Biomedical Engineering Reference
In-Depth Information
Table 12.3
Anticoagulants that are used therapeutically or display therapeutic potential
Anticoagulant
a
Structure
Source
Molecular mass (Da)
Heparin
Glycosaminoglycan
Beef lung, pig gastric mucosa
3 000-40 000
Dicoumarol
Coumarin-based
Chemical manufacture
336.3
Warfarin
Coumarin-based
Chemical manufacture
308.4
Hirudin
Polypeptide
Leech saliva, genetic
engineering
7 000
Ancrod
Polypeptide
Snake venom, genetic
engineering
35 000
Protein C
Glycoprotein
Human plasma
62 000
a
Dicoumarol and related molecules are generally used over prolonged periods, whereas heparin is used over shorter periods.
Hirudin has recently been approved for general medical use, while ancrod remains under clinical investigation.
stroke (in an effort to prevent recurrent episodes). The major anticoagulants used for therapeutic
purposes are listed in Table 12.3.
Heparin is a carbohydrate-based (glycosaminoglycan) anticoagulant associated with many tis-
sues, but mainly found stored intracellularly as granules in mast cells that line the endothelium
of blood vessels. Upon release into the bloodstream, heparin binds to and thereby activates an
additional plasma protein, namely antithrombin. The heparin-antithrombin complex then binds a
number of activated clotting factors (including IIa, IXa, Xa, XIa and XIIa), thereby inactivating
them. The heparin now disassociates from the complex and combines with another antithrombin
molecule, thereby initiating another turn of this inhibitory cycle.
Heparin was originally extracted from liver (hence its name), but commercial preparations are
now obtained by extraction from beef lung or porcine gastric mucosa.
Although the product has proven to be an effective (and relatively inexpensive) anticoagu-
lant, it does suffer from a number of clinical disadvantages, including the need for a cofactor
(antithrombin III) and poorly predictable dose responses. Despite such disadvantages, however,
heparin still enjoys widespread clinical use.
The vitamin K antimetabolites dicoumarol and warfarin are related coumarin-based anti-
coagulants which, unlike heparin, may be administered orally. These compounds induce their
anticoagulant effect by preventing the vitamin K-dependent
-carboxylation of certain blood
factors, specifi cally factors II, VII, IX and X. Upon initial hepatic synthesis of these coagula-
tion factors, a specifi c carboxylase catalyses the
γ
-carboxylation of several of their glutamate
residues (for example, 10 of the fi rst 33 residues present in prothrombin are γ-carboxygluta-
mate). This post-translational modifi cation is required in order to allow these factors to bind
Ca
2
ions, which is a prerequisite to their effective functioning. Vitamin K is an essential
cofactor for the carboxylase enzyme, and its replacement with the antimetabolite dicoumarol
renders this enzyme inactive. As a consequence, defective blood factors are produced that
hinder effective functioning of the coagulation cascade. The only major side effect of these
oral anticoagulants is prolonged bleeding; thus, the dosage levels are chosen with care. Dicou-
marol was fi rst isolated from spoiled sweet clover hay, as the agent that promoted haemorrhage
disease in cattle. Both dicoumarol and warfarin have also been utilized (at high doses) as rat
poisons.
γ
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