PhD Immunology

2008

The University of the West Indies

2017

Intravascular haemolysis increases free haemoglobin (fHb) concentration. This drives the production of reactive oxygen species, which bind rapidly and irreversibly to nitric oxide, thereby annulling its antithrombotic, vasodilatory and anti-inflammatory effects. These mechanisms have been indicated in multiple vascular disorders. Under normal physiological and genetic conditions, fHb is cleared by the haemoglobin-scavenging mechanism (HSM); which includes being bound by haptoglobin (Hp), internalized by monocytes bearing the haemoglobin scavenger receptor, CD163, and metabolised via the heme-oxygenase (HO)-1 enzyme into anti-oxidant metabolites. This triggers an IL-10 positive feedback loop which augments CD163 expression; thereby increasing haemoglobin-scavenging capacity and limiting the vascular insult. In this thesis, I investigated the induction of the HSM in two haemolytic conditions. Cardio-pulmonary bypass (CPB) was chosen as the model of acute haemolysis because of its iatrogenic nature. I demonstrated that during CPB, serum Hp was temporarily consumed, reaching its nadir 2hrs intra-operatively; while the surface CD163 and HO-1 expression were up-regulated, reaching their peaks 24hrs post-operatively. Homozygous sickle cell disease (HbSS) was chosen as the model of chronic haemolysis because of its relevance to the Barbadian population – one of mainly African descent. In steady-state HbSS, haemolysis was linked with exhaustion of serum Hp and suppression of CD163 compared to HbAA. To investigate the clinical impact of this molecular aberration, a history of select SCD-related conditions was ascertained. Urine samples were analyzed for albumin: creatinine ratio and echocardiograms were analyzed for the tricuspid regurgitant jet velocity (TRJV). Using logistic regression, I demonstrated an association between decreased Hp levels and the increased odds of having albuminuria (urinary protein/creatinine ratio of >30mg/g). This association presents a possible bridge between the primary pathological process (haemolysis) and clinical endpoints. Future work could consider Hp replacement therapy as a viable therapeutic prospect aimed at restoring the positive feedback loop and conferring vascular protection.