Transfusional iron overload in children with sickle cell anemia on chronic transfusion therapy for secondary stroke prevention

Kwiatkowski, Janet L.; Cohen, Alan R.; Garro, Julian; Álvarez, Ofelia; Nagasubramanian, Ramamorrthy; Sarnaik, Sharada A.; Thompson, Alexis A.; Woods, Gerald M.; Schultz, William H.; Mortier, Nicole A.; Lane, Peter A.; Mueller, Brigitta U.; Yovetich, Nancy A.; Ware, Russell E.

doi:10.1002/ajh.22228

Cited by 20 publications

(8 citation statements)

References 19 publications

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“…The four key biomarkers in our study represent patho‐biological processes that have been described to be associated with cerebrovascular disease in SCA, i.e., cerebral ischemia, endothelial activation, vascular cell proliferation, and thrombosis . Our data also support the concepts outlined by Hebbel et al and Kato et al , that sickle cell‐associated vasculopathy is mediated by endothelial dysregulation and inflammation and that mitigating these pathologies (in this case, using PRBC transfusion) will result in improved clinical outcome, as was observed in the STOP study. A surprising finding for us was the observation of higher baseline biomarkers levels among subjects randomized to SC compared with those randomized to receive transfusion.…”

Section: Discussionsupporting

confidence: 87%

“…There is no safe time to discontinue chronic PRBC transfusion because the stroke risk reverts to pre‐intervention levels . Chronic PRBC transfusion is associated with significant iron overload and currently, hydroxyurea is being investigated as an alternative in order to mitigate the complications of iron overload . In addition, chronic PRBC transfusions cannot effectively prevent silent cerebral infarcts (SCI) in subjects with advanced cerebral vasculopathy .…”

Section: Introductionmentioning

confidence: 99%

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Frequent red cell transfusions reduced vascular endothelial activation and thrombogenicity in children with sickle cell anemia and high stroke risk

et al. 2013

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Stroke is one of the most disabling complications of sickle cell anemia (SCA). The molecular mechanisms leading to stroke in SCA or by which packed red blood cell (PRBC) transfusion prevents strokes are not understood. We investigated the effects of PRBC transfusion on serum biomarkers in children with SCA who were at high-risk for stroke. Serum samples from 80 subjects were analyzed, including baseline, study exit time point and 1 year after study exit. Forty of the 80 samples were from subjects randomized to standard care and 40 from transfusion arm. Samples were assayed for levels of BDNF, sVCAM-1, sICAM-1, MPO, Cathepsin-D, PDGF-AA, PDGF-AB/BB, RANTES (CCL5), tPAI-1, and NCAM-1 using antibody immobilized bead assay. Significantly lower mean serum levels of sVCAM-1 (2.2 × 106 ± 0.8 × 106 pg/mL vs. 3.1 × 106 ± 0.9 × 106 pg/mL, P < 0.0001), Cathepsin-D (0.5 × 106 ± 0.1 × 106 pg/mL vs. 0.7 × 106 ± 0.2 × 106 pg/mL, P < 0.0001), PDGF-AA (10556 ± 4033 pg/mL vs. 14173 ± 4631 pg/mL, P = 0.0008), RANTES (0.1 × 106 ± 0.07 × 106 pg/mL vs. 0.2 × 106 ± 0.06 × 106 pg/mL, P < 0.006), and NCAM-1 (0.7 × 106 ± 0.2 × 106 pg/mL vs. 0.8 × 106 ± 0.1 × 106 pg/mL, P < 0.0006) were observed among participants who received PRBC transfusion, compared to those who received standard care. Twenty or more PRBC transfusion over 4 years was associated with lower serum levels of sVCAM-1 (P < 0.001), PDGF-AA (P = 0.025), and RANTES (P = 0.048). Low baseline level of BDNF (P = 0.025), sVCAM-1 (P = 0.025), PDGF-AA (P = 0.01), t-PAI-1 (P = 0.025) and sICAM-1 (P = 0.022) was associated with higher probability of stroke free survival. Beyond improving hemoglobin levels, our results suggest that the protective effects of PRBC transfusion on reducing stroke in SCD may result from reduced thrombogenesis and vascular remodeling.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Frequent red cell transfusions reduced vascular endothelial activation and thrombogenicity in children with sickle cell anemia and high stroke risk

