Historical Evolution
From Bloodletting to Oxygen Therapeutics
Medicine spent centuries treating disease by removing blood. Transfusion reversed that logic. Blood groups, blood banking and donor systems followed, then artificial blood, blood substitutes and HBOCs. The modern question is narrower: which function is failing, and what has to be restored first?
In Brief
What changed over time.
The key steps were practical: transfuse blood, understand compatibility, store it safely, test it and build donor systems that could work at scale.
The twentieth century added a second problem: could oxygen transport be supported without depending entirely on donor red cells? That led to perfluorocarbon products, artificial-blood programs and HBOCs. Results were mixed.
Transfusion practice also changed. The old 10/30 rule gave way to more restrictive and individualized decisions. In emergency medicine, physiology and signs of shock may matter before a laboratory hemoglobin result is available.
The practical question is no longer only how to replace blood. It is also which function is failing and what needs to be restored first.
Ancient medicine to 1818
From removing blood to giving it back.
Bloodletting
Bloodletting became one of medicine’s longest-lived therapeutic practices. For centuries, disease was often treated by removing blood rather than replacing it.
William Harvey
Harvey’s description of systemic blood circulation transformed how the cardiovascular system was understood and made controlled transfusion scientifically imaginable.
Richard Lower
AABB’s transfusion history records the first successful animal-to-animal blood transfusion in England, keeping dogs alive with blood from other dogs.
AABB transfusion historyAnimal-to-human transfusion
Jean-Baptiste Denis in France and Richard Lower in England separately reported transfusions from lambs to humans. Severe reactions later helped end the practice for centuries.
PubMed historical reviewJames Blundell
Blundell pioneered human-to-human transfusion. AABB records his landmark use of human blood in the treatment of severe blood loss, including postpartum hemorrhage.
AABB transfusion history1900-1901
Karl Landsteiner: compatibility becomes science.
Landsteiner demonstrated that human blood is not immunologically identical, laying the foundation for the ABO system and safer transfusion. He received the 1930 Nobel Prize in Physiology or Medicine for the discovery of human blood groups.
ABO was only the beginning. More than 125 years later, human blood compatibility is still being resolved at greater molecular depth.
Explore the Blood Group Discovery Timeline: ABO → 49 ISBT systems
1937 to 1985
Blood banking scales, and infectious risk becomes impossible to ignore.
The blood bank
Stored blood transformed transfusion from an immediate donor-to-patient act into inventory that hospitals could prepare before an emergency.
Red Cross donor systems scale
Plasma for Britain began in 1940. The American Red Cross began its National Blood Donor Service for the U.S. military on 4 February 1941 and launched its national civilian blood program in 1948.
American Red Cross historical dates
HIV/AIDS changes blood safety
The HIV/AIDS crisis exposed the vulnerability inherent in transferring human biological material between people. Infectious-disease screening, donor selection and public expectations of blood safety changed profoundly, while interest in non-donor oxygen carriers intensified.
The map of human blood compatibility is still expanding
Blood-group science did not stop with ABO or Rh. In June 2026, the ISBT Working Party approved the 49th recognized human blood group system, JAMA, and it entered the official August 2026 database release. That release listed 49 blood group systems and 400 red-cell antigens. More than 125 years after Landsteiner, transfusion medicine is still discovering new layers of compatibility.
This continuing expansion changes how we think about blood itself. Blood is not a simple fluid or a single laboratory number. It is a living, continuously renewing biological tissue and regulatory system with cellular, immunological, vascular and biochemical layers. Human red cells circulate for about 120 days and are replaced continuously, while platelets, leukocytes, plasma proteins and other components turn over on different timescales. The more precisely we study blood, the more complexity we find, and there is still much to understand.
Blood Groups: From ABO to 49 ISBT SystemsISBT August 2026 release
Compatibility had improved. Storage had improved. Blood banking had scaled. But dependence on human donors and biological risk remained.
1940s → 1990s
The search for artificial blood becomes the search for oxygen transport.
Researchers increasingly asked whether the oxygen-carrying function of red cells could be supported without transfusing intact donor erythrocytes. Two major technology families emerged: perfluorocarbon oxygen carriers and hemoglobin-based oxygen carriers.
