Purification and analysis of a protein cocktail capable of scavenging cell‐free hemoglobin, heme, and iron

Pires, Ivan S.; Govender, Krianthan; Muñoz, Carlos; Williams, Alexander T.; O'Boyle, Quintin; Savla, Chintan; Cabrales, Pedro; Palmer, Andre F.

doi:10.1111/trf.16393

Cited by 5 publications

(7 citation statements)

References 59 publications

(70 reference statements)

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“…Although all are important areas of ongoing investigation, a full discussion is beyond the scope of this review. Of note, there have also been reports of using plasma exchange to treat hemolysis in cardiopulmonary bypass ( 65 ), and multiple groups are working on novel peptides or chemical strategies to remove CFH and its degradation products ( 66 , 67 ). However, here we will focus on drugs that are in current clinical use or have been studied extensively in animals.…”

Section: Resultsmentioning

confidence: 99%

“…a Protein cocktail generated by tangential flow filtration of human Cohn fraction IV, which includes albumin (40%), transferrin (35%), haptoglobin (10%), hemopexin (5%), ceruloplasmin (5%), and vitamin D-binding protein (5%). Note that ceruloplasmin catalyzes oxidation of Fe 2+ to Fe 3+ and vitamin D-binding protein scavenges actin which is released during hemolysis (67). Due to space constraints, studies in which cell-free hemoglobin or its breakdown products were directly administered and their actions were modulated by administration of a therapeutic were not included.…”

Section: Discussionmentioning

confidence: 99%

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Cell-Free Hemoglobin in the Pathophysiology of Trauma: A Scoping Review

Ross,

Robles,

Mazer

et al. 2024

Critical Care Explorations

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OBJECTIVES: Cell-free hemoglobin (CFH) is a potent mediator of endothelial dysfunction, organ injury, coagulopathy, and immunomodulation in hemolysis. These mechanisms have been demonstrated in patients with sepsis, hemoglobinopathies, and those receiving transfusions. However, less is known about the role of CFH in the pathophysiology of trauma, despite the release of equivalent levels of free hemoglobin. DATA SOURCES: Ovid MEDLINE, Embase, Web of Science Core Collection, and BIOSIS Previews were searched up to January 21, 2023, using key terms related to free hemoglobin and trauma. DATA EXTRACTION: Two independent reviewers selected studies focused on hemolysis in trauma patients, hemoglobin breakdown products, hemoglobin-mediated injury in trauma, transfusion, sepsis, or therapeutics. DATA SYNTHESIS: Data from the selected studies and their references were synthesized into a narrative review. CONCLUSIONS: Free hemoglobin likely plays a role in endothelial dysfunction, organ injury, coagulopathy, and immune dysfunction in polytrauma. This is a compelling area of investigation as multiple existing therapeutics effectively block these pathways.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cell-Free Hemoglobin in the Pathophysiology of Trauma: A Scoping Review

Ross,

Robles,

Mazer

et al. 2024

Critical Care Explorations

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“…In addition to engineering molecular systems capable of performing multiple functions such as the apoHb-Hp complex or the Hpx-Hp fusion protein, an alternative strategy is the use of scavenger protein mixtures to scavenge multiple hemolytic by-products. Although this could be accomplished with the use of purified proteins such as Hp, Hpx, and Tf, one approach relies on the purification of a protein cocktail containing these varied therapeutic agents starting from human plasma fraction IV (FIV) (117). FIV is a by-product from the plasma fractionation industry that enables the material to be readily available and sustainably sourced.…”

Section: Protein Scavenging Cocktailmentioning

confidence: 99%

Engineering Therapeutics to Detoxify Hemoglobin, Heme, and Iron

Pires

Berthiaume

Palmer

2023

Annu. Rev. Biomed. Eng.

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Hemolysis (i.e., red blood cell lysis) can increase circulatory levels of cell-free hemoglobin (Hb) and its degradation by-products, namely heme (h) and iron (Fe). Under homeostasis, minor increases in these three hemolytic by-products (Hb/h/Fe) are rapidly scavenged and cleared by natural plasma proteins. Under certain pathophysiological conditions, scavenging systems become overwhelmed, leading to the accumulation of Hb/h/Fe in the circulation. Unfortunately, these species cause various side effects such as vasoconstriction, hypertension, and oxidative organ damage. Therefore, various therapeutics strategies are in development, ranging from supplementation with depleted plasma scavenger proteins to engineered biomimetic protein constructs capable of scavenging multiple hemolytic species. In this review, we briefly describe hemolysis and the characteristics of the major plasma-derived protein scavengers of Hb/h/Fe. Finally, we present novel engineering approaches designed to address the toxicity of these hemolytic by-products.

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“…Therefore, the introduction of pHb into the circulation can ultimately lead to damage within multiple organ systems. 83…”

Section: Extracorporeal Circulation and The Microcirculationmentioning

confidence: 99%

The Disconnect Between Extracorporeal Circulation and the Microcirculation: A Review

2022

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Extracorporeal circulation (ECC) procedures, such as cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO), take over the function of one or more organs, providing clinicians time to treat underlying pathophysiological conditions. ECMO and CPB carry significant mortality rates for patients, despite prior decades of research focused on the resulting failure of critical organs. Since the focus of these procedures is to support blood flow and provide oxygen-rich blood to tissues, a shift in research toward the effects of ECMO and CPB on the microcirculation is warranted. Along with provoking systemic responses, both procedures disrupt the integrity of red blood cells, causing release of hemoglobin (Hb) from excessive foreign surface contact and mechanical stresses. The effects of hemolysis are especially pronounced in the microcirculation, where plasma Hb leads to nitric oxide scavenging, oxidization, formation of reactive oxygen species, and inflammatory responses. A limited number of studies have investigated the implications of ECMO in the microcirculation, but more work is needed to minimize ECMO-induced reduction of microcirculatory perfusion and consequently oxygenation. The following review presents existing information on the implications of ECMO and CPB on microvascular function and proposes future studies to understand and leverage key mechanisms to improve patient outcomes.

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Purification and analysis of a protein cocktail capable of scavenging cell‐free hemoglobin, heme, and iron

Cited by 5 publications

References 59 publications

Cell-Free Hemoglobin in the Pathophysiology of Trauma: A Scoping Review

Cell-Free Hemoglobin in the Pathophysiology of Trauma: A Scoping Review

Engineering Therapeutics to Detoxify Hemoglobin, Heme, and Iron

The Disconnect Between Extracorporeal Circulation and the Microcirculation: A Review

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