Does increased red blood cell deformability raise the risk for osteonecrosis in sickle cell anemia?

To the editor:

The pathogenesis of osteonecrosis in sickle cell anemia (SCA) remains unknown. Blood hyperviscosity has been suggested as a factor involved in the genesis of osteonecrosis,¹  but has not been studied until now. We hypothesized that abnormal hemorheology could play a role in this complication. Hematologic and hemorheologic parameters were assessed in SCA patients with (OST+; n = 30) or without (OST−; n = 67) osteonecrosis. Osteonecrosis was diagnosed as previously described.²  The study was conducted according to the Declaration of Helsinki guidelines and was approved by the Regional Ethics Committee. The results are reported in Table 1. OST+ patients were older than OST− patients (P < .05) and more had a history of vaso-occlusive crises (VOC) within the previous year (P < .05) and a higher frequency of α-thalassemia (P < .05), confirming previous studies.^3-5  Although the OST+ group exhibited higher hemoglobin (Hb) and hematocrit and a lower hemolytic component than the OST− group (P < .01), blood viscosity was not significantly different between the 2 groups (P < .20). In contrast, red blood cell (RBC) deformability (P < .001) and aggregation (P < .05) were increased in the OST+ group. The hydroxyurea (HU) treatment frequency was not significantly different between the 2 groups (P < .20). As HU is known to modulate RBC deformability,⁶  we analyzed the data as a function of HU therapy independently of osteonecrosis and found that HU-treated patients had lower blood viscosity and greater RBC deformability (data not shown). Excluding HU-treated patients from the cohort did not change the results (Table 1).

A binary (OST−/OST+) multivariate logistic model was used to identify factors associated with osteonecrosis in SCA patients and included age, Hb, RBC aggregation and deformability, hemolytic component, α-thalassemia status, and previous history of VOC as covariates. The overall model was significant (χ² = 30.192; df = 7; P < .0001) and retained age (odds ratio [OR]: 1.06; 95% confidence interval [CI]: 1.01-1.12; P < .05), Hb (OR: 2.24; 95% CI: 1.19-4.18; P < .05), and RBC deformability (OR: 1.15; 95% CI: 1.01-1.33; P < .05) as independent factors statistically associated with osteonecrosis. Two other binary multivariate logistic models were tested: one included the previous parameters plus blood viscosity and HU therapy and the other excluded all HU patients. The results were similar to those in the first model (data not shown).

Our study demonstrates that increased RBC deformability is associated with osteonecrosis in SCA. Irregularly shaped, deformable sickle RBCs were previously shown to be more adherent than rigid, irreversibly sickle RBCs,⁷  hence triggering vascular occlusion.⁸  The greater RBC deformability found in the OST+ group is probably caused by the greater frequency of patients with α-thalassemia in this group because patients with α-thalassemia had greater RBC deformability (0.18 ± 0.05) than patients without RBC deformability (0.15 ± 0.06, P < .05). Although higher Hb levels were observed in patients with osteonecrosis, the data do not support a significant role for blood viscosity in the pathogenesis of this complication, even after excluding data from patients under HU therapy. Further studies will be required to delineate the mechanisms by which RBC deformability raises the risk for osteonecrosis.