Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease

Estcourt, Lise J; Kohli, Ruchika; Hopewell, Sally; Trivella, Marialena; Wang, Winfred C.

doi:10.1002/14651858.cd003146.pub4

Cited by 14 publications

(18 citation statements)

References 132 publications

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Section: Discussionmentioning

confidence: 99%

“…Exchange transfusion should be considered early during the course of symptomatic COVID-19 infection in sickle cell disease patients, as it may significantly improve their clinical outcomes. 20,21 The clinical course of patients with sickle cell disease and COVID-19 is varied. One case series evaluated 5 patients with sickle cell disease who were diagnosed with COVID-19 in 2020 with symptomatology that ranged from mild upper respiratory tract symptoms to an 8-day hospitalization necessitating PRBC transfusion.…”

Section: Discussionmentioning

confidence: 99%

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Catastrophic Neurological Complications in 2 Patients With Sickle Cell Disease and COVID-19

Clarke

Benameur

Wiley

et al. 2022

Journal of Investigative Medicine High Impact Case Reports

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Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is commonly associated with neurological complications. Patients with sickle cell disease are at increased risk of developing neurologic complications throughout their lifetimes and often have underlying cardiopulmonary comorbidities that may predispose them to poor outcomes during serious infections. In this case series, we describe 2 patients with sickle cell disease who developed devastating neurologic complications following SARS-CoV-2 infection, which ultimately led to brain edema and death. We highlight the unusual manifestations of coronavirus disease 2019 in patients with sickle cell disease and address the risk of these patients to develop catastrophic neurologic injury due to COVID-19, if not recognized promptly.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Catastrophic Neurological Complications in 2 Patients With Sickle Cell Disease and COVID-19

Clarke

Benameur

Wiley

et al. 2022

Journal of Investigative Medicine High Impact Case Reports

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“…Blood transfusion and red cell exchange are another therapeutic option that reduces the concentration of circulating sRBCs by introducing normal RBCs, which can decrease the occurrence of complications like VOC and stroke (Estcourt et al, 2020). A common indication for chronic transfusion is an abnormal transcranial Doppler (TCD) ultrasound velocity across the vessels of the circle of Willis, indicating increased risk of stroke, or an overt stroke (Adams et al, 1992(Adams et al, , 1998.…”

