Transcranial Doppler Measures In Patients with Sickle Cell Disease at High Risk for Stroke and Receiving Hydroxyurea: The HyRetro Ancillary Study.

Abstract 1620

Children with sickle cell disease (SCD) and increased Transcranial Doppler (TCD) sonography velocity measures are at increased risk for stroke. Although chronic transfusion decreases this risk ten fold, this form of therapy is burdensome, and includes risk of iron overload. Although it has been established that the risk of stroke is still present even after 30 months of transfusion therapy, the total length of transfusion therapy required is not known. Hydroxyurea (HU) therapy is effective in preventing SCD complication, although its effect in preventing SCD central nervous system complications is less clear and a matter of current investigation. During one of the clinical trials (STOP2), an ancillary study was conducted to examine TCD velocities in 76 patients with SCD receiving hydroxyurea (HU) for a variety of indications. TCD measures were defined as the highest time-averaged maximum mean velocity of one of 8 measures (from the following cerebral arteries: LMCAVM, LM1VM, LBIFVM, LDICAVM, RMCAVM, RM1VM, RBIFVM and RDICAVM), as per STOP protocol. Results from 10 patients at high risk for stroke (defined as one or more TCD >=200 cm/sec) were evaluated for the present analysis. Average age at start of HU was 10.7 +/− 3.2 standard deviation (SD) years, 6 were female. Eight did not receiving chronic transfusion in STOP (randomized observation arm STOP n=4; observed non randomized in STOP n=4), and 2 were on transfusion (randomized transfusion arm STOP n=1; STOP/STOP2 with cross over n=1). Reasons for HU therapy included primary stroke prevention (n=6); secondary stroke prevention (TIA n=1; overt ischemic stroke n=1), vaso-occlusive or acute chest episodes (n=2). Averaged HU dose (available in 8) was 15 +/− 3 SD mg/kg. Averaged measures, off and on HU for each patient, were used to calculate means. Averaged hematological indices on treatment were as follows: white blood cell count 10.2 +/− 1.8 SD × 10^3/mm^3, hemoglobin 8.1 +/− 0.7 gm/dL; Mean Corpuscular Volume 105.6 +/− 6.7 cu μm; reticulocyte count 11.1 +/− 2.3 %. Averaged hemoglobin F, available in 8, was 16.1 +/− 5.7 %. Results are in table:

One patient receiving HU for secondary stoke prevention suffered an overt stroke. This patient had a first overt stroke 24 months prior to start of HU therapy. MRI showed right frontal watershed and bilateral lacunar infarcts. Severe stenosis of the left MCA was noted. Patient had a repeat stroke 13 months after start of HU. MRI showed ischemia with watershed distribution of the left frontal lobe, stenosis of A2 and occlusion of A1 segments. Three TCD before and two after start of HU were all > 220 cm/sec. Overall, decreasing TCD velocities were noted in 60% prior to HU (STOP transfusion, n=2) and in 50% on HU (STOP transfusion, n=0). In conclusion, TCD velocities decreased significantly in high risk patients receiving HU, that were not transfused in STOP. However, these results require cautious interpretation, as numbers of patients are small, and length of observation varied. Patients with very high TCD measures remain at risk. Further studies may elucidate if there is a role for HU in patients with abnormal TCDs.