Prior to starting medical school, I seriously underestimated how often blood is utilized in the hospital. I previously imagined that blood was only needed during massive traumas or in surgeries with complications. However, According to the Association for Blood Donor Professionals, one in seven hospitalized patients needs blood. The demand for blood transfusions today often outpaces the rate of donations, and only 3% of the U.S. population donates blood each year.1
I recently came across an article in Nature Biotechnology from 1998 discussing the promise of a “fake blood” product being developed by a company called Hemosol. This cell-free hemoglobin product was in Phase II clinical trials at the time and was projected to hit the market by the year 2000.2 In 2025, however, no FDA-approved hemoglobin-based oxygen carrier products are available for clinical use in humans. This prompted me to explore what went wrong with Hemosol and where we stand today with blood substitutes.
Shortly after publishing that article, Hemolink, Hemosol’s product, faced significant challenges during the latter half of its Phase II trials, in the form of Adverse events, including hypertension, cardiotoxicity, stroke, and increased mortality.3 As a polymerized human hemoglobin product, Hemolink was intended to serve as a nearly limitless replacement for most blood transfusions, while effectively eliminating storage complications, immunogenic reactions, and infections associated with whole blood transfusions.4 The problem with acellular hemoglobin, however, is that the body is not accustomed to processing large amounts of free hemoglobin entering the bloodstream at once.
Research on hemolytic diseases, sepsis, and trauma has shown how free hemoglobin contributes to endothelial dysfunction and organ damage.5 When free hemoglobin overwhelms the body’s scavenging mechanisms, it induces vasoconstriction by binding nitric oxide and removing it from circulation. Additionally, hemoglobin increases free radical production, and thus causes oxidative damage to tissues. Once the conjugated hemoglobin is broken down, free heme activates local inflammation of the endothelium, triggering complement activation and neutrophil chemotaxis.5 All of these mechanisms compound to produce the side effects of hypertension, nephrotoxicity, acute kidney injury, hepatotoxicity, among many others.
Hemosol and other biotech companies attempted to overcome this by conjugating and modifying their products.6 While some companies found moderate success, the negative publicity from safety data proved too damaging for Hemosol to recover.
By mid-2003, Hemosol’s market value had dropped to $23 million from a peak of $600 million in 2000. To compound their struggles, the company laid off over 60% of its employees, and their CEO passed away from cancer during this turbulent period.3,7 By 2005, the company declared insolvency after multiple quarters of net income losses.8
Despite Hemosol’s tragic downfall, some products show promise for the future of cell-free hemoglobin. Hemopure,9 a product that uses polymerized bovine hemoglobin as an oxygen carrier, faced similar challenges to Hemolink in the early 2000s but managed to survive the standstill in Phase III trials. Although it has a similar side effect profile, Hemopure is approved for human use in both South Africa and Russia.4
What lessons can we learn from the journey these companies went through in the early 2000’s? Hemosol, and the entire scientific community, were in a race to bring these products to market. There was a good reason for the rush, but perhaps some of the motivation was clouded by what might have been a large stake in a market that is potentially worth billions of dollars.
Although challenges remain, we should not give up on the potential of acellular hemoglobin products. If these technological hurdles can be addressed, blood substitutes could provide crucial support in a market constantly battling shortages. Additionally, blood substitutes could be life-saving for individuals who refuse traditional blood transfusions due to religious beliefs, and in environments where storage of whole blood is not feasible.
References
1. ADRP – U.S. Blood Donation Statistics and Public Messaging Guide. Accessed January 5, 2025. https://adrp.org/statsguide?utm_source=chatgpt.com
2. Glaser V. Fake blood market gets hemoglobin transfusion from reticulocytes. Nat Biotechnol. 1998;16(8):709-709. doi:10.1038/nbt0898-709
3. Tests leave Hemosol in critical condition. The Globe and Mail. https://www.theglobeandmail.com/report-on-business/tests-leave-hemosol-in-critical-condition/article1162984/. June 21, 2003. Accessed January 8, 2025.
4. Chen L, Yang Z, Liu H. Hemoglobin-Based Oxygen Carriers: Where Are We Now in 2023? Medicina (Kaunas). 2023;59(2):396. doi:10.3390/medicina59020396
5. Ross JT, Robles AJ, Mazer MB, Studer AC, Remy KE, Callcut RA. Cell-Free Hemoglobin in the Pathophysiology of Trauma: A Scoping Review. Crit Care Explor. 2024;6(2):e1052. doi:10.1097/CCE.0000000000001052
6. Sen Gupta A. HEMOGLOBIN-BASED OXYGEN CARRIERS: CURRENT STATE-OF-THE-ART AND NOVEL MOLECULES. Shock. 2019;52(1):70-83. doi:10.1097/SHK.0000000000001009
7. Ex-Hemosol boss dies of cancer. The Globe and Mail. https://www.theglobeandmail.com/report-on-business/ex-hemosol-boss-dies-of-cancer/article25285654/. June 5, 2003. Accessed January 8, 2025.
8. Hemosol declares insolvency; shares under review by TSX. CBC News. https://www.cbc.ca/news/business/hemosol-declares-insolvency-shares-under-review-by-tsx-1.550185. November 25, 2005. Accessed January 8, 2025.
9. Hemopure | HbO2 Therapeutics. Accessed January 8, 2025. https://www.hbo2therapeutics.com/our-product
Benson Lagusis is a member of the University of Arizona College of Medicine - Phoenix Class of 2026. He graduated with a B.S. in Exercise Science from Northern Arizona University before earning a Master's degree in Biomedical Sciences from Midwestern University. Benson played baseball in college, and is interested in sports medicine and health promotion/education. During his free time, Benson is an avid hiker, reader, and Netflix binge-watcher.