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Hamostaseologie 2018; 38(04): 203-210
DOI: 10.1055/s-0038-1675144
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Platelet Signaling in Primary Haemostasis and Arterial Thrombus Formation[*]: Part 1

Rüdiger E. Scharf
1   Division of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, University Blood Center, and Haemophilia Comprehensive Care Center, Institute of Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University Medical Center, Düsseldorf, Germany
2   Biological Medical Research Center, Heinrich Heine University, Düsseldorf, Germany
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Further Information

Publication History

13 April 2018

18 September 2018

Publication Date:
23 October 2018 (online)

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Abstract

Platelets react immediately in response to traumatic vascular injury by adhesion, activation, aggregation and subsequent haemostatic plug formation. While this reaction pattern is essential for haemostasis, platelet responses can also cause occlusive thrombi in diseased arteries, leading to myocardial infarction or stroke. Initially, flowing platelets are captured from the circulation to vascular lesions. This step is mediated by glycoprotein (GP) Ib-IX-V interacting with immobilized von Willebrand factor (VWF) on exposed subendothelial components. Tethered platelets can now bind to collagen through GPVI and integrin α2β1. Outside-in signals from the adhesion receptors act synergistically with inside-out signals from soluble stimuli and induce platelet activation. These mediators operate through G protein–coupled receptors and reinforce adhesion and activation. Typical manifestations of activated platelets include calcium mobilization, procoagulant activity, cytoskeletal reorganization, granule secretion and aggregation. This requires activation of integrin αIIbβ3 with shifting into a high-affinity state and is indispensable to bind soluble fibrinogen, VWF and fibronectin. The multiple interactions and the impact of thrombin result in firm adhesion and recruitment of circulating platelets into growing aggregates. A fibrin meshwork supports stabilization of haemostatic thrombi and prevents detachment by the flowing blood. This two-part review provides an overview of platelet activation and signal transduction mechanisms with a focus on αIIbβ3-mediated outside-in signaling in integrin variants. In the first part, a three-stage model of platelet recruitment and activation in vivo is presented. Along with that, platelet responses upon exposure to thrombogenic surfaces followed by platelet-to-platelet interactions and formation of haemostatic thrombi are discussed. Moreover, several determinants involved in pathological thrombosis will be reviewed.

Zusammenfassung

Bei traumatischer Gefäßwandverletzung reagieren Plättchen unverzüglich mit Adhäsion, Aktivierung, Aggregation und nachfolgender Bildung eines hämostatischen Pfropfs. Dieses Reaktionsmuster ist essentiell für die Hämostase, kann aber in krankhaft veränderten Gefäßen okkludierende Thromben hervorrufen, die einen Herzinfarkt oder Schlaganfall auslösen. Initial werden zirkulierende Plättchen im Bereich von Gefäßwandläsionen eingefangen. Dieser Schritt wird durch Wechselwirkung von Glykoprotein (GP) Ib-IX-V mit immobilisiertem von-Willebrand-Faktor (VWF) auf freigelegten Subendothelkomponenten vermittelt. Die 'angegurteten' Plättchen binden nun über GPVI und Integrin α2β1 an Kollagen. Die von Adhäsionsrezeptoren ausgelösten 'Outside-in'-Signale wirken in Synergie mit 'Inside-out'-Signalen diffusibler Agonisten und aktivieren die Plättchen. Diese Mediatoren wirken über G-Protein-gekoppelte Rezeptoren und verstärken Adhäsion und Aktivierung. Typische Funktionsäußerungen aktivierter Plättchen sind Kalziummobilisierung, prokoagulatorische Aktivität, Umorganisation des Zytoskeletts, Granulasekretion und Aggregation. Letzteres setzt Aktivierung von Integrin αIIbβ3 mit Übergang in einen hochaffinen Zustand voraus und ist unabdingbar für die Bindung löslichen Fibrinogens, VWF und Fibronektins. Die multiplen Interaktionen führen unter Einfluss von Thrombin zur Verfestigung der Adhäsion und durch Einbeziehung zirkulierender Plättchen zur Größenzunahme des Aggregats. Ein Fibrinnetz fördert die Stabilisierung hämostatischer Thromben und wirkt ihrer Ablösung durch den Blutstrom entgegen. Diese zweiteilige Übersicht erörtert Abläufe bei Plättchenaktivierung und Signaltransduktion und rückt αIIbβ3-vermittelte 'Outside-in'-Signalvorgänge bei Integrinvarianten in den Mittelpunkt. In Teil I wird ein 3-stufiges Model zur Plättchenrekrutierung und -aktivierung vorgestellt. Thrombozytäre Funktionsäußerungen bei Exposition thrombogener Oberflächen und Plättchen-Plättchenwechselbeziehungen mit nachfolgender Thrombusbildung werden im Detail besprochen. Auch wird auf verschiedene Einflussgrößen eingegangen, die unter pathologischen Bedingungen eine Thrombose hervorrufen.

Keywords

platelet adhesion - activation - aggregation - thrombus formation - integrin αIIbβ3

Schlüsselwörter

Plättchenadhäsion - Aktivierung - Aggregation - Thrombusbildung - Integrin αIIbβ3

* Dedicated to the memory of Prof. Ernst F. Lüscher (1916–2002), who was my postdoc mentor.


 

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