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CLINICAL NEWS

Written in Blood

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 coauthors 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 vasoocclusive 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 :

• SS-Sβ 0 ( n = 1,751 )

• SC ( n = 495 )

• Sβ + ( n = 161 )

Clinical characteristics were similar among the phenotypes , but SS-Sβ 0 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-Sβ 0 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 Sβ 0 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 Sβ 0 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 Sβ 0 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 Sβ 0 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 Sβ 0 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 .

REFERENCE

Dubert M , Elion J , Tolo A , et al . Degree of anemia , indirect markers of hemolysis , and vascular complications of sickle cell disease in Africa . Blood . 2017 September 20 . [ Epub ahead of print ]

TABLE 2 . Associations Between SCD-Related Vascular Complications and Indirect Hemolysis Index

34 ASH Clinical News November 2017