Synthetic Blood Products - A Note from Anaesthesiology Textbooks

Overview

"Many years of effort have gone into the search for an oxygen-carrying substitute for RBCs. Most potential substances still require hemoglobin derived from bovine or human sources."

• Barash's Clinical Anesthesia, 9e (p. 1291)

1. Advantages Over Donated Blood (Theoretical)

• No type and crossmatch required - universally compatible
• No risk of transmitting infectious viruses (HIV, hepatitis B/C, etc.)
• Long shelf life compared to donated RBCs (42-day maximum for stored PRBCs)
• Immediately available - no blood bank processing delays
• Suitable for patients who refuse allogeneic transfusion (e.g., Jehovah's Witnesses)
• Potentially useful in mass casualty and battlefield settings

2. Perfluorocarbon (PFC) Emulsions

Fluosol-DA

• The most notable PFC product
• FDA-approved for perfusion of ischemic tissues during percutaneous coronary intervention (PCI)
• Critical limitation: only carried meaningful oxygen when PaO2 exceeded 300 mmHg - requiring supplemental high-flow oxygen
• Withdrawn from the market in 1994 due to limited utility

Perfluorooctyl Bromide

• Carries 3-4 times more O2 than Fluosol-DA
• Longer half-life and fewer complications than Fluosol
• Not currently available on the market

Early Trials

• Initial studies with PFCs demonstrated renal toxicity and immune system inhibition
• Active research continues into new formulations

"Oxygen-avid perfluorocarbon chemicals underwent international trials, but the initial studies demonstrated renal toxicity and immune system inhibition."

• Barash's Clinical Anesthesia, 9e

3. Haemoglobin-Based Oxygen Carriers (HBOCs)

• Human sources (pooled or donor Hb)
• Bovine sources (animal-derived Hb)
• Recombinant technology (genetically engineered)

Why Modification is Necessary

1. Nephrotoxicity - free Hb is filtered by the kidney and causes tubular damage
2. Short intravascular half-life - Hb tetramers dissociate quickly
3. Unfavourable O2 affinity - stroma-free Hb has a left-shifted oxygen dissociation curve (high O2 affinity, poor tissue delivery)
4. Nitric oxide (NO) scavenging - free acellular Hb avidly scavenges NO, causing severe arteriolar vasoconstriction of microvascular structures, impairing organ perfusion

Chemical Modification Strategies

• Increase P50 (right-shift the O2 dissociation curve for better tissue offloading)
• Extend intravascular half-life
• Reduce nephrotoxicity

Recombinant Haemoglobin

• rHb 1.1 - produced in Escherichia coli; normal O2-carrying capacity, but plagued by severe microvascular vasoconstriction due to NO scavenging
• rHb 2.0 - next iteration; minimised NO scavenging and caused little arteriolar vasoconstriction compared with rHb 1.1 and diaspirin crosslinked Hb
• Despite this, vasoconstriction may still prove to be their ultimate downfall
• Acellular Hb solutions have not overcome the challenges of renal failure, cardiac toxicity, and hypertension

4. Specific HBOC Products

HBOC-201 (Hemopure, Biopure Corporation)

• Hemoglobin glutamer-250 (bovine)
• Developed from ultra-purified bovine RBCs glutaraldehyde-polymerised
• P50 = 43 mmHg (vs. 26 mmHg for human blood) - potentially delivers O2 to tissues at least as well as, if not better than, human RBCs
• Available in the USA under the FDA Expanded Access (compassionate use) programme
• Used clinically in severe sickle cell crisis, patients who refuse RBCs (Jehovah's Witnesses), and cases where compatible blood is unavailable
• Available in South Africa for standard clinical use (where donor blood shortages exist)

HemeAct

• Haemoglobin bonded to albumin proteins
• Active research product
• Tested in rats without the hypertensive or coagulopathic side effects seen with other oxygen carriers
• Considered to have significant potential

"There is also active research on a product called 'HemeAct' which offers hemoglobin bonded to albumin proteins... tested in rats without the hypertensive or coagulopathic side effects commonly seen with other oxygen carriers."

• Barash's Clinical Anesthesia, 9e

5. Clinical Trial Outcomes - Safety Concerns

• 16 clinical trials
• 5 HBOC products
• 3,711 patients

• Significantly increased risk of myocardial infarction with HBOC use
• Significantly increased risk of death with HBOC use
• This risk was consistent across all technologies (crosslinked, polymerised, or conjugated)
• An accompanying editorial concluded that a 30% increased risk of death and a threefold increase in myocardial infarction risk should preclude additional studies

"Natanson and colleagues performed a cumulative meta-analysis on 16 trials involving 5 products and 3,711 patients. They concluded that there was a significantly increased risk for myocardial infarction and death when HBOCs were given, an outcome found among all the technologies."

• Miller's Anesthesia, 10e (p. 6609)

6. Platelet Substitutes

• No clinically available platelet alternative exists
• Research directions include synthetic platelet-like particles designed to mimic the haemostatic function of platelets
• "Although there are currently no clinically available RBC alternatives, it seems not only possible, but likely that a suitable blood substitute will be offered in the future." - Barash's Clinical Anesthesia, 9e

7. Current Status and Future Directions

Status as of current editions:

• No synthetic blood product is approved for routine clinical use in most countries
• HBOC-201 (Hemopure) remains available via FDA Expanded Access in the USA and is licensed in South Africa
• The fundamental obstacle remains the vasopressor / NO-scavenging effect of acellular haemoglobin

Active research avenues:

1. Genetically engineered recombinant haemoglobin - offers cell-free functional Hb molecules that do not act as oxygen scavengers and present no infectious transmission risk
2. Hb-albumin conjugates (HemeAct) - avoids hypertensive and coagulopathic side effects
3. New perfluorocarbon formulations - with improved O2 carrying capacity
4. Liposome-encapsulated haemoglobin - structural mimicry of RBCs

Summary Table

• Miller's Anesthesia, 2-Volume Set, 10th Edition - Chapter 45: Transfusion Medicine (pp. 6608-6609)
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Edition - "RBC and Platelet Substitutes" (pp. 1290-1291)