, makes the best use of platelet function testing to tailor antiplatelet therapy to individual needs. In this sphere, the lab leads projects on individualized aspirin therapy in type 2 diabetes, investigation into platelet function alterations during heat waves, and platelet function testing in the context of bleeding and thrombosis in cardiovascular disease.

To carry out these projects, the lab is equipped with molecular and cellular biology equipment, including a flow cytometer and a cell culture room to harvest megakaryocytes and other cells. Various platelet function devices are used daily in the lab, including aggregometers, Multiplate, T-TAS, ROTEM, and VerifyNow devices.

The lab members

A dynamic and hard-working group of platelet researchers form the heart of the lab, and include research associate Mélanie Welman, post-doctoral fellow Georges Jourdi, PhD candidate Imane Boukhatem and PhD student Samuel Fleury. The lab also welcomes many undergraduate and graduate students for internship opportunities, from Canada and abroad.

The projects

1) Neurotrophins in platelet and megakaryocyte biology (led by Imane Boukhatem and Samuel Fleury)

The brain-derived neurotrophic factor (BDNF) protein has been mainly studied in the brain, where it promotes

neuronal growth and survival through its binding to the tropomyosin receptor kinase B (TrkB) and the 75 kDa pan-neurotrophic receptor (p75^NTR). Interestingly, BDNF is also found within platelets, where its concentrations can reach up to 1000-fold those found in neurons. Being secreted from alpha granules upon activation,[1] BDNF in the cardiovascular system contributes to endothelial regeneration upon vascular injury. Moreover, our lab has recently reported that BDNF has an autocrine/paracrine role as an inducer of platelet activation and secretion in vitro, and that this effect is mediated through a truncated form of its main receptor TrkB.[2] In addition, neurotrophin receptor p75^NTR, which binds all neurotrophins and their precursor proneurotrophins, was also reported in platelets by our laboratory,[3] suggesting that other neurotrophins could also affect platelet function. The work to understand if/how p75^NTR plays a role in platelet and megakaryocyte biology is ongoing.

2) BDNF: a novel actor in hemostasis and thrombosis (led by Georges Jourdi)

The exact pathophysiological role of BDNF in hemostasis and thrombosis remains to be elucidated. BDNF was shown to markedly modify the fibrin clot profile in a purified system thus enhancing clot lysis. The effects of BDNF on platelet function and fibrin clot properties suggest new mechanisms by which BDNF might be implicated in cardiovascular physiopathology. We hence seek to extensively study the role of BDNF in hemostasis and thrombosis by carrying out a project articulated around three axes: (a) characterization of the mechanism of regulation of BDNF bioavailability in circulation; (b) evaluation of the contribution of BDNF to hemostasis and thrombosis in appropriate in vivo animal models; and (c) investigation of whether natural genetic variants of BDNF or its receptors affect platelet and hemostatic functions in subjects among the 17,000 genotyped participants of the Montreal Heart Institute biobank. Our findings will be of pathophysiological interest and will inform on possible new therapeutic interventions targeting BDNF signaling and/or circulating level in cardiovascular patients.

3) Assessing Pharmacokinetics and Pharmacodynamics of daily Enteric-coated Aspirin in patients with StablE Diabetes: APPEASED study Phase 1 (led by Mélanie Welman)

Diabetes is a major risk factor for atherosclerotic cardiovascular diseases and is responsible for more than 1.3 million yearly deaths globally, a figure that is continuously increasing. While aspirin is the cornerstone of secondary prevention in patients with established cardiovascular disease, its role in primary prevention in high-risk patients remains uncertain, as reflected by low-grade, discordant guideline recommendations. Phase III primary prevention clinical trials have studied enteric-coated (EC) formulations administered once daily, strategies that may not be well adapted to the pharmacokinetics of the drug, especially in overweight patients, a common characteristic among patients suffering from type 2 diabetes.[4] Therefore, the formulations and dosing schedules studied in previous trials defining current routine clinical practice may not reflect the full therapeutic potential of the drug in patients with diabetes, which can potentially have important clinical implications from a public health perspective. In this study, we seek to characterize the prevalence of incomplete platelet inhibition after exposure to EC aspirin at a dose of 81 mg once daily in patients with type 2 diabetes, in the hope of identifying mechanisms of suboptimal platelet inhibition, and testing alternative therapeutic strategies in these patients.

Interested in joining us for an internship or considering graduate or postdoctoral studies? Reach out to marie.lordkipanidze@umontreal.ca, and follow us on twitter: @Mtl_PlateletLab

References

[1] Le Blanc J, Fleury S, Boukhatem I, Bélanger JC, Welman M, Lordkipanidzé M. Platelets selectively regulate the release of BDNF, but not that of its precursor protein, proBDNF. Front Immunol 2020; 11: 575607; doi: 10.3389/fimmu.2020.575607

[2] Boukhatem I, Fleury S, Welman M, Le Blanc J, Thys C, Freson K, Best MG, Würdinger T, Allen BG, Lordkipanidzé M. The Brain-Derived Neurotrophic Factor prompts platelet aggregation and secretion. Blood Adv 2021; 5: 3568–3580. doi: 10.1182/bloodadvances.2020004098

[3] Fleury S*, Boukhatem I*, Le Blanc J, Welman M, Lordkipanidzé M. Tissue-specificity of antibodies raised against TrkB and p75^NTR receptors; implications for platelets as models of neurodegenerative diseases. Front Immunol 2021; 12: 606861; doi: 10.3389/fimmu.2021.606861

[4] Del Bianco-Rondeau M, Robert-Halabi M, Bloom S, Rhabasa-Lhoret R, Tardif JC, Lordkipanidzé M, Marquis-Gravel G. Aspirin for Primary Cardiovascular Prevention in Patients with Diabetes: Uncertainties and Opportunities. Thromb Haemost 2022; in press