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Dextran 1 Dextran 40 Dextran 60 Dextran 70 Dextran 110 Gelatin
The majority of blood substitutes currently in use function only as plasma expanders. These maintain blood pressure by providing vascular fluid volume after haemorrhage, burns, sepsis or shock. While standard electrolyte solutions, such as physiological saline, may be administered, their effect is transitory as they subsequently diffuse back out of the vascular system.
Alternatively, colloidal plasma expanders (Table 9.3) are used. When administered at appropriate concentrations, they exert an osmotic pressure similar to that of plasma protein, hence vascular volume and blood pressure are maintained. The major disadvantages of colloidal therapy include its relatively high cost, and the risk of prompting a hypersensitivity reaction. Determined efforts to develop blood substitutes were initiated in 1985 by the US military, concerned about the issue of blood supply to future battlefields.
Dextrans (polysaccharides; Figure 9.1) of various molecular masses, usually 1, 40, 60, 70 or 110 kDa, are often used as plasma expanders. These polysaccharides are produced naturally by
Figure 9.1. Dextran is a homopolysaccharide composed exclusively of D-glucose monomers linked predominantly by 1-6 glycosidic bonds (as in the fragment of dextran backbone shown above). Different dextran preparations vary only in molecular mass and their degree of branching
BLOOD PRODUCTS AND THERAPEUTIC ENZYMES 355
various microorganisms, although commercial production is undertaken almost exclusively using Lactobacteriaceae (usually Leuconostoc mesenteroides, grown on sucrose as carbon source). Native dextrans usually display a high molecular mass, and those used clinically are usually prepared by depolymerization of the native molecule, or sometimes by direct synthesis.
Higher molecular mass dextrans (particularly dextran 70, 75 and 110) are used to promote short-term expansion of plasma volume thus preventing/treating shock due to blood loss. A 6% w/v solution of these dextrans exerts an osmotic pressure similar to that of plasma proteins. Generally, an initial dose of 500 ml-1 litre is administered by i.v. infusion. Dextrans also inhibit the aggregation of red blood cells. Thus, they are often used to prevent/treat post-operative thrombo-embolic disorders (see later in this chapter) and to improve blood flow.
The lower molecular mass dextran 40 (40 kDa) exhibits similar therapeutic effects to the higher molecular mass dextrans, although it must be used at slightly higher concentrations (10%, w/v) in order to achieve the same osmotic pressure.
Dextrans may also promote a number of negative effects. Dextrans 40 and 70 have been associated with acute renal failure, although the mechanism by which this is induced is unclear. Infusion of dextrans can also prompt severe anaphylactic shock. Many patients exhibit anti-dextran antibodies, including some who have not been previously administered dextran (antibodies may be generated in response to dextran-like dietary or bacterial polysaccharides to which the patient has previously been exposed).
To prevent severe anaphylactic responses, administration of a small volume (10-20 ml) of low molecular mass dextran (Dextran 1) is often undertaken immediately prior to infusion of the higher molecular mass product. Circulatory anti-dextran antibodies will be ‘mopped up’ by binding to the lower molecular mass dextran. This prevents formation of high molecular mass dextran-immune complexes/precipitates which often underscore the severe anaphylactic response.
Human serum albumin (HSA) is the single most abundant protein in blood (Table 9.4). Its normal concentration is approximately 42 g/litre, representing 60% of total plasma protein. The vascular system of an average adult thus contains in the region of 150 g of albumin. HSA is responsible for over 80% of the colloidal osmotic pressure of human blood. More than any other plasma constituent, HSA is thus responsible for retaining sufficient fluid within blood vessels. It has been aptly described as the protein that makes blood thicker than water.
Albumin molecules also temporarily leave the circulation, entering the lymphatic system, which harbours a large pool of this protein (up to 230 g in an adult). Lower quantities of albumin are also present in the skin.
In addition to its osmoregulatory function, HSA serves a transport function. Various metabolites travel throughout the vascular system predominantly bound to HSA. These include fatty acids, amino acids, steroid hormones and heavy metals (e.g. copper and zinc), as well as many drugs.
HSA is a 585 amino acid, 65.5 kDa polypeptide. It is one of the few plasma proteins that is unglycosylated. A prominent feature is the presence of 17 disulphide bonds, which helps stabilize the molecule’s 3-D structure. HSA is synthesized and secreted from the liver, and its gene is present on human chromosome 4.