Hemoglobin-Based Oxygen Carriers – Are We There Yet?

Jahr and colleagues¹ recently summarized the history of hemoglobin-based oxygen carriers (HBOCs) to the present day, comparing biochemical and biophysical properties, safety concerns, and therapeutic potential as alternatives to packed red blood cell (PRBC) transfusions.

HBOCs have been investigated for nearly a century as synthetic oxygen carriers in situations including the unavailability of rare antigen-negative PRBCs, combat, rural trauma, disasters, and religious objections to PRBC use. Despite decades of research FDA has not yet approved HBOC use in the U.S., primarily due to safety concerns.

HBOCs can be categorized by the chemical modifications used to create a viable product, which produce cross-linked, polymerized, conjugated, encapsulated, and naturally polymerized hemoglobin (Hb). Each class aims to stabilize free Hb, prevent rapid clearance, reduce toxicity, and enhance oxygen delivery. Each HBOC has general advantages and disadvantages, but be aware that the safety profiles are product-specific and not necessarily class-specific.

First-generation HBOCs: cross-linked hemoglobins; include diaspirin cross-linked Hb (DCLHb) (HemAssist) and recombinant Hb (Optro). Currently discontinued.

Advantages:

• Crosslinking reduces dissociation of tetramers into toxic dimers.
• They exhibit low autoxidation rates.

Disadvantages:

• They have high rates of nitric oxide (NO) scavenging (depletion), causing vasoconstriction.
• Clinical outcomes included high mortality rates in trauma patients, hypertension, and cardiac toxicity.

Second-generation HBOCs: polymerized hemoglobins; include polymerized human Hb (PolyHeme), polymerized bovine Hb (HBOC-201 [Hemopure] and Oxyvita²), and polymerized bovine Hb for veterinary use (Oxyglobin).

Advantages:

• They generally have less heme loss than cross-linked hemoglobins.
• Oxyvita is lyophilized for easy storage and transport.
• Hemopure has shown clinical efficacy in expanded access programs for severe anemia in the U.S. and is approved for acute anemia in South Africa.

Disadvantage:

• PolyHeme was associated with higher mortality rates and serious adverse events in clinical trials and was discontinued.

Third-generation HBOCs: conjugated hemoglobins; include human Hb conjugated with polyethylene glycol (Hemospan) and PEGylated bovine Hb (Sanguinate).

Advantage:

• Hemospan and Sanguinate produce less vasoconstriction than some other HBOCs.²

Disadvantages:

• They have increased heme loss.
• Two conjugated hemoglobins, including Hemospan, failed in phase 3 clinical trials.

New-generation HBOCs, encapsulated hemoglobins; include Hb-containing nanoparticles with pH-responsive oxygen affinity (ErythroMer) and hemoglobin vesicles.

Advantages:

• ErythroMer mimics red blood cells in size and pH-responsive oxygen affinity.
• Encapsulation potentially avoids extravasation, seen with earlier HBOCs.

Disadvantages:

• Clinical studies have not been completed.

New generation HBOCs, naturally polymerized hemoglobins; include HEMO₂life (Hemarina’s M101 marine worm hemoglobin, an extracellular Hb).

Advantages:

• HEMO₂life has demonstrated efficacy in organ preservation and is approved for perfusion of transplanted kidneys in the EU.
• No vasoactive side effects have been reported for HEMO₂life.

Disadvantage:

• Further human trials of HEMO₂life are needed to establish safety for intravenous use.

While early HBOCs were plagued by safety issues tied to oxidative stress, NO scavenging, and heme loss, new-generation encapsulated, naturally polymerized, and genetically engineered HBOCs show potential in overcoming these past limitations. HEMO₂life has received regulatory approval for ex-vivo kidney preservation in the EU, and Hb vesicles are undergoing phase 1 clinical trials.

For regulatory approval and clinical adoption, future HBOCs must be safe for recipients, resolve toxicity concerns related to oxidative stress and NO scavenging, and show efficacy in randomized controlled clinical trials. Physicians and other care providers should remain informed about their evolving safety profiles and potential indications for trauma, surgery, and critical care.

References:

1. Jahr JS, MacKinnon K, Baum VC, Alayash Al. Hemoglobin-based oxygen carriers: Biochemical, biophysical differences, and safety. Transfusion. 2025;65(2):386-396.
2. Chen L, Yang Z, Liu H. Hemoglobin-based oxygen carriers: where are we now in 2023? Medicina (Kaunas). 2023;59:396.