As we continue to gain insights on the pathophysiology of sickle cell disease, the novel mechanisms and understanding can lead to potential targets for diagnostics and therapies.  Here we explore two different such pathways and review the current novel diagnostic approaches to sickle cell disease. 

Dr. Novelli will describe how heme released from hemolyzed red blood cells in sickle cell disease leads to acute and chronic complications. The presentation will review the multiple downstream pathological effects of heme release including platelet activation, oxidative stress, cellular hyper adhesion, and sterile inflammation and how these mechanisms of disease lead to acute vaso-occlusive and chronic complications including renal dysfunction and pulmonary hypertension. Dr. Novelli will also highlight the principal treatments currently available and those in development to counter heme-mediated pathology.

De Franceschi will discuss the activation of the complement systems in the sickle cell disease. Previous studies have shown a key role of complement activation in chronic inflammatory processes characterized by hemolysis and vascular endothelial damage such as paroxysmal nocturnal hemoglobinuria (PNH). This brings complement at the crossroad between inflammatory vasculopathy and hemolysis.  In patients with sickle cell disease (SCD), activation of the alternative pathway (AP) has been reported as (i) increased c5b9 plasma level; (ii) deposition of C3d on red cells; (iii) reduction in plasma factor B and D, modulating complement activation; (iv) decrease plasma FH, the major soluble regulator of AP activation. These observations are further supported by the evidence of vascular deposition of C5b9 in patients’ skin biopsies and in glomeruli, being kidney vulnerable to complement mediated damage. Here, we will present the main results on studies in both cell-based and mouse-based models of SCD, showing the role of free heme in activation of complement and in particular of the AP in SCD. We will describe the negative impact of free heme on AP modulators, highlighting the role of complement related thrombotic microangiopathy as an additional element to the high biocomplexity of SCD. We will also present data on cases collection of SCD patients with severe sickle cell related clinical manifestations treated with eculizumab, a complement inhibitor. Collectively, these data generate the rationale to design clinical studies with inhibitors of complement.

Dr. Jeffrey Chalmers notes that while a variety of cell therapy approaches are being pursued to cure SCD, there are still significant needs, which will continue to exist, for improved technology monitor, and evaluate SCD patients. Multiple novel testing techniques in the field including RBC health evaluation, Gazelle, and measurement of adhesion will be presented/discussed.