Historical Perspective
From Bloodletting to Oxygen Therapeutics
For centuries, medicine removed blood to treat disease. Then it learned to replace blood to save life. Then came blood groups, blood banking, donor systems, artificial blood and blood substitutes. Today the question is changing again: not only how to replace blood, but which biological function must be restored first.
In Brief
The history is a sequence of changing questions.
Medicine first learned that blood could be removed, then that it could be transfused, then that donor and recipient compatibility mattered, and finally how to collect, test, store and distribute blood at scale.
The twentieth century added another ambition: create artificial blood or blood substitutes that could reduce dependence on donor blood. Some technologies failed, some reached late-stage clinical development, and a small number reached regulatory or clinical use.
At the same time, transfusion medicine itself moved away from a universal “10/30” trigger toward more restrictive and individualized decisions, while emergency medicine increasingly relies on physiology and symptoms when laboratory values are unavailable or too slow.
The trajectory leads to a different question: not only how to replace blood, but which function is failing and which function must be restored first.
Ancient medicine → 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 → 1985
Blood becomes infrastructure, then biological risk becomes visible.
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.
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
Hemoglobin leaves the red cell.
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 carrying oxygen was possible, while also uncovering vascular, oxidative and molecular constraints that earlier designs had underestimated.
Programs discontinued
HemAssist · PolyHeme · HemoLink
Advanced programs were stopped or failed to obtain approval after clinical or development setbacks. Their experience became part of the physiological evidence base for later oxygen-carrier design.
What the field learned
NO · oxidation · P50 · molecular size · microcirculation
The key question changed from whether hemoglobin could bind oxygen to whether an extracellular carrier could deliver oxygen safely within vascular and tissue biology.
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 DiscoveryThe 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 → 2022
Oxygen biology becomes deeper than the hemoglobin number.
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 later became highly relevant to HBOC physiology because extracellular hemoglobin can scavenge NO and alter vascular tone.
Nobel Prize 1998BHOC evidence: NO scavenging & vasoconstriction
HEMARINA founded
HEMARINA was founded in France and developed M101, an extracellular hemoglobin derived from the marine worm Arenicola marina, opening a different pathway for oxygen-carrier application.
HEMARINA company profileCells 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 central cellular variable.
Nobel Prize 2019HEMO2life 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
More blood earlier. Less donor blood when safely possible. Less reliance on one number.
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. The direction is clear: move blood closer to the patient and earlier in the resuscitation timeline.
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.