Re‐assessing the effect of fetal hemoglobin on stroke in the Cooperative Study of Sickle Cell Disease

To the Editor: Fetal hemoglobin (HbF) is the main modifier of sickle cell disease (SCD) severity, with high HbF being associated with a lower risk of death, pain, and acute chest syndrome. The historical Cooperative Study of Sickle Cell Disease (CSSCD), a prospective study led in United States from 1978 to 1988, played an essential role in identifying or confirming the protective effect of HbF on SCD-related complications. However, whether HbF has a protective effect on stroke, a devastating complication of SCD, remains controversial. Indeed, the CSSCD did not identify an association with overt stroke, nor did the subsequent ancillary study on silent infarct. In contrast, other studies have found that higher HbF level was associated with lower risk of overt stroke and silent infarct. Several genetic studies have also found that HbF-associated variants influence stroke risk. These discrepancies are difficult to reconcile and complicates our understanding of SCD pathophysiology and patient counseling. Moreover, hydroxyurea usage has been generalized but the optimal dosage is unclear, and whether HbF level is a proxy for stroke protection is unknown. Finally, given recent major advances in gene therapy approaches to increase HbF level, whether a protective effect on stroke is expected has major implications. Conclusions from the CSSCD are important as it remains the largest prospective SCD study to date and was conducted before the generalization of disease-modifying therapies (no patients were receiving hydroxyurea and only a few were enrolled in chronic transfusion program). The original CSSCD publication only reported the univariate association of HbF with incident ischemic stroke in SS patients (p = .106). Because this analysis was restricted to a subgroup of patients and a subtype of stroke (resulting in limited statistical power because of its small sample size [n = 31 cases]), its findings are difficult to generalize. Thus, we re-analyzed the CSSCD data by performing multivariate analyses that consider: (1) incident and prevalent strokes, (2) all subtypes of stroke (which is relevant given that magnetic resonance imaging was not performed in the CSSCD), and (3) all hemoglobin (Hb) genotypes. We analyzed the complete CSSCD database, with information from 4082 patients and a mean age at inclusion (±SD) of 13.6 ± 12.6 years (Supplemental Table 1). We retrieved HbF values for 2970 patients, including 2252 with the SS genotype. The initial report used a representative HbF value based on all HbF measures recorded for each patient. As this original value was unavailable to us, we used a mean HbF value that had been previously validated in clinical and genetic studies of the CSSCD. We acknowledge that this HbF value might slightly differ from the initial analysis. We also note that our database included fewer patients with unknown Hb genotypes (101 vs. 139 in the initial article). A total of 57 patients (1% of the cohort) had received, or were suspected of having received, a transfusion. No HbF value was available for these patients, and they were not included in the present analyses. To confirm the validity of our dataset, we repeated several analyses previously done in the CSSCD. We used logistic (for binary variables) or quasi-Poisson (for continuous variables) regression adjusted for age and sex to analyze the effect of HbF on other SCD complications. We confirmed the protective effect of HbF on pain, acute chest syndrome, leg ulcer, priapism, and survival in SS patients (Supplemental Table 2). We retrieved the same prevalence of history of stroke at inclusion as the initial report (n = 153, of which 104 had HbF value, Supplemental Table 1). For these cases, the report form did not indicate the stroke subtype. We found a slightly higher number of patients with incident stroke (n = 94 vs. n = 87 in the original report, considering all stroke subtypes, all Hb genotypes, and only patients with no history of stroke at inclusion). Incident strokes were divided in the database in three subtypes: ischemic, hemorrhagic, and transient ischemic attack. As in the original article, our analyses of incident stroke only considered the 2866 patients with HbF value and without a history of stroke at inclusion. We used Cox proportional hazard regression to compute univariate hazard ratio (HR) for HbF. We also computed multivariate HR by adjusting for sex and age at entry ± Hb genotype. We used logistic regression to compute odds ratio (OR) for the association with history of stroke at inclusion using both univariate and multivariate models. We computed HR and OR for a 1% increase in HbF value. We used the surv_cutpoint function based on maximally selected rank statistics (R software, packages survminer and maxstat) to determine the optimal HbF cutpoint for the association with history of stroke at inclusion and we compared the two groups using the logrank test. First, we reproduced the published lack of association in univariate analysis between HbF and incident ischemic stroke in the SS subgroup (p = .06, Figure 1A and Supplemental Table 3). However, in multivariate Cox regression models, the effect of HbF on ischemic stroke was nominally significant when considering the SS subgroup (HR 0.90, 95% confidence interval [CI] 0.80–0.99, p = .038) or all Hb genotypes (HR 0.90, 95% confidence interval [CI] 0.81–0.99, p = .047). We did not identify an association between HbF level and incident hemorrhagic stroke, in either univariate or multivariate models. Considering all subtypes of incident stroke, we found that Received: 20 June 2023 Revised: 21 July 2023 Accepted: 25 July 2023