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Outline Discovery of blood Important tasks of blood Why blood substitutes? Some current developments and products Risks and Benefits

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Discovery of Blood GroupsDiscovery of Blood Groups (1868-1943 ) Karl Landsteiner (1901) Blood of two people under contact agglutinates Due to blood serum (blood plasma) Identified blood groups A, B, C (later named O) (1907) First successful blood transfusion (Reuben Ottenberg, Mount Sinai Hospital, New York) [1]

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Principle Tasks of BloodPrinciple Tasks of Blood Transport Oxygen throughout body Release oxygen to tissues pick up carbon Hemoglobin - Oxygen-carrying protein containing erythrocytes (Red Blood Cells) White Blood Cells Immune Response Platelets Blood Clotting, wound healing

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Reasons For Blood Substitutes Human RBC have strict storage requirements Designed to prolong clinical effectiveness, reduce risk bacterial infection Blood Substitutes more amenable to sterilization Do not require cross-matching Donor Blood Shortages Short-term replacement of blood during surgery

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The Ideal Blood SubstituteThe Ideal Blood Substitute Require no cross-matching, compatibility testing Suitable for long-term storage (room temperature) Survive circulation for several weeks (intravascular dwell time) before being cleared by kidney Side-effect free Free of pathogens Effectively deliver oxygen to tissues

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Current DevelopmentsCurrent Developments Derived from Hemoglobin: Hemoglobin-based Oxygen Carriers (HBOCs) Those that use perfluorocarbon emulsions

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Hemoglobin-Based Oxygen Carriers Cell-free solution of hemoglobin as a blood substitute Hemoglobin maintains ability to transport oxygen outside of red blood cells Compatibility testing not required Can be sterilized by ultrafiltration and low heat

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Hemoglobin ProductsHemoglobin Products Polyheme-polymerized human hemoglobin product Northfield Laboratories Hemopure-polymerized hemoglobin from bovine red blood cells Biopure/Biotech Approved in South Africa Phase III clinical trials in U.S. Hemolink-partially polymerized human hemoglobin Hemsosol Under FDA Review

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Polyheme Uses expired human blood Hemoglobin solution, no intact red blood cells Manufacturing steps reduce risk of viral infection Shelf life of 12 months Can be stored at room temperature Only provides oxygen carrying capacity Intravascular dwell time shorter than 120 days (RBC)

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Clinical TrialsClinical Trials Finished Phase III trauma trial in June 2006 December 19, 2006 preliminary results released 13.2% died vs. 9.6% control group Re-evaluation of study database-no new trials Result: No FDA approval thus far

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Hemopure Developed by OPK Biotech Based on chemically stabilized bovine (cattle) hemoglobin Use in humans as oxygen delivering bridge when blood is not available Stable for 36 months at room temperature Compatible with all blood types

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Hemopure Carried in the plasma Transports oxygen wherever plasma flows (partial blockages or constricted vessels) Holds same amount of oxygen as hemoglobin Release oxygen more readily Introducing Hemopure into bloodstream may help RBSc offload more oxygen to tissues than would otherwise.

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Clinical TrialsClinical Trials Last human test (date unknown) FDA imposed ban on further clinical trials due to safety concerns Animal testing has been ensued Hemopure approved for human use and commercial sale in South Africa in April 2001 Result: No FDA approval thus far

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Hemolink Developed by Hemosol Highly purified human hemoglobin-based oxygen carrier Approved for clinical trials in primary cardiac bypass surgery (early 2000s) Currently no FDA approval

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Perfluorocarbon Perfluorocarbons Molecules structurally similar to hydrocarbons Hydrogen atoms replaced with fluorine atoms Perfluorocarbon Liquids have excellent capacity for carrying oxygen and carbon dioxide Oxygen dissolves in chemically inert perfluorocarbon liquid Can be easily extracted by oxygen-deprived tissue http://www.md.ucl.ac.be/virtanes/pastedoct99.html

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Perfluorocarbon ProductsPerfluorocarbon Products Fluosol DA Approved by FDA as a blood substitute for heart surgery Green Cross Corp. of Japan (1989-1992) Used in more than 40,000 human subjects Difficulty in storage and re-use-production ended Oxygent Developed by Alliance Pharmaceuticals Stage II/III clinical trials Study in 2008 As of February 2005, no FDA approval-safety http://www.pharmaceuti calonline.com/doc/allian ce-pharmaceutical-baxter- to-collaborate-0001

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Risk Vs. BenefitRisk Vs. Benefit Safety of Donor Blood Supply Risk of transfusion-associated HIV infection as low as 1 per 185,000 Risk of transfusion-associated infection of Hepatitis C Virus (HCV) between 1 per 300,000 and 1 per 600,000- compared to 1 per 103,000 in early 1990s New blood substitutes could potentially carry unknown risks Intravascular dwell times need to be increased Cost needs to be competitive Obtaining and processing sufficient amounts must be overcome

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