Key Points: A significant fraction of cell-free heme in plasma is contained in circulating erythrocyte MPs, particularly during hemolysis. Heme-laden MPs can transfer heme to vascular endothelium and mediate oxidative stress, vascular dysfunction, and vasoocclusions.

In hemolytic diseases, such as sickle cell disease (SCD), intravascular hemolysis results in the release of hemoglobin, heme, and heme-loaded membrane microvesicles in the bloodstream. Intravascular hemolysis is thus associated with inflammation and organ injury. Complement system can be activated by heme in vitro. We investigated the mechanisms by which hemolysis and red blood cell (RBC) degradation products trigger complement activation in vivo. In kidney biopsies of SCD nephropathy patients and a mouse model with SCD, we detected tissue deposits of complement C3 and C5b-9. Moreover, drug-induced intravascular hemolysis or injection of heme or hemoglobin in mice triggered C3 deposition, primarily in kidneys. Renal injury markers (Kim-1, NGAL) were attenuated in C3 ^–/– hemolytic mice. RBC degradation products, such as heme-loaded microvesicles and heme, induced alternative and terminal complement pathway activation in sera and on endothelial surfaces, in contrast to hemoglobin. Heme triggered rapid P selectin, C3aR, and C5aR expression and downregulated CD46 on endothelial cells. Importantly , complement deposition was attenuated in vivo and in vitro by heme scavenger hemopexin. In conclusion, we demonstrate that intravascular hemolysis triggers complement activation in vivo, encouraging further studies on its role in SCD nephropathy. Conversely, heme inhibition using hemopexin may provide a novel therapeutic opportunity to limit complement activation in hemolytic diseases.

Background: Although a blood genetic disease, sickle cell disease (SCD) leads to a chronic vasculopathy with multiple organ involvement. We assessed arterial stiffness in SCD patients and looked for associations between arterial stiffness and SCD-related vascular complications. Methods: The CADRE (Coeur Artères et Drepanocytose, ie, Heart Arteries and Sickle Cell Disease) study prospectively recruited pediatric and adult SCD patients and healthy controls in Cameroon, Ivory Coast, Gabon, Mali, and Senegal. Patients underwent clinical examination, routine laboratory tests (complete blood count, serum creatinine level), urine albumin/creatinine ratio measure, and a measure of carotid-femoral pulse wave velocity (cf-PWV) and augmentation index (AI) at a steady state. The clinical and biological correlates of cf-PWV and AI were investigated by using a multivariable multilevel linear regression analysis with individuals nested in families further nested in countries. Results: Included were 3627 patients with SCD and 943 controls. Mean cf-PWV was lower in SCD patients (7.5±2.0 m/s) than in controls (9.1±2.4 m/s, P <0.0001), and lower in SS-Sβ ⁰ than in SC-Sβ ⁺ phenotypes. AI, corrected for heart rate, increased more rapidly with age in SCD patients and was higher in SCD than in control adults. cf-PWV and AI were independently associated with age, sex, height, heart rate, mean blood pressure, hemoglobin level, country, and hemoglobin phenotype. After adjustment for these correlates, cf-PWV and AI were associated with the glomerular filtration rate and osteonecrosis. AI was also associated with stroke, pulmonary hypertension, and priapism, and cf-PWV was associated with microalbuminuria. Conclusions: PWV and AI are deeply modified in SCD patients in comparison with healthy controls. These changes are independently associated with a lower blood pressure and a higher heart rate but also with the hemoglobin phenotype. Moreover, PWV and AI are associated with several SCD clinical complications. Their prognostic value will be assessed at follow-up of the patients.

Pulse pressure (PP) is an independent predictor of myocardial infarction, mainly above 50 years of age. In subjects with preserved ejection fraction (EF), aortic PP predicts the severity of coronary atherosclerosis. Comparable findings in subjects with reduced EF have not been evaluated. In 1337 subjects with severe coronary ischaemic disease, intra-aortic and brachial blood pressures were measured together with EF and coronary angiography to evaluate cardiac function, the presence of coronary stenosis and/or occlusions or calcifications. The presence (odds ratio±95% CI) of coronary calcification was marginally but not significantly associated (P=0.06) to increased aortic PP (1.32 (0.97–1.80)), whereas that of coronary occlusion was significantly associated (P<0.01) with decreased aortic PP (0.62 (0.42–0.91)), even after adjustment to EF and heart rate. Increased aortic PP did not correlate with stenosis number. No comparable predictive value was observed using intra-aortic or non-invasive brachial systolic blood pressure (SBP) or diastolic blood pressure (DBP). In high cardiovascular risk populations, even in the presence of reduced EF and high heart rate, intra-aortic PP, but not SBP or DBP, is a significant predictor of coronary occlusions and possibly calcifications, but not stenosis.