Perftoran enters clinical and military medicine
A 2024 historical review reports the first Phase I infusion of Perftoran in June 1984 and its use in Soviet military medical units in Afghanistan in October-November 1984. The review also records treatment of fat embolism there and describes later use in military and civilian medicine.
Pirogov Russian Journal of Surgery historical reviewFluosol reaches FDA approval
Fluosol-DA became an FDA-approved perfluorocarbon oxygen-carrying emulsion, but was later discontinued. The episode demonstrated both the feasibility and the practical limitations of early artificial oxygen carriers.
Artificial blood historical reviewPerftoran registered in Russia
Perftoran was registered in Russia in February 1996 as an oxygen-carrying blood substitute and used in military and civilian medical care.
Perftoran reviewHBOC era
When hemoglobin leaves the red cell, manufacturing becomes part of the biology.
Hemoglobin-based oxygen carriers attempted to stabilize hemoglobin outside its natural red-cell environment while retaining oxygen transport. Multiple programs reached human studies and some reached Phase III. The field demonstrated that oxygen transport was possible, but it also showed that an HBOC is not defined by hemoglobin concentration alone. Source material, purification, molecular size distribution, oxygen affinity, oxidation rate, nitric-oxide reactivity, heme loss and residual contaminants can materially change biological behavior.
Purity, endotoxin and quality control became measurable design variables.
Early cell-free hemoglobin work made it difficult to separate toxicity caused by hemoglobin itself from toxicity caused by contaminants. By 1991, investigators explicitly defined a meaningful “pure hemoglobin” preparation as one free of bacterial endotoxin, red-cell membrane phospholipids and residual proteins or peptides.
During early production of αα-cross-linked hemoglobin, investigators later reported lipopolysaccharide contamination ranging from approximately 1 to >100 ng/mL in multiple initial manufacturing samples. Quantitative endotoxin testing allowed contamination sources to be identified and process areas to be made endotoxin-free. Modern oxygen-carrier manufacturing therefore treats bioburden, sterility, endotoxin limits, residual proteins and process consistency as product-critical quality attributes.
Endotoxin cannot be established retrospectively as the single explanation for HBOC failures. Our interpretation is nevertheless that poorly controlled or incompletely characterized endotoxin burden may have made a meaningful contribution to toxicity in at least some early products and may have confounded attribution of inflammatory effects to hemoglobin itself. The contribution would have depended on the product, dose, manufacturing process and clinical context.
Other mechanisms remain important. NO scavenging is not a binary class property: its biological impact depends on molecular design, concentration, reaction kinetics, extravasation, redox behavior and formulation. Oxidation, methemoglobin formation, heme release, molecular-size distribution and indication-specific physiology can also differ substantially from one HBOC to another.
Not all HBOCs are the same. The 2008 Natanson meta-analysis was a pivotal class-level safety signal across five different products and strongly influenced the field. A decade later, FDA scientists performed a side-by-side molecular and biochemical comparison of the clinically tested HBOCs and published it under the title All HBOCs Are Not Created Equally. A 2025 review co-authored by an FDA CBER scientist further emphasized that chemically different HBOCs should not automatically be linked to the same adverse-effect profile and should be evaluated product by product. This does not erase the historical safety signal; it changes how that signal should be interpreted for different molecules, formulations and generations.
Sources: Natanson et al., JAMA, 2008 · FDA CBER / Meng et al., 2018 · Jahr et al., Transfusion, 2025. Full source links are listed in References & Source Notes below.
Major discontinued human clinical HBOC programs
This table covers the major discontinued clinical-stage HBOC programs repeatedly documented in comparative reviews. Not every program ended because of a formal FDA rejection: some stopped because of mortality or cardiac safety signals, failed efficacy endpoints, inadequate clinical performance or financing. Hemopure/HBOC-201 is intentionally not listed as a “failed product” because it achieved regulatory approval outside the United States and later continued under successor ownership.
2025 comparative HBOC safety review Clinical-program status review
Biopure is a different historical case: manufacturing continuity failed, not the existence of the underlying hemoglobin platform.
