Decades after the cooperative study: A re‐examination of systemic blood pressure in sickle cell disease

Multiple studies have reported that patients with SCD have lower systemic blood pressures when compared with age-, sex-, and race-matched controls (1–4). This was confirmed by the Cooperative Study of Sickle Cell Disease (CSSCD), a natural history study of SCD in the United States (4). With the recent advances in the care of patients with SCD, we compared systolic and diastolic blood pressure (SBP and DBP) measurements in a patient cohort followed at our clinical center with values obtained in the CSSCD and from healthy, control subjects. Furthermore, we evaluated the association of SBP and DBP with clinical and laboratory variables in our patient cohort. Blood pressure measurements were obtained in 156 SCD patients in the UNC cohort and 1232 patients in the CSSCD cohort. Patients in the UNC cohort were older and had a higher BMI than patients in the CSSCD cohort (Table 1). The UNC cohort also had a significantly higher proportion of patients with a diagnosis of hypertension and patients on antihypertensive medications. Table 1 Baseline Clinical and Laboratory Characteristics of Study Subjects Patients in the UNC and CSSCD cohorts were categorized into 2 groups based on presumed disease severity - SS/SD/Sβ0 thalassemia and SC/Sβ+ thalassemia, without consideration of alpha and delta thalassemia status. There were 129 patients in the SS/SD/Sβ0 thalassemia group (83%) and 27 patients in the SC/Sβ+ thalassemia group (17%) in the UNC cohort, with 899 patients in the SS/SD/Sβ0 thalassemia group (73%) and 333 patients in the SC/Sβ+ thalassemia group (27%) in the CSSCD cohort. The SBP in the SS/SD/Sβ0 thalassemia group was significantly higher in the UNC cohort than in the CSSCD cohort (122 ± 15 mm Hg vs. 113 ± 14.5 mm Hg, p < 0.0001), but there was no difference in the DBP when both cohorts were compared (69 ± 10.5 mm Hg vs. 69 ± 10.5 mm Hg; p = 0.8). Similarly, in the SC/Sβ+ thalassemia group, the SBP was significantly higher in the UNC cohort (131 ±12 mm Hg vs. 116 ±15.5 mm Hg; p < 0.0001), but no difference was observed when the DBP in both cohorts were compared. When all the SCD patients were stratified by age, the SBP in the UNC cohort was higher in male patients in the 35 – 44-year age group and female patients in the 18 – 24-year, 25 – 34-year and 35 – 44-year age groups compared with the CSSCD cohort (supplementary data, Figure 1; Table 1). We compared the SBP and DBP in SCD patients in the UNC cohort with values from 24 healthy, African-American control subjects without SCD (genotype- AA; median age: 37 years [IQR: 26, 49 years]; BMI: 30.5 [IQR: 25.6, 36.7]). No significant differences were observed in the SBP or DBP when both groups were compared. Furthermore, there were no significant differences in the SBP and DBP when patients in the SS/SD/Sβ0 group were compared with healthy controls. However, patients in the SC/Sβ+ group had significantly higher SBP when compared with healthy controls (130.9 ± 12.1 mm Hg vs. 120.9 ± 11.3 mm Hg, p = 0.01), although no difference was observed in the DBP when both groups were compared. Significant correlations were observed between SBP and age (ρ = 0.37, p < 0.0001) and BMI (ρ = 0.41, p < 0.0001) (Table 2). Patients with a history of hypertension as well as those on antihypertensive therapy had significantly higher SBP than those without such history or therapy. Modest correlations were observed between SBP and white blood cell count, hemoglobin, reticulocyte count, lactate dehydrogenase, total bilirubin, indirect bilirubin, and placenta growth factor (PIGF) (Table 3). There were significant correlations between DBP and age and BMI. Modest correlations were also observed between DBP and hemoglobin, platelet count, reticulocyte count, total bilirubin, and indirect bilirubin. There were no significant associations between the evaluated SCD-related clinical complications and either SBP or DBP. Table 2 Association of Systolic and Diastolic Blood Pressure with Clinical Variables in UNC Cohort Table 3 Association of Systolic andDiastolic Blood Pressure with Laboratory Variables in UNC Cohort After controlling for other covariates, SBP was significantly associated with age (estimate: 0.30, p = 0.0026), BMI (estimate: 0.76, p < 0.0001), prior diagnosis of hypertension (estimate: 6.48, p = 0.027), absolute neutrophil count (estimate: −1.18, p = 0.023), but not with lactate dehydrogenase (estimate: 0.0017, p = 0.49) or hemoglobin (estimate: 1.01, p = 0.14). This means that we expect an increase in SBP by 0.30 mm Hg for every 1 year increase in age; an increase in SBP by 0.76 mm Hg for every 1 kg/m2 increase in BMI; and a decrease in SBP by 1.18 mm Hg for every 1 × 109/L increase in