reid gallant | University of Toronto (original) (raw)

Papers by reid gallant

Circulation, Nov 19, 2019

Case Reports in Hematology, 2022

We report a case of pure white cell aplasia (PWCA) postthymoma resection in a 74-year-old male pr... more We report a case of pure white cell aplasia (PWCA) postthymoma resection in a 74-year-old male presenting with a 2-week history of fevers, night sweats, and severe febrile neutropenia. His pure white cell aplasia was treated with intravenous immunoglobulin (IVIg), granulocyte colony-stimulating factor (G-CSF), prednisone, and cyclosporine with a mixed response. He also developed immune thrombocytopenia, which responded well to a short course of eltrombopag. With continued cyclosporine treatment, his platelet counts were stable after stopping eltrombopag. The patient's cyclosporine treatment was complicated by renal failure, resulting in cessation of cyclosporine. His PWCA and immune thrombocytopenia significantly worsened after stopping cyclosporine, and unfortunately, he died from multiorgan failure and sepsis.

Journal of Personalized Medicine, 2021

Aspirin (ASA) therapy is proven to be effective in preventing adverse cardiovascular events; howe... more Aspirin (ASA) therapy is proven to be effective in preventing adverse cardiovascular events; however, up to 30% of patients are non-sensitive to their prescribed ASA dosage. In this pilot study, we demonstrated, for the first time, how ASA non-sensitivity can be diagnosed using Plateletworks®, a point-of-care platelet function test. Patients prescribed 81 mg of ASA were recruited in a series of two successive phases—a discovery phase and a validation phase. In the discovery phase, a total of 60 patients were recruited to establish a cut-off point (COP) for ASA non-sensitivity using Plateletworks®. Each sample was simultaneously cross-referenced with a light transmission aggregometer (LTA). Our findings demonstrated that >52% maximal platelet aggregation using Plateletworks® had a sensitivity, specificity, and likelihood ratio of 80%, 70%, and 2.67, respectively, in predicting ASA non-sensitivity. This COP was validated in a secondary cohort of 40 patients prescribed 81 mg of ASA ...

fibrinogen-independent platelet aggregation and fibronectin-mediated protein wave of hemostasis

Research and Practice in Thrombosis and Haemostasis, 2021

Atherosclerosis Supplements, 2018

Materials Today Communications, 2021

Abstract Novel tantalum-containing meso-porous bioactive glass (Ta-MBG) powders, developed via th... more Abstract Novel tantalum-containing meso-porous bioactive glass (Ta-MBG) powders, developed via the sol-gel process, have demonstrable hemostatic properties. However, powders can create dust in the operating environment and may be washed away if profuse bleeding occurs. Powders may not adequately compress wound tissue, and in certain circumstances, a thick callus can form, which is challenging to remove. Fibrous forms of MBGs offer advantages over powders for hemostatic applications, yet they appear comparatively under-researched. In this study, Ta-MBG compositions were successfully designed and fabricated into fibrous mats using electrospinning. State-of-the-art imaging techniques were used to investigate the mats. The individual fibres were ∼300 nm in diameter and contained porosity (1−50 nm). There was also micrometre-sized -porosity (1−2 μm) – this constituted the pore space between the matted fibres, unlike the Ta-MBG powders, which comprised of uni-modal channels (pore size: 4 nm) within the particles themselves. Hierarchical micro-nano porosity is known to enhance the activation of coagulation proteins. The surface area and pore volume of the fibrous mats were a maximum of 61 m2 g−1, 0.23 cm3 g−1 compared to 374 m2 g−1, 0.27 cm3 g−1 for powders. The surface area is an important property facilitating blood fluid sorption and enhancing clotting. The measured zeta potential of the fibres was more highly-negative than that of powder; a highly-negative zeta potential can provide a stable matrix for hemostasis. Overall, the texture of the fibrous mats, the easily-accessible micron-sized pores, the presence of tantalum, the hierarchical porosity, the favourable zeta potential, and the naturally biomimetic architecture are important attributes which make the fibrous mats developed here an attractive alternative for hemostatic applications.

