Abstract
Background: Sickle cell disease (SCD) patients have altered blood rheology due to erythrocyte abnormalities, including increased aggregation and reduced deformability, which together affect microcirculatory blood flow and tissue perfusion. At equal hematocrit, sickle cell blood viscosity is increased compared to normal individuals. The hematocrit to viscosity ratio (HVR) is a measure of red blood cell (RBC) oxygen carrying capacity, and is reduced in SCD with clinical consequences related to altered blood flow and reduced tissue oxygenation. Erythrocyte transfusions reduce HVR at low shear rates that mimic venous circulation, and do not change HVR at high shear rates that mimic arterial blood flow. Hydroxyurea is a safe and effective therapy for SCD; however, its effects on sickle cell rheology and HVR have not been fully investigated. Evaluating the effects of hydroxyurea on viscosity is especially critical, before its use is extended widely to patients with cerebrovascular disease or genotypes with higher hematocrit and higher viscosity such as Hemoglobin SC (HbSC).
Methods: To determine the effects of hydroxyurea on viscosity and HVR, we designed a prospective study to measure whole blood viscosity at 45 s-1 (low shear) and 225 s-1(high shear) rates in pediatric patients with SCD using a Brookfield cone and plate viscometer under oxygenated conditions. Venous blood samples (1-3mL) were collected in EDTA and analyzed no more than 4 hours after phlebotomy; samples were run in duplicate by persons blinded to the patient’s sickle genotype and treatment status. Laboratory values were obtained using an ADVIA hematology analyzer. Samples were analyzed from three non-overlapping cohorts of patients with SCD and HbAA individuals for comparison: untreated HbSS patients (n= 43), HbSS patients treated with hydroxyurea at maximum tolerated dose (n=98), untreated HbSC patients (n=53) and HbAA patients (n=19). Laboratory parameters that differed significantly among the SCD groups were analyzed by simple linear regression.
Results: Patient characteristics and viscosity measurements are shown in the Table. Within the SCD population, the viscosity was lowest among the untreated HbSS patients, presumably due to their low hematocrit, while viscosity was higher in HbSS patients on hydroxyurea and HbSC patients. When the HVR was calculated for each group, no significant difference was identified between untreated HbSS and untreated HbSC patients. However, hydroxyurea treatment significantly increased HVR at both 45s-1 and 225 s-1 (p<0.001), indicating that the slightly increased viscosity in this cohort was more than compensated by a higher hematocrit. Correlations were tested for hemoglobin (Hb), mean corpuscular volume (MCV), white blood cell count (WBC), absolute neutrophil count (ANC), absolute reticulocyte count (ARC), % fetal hemoglobin (HbF), and average red cell density in g/dL with HVR, at both shear rates. The hydroxyurea-associated HVR increase at both shear rates was independent of %HbF or MCV, but the increased HVR at 225 s-1was associated with lower WBC (p<0.001), lower ANC (p=0.002), and lower red cell density (p=.009).
Conclusions: We provide prospective data on whole blood viscosity measurements in a large cohort of children with SCD. Hydroxyurea increases the hematocrit in HbSS patients more than the viscosity, and thus improves HVR. These findings imply that hydroxyurea improves RBC oxygen transport at both high and low shear rates, which should confer clinical benefits, and these effects are independent of HbF induction. Concerns about hydroxyurea increasing whole blood viscosity and reducing tissue oxygenation in children with cerebrovascular disease or HbSC patients may not be warranted, if the same beneficial HVR effects are achieved.
Abstract 2717. Table 1. Patient characteristics. Viscosity was typically measured in duplicate and averaged for each patient. HVR at 45 s-1 and 225s-1 was calculated as hematocrit/viscosity. Results are presented as mean ± 2SD. HbAAn=19 HbSS, untreatedn=43 HbSS, on Hydroxyurean=98 HbSCn=53 Age (years) 15.4 ± 3.8 10.4 ± 5.1 10.7 ± 3.4 10.5 ± 4.3 Hemoglobin (gm/dL) 13.5 ± 1.7 8.5 ± 1.0 9.9 ± 1.4 11.0 ± 1.2 Hematocrit (%) 40.9 ± 5.3 25.5 ± 3.1 28.4 ± 3.7 31.3 ± 3.2 Viscosity (cP) at 45s-1 5.3 ± 0.9 4.6 ± 1.2 4.3 ± 0.9 5.5 ±0.9 HVR at 45s-1 7.5 ± 0.9 5.8 ± 1.1 6.75 ± 1.0 5.77 ± 0.7 Viscosity (cP) at 225s-1 3.8 ± 0.5 3.3 ± 0.5 3.4 ± 0.5 4.1 ± 0.5 HVR at 225s-1 10.3 ± 0.7 7.7 ± 0.8 8.53 ± 0.8 7.72 ± 0.6
Disclosures
Off Label Use: Hydroxyurea is not FDA approved for use in pediatric sickle cell patients.
G008 Fibrinogen and whole blood low shear viscosity in essential hypertension