Unlike the discontinued candidates listed above, Biopure had already crossed major regulatory and commercial boundaries. Oxyglobin was authorized in the United States and Europe, Hemopure was authorized for human use in South Africa, and Biopure had built and validated an industrial manufacturing platform.
The manufacturing record shows repeated operational disruption. Plant expansion and revalidation caused a six-month Cambridge shutdown and major Oxyglobin backorders in 2001-2002; FDA approved the expanded facilities in early 2003. After co-founder Carl W. Rausch moved from CEO to Vice Chairman and Chief Technology Officer in 2002, major workforce and cost reductions in 2003-2004 cut manufacturing capacity so sharply that Biopure reported it could no longer produce enough Oxyglobin to meet demand. The Cambridge site later received an MHRA GMP certificate in 2007. Manufacturing was then suspended again during the severe curtailment of operations that preceded the 2009 bankruptcy.
The historical record therefore supports a distinction between product technology and company execution. Production capability, staffing, validation, QA/QC discipline and continuity of the manufacturing organization are part of a biologic product. When that system is lost, an authorized technology can disappear from practical use even if the molecule itself has not been invalidated. Available primary records document shutdown, revalidation and loss of operating continuity; they do not establish a formal FDA or MHRA revocation of Biopure's GMP certificate.
Oxyglobin
The FDA approved Oxyglobin (hemoglobin glutamer-200, bovine), sponsored by Biopure Corporation, on 12 January 1998 for veterinary use.
FDA NADA 141-067 FOI SummaryHemopure / HBOC-201
South Africa’s Medicines Control Council approved Hemopure for acutely anemic adult surgical patients for the purpose of eliminating, reducing or delaying allogeneic red-cell transfusion. Biopure described the product as an oxygen therapeutic.
Biopure Annual Report 2001
The language changes
Scientific literature increasingly described these technologies as oxygen therapeutics. In 2004, FDA scientist Abdu Alayash explicitly called “blood substitute” and “artificial blood” misnomers because oxygen carriers do not perform all functions of blood.
Nature Reviews Drug DiscoveryRegulatory and real-world milestones
Hemopure and Oxyglobin crossed different regulatory boundaries.
These records matter because they separate the history of a technology from the history of a single regulatory jurisdiction. Human Hemopure and veterinary Oxyglobin did not follow the same pathway.
Hemopure / HBOC-201
Human-use history
- South Africa, 2001: Hemopure received marketing authorization for acutely anemic adult surgical patients to eliminate, reduce or delay allogeneic red-cell transfusion.
- South Africa, 2006: Biopure reported its first commercial Hemopure sales for human use. Fiscal-year revenue was reported as $37,000.
- Russia, 2010 to 2015: Hemopure was registered as Гемопюр®, registration ЛП-000011. The historical registration expired in 2015.
- United States: Hemopure is not FDA-approved for routine marketing. FDA Expanded Access has provided a pathway for qualifying patients with life-threatening anemia when standard transfusion is not available or suitable.
- Europe: Hemopure has no EMA human marketing authorization. Published experience includes clinical studies and named-patient or compassionate-use treatment in Europe.
Oxyglobin
Veterinary approval and commercial use
- United States, 12 Jan 1998: FDA approved Oxyglobin, hemoglobin glutamer-200 (bovine), under NADA 141-067 for anemic dogs.
- European Union, 29 Nov 1999: Oxyglobin received EU marketing authorization, EU/2/99/015. The EMA regulatory record remains available and was updated in October 2025.
- Commercial experience: by 2002, Biopure reported more than 115,000 Oxyglobin units sold following U.S. and European authorization.
Military trauma research
U.S. Navy and Department of Defense support
In 2003, the U.S. Naval Medical Research Center signed a Cooperative Research and Development Agreement with Biopure for the proposed RESUS out-of-hospital trauma program. Biopure also reported Navy collaboration on preclinical next-generation HBOC work under the Hematomimetics Program. By 2008, company filings reported $22.5 million in U.S. congressional Department of Defense appropriations for Hemopure trauma development, including $16 million to the Navy and $6.5 million to the Army. This documents historical research support; it is not a current military endorsement or regulatory approval.
