Erythrocyte pyruvate kinase activation in red cell disorders

Federti, Enrica; Franceschi, Lucia De

doi:10.1097/moh.0000000000000758

Cited by 7 publications

(6 citation statements)

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“…The 2,3-DPG /ATP ratio is critical to ensure normal functioning and survival of red cells into the peripheral circulation. 6,54 In addition, the existing cross-connection between glycolysis and the pentose phosphate shunt crucially contributes the production of nicotinamide adenine dinucleotide phosphate (NADPH) and nicotinamide adenine dinucleotide (NADH) (Figure 2, 3). Of note a substantial portion of key anti-oxidant systems such as glutathione (GSH), are NADH or NADPH dependent.…”

Section: Agents Targeting Erythroid Metabolismmentioning

confidence: 99%

“…[58][59][60][61] The development of PK activators has changed the scenario of the treatment of patients with PK deficiency, but also of other red cell disorders characterized by either severe oxidation as in thalassemias and SCD (Figure 1) or relative PK deficiency as in HS. 54,62,63 . Three oral drugs targeting PK function have been recently evaluated (i) mitapivat and AG-946, which bind the PK enzyme pocket at the dimerdimer interface, resulting in PK activation of both PK-R and PK-M2; and (ii) etavopivat, a selective oral PK-R activator.…”

Section: Agents Targeting Erythroid Metabolismmentioning

confidence: 99%

“…Three oral drugs targeting PK function have been recently evaluated (i) mitapivat and AG-946, which bind the PK enzyme pocket at the dimerdimer interface, resulting in PK activation of both PK-R and PK-M2; and (ii) etavopivat, a selective oral PK-R activator. 54 Mitapivat has been approved by FDA and the EMA for treatment of hemolytic anemia in adult patients with PK deficiency (Table 4S). 64,65 Pre-clinical studies in a mouse model for -thalassemia have shown the beneficial effects of mitapivat on both ineffective erythropoiesis and chronic hemolytic anemia with an accompanying improvement of iron homeostasis.…”

Section: Agents Targeting Erythroid Metabolismmentioning

confidence: 99%

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Novel therapeutic approaches in thalassemias, sickle cell disease, and other red cell disorders

Pinto,

Mazzi,

De Franceschi

2024

Blood

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In this last decade, a deeper understanding of the pathophysiology of hereditary red cell disorders and the development of novel classes of pharmacologic agents have provided novel therapeutic approaches to thalassemias, sickle cell disease (SCD) and other red cell disorders. Here, we analyze and discuss the novel therapeutic options according to their targets and taking into consideration the complex process of erythroid differentiation, maturation, and survival of erythrocytes in the peripheral circulation. We focus on active clinical exploratory and confirmatory trials on thalassemias, SCD and other red cell disorders. Beside -thalassemia and SCD, we found that the development of new therapeutic strategies has allowed the design of clinic studies also for hereditary red cell disorders still lacking valuable therapeutic alternative such as -thalassemias, congenital dyserythropoietic anemia or Blackfan Diamond anemia. In addition, reduction of heme synthesis, which can be achieved by the repurposed anti-psychotic drug Bitopertin, might affect not only hematological disorders but multiorgan diseases such as erythropoietic protoporphyria. Finally, our review highlights the current state of therapeutic scenarios, in which multiple indications targeting different red cell disorders are being considered for a single agent. This is welcome change which will hopefully expand therapeutic option for patients affected by thalassemias, SCD and other red cell disorders.

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Section: Agents Targeting Erythroid Metabolismmentioning

confidence: 99%

Section: Agents Targeting Erythroid Metabolismmentioning

confidence: 99%

Section: Agents Targeting Erythroid Metabolismmentioning

confidence: 99%

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Novel therapeutic approaches in thalassemias, sickle cell disease, and other red cell disorders

Pinto,

Mazzi,

De Franceschi

2024

Blood

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“…It is well known that inflammation, infection, tumors and immunodeficiency can activate circulating blood cells and inflammatory cells [7][8][9] . Activated blood cells such as erythrocytes, leukocytes and platelets have been shown to induce a prethrombotic state in the body [10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

Procoagulant effect of phosphatidylserine exposed to extracellular vesicles, blood cells and endothelial cells in patients with aortic stenosis

