Breaking the rules on artifical blood

03/10/04

Numerous past attempts to develop synthetic blood have failed because doctors got the basic science wrong, claim a handful of researchers.

This week it was announced that a blood substitute based on their alternative theories is looking promising in an early trial. Developing a suitable blood substitute for people has been a major effort for decades. An artificial blood would relieve shortages and prevent patients being infected by contaminated supplies.

Ideally, it could be given to anyone without triggering rejection, so accident victims could be given transfusions immediately without testing to see what blood group they are. And a long-lasting form that does not need to be kept cold would be ideal for use in disasters, wars and remote areas. But company after company has worked on substitutes only to abandon their efforts because of safety concerns.

Most blood substitutes are based on various forms of haemoglobin, the protein that carries oxygen in most animals. The guiding principles are that artificial blood should be thinner than real blood, so that it circulates easily, and have a low affinity for oxygen, so that it releases oxygen easily.

In the past decade, initial trials of several substitutes looked promising. But it turned out many had a disastrous effect- they made capillaries collapse, shutting off the oxygen supply to tissues.

The reason, most researchers think, is that the haemoglobin in artificial bloods is free-floating, instead of being enclosed in red blood cells.

This allows it to enter the spaces between cells, where it mops up nitric oxide- a molecule that helps keep blood vessels open. But Marcos Intaglietta of the University of California, San Diego, is one of a small number of scientists who think the physical characteristics of blood substitutes are to blame.

He argues that they thin the blood, reducing shear stress in the capillaries and leading to vasoconstriction. Creating artificial blood with a low affinity for oxygen is also a mistake, says Robert Winslow, founder of blood substitute company Sangart of San Diego. He says current blood substitutes release their oxygen in the arteries instead of in the capillaries like normal blood.

This early release can itself trigger vasoconstriction. Winslow's company has put these ideas to the test with a blood substitute called MP4. It contains haemoglobin molecules coated with polyethylene glycol to make them bulkier, so the resulting fluid is thicker, or more viscous, than normal blood. The coating also gives MP4 a higher affinity for oxygen than other substitutes.

Studies have shown that MP4 releases oxygen in the capillaries, as intended. This week Sangart announced that a small trial involving around 20 patients in Sweden has produced positive results.

Details have not yet been released, but other tests in which pigs were given MP4 revealed no signs of vasoconstriction (Journal of Applied Physiology, DOI: 10.1152/japplphysio.00530.2003).

Tests in hamsters that had lost a lot of blood showed they actually fared better when given MP4 than real blood (Critical Care Medicine, vol 31, p 1824). The animals needed less MP4 than real blood to oxygenate their tissues. The researchers think this is because it releases oxygen only where levels are lowest.

Is the apparent success of MP4 proof that Winslow and his colleagues are right? Not necessarily, says John Olson, an expert in blood substitutes at Rice University in Houston, Texas. He thinks MP4 works well simply because the coated haemolglobin is too big to squeeze into the spaces between cells and destroy nitric oxide.

Viscosity and oxygen affinity are probably not the key factors. Intaglietta, however, can point to recent experiments that suggest viscosity is important. At the moment, when patients lose blood, they are initially given salt water to replace the lost volume. But too much saline thins the blood, leading to vasoconstriction.

Intaglietta's team has shown that if animals are given a "plasma expander" that has a higher viscosity than saline, their capillaries stay open. Animals given this expander can survive longer than those given saline, even when their blood oxygen falls to levels that would normally be fatal.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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