ASH Clinical News ACN_4.2_FULL_ISSUE | Page 26

Written in Blood

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 ( CaO 2

),” the authors wrote in Blood . “ We hypothesized that exchange transfusions decrease CBF and OEF by increasing CaO 2

, 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 ( CMRO 2

) 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-ß 0 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- ß 0 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

TABLE . Transfusion Decreases in CBF and OEF

CBF ( mL / 100 g / min )

OEF (%)

CMRO 2

( mL / 100 g / min )

Gray matter 108.7 ( IQR = 90.5-129.4 )

White matter 59.5 ( IQR = 48.0-72.5 )

Whole brain 34.4 ( IQR = 32.1-38.5 )

Gray matter 35.1 ( IQR = 32.9-37.4 )

White matter 33.5 ( IQR = 31.1-38.9 )

Whole brain 3.2 ( IQR = 2.7-3.6 )

Gray matter 4.0 ( IQR = 3.3-4.3 )

White matter 2.4 ( IQR = 1.9-3.0 )

99.5 ( IQR = 84.4-122.4 )

55.7 ( IQR = 48.8-60.7 )

31.2 ( IQR = 29.6-33.8 )

32.5 ( IQR = 30.6-33.9 )

30.6 ( IQR = 28.8-33.8 )

3.2 ( IQR = 2.5-3.7 )

4.0 ( IQR = 3.1-4.4 )

2.3 ( IQR = 1.9-2.5 ) 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 CMRO 2

( defined as CaO 2 × 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 CaO 2

( 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 CaO 2

. CTT decreased whole brain CBF and OEF without significant change in CMRO 2

, the authors reported . Responses in tissue-segmented CBF , OEF , and CMRO 2 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

0.01

0.03

< 0.0001

< 0.0001

< 0.0001

CBF = cerebral blood flow ; OEF = oxygen extraction fraction ; CMRO 2 = cerebral metabolic rate of oxygen utilization ;

IQR = interquartile range

0.07

0.08

0.10

— KRISTIN P . GUILLIAMS , MD

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 .

REFERENCE

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 ]

24 ASH Clinical News January 2018 Annual Meeting Edition