Chronic hyper-hemolysis in sickle cell anemia: association of vascular complications and mortality with less frequent vasoocclusive pain

James G Taylor 6th, Vikki G Nolan, Laurel Mendelsohn, Gregory J Kato, Mark T Gladwin, Martin H Steinberg, James G Taylor 6th, Vikki G Nolan, Laurel Mendelsohn, Gregory J Kato, Mark T Gladwin, Martin H Steinberg

Abstract

Background: Intravascular hemolysis in sickle cell anemia could contribute to complications associated with nitric oxide deficiency, advancing age, and increased mortality. We have previously reported that intense hemolysis is associated with increased risk of vascular complications in a small cohort of adults with sickle cell disease. These observations have not been validated in other populations.

Methods: The distribution of serum lactic dehydrogenase (LDH) values was used as a surrogate measure of intravascular hemolysis in a contemporaneous patient group and an historical adult population from the Cooperative Study of Sickle Cell Disease (CSSCD), all with sickle cell anemia. Chronic hyper-hemolysis was defined by the top LDH quartile and was compared to the lowest LDH quartile.

Results: Hyper-hemolysis subjects had higher systolic blood pressure, higher prevalence of leg ulcers (OR 3.27, 95% CI 1.92-5.53, P<0.0001), priapism (OR 2.62, 95% CI 1.13-6.90, P = 0.03) and pulmonary hypertension (OR 4.32, 95% CI 2.12-8.60, P<0.0001), while osteonecrosis (OR 0.32, 95% CI 0.19-0.54, P<0.0001) and pain (OR 0.23, 95% CI 0.09-0.55, P = 0.0004) were less prevalent. Hyper-hemolysis was influenced by fetal hemoglobin and alpha thalassemia, and was a risk factor for early death in the CSSCD population (Hazard Ratio = 1.97, P = 0.02).

Conclusions: Steady state LDH measurements can identify a chronic hyper-hemolysis phenotype which includes less frequent vasooclusive pain and earlier mortality. Clinicians should consider sickle cell specific therapies for these patients, as is done for those with more frequent acute pain. The findings also suggest that an important class of disease modifiers in sickle cell anemia affect the rate of hemolysis.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Selection of adult sickle cell…
Figure 1. Selection of adult sickle cell anemia subjects for LDH analysis.
Panel A: Selection process in the NIH study that identified subjects with the highest and lowest LDH values. * Includes both sickle cell disease cases and 10 subjects for whom no DNA sample was collected. † Of the 21 subjects excluded from analysis, 14 had an excessive hemolysis index for LDH, 2 had no labs drawn, 4 had ALT values greater than 80 IU/L, and 1 had aplastic anemia. Panel B: Selection in the validation study from the CSSCD. ‡ 172 had ALT values greater than 80 IU/L. § Two were excluded with unexpectedly low LDH values.
Figure 2. LDH distributions in sickle cell…
Figure 2. LDH distributions in sickle cell anemia.
Panel A: LDH distribution at NIH. Blue bars indicate either the Low LDH study group defined by LDH below 278.0 IU/L or the high LDH group (LDH above 451.0 IU/L). Panel B: LDH distribution among NIH subjects with Hemoglobin SC disease and sickle β+ thalassemia. Panel C: Distribution of median LDH values from up to three LDH measurements in the CSSCD. The blue bars show the Low LDH (at or below the LDH 25th percentile of 340.5 IU/L) and the High LDH (at or above the 75th percentile of 546.0 IU/L) study groups, respectively. * Two were excluded from the Low LDH group for unexpectedly low LDH values. Panel D: LDH distribution among healthy controls.
Figure 3. Stability of steady state LDH…
Figure 3. Stability of steady state LDH values from the CSSCD.
The stability of steady state hemolytic rate is demonstrated by analysis of 3 serial LDH measurements in 225 CSSCD subjects (repeated measures of ANOVA, P = 0.66).
Figure 4. Clinical manifestations associated with hyper-hemolysis…
Figure 4. Clinical manifestations associated with hyper-hemolysis in sickle cell anemia.
Panel A: Odds ratios and confidence intervals for associations with hemolysis in the NIH study. • = P value ≤0.05; ○ = P value not significant. Panel B: Associations in the CSSCD population. Panel C: Summary odds ratios for associations between hyper-hemolysis and 8 clinical endpoints in a combined analysis of the NIH and CSSCD populations.
Figure 5. Hyper-hemolysis is associated with early…
Figure 5. Hyper-hemolysis is associated with early mortality in the CSSCD.
Kaplan Meier survival curve for the CSSCD according to LDH group for 224 subjects. Early mortality was associated with the high LDH group by logrank test (Hazard ratio 1.97, 95% confidence interval 1.14–3.41, P = 0.02).

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