Platelet Dysfunction During Mechanical Circulatory Support
| Autor: | Marvin J. Slepian, Samuel Miller-Gutierrez, Jawaad Sheriff, Yana Roka-Moiia, Joseph E. Italiano, Daniel E. Palomares, Danny Bluestein |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Blood Platelets
Male 0301 basic medicine medicine.medical_specialty Platelet Aggregation Down-Regulation Platelet Glycoprotein GPIIb-IIIa Complex 030204 cardiovascular system & hematology Mechanotransduction Cellular Article 03 medical and health sciences 0302 clinical medicine Platelet degranulation Downregulation and upregulation Cell-Derived Microparticles Internal medicine Coagulopathy medicine Humans Platelet Platelet activation Receptor Chemistry medicine.disease Thrombosis Adenosine Diphosphate P-Selectin 030104 developmental biology Endocrinology Platelet Glycoprotein GPIb-IX Complex Circulatory system Female Stress Mechanical Cardiology and Cardiovascular Medicine Oligopeptides |
| Zdroj: | Arterioscler Thromb Vasc Biol |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Objective: Mechanical circulatory support has emerged as lifesaving therapy for patients with advanced heart failure. However, mechanical circulatory support remains limited by a paradoxical coagulopathy accompanied by both thrombosis and bleeding. While mechanisms of mechanical circulatory support thrombosis are increasingly defined, mechanical circulatory support-related bleeding, as related to shear-mediated alteration of platelet function, remains poorly understood. We tested the hypothesis that platelet exposure to elevated shear stress, while a defined prothrombotic activator of platelets, coordinately induces downregulation of key platelet adhesion receptors GPIb-IX-V, α IIb β 3 , and P-selectin, thus decreasing platelet functional responsiveness to physiological stimuli. Approach and Results: Human gel-filtered platelets were exposed to continuous or pulsatile shear stress in vitro. Surface expression of platelet receptors and platelet-derived microparticle generation were quantified by flow cytometry. Shedding of receptor soluble forms were assessed via ELISA, and platelet aggregation was measured by optical aggregometry. We demonstrate that platelet exposure to elevated shear stress led to a downregulation of GPIb and α IIb β 3 receptors on platelets with a progressive increase in the generation of platelet-derived microparticles expressing elevated levels of α IIb β 3 and GPIb on their surface. No shear-mediated shedding of GPIb and β 3 subunit soluble fragments was detected. Soluble P-selectin was extensively shed from platelets, while surface expression of P-selectin on platelets was not significantly altered by shear. Shear-mediated downregulation of GPIb and α IIb β 3 on platelets was associated with an evident decrease of platelet aggregatory response induced by ADP and TRAP 6 (thrombin receptor activating peptide 6). Conclusions: Our data clearly indicate that accumulation of shear stress, consistent with supraphysiologic conditions characterizing device-supported circulation (1) induces adequate platelet degranulation, yet (2) causes downregulation of primary platelet adhesion receptors via ejection of receptor-enriched platelet-derived microparticles, thus mechanistically limiting platelet activation and the aggregatory response. |
| Databáze: | OpenAIRE |
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