Arterial Thrombus Stability: Does It Matter and Can We Detect It?

Diana A. Gorog, MBBS, MD, PD; Zahi A. Fayad, PD; Valentin Fuster, MD, PD

Disclosures

J Am Coll Cardiol. 2017;70(16):2036-2047. 

In This Article

Abstract and Introduction

Abstract

The spontaneous lysis of a coronary thrombus is a natural protective mechanism against lasting occlusion and downstream infarction. Thrombus stability is thus a direct determinant of clinical outcome. Compared with the extensive study of the crucial role of platelets, coagulation, and flow in arterial thrombosis, little attention has been paid to factors affecting thrombus stability, despite evidence linking impaired spontaneous fibrinolytic activity with acute coronary events. We summarize experimental evidence for the importance of thrombus stability and highlight the need for physiologically relevant tests to assess spontaneous disintegration/fibrinolysis of platelet-rich thrombi under arterial flow conditions, review techniques to assess thrombus stability in vitro, and describe novel imaging techniques to characterize thrombosis in vivo. Such techniques may allow tailoring of pharmacotherapy to potentiate thrombus instability, through fragmentation of platelet thrombi and/or enhanced endogenous fibrinolysis, to reduce infarct size.

Introduction

The stability of an arterial thrombus, specifically the strength of its attachment to the vessel wall and its resistance to dislodgment by flowing blood, will determine the clinical sequelae of the thrombotic occlusion, namely the extent of subsequent downstream tissue damage[1] (Central Illustration). Understanding the crucial role of platelets, coagulation, and flow conditions in the mechanism of coronary thrombus formation has translated into the application of potent antiplatelet and anticoagulant agents for the treatment and prevention of thrombosis. In contrast, the determinants of thrombus stability, namely factors that confer stability on an arterial thrombus and impart resistance to arterial flow and shear conditions, have been far less well explored and have resulted in no new pharmacologic approaches or better targeting of currently available treatments.

In vitro studies of thrombus stability have been largely confined to the assessment of fibrinolysis (plasma or whole blood clot lysis) under low-flow conditions, to the assessment of the structure and density of the fibrin meshwork, and to the study of the effects of various fibrinolysis inhibitors.[2,3] It is increasingly recognized that the in situ generation of thrombin from within the platelet thrombus, as well as platelet- and leukocyte-derived integrins and plasma coagulant proteins, exert a profound effect on thrombus stability.[4,5] Because thrombin generation is inhibited by citrate, the contribution of thrombin to stability cannot be assessed by using anticoagulated blood.[6] Thrombus instability results in the formation of macroemboli or microemboli, whose susceptibility to lysis in the circulation will determine the downstream clinical sequelae. Currently available antiplatelet medications inhibit thrombus formation by preventing platelet activation and/or aggregation in response to specific agonists, but the in vivo antithrombotic effects, including the specific effects of such medications on thrombus stability and endogenous fibrinolysis, are largely unknown.

Since the last review of this subject in 2006,[7] significant advances have been made in understanding the mechanisms that confer stability on an arterial thrombus. The aim of the present review was to assess the relevance of key mediators of thrombus stability in determining clinical outcome and to discuss techniques currently available for assessing this subject. The importance of the assessment of coronary thrombus stability is 2-fold. First, there is a need to assess the "thrombotic status" of an individual to predict the likelihood of occlusive thrombus formation and to assess the likely response to different medications, using in vitro or ex vivo techniques. Second, there is a need to detect and image the state of the coronary thrombus in vivo, whether stable or unstable, when a coronary thrombotic event occurs, and to visualize downstream myocardium and assess response to pharmacotherapy by using noninvasive imaging modalities.

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