Current issues in blood transfusion for sickle cell disease

Wahl, S.; Quirolo, Keith

doi:10.1097/mop.0b013e328321882e

Cited by 79 publications

(93 citation statements)

References 58 publications

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“…3,23,24 Moreover, severe forms of SCD and β-thalassemia require a blood transfusion regimen that further increases the amount of circulating Hb/heme, thus exacerbating oxidative stress. 25,26 Although an iron chelation therapy is routinely associated with a transfusion regimen, 27,28 no heme chelation therapy has been developed to date that specifically prevents heme-induced endothelial damage and oxidative stress.We previously showed that heme-overloaded Hx-null mice suffered from endothelial damage and vascular congestion, thus highlighting the critical role of Hx in preventing vascular damage.29 Therefore, we hypothesized that Hx could be administered as a drug in hemolytic diseases to prevent heme-driven endothelial dysfunction and oxidative injury. To test this hypothesis, we chose 2 mouse models of SCD and β-thalassemia, 30-32 and we evaluated the effect of an Hx-based therapy in these animals.…”

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Hemopexin Therapy Improves Cardiovascular Function by Preventing Heme-Induced Endothelial Toxicity in Mouse Models of Hemolytic Diseases

et al. 2013

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Background-Hemolytic diseases are characterized by enhanced intravascular hemolysis resulting in heme-catalyzed reactive oxygen species generation, which leads to endothelial dysfunction and oxidative damage. Hemopexin (Hx) is a plasma heme scavenger able to prevent endothelial damage and tissue congestion in a model of heme overload. Here, we tested whether Hx could be used as a therapeutic tool to counteract heme toxic effects on the cardiovascular system in hemolytic diseases. Methods and Results-By using a model of heme overload in Hx-null mice, we demonstrated that heme excess in plasma, if not bound to Hx, promoted the production of reactive oxygen species and the induction of adhesion molecules and caused the reduction of nitric oxide availability. Then, we used β-thalassemia and sickle cell disease mice as models of hemolytic diseases to evaluate the efficacy of an Hx-based therapy in the treatment of vascular dysfunction related to heme overload. Our data demonstrated that Hx prevented heme-iron loading in the cardiovascular system, thus limiting the production of reactive oxygen species, the induction of adhesion molecules, and the oxidative inactivation of nitric oxide synthase/nitric oxide, and promoted heme recovery and detoxification by the liver mainly through the induction of heme oxygenase activity. Moreover, we showed that in sickle cell disease mice, endothelial activation and oxidation were associated with increased blood pressure and altered cardiac function, and the administration of exogenous Hx was found to almost completely normalize these parameters. 12,13,16 In hemolytic diseases, the high rate of hemolysis results in the saturation and depletion of the plasma Hb/heme scavenging systems 17 and leads to a buildup of Hb and heme in the circulation that mediates pro-oxidant and proinflammatory effects on vessel endothelial cells. Conclusions-Hemopexin 18Although many mechanisms contribute to the complex pathophysiology of hemolytic diseases as SCD and β-thalassemia, a unifying theme is represented by the dysfunction of the vascular endothelium and the highly pro-oxidant plasma environment. 1,[19][20][21][22] SCD is characterized by recurring episodes of painful vasoocclusion, leading to ischemia/reperfusion injury and organ damage.6,23 Endothelial dysfunction, inflammation, and activated monocytes, neutrophils, platelets, and dense red cells all contribute to sickle cell crisis.4,23 β -Thalassemia is frequently complicated by thromboembolic events resulting from coagulation abnormalities and damaged red cells exposing phosphatidylserine, to which endothelial activation and oxidative stress strongly contribute. 3,23,24 Moreover, severe forms of SCD and β-thalassemia require a blood transfusion regimen that further increases the amount of circulating Hb/heme, thus exacerbating oxidative stress. 25,26 Although an iron chelation therapy is routinely associated with a transfusion regimen, 27,28 no heme chelation therapy has been developed to date that specifically prevents heme-induced endot...

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Hemopexin Therapy Improves Cardiovascular Function by Preventing Heme-Induced Endothelial Toxicity in Mouse Models of Hemolytic Diseases

et al. 2013

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“…Evidence has been accumulating to support the value of RBC transfusion therapy as an effective treatment for many complications associated with SCD, including reduction of the risk of stroke in children [30][31][32][33]. The landmark stroke prevention trial (STOP) demonstrated that the probability of remaining stroke-free was increased by 92% with long-term transfusion therapy in children with SCD.…”

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confidence: 99%

Iron chelation therapy for patients with sickle cell disease and iron overload

Inati¹,

Khoriaty²,

Musallam³

et al. 2010

American J Hematol

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A 21-year-old male with sickle cell disease (SCD) presented with severe pallor. He had received a total of 100 red blood cell (RBC) units in his lifetime, had a mean serum ferritin level of 3133 ng/ml, and liver iron concentration (LIC) of 12 mg Fe/g dry weight (dw). He was started on subcutaneous deferoxamine (DFO) infusions at a dose of 56 mg/kg/d, five days a week (equivalent to 40 mg/kg/d, seven days a week) and continued to receive 8-10 RBC units/year as treatment for pain. During the first six months of chelation therapy, his serum ferritin levels fell by around 50% of the pretreatment value, but then started to increase back up to the baseline values. The patient was noncompliant with DFO therapy. He experienced pain at the site of injection, could not sleep and was concerned about carrying a pump and not being accepted by his peers. He dropped out of college and abstained from all social activities. He was referred to a psychologist; however, this failed to improve compliance and he opted to stop DFO therapy altogether.The role of iron chelation therapy has long been acknowledged in the management of iron overload in patients receiving blood transfusion therapy; however, data specific to the treatment of patients with SCD are limited. DFO (Desferal 1 ; Novartis Pharma AG, Basel, Switzerland) was the first iron chelator to be licensed, more than 40 years ago, for chronic iron overload as a result of transfusion-dependent anemia and remains the current reference standard iron chelator. The efficacy and safety of DFO is well established in patients with b-thalassemia major [1-3]; however, clinical evaluation in SCD-specific populations is limited. Early small-scale studies of transfused patients with SCD showed that DFO was able to increase urinary iron excretion [4,5] and intensive chelation regimens in heavily iron-overloaded patients with SCD showed acceptable efficacy and safety [6][7][8]. In these small-scale studies, there were no reported incidences of impaired hearing or visual acuity, toxicities that have been noted in patients with b-thalassemia major and other rare anemias when doses are inappropriately high for the level of iron overload [9]. However, careful regulation of dosage and regular audio-visual monitoring is still advised. Increased zinc excretion demonstrated at very high DFO doses (180 mg/kg) [8] may lead to extreme zinc deficiency in patients with SCD who may already have decreased plasma zinc levels [10]. The verification of possible adverse events specific to patients with SCD most certainly requires further study.The major limitation of DFO is the requirement for frequent, slow parenteral administration, which can be painful and inconvenient. Compliance has a noticeable impact on a patient's response to therapy and can have serious consequences, as described in this case. In patients with b-thalassemia major, the demands of DFO therapy have been shown to have a negative impact on quality of life and mental health [11]. The impact of infusions may be greatest for adolescents and y...

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“…Therefore, either plasma-purified or recombinant HPX (rHPX) administration could be associated with blood transfusion (11) in patients with anemia as a specific target therapy to enhance the efficiency of blood transfusion (3). This therapeutic strategy is expected to improve the health status of hemolytic patients by attenuating their endothelial and cardiovascular disorders (8).…”

Section: Introductionmentioning

confidence: 99%