Medicina, 2020

Background and Objectives: Aspirin (acetylsalicylic acid—ASA) is a first-line antiplatelet therap... more Background and Objectives: Aspirin (acetylsalicylic acid—ASA) is a first-line antiplatelet therapy provided to patients with coronary artery disease (CAD). However, it has been demonstrated that 20–30% of these patients are non-sensitive to their ASA therapy. ASA non-sensitivity is a phenomenon where low-dose ASA (81–325 mg) does not completely inhibit arachidonic-acid-induced platelet aggregation, putting patients at risk of adverse cardio-thrombotic events. Ticagrelor is a P2Y12 receptor inhibitor and alternative antiplatelet that has been approved to reduce the risk of stroke, myocardial infarction, and overall cardiovascular-related death. In this study, we aimed to identify ASA non-sensitive patients and evaluate if they would be sensitive to ticagrelor. Materials and Methods: For this pilot study, thirty-eight patients with CAD taking 81 mg ASA were recruited. Blood samples were collected from each patient and platelet rich plasma (PRP) from each sample was isolated. Light-tra...

Diagnostics, 2020

Acetylsalicylic acid (ASA), also known as aspirin, appears to be ineffective in inhibiting platel... more Acetylsalicylic acid (ASA), also known as aspirin, appears to be ineffective in inhibiting platelet aggregation in 20–30% of patients. Light transmission aggregometry (LTA) is a gold standard platelet function assay. In this pilot study, we used LTA to personalize ASA therapy ex vivo in atherosclerotic patients. Patients were recruited who were on 81 mg ASA, presenting to ambulatory clinics at St. Michael’s Hospital (n = 64), with evidence of atherosclerotic disease defined as clinical symptoms and diagnostic findings indicative of symptomatic peripheral arterial disease (PAD), with an ankle brachial index (ABI) of <0.9 (n = 52) or had diagnostic features of asymptomatic carotid arterial stenosis (CAS), with >50% stenosis of internal carotid artery on duplex ultrasound (n = 12). ASA compliance was assessed via multisegmented injection-capillary electrophoresis-mass spectrometry based on measuring the predominant urinary ASA metabolite, salicyluric acid. LTA with arachidonic ac...

Journal of Biomaterials Applications, 2020

This study evaluates the hemostatic properties of tantalum-containing mesoporous bioactive glasse... more This study evaluates the hemostatic properties of tantalum-containing mesoporous bioactive glasses (Ta-MBGs) through a suite of in-vitro methods: hemolysis percentage, zeta potential, blood coagulation assays (Activated Partial Thromboplastin Time – APTT and Prothrombin Time - PT) and cytotoxicity tests. Five compositions of Ta-MBG, with x mol% Ta2O5 added to the glass series (80- x)SiO2-15CaO-5P2O5- xTa2O5 where x=0 (0Ta), x=0.5 (0.5Ta), x=1 (1Ta), x=5 (5Ta), and x=10 (10Ta) mol%, were synthesised. The hemostatic potential of all the Ta-MBGs was confirmed by their negative zeta potential (–23 to –31 mV), which enhances the intrinsic pathway of blood coagulation. The hemolysis percentages of all Ta-MBGs except 10Ta showed statistically significant reductions compared to the same experiments carried out both in the absence of a sample (‘no treatment’ group) and in the presence of 10Ta. These observations validate the consideration of Ta-MBGs as hemostatic agents as they do not cause ...

Blood, 2019

Introduction: Fibrinogen (Fg) and von Willebrand factor (VWF) have been considered essential for ... more Introduction: Fibrinogen (Fg) and von Willebrand factor (VWF) have been considered essential for platelet adhesion and aggregation. However, platelet aggregation still occurs in mice lacking Fg and/or VWF or plasma fibronectin but not β3 integrin (JCI, 2000; JTH, 2006; Blood, 2009; JCI, 2014). This suggests that other non-classical αIIbβ3 integrin ligand(s) mediate platelet aggregation. α-dystroglycan (α-DG) is a component of the dystrophin-glycoprotein complex that binds extracellular matrix proteins containing laminin-G like domains via unique heteropolysaccharide [-GlcA-β1,3-Xyl-α1,3-]n called matriglycan, which can be targeted specifically with monoclonal antibody IIH6C4. Although α-DG was identified in a recent proteomic study of platelet releasate, its membrane expression and function in platelets have never been investigated. Methods and Results: Using the anti-α-DG monoclonal antibody IIH6C4, we found expression of α-DG in mouse and human resting platelets in Western blots. ...

Food & Function, 2019

Coenzyme Q10 (CoQ10) exists in a wide variety of foods and has promising cardiovascular benefits.... more Coenzyme Q10 (CoQ10) exists in a wide variety of foods and has promising cardiovascular benefits. However, its effects on platelets and integrin αIIbβ3 signaling during atherosclerosis have not been previously...

