Blood substitute

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Blood substitutes are used to supply oxygen to individual or all organs, for example when suitable donor blood is acutely unavailable (e.g. after accidents or during operations) or specific organs need to be supplied with oxygen . Excessive blood loss can lead to a breakdown in the supply of oxygen to the brain and the entire body, which can result in severe brain damage or death.

A distinction is made between volume expanders (liquids that dilute the remaining blood and supplement it so that the blood circulation can function again), which cannot take on any physiological function of the blood, and blood substitutes in the narrower sense . The latter should primarily be able to actively take over the oxygen transport. In the past there were two basic directions of development: blood substitutes based on the red blood pigment hemoglobin , and blood substitutes based on perfluorocarbon . Advantages over donated blood are the lack of risk of transmitting diseases (e.g. AIDS , hepatitis B and others), the lack of blood group specificity and the longer shelf life. Today, methods of stem cell medicine (“ blood pharming ”) are also in focus.

Hemoglobin-based blood substitutes

Blood substitutes based on the red blood pigment hemoglobin (hemoglobin-based blood substitutes, HBBS; English: Hemoglobin based oxygen carrier, HBOC ) use human hemoglobin from expired blood reserves or from biotechnological production as well as foreign hemoglobin ( e.g. from cattle or pigs) as starting materials .

Native hemoglobin is a protein compound that consists of 4 subunits (α 2 β 2 - tetramer ), of which one α subunit is stably linked to one β subunit (αβ dimer ). Outside of the erythrocytes , hemoglobin has a very short half-life . It is unstable and quickly breaks down into its two dimers, which have a strong nephrotoxic (kidney-damaging) effect. Hemoglobin has an S-shaped oxygen binding curve, the oxygen binding property in the physiological range being sensitive to the oxygen partial pressure. Among other things, the concentration of 2,3-bisphosphoglycerate (2,3-BPG) plays an important role, which is too low outside of the red blood cells to ensure an adequate supply of oxygen to the surrounding tissue. Hemoglobin also penetrates the walls of the blood vessels and binds nitric oxide , a vasodilator substance. The result is a rise in blood pressure and a reduced blood flow to the tissue, which can assume undesirable dimensions.

For these reasons, hemoglobin must be modified accordingly before it can be used as a donor blood substitute. There are different approaches to this:

  • Intramolecular cross-linking to stabilize the tetrameric structure of the hemoglobin and to prevent the breakdown into the toxic dimers. Two dimers are crosslinked either between their α-subunits or between the β-subunits (e.g. with O, O-succinyldi (salicylic acid) or 2-nor-2-formylpyridoxal-5-phosphate).
  • Recombinant production of human hemoglobin, the two dimers of which are stably linked to one another via a corresponding modification in the amino acid sequence of their α-subunits.
  • Binding of pyridoxal-5-phosphate to human hemoglobin to improve its oxygen binding properties (pyridoxylation).
  • Intermolecular cross-linking to get larger molecules. Polyaldehyde compounds such as glutaraldehyde or o-raffinose are used as crosslinking agents. Hemoglobin glutamer , for example, has an average molecular weight that is roughly three to four times that of hemoglobin.
  • Attachment of macromolecules to hemoglobin, such as dextrans , polysaccharides , hydroxyethyl starch , or synthetic water-soluble macromolecules such as polyethylene glycols (conjugation). Larger molecules have a longer half-life and are less vasoconstricting.
  • Packaging of the hemoglobin in liposomes or artificial membrane envelopes ("artificial red blood cells").

Of the hemoglobin-based developments, two hemoglobin-glutamer preparations made from bovine hemoglobin have been approved so far (in South Africa the preparation Hemopure for use in human medicine, in the USA and Europe oxyglobin for use in veterinary medicine).

Perfluorocarbons

Synthetically produced perfluorocarbons (PFC) such as perflunafen or perflubron dissolve oxygen and carbon dioxide very well and are chemically inert. Since they cannot be mixed with water, they have to be dispersed in water as very fine droplets with a suitable, physiologically compatible emulsifier . The mean droplet diameter is around 100-200 nm. The emulsion , to which other substances such as salts are added to adjust the osmotic and oncotic pressure , is miscible with blood and can partially replace it in the bloodstream , taking over the oxygen transport. The oxygen content of the perfluorocarbons is directly proportional to the oxygen partial pressure (linear oxygen bond graph ). Perfluorocarbons are not metabolized, but exhaled through the lungs.

A disadvantage of perfluorocarbon emulsions is that they put a lot of strain on the reticuloendothelial system (RES), the cells of which phagocytize and store the emulsion droplets . This can lead to disorders of the immune system.

In the USA and a few European countries, Fluosol was the only parenteral perfluorocarbon emulsion to be approved for the first time in 1989 for the oxygen supply of the heart muscle during percutaneous transluminal coronary angioplasty . In the treatment of anemia , however, Fluosol had shown no benefit and is therefore not indicated as a replacement for blood loss. In 1994 the manufacturer took it off the market. In Russia and Mexico there is a similar product on the market with a number of indications for clinical use ( Perftoran , Perftec ). These first generation emulsions contain 20% (weight / volume) of a mixture of perflunafen and perfluoro- N -4- (methylcyclohexyl) piperidine , are stabilized with a synthetic emulsifier based on poloxamer and only have a longer shelf life when frozen. Because of their oxygen-binding properties , they are most effective under artificial oxygen ventilation .

Experimental perfluorocarbon emulsions of the second generation (for example Oxygent , Oxycyte ) are able to absorb more oxygen, contain better tolerated emulsifiers and have a more favorable chemical-physical stability. Compared to the older developments, they contain much higher concentrations of perfluorocarbons, whereby the cyclic perflunafen also gives way to compounds with a higher gas-dissolving power, such as the linear bromine-containing perflubron. Substances of biological origin such as phospholipids from egg or soy lecithin act as emulsifiers . The emulsions are stable when stored cold. Possible areas of application are the targeted supply of oxygen to certain organs, such as the brain following a traumatic brain injury .

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Individual evidence

  1. ↑ G. Rüschmeyer: Artificial blood in our veins . March 31, 2019 ( faz.net ).
  2. ^ Vidal , List of Medicines for Russia (Russian).