Markers of Thrombosis

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In clinical practice, limited means exist to assess the physiologically relevant balance between in vivo anticoagulation and thrombosis. Ideally, if tests were readily available that reflected active intravascular thrombosis, clot dissolution, and thrombotic potential, treatment could be tailored more precisely. Conceptually, these markers could also be used to provide mechanistic and prognostic information.

Thrombin, a 308-amino acid serine protease, plays a central role in the natural history of ruptured atherosclerotic plaques. Thrombin, in essence, determines the extent of thrombus formation at sites of vascular injury. Thrombin activity can be assessed in plasma by measuring fibrinopeptide A (FPA) concentrations. Actually, FPA represents fibrin formation resulting from thrombin's activity on fibrinogen. Thrombin generation is represented by plasma concentrations of prothrombin activation fragment 1.2, throm-bin-antithrombin complexes, and APC (Fig. 17).

Eisenberg and colleagues (157) reported previously that thrombin activity was increased among patients with acute coronary thrombosis. Our group has shown that both thrombin activity and platelet activity (determined by the expression of surface proteins using flow cytometry) are increased in acute coronary syndromes and that heightened activity persists even after the acute clinical symptoms have resolved (158). Plasma markers of thrombin activity and generation may provide useful information during the early assessment of patients with MI at rest in whom electrocardiographic changes are either absent or nondiagnostic. In this setting, elevations in FPA, thrombin-antithrom-bin complexes, and prothrombin activation fragment 1.2 may identify patients with

Fig. 17. The conversion of prothrombin to thrombin is mediated by the prothrombinase complex (coagulation factors Va and Xa, phospholipid, and calcium [Ca2+). This enzymatic reaction typically takes place on existing platelet aggregates; however, it can also occur on a dysfunctional endothelial surface. During the generation of thrombin, which can be neutralized to some degree through binding to antithrombin (thrombin-antithrombin duplex [TAT]), a peptide fragment (prothrombin activation peptide F1.2) appeared in plasma where it can be measured. The thrombin-medicated conversion of fibrinogen to fibrin yields two peptides, fibrionpeptide A (FPA) and fibronopeptide B (FPB). Newly generated thrombin can either be complexed to antithrombin (TAT) or participate in the conversion of fibrinogen to fibrin. D-Dimer is a breakdown product of fibrin.

Fig. 17. The conversion of prothrombin to thrombin is mediated by the prothrombinase complex (coagulation factors Va and Xa, phospholipid, and calcium [Ca2+). This enzymatic reaction typically takes place on existing platelet aggregates; however, it can also occur on a dysfunctional endothelial surface. During the generation of thrombin, which can be neutralized to some degree through binding to antithrombin (thrombin-antithrombin duplex [TAT]), a peptide fragment (prothrombin activation peptide F1.2) appeared in plasma where it can be measured. The thrombin-medicated conversion of fibrinogen to fibrin yields two peptides, fibrionpeptide A (FPA) and fibronopeptide B (FPB). Newly generated thrombin can either be complexed to antithrombin (TAT) or participate in the conversion of fibrinogen to fibrin. D-Dimer is a breakdown product of fibrin.

Fig. 18. Activated platelets undergo numerous structural and functional changes. Surface markers of activation, including P-selectin, can be measured using flow cytometry as can platelet-leukocyte het-erotypic aggregates.

active coronary artery disease (159). D-Dimer, a breakdown product of fibrin, has shown promise as a diagnostic marker among patients with venous thromboembolic disease and is currently being evaluated in the setting of acute coronary syndromes. Rapid bedside tests are available that may be useful in the early management of these patients. The combined measurement of several biochemical markers that reflect decreased myocardial perfusion (troponin), inflammation (fibrinogen, CRP, amyloid A protein, leukocyte activation) and thrombosis (platelet activation, thrombin generation, fibrin formation, thrombin-mediated platelet activation) (Fig. 18) or combination markers (platelet-leukocyte aggregates, fibrinogen-P-selectin interaction) could potentially offer the greatest wealth of information on the pathobiology, prevention, and treatment of acute coronary syndromes (160).

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