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Hemoglobin-Based Oxygen Carriers: Brief History, Pharmacology and Design Strategies, Review of the Major Products in Clinical Trials, On-Going Studies, and Coagulation Concerns

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Blood Substitutes and Oxygen Biotherapeutics

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Abstract

Transfusion of erythrocytes (RBC) to treat acute or chronic anemia has significant drawbacks, given the risks of transfusion, volunteer donor requirements, limited supply with increasing demand, especially during a pandemic such as COVID-19, and erythrocytes are often unavailable in emergency situations or where blood is not an option. Significant research has been undertaken for almost 100 years to attempt to replicate the functions of RBCs with oxygen carriers/oxygen therapeutics based on hemoglobin. Oxygen carriers that have been evaluated are hemoglobin-based oxygen carriers (HBOCs). HBOCs utilize hemoglobin (Hb) to transport oxygen around the body. Blood transfusion may be critical therapy in hemorrhagic trauma, various pathologies both acute and chronic, and surgical interventions. It has some important goals: the first and most important is to recover oxygen delivery to organs, additionally, when restoration of circulating blood volume is achieved, maintenance of adequate blood pressure to ensure enough blood flow to deliver the oxygen to the microcirculation and resolving oxygen debt.

This chapter will review the history of HBOCs, discuss how HBOCs have been designed and how developed HBOCs differ from each other based on their pharmacology and physiology, highlight all major products to undergo human trials including one extensively studied product approved for human use in two countries (Hemopure), introduce newer products still under development, and finally present translational and clinical trials studying whether or not certain HBOCs may cause coagulation issues.

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Abbreviations

°C:

degrees centigrade

2-3 DPG:

2,3 Diphosphoglycerate

CABG:

coronary artery bypass graft

cADP:

collagen and adenosine diphosphate, a reagent for PFA-100 measurement of platelet adhesion

cEPI:

collagen and epinephrine, a reagent for PFA-100 measurement of platelet adhesion

CO:

carbon monoxide

Cu:

copper

DBBF:

bis(dibromosalicyl) fumarate

dL:

deciliter

EU:

European Union

FDA:

United States Food and Drug Administration

g:

gram

g/dL:

gram per deciliter

Hb:

hemoglobin

Hb4:

Four strands of hemoglobin to form tetramer

HBOC:

Hemoglobin-based oxygen carrier

HIV:

Human immunodeficiency virus

IND:

Investigational New Drug Application

kDa:

kilodalton

L:

liter

Lys:

lysine

M:

molar concentration

M101:

HEMO2-life

MA:

Massachusetts

MAL-PEG:

maleimido polyethylene glycol

mg/dL:

milligrams per deciliter

NO:

nitric oxide

O2:

oxygen

PEG:

Polyethylene glycol

PFA-100:

Platelet Function Analyzer-100

PLP:

pyridoxal-5′-phosphate

pRBC:

packed red blood cells

r:

recombinant

RBC:

red blood cell

SFH:

Stroma Free Hemoglobin

SOD:

superoxide dismutase

TACO:

Transfusion associated circulatory overload

US:

United States

Zn:

zinc

α:

alpha

β:

beta

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Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Jonathan S. Jahr

  2. University of Queensland-Ochsner Medical School, New Orleans, LA, USA

    Kimia Roghani

  3. Dental Medicine, University Dentistry Clinical Center of Kosovo, Pristina, Republic of Kosovo

    Yll Buqa

  4. Drexel University, College of Medicine, Philadelphia, PA, USA

    Allen Rojhani

  5. Stanford University, School of Medicine, Stanford, CA, USA

    Preya Jhita

  6. Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, School of Medicine, Providence, RI, USA

    Hae Won Kim

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  1. Jonathan S. Jahr
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Correspondence to Jonathan S. Jahr .

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Editors and Affiliations

  1. Anesthesiology & Critical Care, University of Pennsylvania, Philadelphia, PA, USA

    Henry Liu

  2. Department of Anesthesiology and Department of Pharmacology, Toxicology, and Neurosciences LSU School of Medicine, Shreveport, LA, USA

    Alan D. Kaye

  3. Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Jonathan S. Jahr

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Jahr, J.S., Roghani, K., Buqa, Y., Rojhani, A., Jhita, P., Kim, H.W. (2022). Hemoglobin-Based Oxygen Carriers: Brief History, Pharmacology and Design Strategies, Review of the Major Products in Clinical Trials, On-Going Studies, and Coagulation Concerns. In: Liu, H., Kaye, A.D., Jahr, J.S. (eds) Blood Substitutes and Oxygen Biotherapeutics. Springer, Cham. https://doi.org/10.1007/978-3-030-95975-3_12

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