The function-first idea did not begin with BHOC. The field itself began moving from “blood substitute” toward “oxygen therapeutics” more than two decades ago. BHOC represents a continuation and evolution of that unfinished idea.
1998 to 2019
Nitric oxide and cellular oxygen sensing change what “oxygen delivery” means.
Nitric oxide and vascular signaling
Robert F. Furchgott, Louis J. Ignarro and Ferid Murad received the Nobel Prize for discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system. This established NO as a central regulator of vascular tone and blood flow.
Nobel Prize 1998BHOC evidence: NO scavenging & vasoconstriction
Red cells emerge as active participants in flow regulation
Pawloski, Hess and Stamler reported in Nature that deoxygenation of red cells can trigger export of hemoglobin-derived NO bioactivity, proposing a mechanism that couples hemoglobin oxygen saturation to vasodilatory signaling. This work helped shift the red blood cell from a purely passive oxygen container toward a model in which it can also participate in matching perfusion to metabolic oxygen demand.
Subsequent work supports the broader concept of RBC-mediated hypoxic vasodilation, but the exact molecular route remains debated. Proposed pathways include S-nitrosohemoglobin/S-nitrosothiol signaling, deoxyhemoglobin-mediated nitrite reduction and ATP release that stimulates endothelial NO production. It is therefore too strong to say that oxygen delivery absolutely “requires hemoglobin to bind NO” through one single pathway.
Pawloski, Hess & Stamler, Nature 2001Cells sense oxygen availability
William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza received the Nobel Prize for discoveries of how cells sense and adapt to oxygen availability. This is not validation of any specific oxygen carrier; it is fundamental evidence that oxygen availability is a regulated cellular variable, not simply a blood concentration measurement.
Nobel Prize 2019BHOC Nobel foundations: oxygen metabolism & physiology
The red cell is not only an oxygen container. Modern physiology supports a feedback model in which falling oxygen saturation can help generate signals that increase local perfusion, coupling oxygen carriage with vascular regulation. The exact biochemical pathway is still under active scientific debate.
Where does the flow regulation occur?
Small arteries and arterioles are classically the primary resistance vessels controlling inflow into capillary beds. Signals generated downstream can be conducted upstream and alter arteriolar tone. Capillaries should not be described as completely passive, however: pericytes can locally alter capillary diameter and RBC distribution in several tissues.
For the article, the scientifically safer conclusion is: system-level oxygen delivery depends on dynamic regulation of vascular resistance, predominantly upstream at the arteriolar level, with additional local control within the capillary network.
Arterioles as primary resistance vessels
Pericytes and capillary flow regulation
A different natural source of hemoglobin
HEMARINA: different biological source, the same fundamental oxygen-delivery function.
HEMARINA belongs here because M101 comes from a completely different animal lineage and biological source: the marine worm Arenicola marina. Human and other vertebrate hemoglobins are carried inside red blood cells, while M101 is a naturally extracellular hemoglobin with a much larger molecular assembly. The structures are different, but the core physiological function is shared: bind oxygen, transport it and make it available to living tissues.
This is the broader biological lesson. Nature does not use one identical hemoglobin design everywhere. It uses different molecular solutions in different species and environments, while preserving the same essential oxygen-delivery purpose. Diversity in form can coexist with unity of function. Oxygen delivery is a foundational requirement of aerobic animal life, even though the specific respiratory pigments and transport systems vary across species.
This cross-species principle is central to BHOC Veterinary and the BHOC Species & Biodiversity Protection Initiative: Every species is different. The need for oxygen is universal.
BHOC Species & Biodiversity Protection Initiative: the science bridge
HEMARINA founded
HEMARINA was founded in France around M101, the naturally extracellular hemoglobin of Arenicola marina. Its unusually large native molecular assembly provides a fundamentally different biological architecture from vertebrate intracellular hemoglobin and became the basis for HEMARINA oxygen-carrier products.
HEMARINAHEMO2life first-in-human kidney results
The OXYOP multicenter study reported first-in-human use of M101 in kidney preservation. Fifty-eight donors were included; no immunological, allergic or prothrombotic effects were reported, and secondary endpoints showed encouraging renal-recovery signals.