Blood, 2018

Integrin αIIbβ3 plays key roles in thrombosis and hemostasis primarily through mediating platelet... more Integrin αIIbβ3 plays key roles in thrombosis and hemostasis primarily through mediating platelet adhesion and aggregation. We recently reported that the active site of thiol-isomerase enzymes, CXXC motif, is expressed twice within the plexin-semaphorin-integrin (PSI) domain across all integrins and species, and the PSI domain of β3 integrin possesses endogenous thiol-isomerase activity, which may be a novel target for anti-thrombotic therapy (Blood, 2017). We developed four mouse anti-mouse β3 integrin PSI domain monoclonal antibodies (mAbs). These mAbs cross-react with β3 PSI domains of human, mouse, pig, rat, and rabbit tested but not other regions of β3 integrin, other integrins or other thiol-isomerase enzymes. They inhibit the thiol-isomerase activity of β3 PSI domain, decrease platelet adhesion/aggregation and thrombosis without increasing bleeding. Interestingly, the inhibitory effect of these mAbs on thrombosis in vivo (no anti-coagulant) was 10-20 times greater than their ...

Molecular Nutrition & Food Research, 2019

SCOPE Platelet integrin αIIbβ3 is the key mediator of atherothrombosis. Supplementation of coenzy... more SCOPE Platelet integrin αIIbβ3 is the key mediator of atherothrombosis. Supplementation of coenzyme Q10 (CoQ10), a fat-soluble molecule that exists in various foods, exerts protective cardiovascular effects. This study aims to investigate whether and how CoQ10 acts on αIIbβ3 signaling and thrombosis, the major cause of cardiovascular diseases. METHODS AND RESULTS Using a series of platelet functional assays in vitro, we demonstrated that CoQ10 reduced human platelet aggregation, granule secretion, platelet spreading, and clot retraction. We further demonstrated that CoQ10 inhibited platelet integrin αIIbβ3 outside-in signaling. These inhibitory effects were mainly mediated by up-regulating cAMP/PKA pathway, where CoQ10 stimulated the A2A adenosine receptor and decreased phosphodiesterase 3A phosphorylation. Moreover, CoQ10 attenuated murine thrombus growth and vessel occlusion in a ferric chloride (FeCl3 )-induced thrombosis model in vivo. Importantly, our randomized, double-blind, placebo-controlled clinical trial in dyslipidemic patients demonstrated that 24-weeks of CoQ10 supplementation increased platelet CoQ10 concentrations, enhanced the cAMP/PKA pathway, and attenuated αIIbβ3 outside-in signaling, leading to decreased platelet aggregation and granule release. CONCLUSION Through up-regulating the platelet cAMP/PKA pathway, and attenuating αIIbβ3 signaling and thrombus growth, CoQ10 supplementation may play an important protective role in patients with risks of cardiovascular diseases. This article is protected by copyright. All rights reserved.

Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2019

Synthesis and characterization of the first mesoporous bioactive glasses (MBGs) containing tantal... more Synthesis and characterization of the first mesoporous bioactive glasses (MBGs) containing tantalum are reported here, along with their potential application as hemostats. Silica MBGs were synthesized using with the molar composition of (80-x)% Si, 15% Ca, 5% P, and x% Ta. It was found that incorporation of >1 mol % Ta into the MBGs changes their physical and chemical properties. Increasing Ta content from 0 to 10 mol % causes a decrease in the surface area and pore volume of ~20 and ~35%, respectively. This is due to the increase in nonbridging oxygens and mismatch of thermal expansion coefficient which created discontinuities in the ordered channel structure. However, the effect is not significant on the amount of ions (Si, Ca, P, and Ta) released, from the sample into deionized water, for short durations (<60 min). In a mouse tail-cut model, a significant decrease in bleeding time (≥50% of average bleeding time) was found for Ta-MBGs compared to having no treatment, Arista, and MBG without Ta. Further studies are proposed to determine the mechanism of Ta involvement with the hemostatic process. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res B Part B, 2019.

Nature communications, Sep 6, 2018

Platelet αIIbβ3 integrin and its ligands are essential for thrombosis and hemostasis, and play ke... more Platelet αIIbβ3 integrin and its ligands are essential for thrombosis and hemostasis, and play key roles in myocardial infarction and stroke. Here we show that apolipoprotein A-IV (apoA-IV) can be isolated from human blood plasma using platelet β3 integrin-coated beads. Binding of apoA-IV to platelets requires activation of αIIbβ3 integrin, and the direct apoA-IV-αIIbβ3 interaction can be detected using a single-molecule Biomembrane Force Probe. We identify that aspartic acids 5 and 13 at the N-terminus of apoA-IV are required for binding to αIIbβ3 integrin, which is additionally modulated by apoA-IV C-terminus via intra-molecular interactions. ApoA-IV inhibits platelet aggregation and postprandial platelet hyperactivity. Human apoA-IV plasma levels show a circadian rhythm that negatively correlates with platelet aggregation and cardiovascular events. Thus, we identify apoA-IV as a novel ligand of αIIbβ3 integrin and an endogenous inhibitor of thrombosis, establishing a link between...

