Previous studies of patients with sickle cell disease (SCD) suggested that certain patients are at risk for “hyperhemolysis,” characterized by a pattern of lower hemoglobin levels and higher levels of hemolysis markers and associated with a higher prevalence of pulmonary hypertension, stroke, leg ulcers, and priapism – the common vascular complications of SCD. However, this “hyperhemolysis risk model” is limited by the use of surrogate markers of hemolysis.
To investigate the validity of this model, Marie Dubert, MD, from the Department of Internal Medicine at Hôpital Européen Georges-Pompidou in Paris, France, and co-authors analyzed a cohort of patients from the CADRE trial (a multinational, prospective, observational study conducted in five sub-Saharan African countries). After examining the association between steady-state hemolysis, anemia, and vascular complications, they found that severe anemia was associated with only some specific complications of SCD, including elevated tricuspid regurgitant jet velocity (TRV) and microalbuminuria, and the complications were not associated with markers of hemolysis – suggesting that the hyperhemolysis risk model does not fully explain these interactions.
The study included 2,407 patients ≥3 years old with SCD. Laboratory tests were performed at steady state (i.e., >15 days after the last vaso-occlusive crisis [VOC]), eight days after fever or infectious disease, and three months after the last transfusion. The degree of hemolysis was estimated from a composite index, which included bilirubin levels or clinical icterus and lactate dehydrogenase (LDH) levels. Patients were categorized into four quartiles, ranging from patients with the lowest hemoglobin level (quartile 1) to patients with increased values of the indirect hemolysis index (quartile 4).
Patients had the following phenotypes:
Clinical characteristics were similar among the phenotypes, but SS-Sβ0 patients were younger than Sβ+ and SC patients (median = 15.0 years [range = 9.0-23.0 years] vs. 21.0 years [range = 14.0-31.0 years]; p value not reported). SS-Sβ0 patients also presented with more frequent VOCs, acute chest syndrome, leg ulcers, priapism, and osteonecrosis than Sβ+ and SC patients (p<0.05).
Less than 2 percent of patients with SCD were receiving hydroxyurea or blood transfusions.
Patients with Sβ0 disease had more frequent icterus than patients with Sβ+ or SC disease (55.8% vs. 13.8% and 8.9%, respectively; p<0.001). Patients with Sβ0 disease also had lower hemoglobin levels (median = 7.9 g/dL vs. 10.9 g/dL and 11.2 g/dL, respectively; p value not reported) and higher levels of hemolysis markers (including reticulocytes, LDH, and bilirubin).
“Consistent with the known differences in hemolytic intensity among the various SCD genotypes, the hemolysis index was significantly different [among] the four groups, with a median index of 0.38 for Sβ0 patients, –1.03 for SC patients, and –1.17 for Sβ+ patients (p<0.001 for all),” the authors reported.
After adjusting for age, sex, country of origin, and SCD phenotype, the authors determined that patients with the highest degree of anemia (i.e., the lowest quartile of hemoglobin values) were significantly more likely to have elevated TRV and microalbuminuria than patients in other quartiles (see TABLE 2). Anemia also was associated with leg ulcers, but only in adults with Sβ0 disease.
A high hemolysis index (i.e., patients in quartile 4) was “weakly associated” with microalbuminuria in the whole population (odds ratio = 1.62; 95% CI 1.19-2.21; p=0.046), and with elevated TRV and microalbuminuria in adults with Sβ0 disease (p=0.2 and p=0.001, respectively; see TABLE 2). “However, we did not consistently observe these associations in children or other SCD phenotypes, and, strikingly, they did not remain significant after adjustment for hemoglobin level,” the authors reported.
There was no significant association between the indirect hemolysis index and the expected vascular complications of SCD, including stroke or priapism, regardless of SCD phenotype. This discrepancy may have been explained by the low use of SCD treatments, which may have affected the incidence of complications and the level of hemolysis.
Also, because patients in Africa are exposed to numerous pathogens, including malaria, “one cannot exclude that part of their hemolysis resulted from asymptomatic infections,” they added. “Translational research studies are necessary to assess the interaction between SCD vasculopathy, malnutrition, and infectious diseases, particularly malaria, in sub-Saharan Africa.”
The study is limited by the use of an indirect index of hemolysis, and it was not validated against direct measurement of hemolysis.
The authors report no financial conflicts.
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