Association Between Hyperhemolysis and Vascular Complications in Sickle Cell Disease Sub-Saharan African Patients

Introduction

About 80 % of sickle cell disease (SCD) patients live in sub-Saharan Africa whereas most studies on SCD are performed in Europe and America. Hyperhemolysis is thought to play a major role in the pathological process of SCD vasculopathy.  Nevertheless, the paradigm of hyperhemolysis is controversial and has never been studied in the African context.  We aim to analyze the association between hemolysis and clinical vascular complications among SCD African patients. 

Methods

CADRE is a multinational cohort of SCD African patients aged 3 years and older, included prospectively and explored in a steady state. All patients from the CADRE cohort in Ivory Coast, Cameroun and Mali were included in the present study. Patients were classified in SS-Sβ⁰ phenotype or SC-Sβ⁺ phenotype. SCD vascular complications (pulmonary arterial hypertension (PAH), microalbuminuria, leg ulcers, priapism, stroke and osteonecrosis) were assessed using clinical examination, laboratory exams and echocardiography. Hemolysis was measured by a composite score, created with a principal component analysis, that included LDH, hemoglobin and bilirubin rates and clinical icterus. The association between hyperhemolysis (upper quartile of the hemolysis score) and the vascular complications was assessed using multivariate regression analysis in the whole population with further stratification by hemoglobin phenotype.

Results

We included 2409 patients among which 1751 SS-Sβ⁰ patients and 658 SC-Sβ⁺ patients. Compared to SC-Sβ⁺ patients, SS-Sβ⁰ patients were younger (15 years old versus 21 years old) and exhibited more leg ulcers (166 (9.5%) versus 24 (3.7%)) and microalbuminuria  (573 (42.4%) versus 119 (20.0%)). The hemolysis score was higher in SS-Sβ⁰ patients as compared to SC-Sβ⁺ patients (median 1.18 versus 0.43, Figure). After adjustment for age, sex and country, hyperhemolysis was associated with microalbuminuria (OR = 1.59 [1.17-2.16]) and priapism (OR=1.58 [1.01-2.49]) (Table). In SS-Sβ⁰ patients, hyperhemolysis was associated with microalbuminuria (OR=1.54 [1.10-2.15]) and there was a trend to an association with PAH (OR=1.65 [0.91-2.98]) and priapism (OR=1.50 [0.95-2.39]). In SC-Sβ⁺ patients, only the association between hyperhemolysis and microalbuminuria remained significant. Sensibility analysis in the adult population showed that hyperhemolysis was significantly associated with all the SCD vascular complications, except for osteonecrosis.

Conclusion

In African SCD patients, associations between hyperhemolysis and SCD vascular complications were statistically significant but of modest magnitude, and depended on the hemoglobin phenotype. These results suggest that in the African context, hemolysis is not a major determinant of the development of SCD vasculopathy.

Table. Associations between SCD complications and hemolysis score (quartiles 1 to 3 versus quartile 4) in the whole population: multivariate analysis with adjustment for age, sex, country and hemoglobin phenotype

		% of patients with the complication		Multivariate analysis
	N event/ N total	Quartiles 1 to 3	Quartile 4	OR	IC 95%	P value
PAH*	115/431	6.14	7.08	1.58	0.89-2.83	0.123
Urine albumin/ creatinine > 30mg/g	724/1991	24.88	45.36	1.59	1.17-2.16	0.004
Leg ulcer, lifetime	190/2409	6.80	11.01	1.20	0.81-1.78	0.355
Priapism, lifetime **	160/1095	13.27	17.90	1.58	1.01-2.49	0.046
Stroke, lifetime	25/2409	0.79	1.77	1.32	0.49-3.54	0.578
Osteonecrosis, lifetime	277/2409	11.22	12.28	1.00	0.70-1.43	1.000

PAH: Pulmonary Arterial Hypertension. * Patients from Mali and Cameroun only ** Males only

Figure. Distribution of the hemolysis score: global population, SS-Sβ⁰ patients and SC-Sβ⁺ patients