First-in-human OXYOP studyHEMO2life CE marking
HEMARINA announced CE marking for HEMO2life as a Class III medical device for use as an additive to organ-preservation solutions, allowing European market access for kidney-graft preservation.
HEMARINA CE-mark press releaseBHOC Transplantation Evidence Hub
Modern donor-system pressure
The blood system became safer. It did not become independent of donors.
global blood donations
WHO reports approximately 120.4 million blood donations worldwide, with major differences in donation rates and access between income groups.
modelled unmet blood-product units
A 2019 Lancet Haematology modelling study estimated 102.36 million units of unmet need across 119 countries with insufficient supply. This is a modelled estimate, not a WHO figure.
WHO Blood safety and availability, 2026 Lancet Haematology modelling study
Blood shortage is not only a low-income-country problem
The American Red Cross declared its first national blood crisis in January 2022 and its second-ever national blood supply crisis in July 2026, after donations fell to a four-year summer low.
American Red Cross 2026 crisis declarationA second strategic donor dependency
WHO reports that only 49 of 168 reporting countries produce plasma-derived medicinal products from domestically collected plasma. A 2025 Vox Sanguinis analysis notes that the United States supplies approximately 70% of the world’s plasma used for these medicines, creating significant supply-chain concentration.
WHO plasma dataVox Sanguinis 2025
COVID-19 becomes a stress test
COVID-19 did not create donor dependency; it exposed it. WHO issued specific guidance on maintaining blood supply during the pandemic because donor attendance, collection and supply continuity were vulnerable to disruption.
WHO blood-supply guidance during COVID-19Modern transfusion medicine
Transfusion decisions became more selective and more dependent on clinical context.
Important distinction: these restrictive thresholds apply principally to hemodynamically stable patients. They should not be presented as the decision rule for uncontrolled hemorrhage or shock, where physiology, active bleeding, perfusion and clinical context can dominate before a laboratory hemoglobin value is available or informative.
Earlier blood
Prehospital transfusion expands
By June 2026, the Prehospital Blood Transfusion Coalition reported more than 400 ground 911 EMS agencies with blood-transfusion programs. These programs move blood closer to the patient and earlier in resuscitation.
Prehospital Blood Transfusion Coalition
BHOC Prehospital / EMS Evidence
Less unnecessary blood
Restrictive transfusion and Patient Blood Management
Modern guidance generally favors restrictive strategies in hemodynamically stable patients. The 2023 AABB international guideline recommends considering transfusion below 7 g/dL for many stable adults, with 7.5-8 g/dL thresholds in selected surgical or cardiovascular contexts.
Hemoglobin and hematocrit are essential measurements. They are not tissue oxygenation.
Hemoglobin concentration and hematocrit describe important components of oxygen-carrying capacity, but neither alone directly measures whether adequate oxygen is reaching tissue. Effective oxygen delivery also depends on cardiac output, saturation, vascular tone, microcirculatory flow, diffusion, extraction and cellular demand.
Hemoglobin tells us how much oxygen-carrying capacity is present. It does not, by itself, tell us whether enough oxygen reaches the cell.
BHOC Research Concept: Oxygen-delivery potency vs hemoglobin concentration
EMS makes the time problem visible.
At the roadside, in an ambulance or inside a helicopter, conventional laboratory hemoglobin may not be available when a treatment decision is needed. Prehospital assessment therefore relies heavily on physiology, perfusion and clinical signs: blood pressure, heart rate, shock index, mental status, skin perfusion, capillary refill, active bleeding and related indicators.
BHOC Research Concept: Are we identifying the oxygen-delivery problem early enough?
2021 → 2026
From the history of blood replacement to a function-first framework.
BHOC project launch
The BHOC project was initiated around the accumulated scientific, clinical, regulatory and manufacturing history of hemoglobin-based oxygen carriers, with the intention of building on that evidence rather than erasing it and starting again.
A function-first paradigm
The BHOC framework was expressed more directly: separate the complexity of blood as a biological system from the time-critical function of oxygen delivery.
Blood is an organ system.
Oxygen delivery is a function.
This is a BHOC conceptual framework, not a claim that standard anatomy has formally reclassified blood in this wording.
