Clinical impact of the haemoglobin scavenging mechanism in Sickle Cell Disease

Investigators & Affiliations:

KR Quimby¹, S Moe², I Sealy², C Nicholls², IR Hambleton¹, RC Landis¹

1 Chronic Disease Research Centre, Tropical Medicine Research Institute, The University of the West Indies, Bridgetown, Barbados
2 Queen Elizabeth Hospital, Barbados

Funding Obtained:

Cave Hill Postgraduate Research Award Fund – 10.2013 – BDS $29,283.20

Start Date:

Jan 2013

End Date:

Jan 2015

Rationale:

Following intravascular haemolysis, free Hb binds to Hp and the complex is internalized via CD163 on monocytes. Subsequent mechanisms culminate in the release of antioxidant molecules and autocrine up‐regulation of monocyte CD163. CD163 up‐regulation increases Hb‐scavenging capacity thereby limiting the vascular insult caused by the pro‐oxidant free heme. We have shown that this mechanism is inhibited in SCD, in particular; there is a depletion of serum Hp. We now aim to explore the correlation of Hp deficiency with select clinical features within our SCD population.

Methods:

Participants were included as outlined in the previous report. Clinical outcome were ascertained as outlined in the previous report.

Main Results:

The odds ratio for having albuminuria increased by 3.57 (1.19 to 11.1) for every 1mg/dL decrease in Hp levels p=0.02. In order to determine if the Hp levels were decreased because they were being lost through a damaged renal filtration system (rather than decreased Hp being a causal factor in renal disease), urinary Hp levels were compared in HbSS and HbAA. There was no evidence for loss of Hp by excretion, since mean urine levels of Hp were significantly lower in HbSS as compared to HbAA mean (sd) 0.03 (.03) vs. 0.13 (.05) p=0.0001. The odds ratio for reporting a pain crisis in the last year increased by 1.31 (95%CI 0.90 to 1.90) for every 1mg/dl decrease in Hp levels p=0.14. The odds of reporting a history of leg ulcer was 1.17 (0.8 to 1.71) for every 1mg/dl decrease in Hp levels p=0.4. For every 1mg/dl decrease in Hp, TRJV increased by 0.11 (95% CI ‐0.6 to 0.28) p=0.18

Expected impact:

A deficiency in Hp is associated with worsening renal disease in SCD. Replacement of Hp may therefore be a viable therapeutic prospect aimed at restoring the positive feedback loop and conferring vascular protection.

Next Steps / Future Plans:

The next steps are:

• Investigate a cause – effect relationship between reduced Hp bioavailability and clinical status – birth cohort
• Investigate the possibility of therapeutic Hp infusions