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Human Myeloperoxidase Enhances Thrombin Induced Phosphatidylserine Exposure in Human Platelets through Tyrosine Kinase/Calcium/Potassium Channels-mediated Pathway

1Belarusian State University, Minsk, Belarus, 2Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russian Federation, 3National Medical Research Centre of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev, Moscow, Russian Federation, 4Institute of Experimental Medicine, St. Petersburg, Russian Federation, 5Federal Research and Clinical Center of Physical‐Chemical Medicine of Federal Medical Biological Agency, Moscow, Russian Federation, 6Lomonosov Moscow State University, Moscow, Russian Federation

Abstract Number: PB0765

Meeting: ISTH 2021 Congress

Theme: Role of Hemostatic System in Cancer, Inflammation and Immunity » Platelets and Inflammation

Background: There is a close relationship between inflammation and coagulation in multiple diseases. Revealing the mechanisms of molecular and cellular connections between these systems is necessary for the development of new therapeutic strategies. One of the local mediators of inflammation is myeloperoxidase (MPO), heme-peroxidase contained mainly in neutrophils. MPO generates cytotoxic oxidants and modulates cellular signal cascades by binding to cellular surfaces. MPO was shown to potentiate platelet aggregation and Ca2+-response, so it may contribute to pathological thrombosis.

Aims: This study was designed to investigate MPO effect on platelet procoagulant activity and to disclose new mechanisms of MPO action.

Methods: Platelets were isolated from citrated blood from healthy volunteers. Single channel ionic currents were registered using patch-clamp technique in cell-attach configuration. Voltage-gated potassium channels were inactivated by patch hyperpolarization. Platelet calcium responses were measured using TIRF microscope by observing CalBryte 590-AM fluorescence. Phosphatidylserine (PS) exposure was measured by flow cytometry using annexin V-Alexa Fluor 647.

Results: MPO (100 nM – 400 nM), incubated with platelets for 15 min, enhanced thrombin-induced PS exposure on platelet surface in a dose-dependent manner without any influence on the number of PS-positive platelets induced by ADP or collagen-related peptide. This effect of MPO was associated with increased frequency (2-fold) and duration of calcium oscillations and with opening of potassium channels (~ 20 pS). Charybdotoxin and genistein canceled the observed effects, revealing the role of tyrosine kinases and Сa2+-induced potassium channels. Although the receptor for MPO on platelet surface is unknown, obtained results indicate that MPO is involved in Сa2+-signaling through activation of tyrosine kinases, probably through ITAMs.

Conclusions: This study reveals new mechanisms of MPO modulating effect on platelet function at sites of inflammation, leading to procoagulant platelet formation. Obtained results might be of potential pharmacological interest in inflammatory and thrombotic disorders.
Work was partly supported by grant B20R-215.

To cite this abstract in AMA style:

A Kokhan , F Balabin , I Gorudko , A Sokolov , A Sveshnikova , E Shamova . Human Myeloperoxidase Enhances Thrombin Induced Phosphatidylserine Exposure in Human Platelets through Tyrosine Kinase/Calcium/Potassium Channels-mediated Pathway [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/human-myeloperoxidase-enhances-thrombin-induced-phosphatidylserine-exposure-in-human-platelets-through-tyrosine-kinase-calcium-potassium-channels-mediated-pathway/. Accessed September 24, 2023.

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