BHOC expands the mission
The BHOC ecosystem now connects human medicine, emergency and prehospital care, transplantation, veterinary medicine, scientific evidence and the BHOC Species & Biodiversity Protection Initiative.
Save lives. We are one blood.
BHOC Species & Biodiversity Protection InitiativeFor centuries, medicine removed blood to treat disease. Then it learned to replace blood to save life. Then it learned to type, test, store and distribute blood. Then science searched for artificial blood and blood substitutes. Now the question is changing again: which function is failing, and which function must be restored first?
That is where BHOC begins.
Historical products, companies and technologies described on this page are included for scientific and historical context. Inclusion does not imply ownership, affiliation, endorsement, equivalence or regulatory continuity with BHOC.
References & source notes
Primary and high-authority sources used in this historical perspective.
- AABB. Transfusion Medicine History.
- Richard Lower: the origins of blood transfusion.
- BHOC Platform. Blood Groups: From ABO to 49 Blood Group Systems.
- American Red Cross. Significant Dates in Red Cross History.
- Krylov NN et al. In searching for perfect blood substitute: creation and application of Perftoran. 2024.
- Maevsky EI et al. Perftoran review.
- FDA. Oxyglobin NADA 141-067 Freedom of Information Summary.
- Biopure Annual Report 2001: Hemopure South Africa approval.
- Alayash AI. Oxygen therapeutics: can we tame haemoglobin? Nature Reviews Drug Discovery. 2004.
- Nobel Prize in Physiology or Medicine 1998: nitric oxide as a signaling molecule.
- Nobel Prize in Physiology or Medicine 2019: cellular oxygen sensing.
- First-in-human use of M101 for kidney organ preservation.
- HEMO2life and renal function after transplantation. Artificial Organs. 2022.
- HEMARINA. HEMO2life CE mark press release, 30 Sep 2022.
- WHO. Blood safety and availability. 12 Jun 2026.
- Roberts N et al. The global need and availability of blood products: a modelling study. Lancet Haematology. 2019.
- American Red Cross. Second-ever national blood supply crisis. 27 Jul 2026.
- Belmonte M. Understanding supply sustainability of plasma-derived medicinal products. Vox Sanguinis. 2025.
- WHO. Maintaining a safe and adequate blood supply during COVID-19. 2021.
- Red Blood Cell Transfusion: 2023 AABB International Guidelines.
- Prehospital Blood Transfusion Coalition.
- Feola M, Simoni J, Canizaro PC. Quality control of hemoglobin solutions: purity before modification. Artificial Organs. 1991.
- Production of modified crosslinked cell-free hemoglobin for human use: quantitative determination of endotoxin contamination.
- Natanson C et al. Cell-Free Hemoglobin-Based Blood Substitutes and Risk of Myocardial Infarction and Death: A Meta-analysis. JAMA. 2008;299(19):2304-2312.
- U.S. FDA CBER. FDA comparison of characteristics of hemoglobin-based oxygen carriers could guide development of safe and effective products; summarizes Meng F et al., “All HBOCs Are Not Created Equally.” 2018.
- Jahr JS et al. Hemoglobin-based oxygen carriers: biochemical, biophysical differences, and safety. Transfusion. 2025.
- Sloan EP et al. DCLHb in severe traumatic hemorrhagic shock. JAMA. 1999.
- PolyHeme USA multicenter Phase III trauma trial.
- Bronkhorst-van der Helm et al. Interference of bovine hemoglobin-based oxygen carrier-201 (Hemopure) on four hematology analyzers. 2023. Regulatory and compassionate-use context.
- European Medicines Agency. Oxyglobin, EU veterinary marketing-authorisation record.
- Biopure Corporation. SEC filing documenting Navy NMRC CRADA, Department of Defense appropriations and first Hemopure commercial sales. 2008 filing.
- Pawloski JR, Hess DT, Stamler JS. Export by red blood cells of nitric oxide bioactivity. Nature. 2001.
- Nitric oxide, vasodilation and the red blood cell: mechanisms and continuing debate.
- The dynamic structure of arterioles: primary resistance vessels and tissue perfusion.
- The coronary capillary bed and pericyte regulation of capillary blood flow.