Thrombosis and haemostasis, Jan 4, 2018

Apoptotic-like phase is an essential step in thrombopoiesis from megakaryocytes. Anthocyanins are... more Apoptotic-like phase is an essential step in thrombopoiesis from megakaryocytes. Anthocyanins are natural flavonoid pigments that possess a wide range of biological activities, including protection against cardiovascular diseases and induction of tumour cell apoptosis. We investigated the effects and underlying mechanisms of cyanidin-3-o-β-glucoside (Cy-3-g, the major bioactive compound in anthocyanins) on the apoptosis of human primary megakaryocytes and Meg-01 cell line in vitro We found that Cy-3-g dose-dependently increased the dissipation of the mitochondrial membrane potential, caspase-9 and caspase-3 activity in megakaryocytes from patients with newly diagnosed acute myeloid leukaemia but not in those from healthy volunteers. In Meg-01 cells, Cy-3-g regulated the distribution of Bak, Bax and Bcl-xL proteins in the mitochondria and cytosol, subsequently increasing cytochrome release and stimulating caspase-9 and caspase-3 activation and phosphatidylserine exposure. However, Cy...

Thrombosis research, 2016

Platelets are small versatile blood cells generated from megakaryocytes in the bone marrow and cl... more Platelets are small versatile blood cells generated from megakaryocytes in the bone marrow and cleared in the reticuloendothelial system. Platelet accumulation (adhesion and aggregation) at the site of injury has been considered the first wave of hemostasis. Interestingly, although fibrinogen and von Willebrand factor (VWF) are documented to be essential for hemostasis, fibrinogen/VWF-independent platelet aggregation and thrombosis still occur. Following platelet activation and phosphatidylserine expression, platelets also contribute to cell-based thrombin generation and blood coagulation - the second wave of hemostasis. Most recently, deposition of fibronectin and other plasma proteins onto the injured vessel wall was identified as a "protein wave" of hemostasis, in which platelets may release their granule proteins and thus also contribute to this very early hemostatic event. Due to the central roles of platelets in hemostasis, excessive platelet clearance may lead to bl...

Current opinion in hematology, Jan 11, 2016

Exposure of subendothelial extracellular matrix (ECM) proteins to the circulation is the key even... more Exposure of subendothelial extracellular matrix (ECM) proteins to the circulation is the key event that initiates platelet accumulation and clot formation after vessel injury. Soluble ECM proteins are also essential for support and regulation of these events. This review discusses the current understanding of ECM proteins in thrombosis and hemostasis. Fibrinogen and von Willebrand factor (VWF) are considered essential for thrombosis and hemostasis. Interestingly, αIIbβ3 integrin-dependent thrombus formation persists in the absence of fibrinogen and VWF, suggesting that other αIIbβ3 ligand (s), likely ECM proteins, can still mediate thrombosis. Fibronectin increases in platelets of fibrinogen-deficient humans and mice. This ECM protein can rapidly deposit onto the injured vessel wall prior to platelet accumulation. By switching from the soluble to insoluble form, plasma fibronectin supports hemostasis and inhibits excessive thrombosis. Fibrin, fibronectin, VWF, vitronectin, neutrophi...

Virologica Sinica, Jan 2, 2016

Bats have been implicated as important reservoir hosts of alpha- and betacoronaviruses. In this s... more Bats have been implicated as important reservoir hosts of alpha- and betacoronaviruses. In this study, diverse coronaviruses (CoVs) were detected in 50 of 951 (positive rate 5.3%) intestinal specimens of eight bat species collected in four provinces and the Tibet Autonomous Region of China by pan-coronavirus RT-PCR screening. Based on 400-nt RNA-dependent RNA polymerase (RdRP) sequence analysis, eight belonged to genus Alphacoronavirus and 42 to Betacoronavirus. Among the 50 positive specimens, thirteen gave rise to CoV full-length RdRP gene amplification for further sequence comparison, of which three divergent sequences (two from a unreported province) were subjected to full genome sequencing. Two complete genomes of betacoronaviruses (JTMC15 and JPDB144) and one nearly-complete genome of alphacoronavirus (JTAC2) were sequenced and their genomic organization predicted. The present study has identified additional numbers of genetically diverse bat-borne coronaviruses with a wide di...