Although chronic transfusion therapy (CTT) reduces the risk of primary or recurrent stroke in pediatric patients with sickle cell anemia (SCA), it introduces long-term medical complications. To better understand the physiologic mechanisms through which CTT mitigates ischemic risk, Kristin P. Guilliams, MD, of the Department of Neurology at the Washington University School of Medicine in St. Louis, Missouri, and researchers evaluated cerebral oxygen metabolism in a small group of children with SCA. The goal was to develop other stroke prevention therapies that mimic CTT’s effects, but without the toxicity burden (i.e., alloimmunization, iron overload, transfusion reactions, and need for intravenous access).
“Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO2),” the authors wrote in Blood. “We hypothesized that exchange transfusions decrease CBF and OEF by increasing CaO2, thereby relieving cerebral oxygen metabolic stress.” Decreased stress could potentially lower stroke risk, they added.
The study used novel, non-invasive magnetic resonance methods, “allowing tissue-level quantification of OEF and cerebral metabolic rate of oxygen use (CMRO2) for the first time in pediatric SCA,” the researchers noted.
Three cohorts of children with SCA undergoing CTT at Washington University were included:
- those with hemoglobin (Hb) SS or S-ß0 thalassemia receiving at least 12 months of CTT for stroke prevention (n=21; median age = 13.1 years; range = 6-21 years)
- age-matched children with Hb SS or Hb S- ß0 thalassemia not receiving CTT (n=21; median age = 11.5 years; range = 6-21 years)
- age-matched healthy siblings without sickle cell trait (control; n=13; median age = 11.2 years; range = 6-17 years)
Patients were excluded if they had sickle cell trait confirmed by laboratory or newborn screen results, were pregnant, had undergone hematopoietic cell transplantation, or had a history of neurologic illness other than stroke. In the healthy control population, patients with a history of any neurologic illness were excluded.
CTT was defined as the manual exchange transfusion or erythrocytapheresis (volume calculated to target post-transfusion hematocrit of 36% and Hb S <30%) performed every four to six weeks, excluding simple transfusion. The manual exchange transfusion protocol involved phlebotomize 10 mL/kg and up to two units (5-20 mL/kg) of packed red blood cells based on pretransfusion Hb.
Researchers measured venous Hb, hematocrit, and Hb levels within 48 hours prior to transfusion and immediately after. Patients underwent MRI within 24 hours before and after transfusion. Investigators then compared global and regional CBF, OEF, and CMRO2 (defined as CaO2 × CBF × OEF) before and after exchange transfusion. One patient was excluded from OEF analysis and two were excluded from CBF analyses based on protocol.
CTT increased median total Hb from 9.1 g/dL (interquartile range [IQR] = 8.8-9.6 g/dL) prior to transfusion, to 10.3 g/dL (IQR=10.2-11.0 g/dL; p<0.001) after transfusion. It also decreased levels of Hb S, from 39.7 percent (IQR=31.7-48.1%) to 24.3 percent (IQR=17.1-33.1%; p<0.001).
At the same time, the median CaO2 (1.36; range not provided) increased from 12.2 mL/dL (IQR=11.7-12.7 mL/dL) to 13.7 mL/dL (IQR=13.2-14.3 mL/dL; p<0.001), confirming that CBF and OEF are often elevated to compensate for the reduction in CaO2.
CTT decreased whole brain CBF and OEF without significant change in CMRO2, the authors reported. Responses in tissue-segmented CBF, OEF, and CMRO2 were similar to whole brain values (see TABLE).
“Although collectively both CBF and OEF decreased by an average of 9 percent post-transfusion, the change in CBF only moderately correlated with change in OEF within individuals (p=0.05), suggesting that CBF and OEF changes in response to transfusion may vary independently,” the researchers noted.
The investigators then compared CTT’s impact on cerebral pathophysiology among the three cohorts, finding that those receiving CTT had similar CBF to patients not on CTT, but a higher CBF than healthy controls.
“This suggests that CTT maintains OEF values lower than non-transfused children [with SCA] throughout the transfusion cycle, thereby reducing chronic cerebral metabolic stress,” the authors wrote. “Surprisingly, neither pre- nor post-transfusion CBF was statistically different between children on CTT, compared [with] non-transfused children [with SCA].”
This single-center study is limited by the small patient population, and the authors noted that it was not powered to assess whether CTT-based change in cerebral metabolic reserve is linked to effective stroke prevention. In addition, the transfusion cohort included patients with vasculopathy, which may have reduced the accuracy of regional CBF quantification.
The authors report no financial conflicts.
Guilliams KP, Fields ME, Ragan DK, et al. Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia. Blood. 2017 December 18. [Epub ahead of print]