Du,

Wang,

Shao

et al. 2024

Preprint

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BackgroundThe mechanism of thrombotic complications in patients with aortic stenosis (AS) is unknown. Our aim was to evaluate the levels of phosphodiesterase (PS) in blood cells, endothelial cells (ECs), and extracellular vesicles (EVs) and its procoagulant activity (PCA) in different degrees of AS.MethodsExposed PS in blood cells, ECs and EVs were analyzed by flow cytometry. PCA was evaluated by clotting time (CT), intrinsic factor Xa (FXa), extrinsic FXa, thrombin and fibrin formation assays. We also evaluated the inhibitory effects of lactadherin (Lact) and anti-tissue factor (anti-TF) on PCA in severe AS patients.ResultsOur results demonstrated that positive phosphatedylserin (PS+) with total EVs, platelet EVs (PEVs), positive tissue factor EVs (TF+EVs), and endothelial-derived EVs (EEVs) levels were significantly higher in mild to severe AS than controls. Patients with AS had significantly higher percentages of PS+red blood cells (RBCs), white blood cells (WBCs), platelets (PLTs) and ECs compared to controls. In addition, we further confirmed that PS+blood cells, ECs and EVs significantly contributed to shortened CT and dramatically increased FXa, thrombin and final fibrin generation in mild to severe AS compared to controls. Furthermore, in severe AS, lactadherin significantly inhibited PCA of PS exposure in blood cells, ECs and EVs, whereas anti-TF had no effect.ConclusionOur study revealed a previously unrecognized association between exposed PS levels on blood cells, ECs and EVs and PCA in AS. Lactadherin promises to be a new therapy by blocking PS to prevent thrombosis in AS patients.

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“…Mitapivat and etavopivat have also been tested in patients with sickle cell disease (SCD), another RBC disorder characterized by a relative PK deficiency. Both PK activators have been reported to ameliorate hemolysis in mouse models of SCD and in proof-of concept studies in small cohorts of patients with SCD ( 22 , 23 ). These findings suggest that PK activators could be potential novel therapeutic options for management of other hereditary RBC disorders such as HS characterized by excess oxidative stress, perturbation of the glycolytic pathway, and/or relative PK deficiency.…”

Section: Introductionmentioning

confidence: 99%

Mitapivat reprograms the RBC metabolome and improves anemia in a mouse model of hereditary spherocytosis

Matte,

Wilson,

Gevi

et al. 2023

JCI Insight

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Hereditary spherocytosis (HS) is the most common, nonimmune, hereditary, chronic hemolytic anemia after hemoglobinopathies. The genetic defects in membrane function causing HS lead to perturbation of the RBC metabolome, with altered glycolysis. In mice genetically lacking protein 4.2 (4.2 –/– ; Epb42), a murine model of HS, we showed increased expression of pyruvate kinase (PK) isoforms in whole and fractioned RBCs in conjunction with abnormalities in the glycolytic pathway and in the glutathione (GSH) system. Mitapivat, a PK activator, metabolically reprogrammed 4.2 –/– mouse RBCs with amelioration of glycolysis and the GSH cycle. This resulted in improved osmotic fragility, reduced phosphatidylserine positivity, amelioration of RBC cation content, reduction of Na/K/Cl cotransport and Na/H-exchange overactivation, and decrease in erythroid vesicles release in vitro. Mitapivat treatment significantly decreased erythrophagocytosis and beneficially affected iron homeostasis. In mild-to-moderate HS, the beneficial effect of splenectomy is still controversial. Here, we showed that splenectomy improves anemia in 4.2 –/– mice and that mitapivat is noninferior to splenectomy. An additional benefit of mitapivat treatment was lower expression of markers of inflammatory vasculopathy in 4.2 –/– mice with or without splenectomy, indicating a multisystemic action of mitapivat. These findings support the notion that mitapivat treatment should be considered for symptomatic HS.

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Erythrocyte pyruvate kinase activation in red cell disorders

Cited by 7 publications

References 61 publications

Novel therapeutic approaches in thalassemias, sickle cell disease, and other red cell disorders

Novel therapeutic approaches in thalassemias, sickle cell disease, and other red cell disorders

Procoagulant effect of phosphatidylserine exposed to extracellular vesicles, blood cells and endothelial cells in patients with aortic stenosis

Mitapivat reprograms the RBC metabolome and improves anemia in a mouse model of hereditary spherocytosis

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