et al. 2013

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“…One observational study showed wide variability in the rise of ferritin in 61 children with SCD who initiated regular transfusions for primary stroke prevention. Multiple studies showed that ferritin levels do not correlate precisely with liver iron concentration in SCD, 91,[161][162][163] and trends in ferritin levels show similar limitations. [164][165][166] Low ferritin levels (,1500 ng/mL) generally correlate with well controlled liver iron concentration: in 1 study, 90% of patients with serum ferritin below 1500 ng/mL had liver iron concentration below 7 mg/g (dw), whereas in another, serum ferritin values of 750 to 1500 ng/mL corresponded to liver iron concentration of 2.5 to 10 mg/g dw in 75% of patients.…”

Section: Remarksmentioning

confidence: 98%

American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support

et al. 2020

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Background: Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific indications and administration of transfusion, as well as screening, prevention, and management of alloimmunization, delayed hemolytic transfusion reactions (DHTRs), and iron overload may improve outcomes. Objective: Our objective was to develop evidence-based guidelines to support patients, clinicians, and other healthcare professionals in their decisions about transfusion support for SCD and the management of transfusion-related complications. Methods: The American Society of Hematology formed a multidisciplinary panel that was balanced to minimize bias from conflicts of interest and that included a patient representative. The panel prioritized clinical questions and outcomes. The Mayo Clinic Evidence-Based Practice Research Program supported the guideline development process. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to form recommendations, which were subject to public comment. Results: The panel developed 10 recommendations focused on red cell antigen typing and matching, indications, and mode of administration (simple vs red cell exchange), as well as screening, prevention, and management of alloimmunization, DHTRs, and iron overload. Conclusions: The majority of panel recommendations were conditional due to the paucity of direct, high-certainty evidence for outcomes of interest. Research priorities were identified, including prospective studies to understand the role of serologic vs genotypic red cell matching, the mechanism of HTRs resulting from specific alloantigens to inform therapy, the role and timing of regular transfusions during pregnancy for women, and the optimal treatment of transfusional iron overload in SCD.

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“…The average duration of previous transfusion therapy was 7·4 ± 3·8 years (median 7·6 years, range 1·5–15·5 years). Most children had previously received chelation: 47 (71%) with deferoxamine for 4·8 ± 3·2 years and 57 (86%) with deferasirox for 1·5 ± 0·8 years prior to study enrollment (Kwiatkowski et al , ).…”

Section: Resultsmentioning

confidence: 99%

Therapeutic phlebotomy is safe in children with sickle cell anaemia and can be effective treatment for transfusional iron overload

et al. 2015

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SUMMARY Serial phlebotomy was performed on sixty children with sickle cell anaemia, stroke and transfusional iron overload randomized to hydroxycarbamide in the Stroke With Transfusions Changing to Hydroxyurea trial. There were 927 phlebotomy procedures with only 33 adverse events, all of which were grade 2. Among 23 children completing 30 months of study treatment, the net iron balance was favourable (−8.7 mg Fe/kg) with significant decrease in ferritin, although liver iron concentration remained unchanged. Therapeutic phlebotomy was safe and well-tolerated, with net iron removal in most children who completed 30 months of protocol-directed treatment.

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Transfusional iron overload in children with sickle cell anemia on chronic transfusion therapy for secondary stroke prevention

Cited by 20 publications

References 19 publications

Frequent red cell transfusions reduced vascular endothelial activation and thrombogenicity in children with sickle cell anemia and high stroke risk

Frequent red cell transfusions reduced vascular endothelial activation and thrombogenicity in children with sickle cell anemia and high stroke risk

American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support

Therapeutic phlebotomy is safe in children with sickle cell anaemia and can be effective treatment for transfusional iron overload

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