absolute neutrophil count. For a binary response such as prior diagnosis of hypertension, the estimated value of 6.48 indicates that having a history of hypertension is predicted to result in an increase in SBP of 6.48 mm Hg compared to no history of hypertension. Similarly, after controlling for other covariates, DBP was significantly associated with age (estimate: 0.25, p = 0.0004), hemoglobin (estimate: 1.71, p = 0.0021), history of smoking (estimate: −4.96, p = 0.0074), but not with lactate dehydrogenase (estimate: −0.00096, p = 0.62). Despite reported lower systemic blood pressures, patients with higher SBP relative to the SCD population appear to be at higher risk for stroke (4, 5), echocardiography-defined pulmonary hypertension (6), albuminuria (7, 8), and increased mortality (4). Given the risk of clinical complications despite the apparent lower blood pressures than those obtained in control populations, it is uncertain whether the usual recommendations for the diagnosis of hypertension apply to patients with SCD. We found a significantly higher SBP in SCD patients followed at our center than was observed in the CSSCD. Furthermore, there were no significant differences when the SBP and DBP in SCD patients followed at our center were compared with healthy, control subjects. This finding is similar to that by Thompson and colleagues which showed no difference in the SBP between a cohort of SCD patients and healthy controls in Jamaica (8). Consistent with a previous report (4), we found an association between SBP and both age and BMI. While patients in the UNC cohort were significantly older than those in the CSSCD, SBP and DBP values in the UNC cohort were higher when specific age groups were compared, suggesting that age is not the primary reason for the blood pressure differences in both patient cohorts. With the known association between weight and systemic blood pressure (9), the higher BMI in the UNC cohort may contribute to their higher blood pressure values compared to patients in the CSSCD. Although it has been suggested that lower systemic blood pressures in SCD may be a result of higher urinary sodium loss due to hyposthenuria (3, 4), intravenous salt loading had no effect on blood pressure (10). Furthermore, individuals with sickle cell trait, who also exhibit hyposthenuria, do not have lower blood pressures than age- and race-matched controls (11). There are conflicting reports on the association of anemia with systemic blood pressure in SCD (3, 4, 12). We observed modest associations between markers of hemolysis and both SBP and DBP on univariate analysis, but only hemoglobin remained significantly associated with DBP on multivariate analysis, suggesting that hemolysis may not play a substantial role in blood pressure modulation in SCD. The inverse correlation between SBP and PlGF on univariate analysis suggests that PlGF may play a role in the regulation of blood pressure in SCD. This angiogenic growth factor is higher in SCD patients than in control subjects (13). As in preeclampsia (14), PlGF may contribute to the modulation of systemic blood pressure in SCD. Depletion of neutrophils in healthy mice reduces SBP and produces an impairment of vascular constriction studied ex vivo (15). This effect was attributed to neutrophil suppression of interferon-mediated inducible nitric oxide synthase expression. The reason for the contradictory finding in SCD patients in our study is uncertain. SCD is referred to as a chronic inflammatory state (16) and patients exhibit elevated leukocyte counts and abnormal activation of various cellular elements (17) even in the non-crisis, “steady state”. Leukocytosis is also a risk factor for multiple complications, including acute chest syndrome (18) hemorrhagic stroke (5), vasoocclusive crises (19) and increased mortality (20). Our study suggests that the inflammatory state, by possibly increasing the rate of complications and disease severity, may produce lower blood pressures in patients with SCD. This study was not primarily designed to evaluate systemic blood pressure in SCD. Blood pressure measurement was performed using different techniques in our patient cohort and the CSSCD. Our patients were recruited from a specialty clinic at a tertiary care medical center, and may not represent all patients with SCD. As with all cross-sectional studies, this analysis demonstrates associations, but cannot prove causation. In conclusion, patients with SCD in our cohort have significantly higher systemic blood pressures compared with a historical cohort. The blood pressures of our patient cohort are not significantly different when compared with control subjects. SBP is associated with age, BMI, history of hypertension and inversely associated with absolute neutrophil count.