Effect of 2,3-Diphosphoclycerate on the Solubility of Deoxy-Sickle Hemoglobin

Swerdlow, Paul; Bryan, Ruth; Bertles, John F.; Poillon, William N.; Hagdoff-Fairchild, B.; Milner, Paul F.

doi:10.3109/03630267709003417

Cited by 21 publications

(3 citation statements)

References 12 publications

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“…As this progresses, the reaction becomes autocatalytic and heterogeneous nucleation occurs on the surface of pre‐existing polymers, leading to robust polymer generation, causing erythrocytes sickling . Polymerisation progression is affected by oxygenation,,3‐diphosphoglycerate (2,3‐DPG) concentration, pH, temperature, saline concentration and carbon monoxide . The rate and kinetics of polymerisation were investigated by Hofrichter and subsequently confirmed by Eaton et al Hofrichter's study of Hb polymerisation was based on calorimetric experiments.…”

Section: Pathophysiology Of the Sickling Mechanismmentioning

confidence: 99%

Insight into the complex pathophysiology of sickle cell anaemia and possible treatment

Piccin

Murphy

Eakins

et al. 2019

European J of Haematology

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Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the β‐globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso‐occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell‐derived microparticle (MP) generation is also involved in the vaso‐occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US‐FDA‐approved therapy to prevent painful vaso‐occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L‐glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA.

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Section: Pathophysiology Of the Sickling Mechanismmentioning

confidence: 99%

Insight into the complex pathophysiology of sickle cell anaemia and possible treatment

Piccin

Murphy

Eakins

et al. 2019

European J of Haematology

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“…P 50 is a measure of oxygen affinity and its increase is described by the Bohr effect (MacDonald, ). P 50 and 2,3‐DPG levels vary widely among patients with sickle cell disease (SCD), but elevated levels appear to decrease Hb S solubility (Poillon et al , , ; Poillon & Kim, ) and increase red cell sickling under hypoxia (Jensen, ; Rogers et al , ), although this has not confirmed by all investigators (Beutler et al , ; Swerdlow et al , ).…”

Section: Oxygen Affinity Of Sickle Erythrocytesmentioning

confidence: 99%

New developments in anti‐sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?

et al. 2016

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Summary The hallmark of sickle cell disease is the polymerization of sickle haemoglobin due to a point mutation in the β-globin gene (HBB). Under low oxygen saturation, sickle haemoglobin assumes the tense (T-state) deoxygenated conformation that can form polymers, leading to rigid erythrocytes with impaired blood vessel transit, compounded or initiated by adhesion of erythrocytes to endothelium, neutrophils and platelets. This process results in vessel occlusion and ischaemia, with consequent acute pain, chronic organ damage, morbidity and mortality. Pharmacological agents that stabilize the higher oxygen affinity relaxed state (R-state) and/or destabilize the lower oxygen affinity T-state of haemoglobin have the potential to delay the sickling of circulating red cells by slowing polymerization kinetics. Relevant classes of agents include aromatic aldehydes, thiol derivatives, isothiocyanates and acyl salicylates derivatives. The aromatic aldehyde, 5-hydroxymethylfurfural (5-HMF) increases oxygen affinity of sickle haemoglobin and reduces hypoxia-induced sickling in vitro and protects sickle cell mice from effects of hypoxia. It has completed pre-clinical testing and has entered clinical trials as treatment for sickle cell disease. A related molecule, GBT440, has shown R-state stabilization and increased oxygen affinity in preclinical testing. Allosteric modifiers of haemoglobin as direct anti-sickling agents target the fundamental pathophysiological mechanism of sickle cell disease.

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“…5–7 Among patients with SCD, P 50 and 2,3-DPG levels vary widely, and more elevated levels appear to decrease solubility of sickle hemoglobin (HbS), 8–10 and to increase red cell sickling under hypoxia, 7,11 although not confirmed by all investigators. 12,13 In vitro manipulation of human sickle blood to reduce 2,3-DPG content in red cells also reduces hypoxia-induced sickling in vitro . 14 Preliminary investigation suggests that decreased oxygen affinity of HbS may be associated with greater clinical symptoms, 8,15 but more investigation is needed to confirm this association.…”

Section: Oxygen Affinity Of Sickle Erythrocytesmentioning

confidence: 99%

Therapeutic Strategies to Alter the Oxygen Affinity of Sickle Hemoglobin

Safo

Kato

2014

Hematology/Oncology Clinics of North America

100

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The fundamental pathophysiology of sickle cell disease involves the polymerization of sickle hemoglobin in its T-state which develops under low oxygen saturation. One therapeutic strategy is to develop pharmacologic agents to stabilize the R-state of hemoglobin, which has higher oxygen affinity and would be expected to have slower kinetics of polymerization, potentially delaying the sickling of red cells during circulation. This therapeutic strategy has stimulated the laboratory investigation of aromatic aldehydes, aspirin derivatives, thiols and isothiocyanates that can stabilize the R-state of hemoglobin in vitro. One representative aromatic aldehyde agent, 5-hydoxymethyl-2-furfural (5-HMF, also known as Aes-103) increases oxygen affinity of sickle hemoglobin and reduces hypoxia-induced sickling in vitro and protects sickle cell mice from effects of hypoxia. It has completed pre-clinical testing and has entered clinical trials. The development of Hb allosteric modifiers as direct anti-sickling agents is an attractive investigational goal for the treatment of sickle cell disease.

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Effect of 2,3-Diphosphoclycerate on the Solubility of Deoxy-Sickle Hemoglobin

Cited by 21 publications

References 12 publications

Insight into the complex pathophysiology of sickle cell anaemia and possible treatment

Insight into the complex pathophysiology of sickle cell anaemia and possible treatment

New developments in anti‐sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?

Therapeutic Strategies to Alter the Oxygen Affinity of Sickle Hemoglobin

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