Plasminogen activator inhibitor type 1 in platelets induces thrombogenicity by increasing thrombolysis resistance under shear stress in an in-vitro flow chamber model.

Autor: Hosokawa K; Research Institute, Fujimori Kogyo Co., Ltd., 1-10-1, Sachiura, Kanazawa-ku, Yokohama, Kanagawa 236-0003, Japan., Ohnishi-Wada T; Research Institute, Fujimori Kogyo Co., Ltd., 1-10-1, Sachiura, Kanazawa-ku, Yokohama, Kanagawa 236-0003, Japan., Sameshima-Kaneko H; Research Institute, Fujimori Kogyo Co., Ltd., 1-10-1, Sachiura, Kanazawa-ku, Yokohama, Kanagawa 236-0003, Japan., Nagasato T; Research Institute, Fujimori Kogyo Co., Ltd., 1-10-1, Sachiura, Kanazawa-ku, Yokohama, Kanagawa 236-0003, Japan; Department of System Biology in Thromboregulation, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan., Miura N; Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24, Koorimoto, Kagoshima 890-0065, Japan., Kikuchi K; Department of Physiology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan; Department of Neurosurgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan., Koide T; Department of System Biology in Thromboregulation, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan., Maruyama I; Department of System Biology in Thromboregulation, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan., Urano T; Department of Medical Physiology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan. Electronic address: uranot@hama-med.ac.jp.
Jazyk: angličtina
Zdroj: Thrombosis research [Thromb Res] 2016 Oct; Vol. 146, pp. 69-75. Date of Electronic Publication: 2016 Sep 04.
DOI: 10.1016/j.thromres.2016.09.002
Abstrakt: Introduction: Despite the proven benefits of thrombolytic therapy with tissue plasminogen activator (t-PA) for peripheral thromboembolism, perfusion failure frequently occurs, particularly in arterial circulation. We evaluated how the modification of fibrinolytic activity affects thrombus formation under flow and static conditions.
Materials and Methods: t-PA-treated human whole-blood samples (n=6) were perfused over a microchip coated with collagen and tissue thromboplastin at different shear rates, and thrombus formation was quantified by measuring flow pressure changes. For comparison, rotational thromboelastometry (ROTEM) was used to evaluate fibrinolytic activity under static conditions.
Results: At a shear rate of 240s -1 , t-PA (200-800IU/ml) concentration-dependently delayed capillary occlusion, whereas at 600s -1 , capillary occlusion was significantly faster and t-PA had limited effects, even at a supra-pharmacological concentration (800IU/ml). In contrast, 200IU/ml t-PA efficiently prevented clot formation in the ROTEM assay. The combined treatment of blood with a specific PAI-1 inhibitor (PAI-039) moderately enhanced the efficacy of t-PA, but only under flow conditions. In addition, 1:1-diluted blood samples of PAI-1-deficient (-/-) mice showed a significant delay of capillary occlusion at 240s -1 , compared with those from wild-type mice (1.55 fold; P<0.001). This delayed occlusion was reproduced in samples containing platelets from PAI-1-/- and plasma from wild type, but was not observed by the opposite combination of blood components.
Conclusions: The present results suggest that the anti-thrombotic efficacy of t-PA is sensitive to arterial shear flow, and that PAI-1 secreted from activated platelets plays an essential role in thrombolytic resistance.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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