The role of erythrocytes in thrombus formation has been often neglected, but some studies have highlighted their active role in thrombotic events. Free-haemoglobin (Hb) has shown to induce oxidative-stress damage. Herein we have investigated the coordinated changes in heme-related proteins in patients with acute-coronary-syndromes (ACS), their association to ongoing thrombosis and their impact on patients' prognosis. The serum proteome of STEMI-patients (N=27) within the first 6h after event-onset and 3d after were compared to controls (N=60). Changes in heme-metabolism were characterized in a second STEMI-group by a dual proteomic approach analyzing in-vivo aspirated coronary thrombi at PCI (N=24) and the associated peripheral-blood changes (N=10). A third STEMI-group (N=132) was studied to analyze the impact of the observed changes in prognosis at 6-months-follow-up. The haptoglobin/hemopexin(Hpg/Hpx)-scavenging-system revealed a time-dependent response after STEMI with an early increase in Hpg circulating levels in the acute phase (P=0.01) and a late increase in Hpx levels 3d after (P=0.045). Beta-Hb content in coronary thrombi was directly correlated with systemic beta-Hb and Hpg (R=0.804,P=0.0029; R=0.859,P=0.0007) levels. The presence of a fully-occlusive thrombus was associated to higher circulating levels of beta-Hb (P=0.03) and unbound-Hpg (P=0.03). ELISA validation demonstrated a decreased survival rate at 6-months follow-up in STEMI-patients with lower Hpg plasma levels at admission (P=0.027). Our results show active Hb-release form erythrocytes in ACS. This release is followed by a systemic early increase in Hpg levels and a late increase in Hpx levels that can co-ordinately help to prevent systemic pro-oxidative effects. The Hb-scavenging ability of haptoglobin is related to patients' prognosis.
Keywords: Acute myocardial infarction; free-heme; haptoglobin; heme-metabolism; hemopexin.