Section: Discussionmentioning

confidence: 99%

Rheological Impact of GBT1118 Cessation in a Sickle Mouse Model

Nebor

Kanne

Pochron

et al. 2020

Blood

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Background: In sickle cell disease (SCD), elevated blood viscosity is a risk factor for vaso-occlusive crisis (VOC). Blood viscosity is influenced by hemoglobin (Hb) levels, red blood cell (RBC) deformability, density, and aggregation. Voxelotor is an HbS polymerization inhibitor that increases the Hb affinity for oxygen and reduces sickling. In human subjects, voxelotor significantly increases Hb levels. A rise in Hb due to voxelotor does not increase blood viscosity the way a similar increase in unmodified HbS would. However, voxelotor transiently modifies HbS, raising concern that if voxelotor was stopped suddenly, the drug induced extra HbS would revert to its unmodified state, causing a significant rise in blood viscosity and increasing the risk of VOC. This effect could continue until the drug induced Hb is eliminated by hemolysis. To investigate this, we treated a sickle mouse model with GBT1118, a voxelotor analog. We then stopped the treatment and determined the effect on whole blood viscosity, the hematocrit-to-viscosity ratio (HVR), a measure of oxygen carrying capacity, and RBC deformability. As GBT1118 has a half-life of 14 hours in SCD mouse, we measured the post-drug effect 48 hours after drug withdrawal. Methods: Ten Townes HbSS mice were fed control chow, 10 were fed chow containing GBT1118 for 7 days, 10 were fed GBT1118 chow for 7 days, and then returned to control chow for 48 hours. RBC deformability was measured by oxygen gradient ektacytometry (Lorrca with Oxygenscan, RR Mechatronics). Blood viscosity was measured with a cone and plate viscometer (Brookfield DVII+). Hb was measured via ADVIA (Siemens). Results: Treatment with GBT1118 significantly increased Hb without increasing blood viscosity. HVR was increased at both 45 s-1 and 225 s-1 shear rates (Figure 1). GBT1118 treatment also improved RBC deformability under both normoxic (EImax) and hypoxic conditions (EImin). Point of sickling (PoS) was reduced, indicating that treated RBC tolerated lower oxygen concentrations before sickling (Figure 2). When the drug was withdrawn for 48 hours, compared to control animals, 1) Hb declined rapidly (7.1 g/dL in control feed, 13.1 g/dL in treated mice compared to 9.0 g/dL after 48 hours off treatment, P<0.001); 2) viscosity did not increase compared to control feed (at shear rate 45 s-1, 12.8 cP after treatment compared to 11.4 cP in control cohort; at shear rate 225 s-1,10.8 cP after treatment compared to 10.3 cP in controls); 3) HVR returned to baseline (at shear rate 45 s-1, 4.5 after treatment compared to 3.6 in controls; at shear rate 225 s-1, 6.6 after treatment compared to 4 cP in controls), 4) EImin remained elevated (0.16 in controls compared to 0.32 after 48 hours off treatment, P<0.001); 5) Elmax and PoS were not significantly different. Conclusions: The GBT1118-treated sickle mouse had a significant rise in Hb and improvement in PoS and deformability. Forty-eight hours after removing the analog compound, Hb dropped markedly, and the PoS was not different from control animals, suggesting a return to native oxygen affinity and clearance of the drug. Interestingly, deformability (EImin) did not return to baseline, suggesting some residual rheological improvement occurred in the red cell population that did not dissipate when the drug was cleared. These data suggest that potential concerns regarding viscosity rising above pre-treatment levels upon sudden cessation of voxelotor are not warranted. This may be due to retained improvement in red cell rheology after voxelotor is stopped combined with rapid return to baseline Hb levels. Further study in patients treated with voxelotor may be needed to determine if voxelotor produces additional benefits, such as reduction in oxidative stress, that outlive its presence in the red cell. Disclosures Pochron: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Oksenberg:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sheehan:Global Blood Therapeutics: Research Funding; Emmaus: Research Funding; Novartis: Research Funding.

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“…By diluting the load of sickle red blood cells in the circulation, chronic blood transfusion may reduce the risk of vaso-occlusion and stroke [30]. However, it also leads to cardiac remodeling, that is, LV dilation from volume overload.…”

Section: Preventive Measures To Cope With Complicationsmentioning

confidence: 99%

Cardiomyopathy in Sickle Cell Disease

Kaur¹,

Aurif²,

Kittaneh³

et al. 2020

Cureus

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Sickle cell disease (SCD) is an inherited disorder that occurs due to point mutation in the betaglobin chain resulting in the production of hemoglobin S that tends to become rigid and sickleshaped under low oxygen concentration. These sickle-shaped red blood cells (RBCs) obstruct the blood vessels leading to reduced blood flow to the organs, causing ischemia and tissue fibrosis. These sickle RBCs being abnormal in shape are frequently sequestered by the spleen, creating a state of chronic anemia in the body. This chronic anemia leads to a high cardiac output state causing cardiac remodeling. To tackle chronic anemia, patients are frequently treated with blood transfusions that makes them more prone to the risk of iron overload (from newly transfused RBCs and iron release from the RBCs that just got sequestered as well as from volume overload) and volume overload causing left ventricular (LV) dilation. The abovementioned mechanism of cardiac hypertrophy, along with LV dilation together, makes SCDrelated cardiomyopathy unique cardiomyopathy with features of restrictive cardiomyopathy with LV dilation. It is interesting to note here that even though there is a presence of LV dilatation, Systolic dysfunction is very uncommon in SCD-related cardiomyopathy.

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Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease

Abstract: Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease.

Cited by 14 publications

References 132 publications

Catastrophic Neurological Complications in 2 Patients With Sickle Cell Disease and COVID-19

Catastrophic Neurological Complications in 2 Patients With Sickle Cell Disease and COVID-19

Rheological Impact of GBT1118 Cessation in a Sickle Mouse Model

Cardiomyopathy in Sickle Cell Disease

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