Increased Platelet Binding to Circulating Monocytes in Acute Coronary Syndromes

Abstract

Background — Present therapies for acute coronary syndromes aim toward limiting platelet–platelet adhesion and aggregation processes. However, platelet–leukocyte interactions may contribute importantly to disease progression in the arterial wall. Recent studies suggest that prevention of platelet–leukocyte binding via P-selectin glycoprotein ligand-1 (PSGL-1) may be beneficial in animal models of vascular injury. Methods and Results — P-selectin–PSGL-1 interactions were found to account for most platelet–monocyte binding observed in peripheral blood samples from healthy donors. However, a significant component of observed adhesion was calcium independent, involving neither PSGL-1 nor P-selectin. Platelet–monocyte interactions were examined in 52 patients admitted within 14 hours of symptom onset, with acute coronary syndromes defined as unstable angina (n=12) and acute myocardial infarction (n=13) or noncardiac chest pain (n=27). When compared with patients with noncardiac chest pain, significantly elevated levels of platelet–monocyte binding were found in patients with acute myocardial infarction (70.1±15.4% versus 45.4±23.3%; P <0.01) and unstable angina (67.4±12.9% versus 45.4±23.3%; P >0.01). Calcium-independent platelet–monocyte binding was significantly elevated in myocardial infarction patients alone (14.7±7.7% versus 6.1±5.96%; P <0.001). Conclusions — There is evidence for a significant P-selectin–independent molecular component to the platelet–monocyte conjugation observed in peripheral blood. Patients with myocardial infarction and unstable angina demonstrate increased total binding of platelets to monocytes. Additionally, calcium-independent adhesion was significantly elevated in patients with evidence of myocardial infarction. These findings demonstrate that novel cation-independent adhesion mechanisms may mediate platelet–monocyte binding, representing a new therapeutic target after vascular injury associated with myocardial infarction.

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…For example, studies with un-separated leukocyte populations reveal a significant increase in platelet-leukocyte complexes in allergic mice and in human asthmatics (Pitchford et al, 2003(Pitchford et al, , 2005. Similar processes occur in patients with COPD (Ferroni et al, 2000), atherosclerosis (Arber et al, 1991;Ott et al, 1996;Neumann et al, 1997;Sarma et al, 2002;Huo et al, 2003) and RA (Joseph et al, 2001;Bunescu et al, 2004). In this regard, experimental models of disease have provided evidence for a requirement of platelets in pulmonary eosinophil and lymphocyte recruitment in rabbits, guineapigs and mice in models of allergic inflammation (LellouchTubiana et al, 1988;Coyle et al, 1990;Pitchford et al, 2003Pitchford et al, , 2005; and neutrophil and monocyte recruitment in atherosclerosis (Arber et al, 1991;Neumann et al, 1997;Hayward et al, 1999) and RA (Schmitt-Sody et al, 2005).…”

“…However, interactions between platelets and inflammatory cells take place during atherosclerosis and this stimulation of an inflammatory response within the atherosclerotic plaque may trigger acute coronary events via reactive oxygen species (ROS) production and MMP secretion (Poubelle and Borgeat, 2002). Substantial clinical evidence demonstrates activation of circulating platelets in diseases with a substantial inflammatory component acting on the vasculature, for example, acute coronary syndromes such as myocardial infarction and unstable angina (Sarma et al, 2002) and atherosclerosis (Massberg et al, 2002). These studies suggest a participation of platelets in the inflammatory responses as well as the recognized events leading to thrombus formation.…”

“…These studies suggest a participation of platelets in the inflammatory responses as well as the recognized events leading to thrombus formation. Platelet binding to leukocytes occurs during acute coronary events, and these heterotypic aggregates are formed as a result of activation by inflammatory mediators (Arber et al, 1991;Ott et al, 1996) and are largely bound via P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) interactions (Sarma et al, 2002). It is worth noting that an increased expression of CD40L occurs on the surface of platelets in acute coronary syndromes (Garlichs et al, 2001), although the significance of this is not yet known, it reveals another mechanism whereby platelets may further stimulate the inflammatory response during atherosclerosis.…”

Effect of High Bolus Dose Tirofiban on the Inflammatory Response Following Percutaneous Coronary Intervention

“…15 In addition, despite blocking the glycoprotein IIb/IIIa receptor with tirofiban, platelets can activate white cells via their P-selectin receptor which binds to P-selectin glycoproteinligand-1 on leukocytes. 16 The clinical and angiographic characteristics of the population studied may also be an importantreason for the absence of anti-inflammatoryeffect. Because of the proven benefit of anti-glycoprotein IIb/IIIa receptor blockade in unstable patients, it was not ethical to withhold tirofiban treatment on such patients.…”

Involvement of platelet glycoprotein Ib in platelet microparticle mediated neutrophil activation

“…Platelet MPs expose platelet-specific antigens on their surface and can adhere to leukocyte in a P-selectin dependent manner [7]. Clinical studies have shown that elevated levels of microparticles were found in patients with disseminated intravascular coagulation [13], unstable angina [14], myocardial infarction [15,16], coronary angiography [17], transient ischemia attacks [18], and diabetes mellitus [19]. A deficiency of platelet MP generation can result in a bleeding disorder characterized with prolonged bleeding time [20].…”