Intravenous infusion of haptoglobin for the prevention of adverse clinical outcome in Sickle Cell Disease.

摘要: Sickle Cell Disease (SCD) is a genetic condition which manifests as altered hemoglobin (Hb) protein that can aggregate under hypoxic conditions. The resultant sickled erythrocytes experience premature hemolysis, releasing an estimated 10g of free Hb (fHb) into the intravascular space. FHb participates in redox reactions creating various reactive oxygen species rapidly and irreversibly scavenge nitric oxide, thereby attenuating its vasodilatory, antithrombotic, anti-inflammatory properties. also induces endothelial expression adhesion molecules, triggering leukocyte margination at vessel wall. These mechanisms participate diverse SCD-associated clinical events including nephropathy, pulmonary hypertension, chronic leg ulceration, ischemic events. exerts direct reno-toxic effect contributing to albuminuria early, frequent manifestation glomerular injury. Under normal conditions, fHb effectively scavenged by Hb-scavenging mechanism (HSM); this involves binding haptoglobin (Hp), uptake via receptor (CD163) on monocytes metabolism heme-oxygenase-1. This culminates increased CD163 release by-products e.g. interleukin-10 (IL-10). In SCD, Hb-binding capacity overwhelmed hemolysis; our previous research shows serum Hp depleted component. deficiency could result harmful consequences circulating going unbridled. hypothesis we explore here infusions, excess concentration, will allow HSM remain functional, achieve improved outcomes, tracking sentinel. Albuminuria was selected because high prevalence SCD relative ease diagnosis monitoring. may be evaluated four phases: Phase 1 determine concentration needed trigger measured induction IL-10 recovery hemopexin. 2 investigate half-life analyzing time-course hemopexin concentration. 3 patient eligibility for therapy, whether treatment or prevention. 4 test efficacy transfusions randomized control trial correction albuminuria. Angiotensin converting enzyme inhibitors (ACEi) are currently first-line however hyperkalemia limits use. Hydroxyurea, has therapeutic value many adverse events, yielded inconsistent effects We proposing addition intervention more proximal hemolytic cascade. Boosting exhausted replacement therapy potential modify multiple downstream