For over 100 years
heparin has attracted interest because of its
anticoagulant powers. Commercial
heparin has now been shown to be a mixture of over 100 different closely related sulfated
polysaccharides of which only 10% activate
antithrombin-III. Fifty years ago the original research teams in Toronto and Stockholm in demonstrating the clinical uses of
heparin observed that antithrombotic activity did not correspond to levels of anticoagulation. It has been shown that: (a)
Heparin accumulates rapidly and specifically in the endothelium against a concentration gradient of hundreds- to thousands-fold. (b) Experimental
thrombosis, however produced, is accompanied by a marked decrease in the electronegative charge of the vessel wall and the charge is restored in all cases by
heparin. (c) The normal electronegative charge is due to
glycosaminoglycans.
Heparin possesses the strongest electronegative charge of these substances and is present in the vessel wall as a component of a larger
heparitin (sulfate)
proteoglycan molecule. (d) Maintenance of the normal electronegative charge depends on adequate supply of
oxygen (adequate blood flow). (e) Commercial
heparin releases
enzymes from the endothelium,
lipoprotein lipase and
histaminase (D.A.O.).
Lipoprotein lipase changes the composition of plasma
lipids and
lipoproteins and
histaminase provides a check for fat absorption. The release of these
enzymes decrease and prevent atherosclerotic changes. (f) After administration of commercial
heparin,
heparin isolated from the plasma has higher
antithrombin activity than that injected. The
heparin taken up by the endothelium is returned with greater activity. The
anticoagulant effect of administered
heparin does not produce
hemorrhage since this requires simultaneous occurrence of defects in the
vascular factor of hemostasis (the result of stress or pituitary-adrenal imbalance) or platelet defect. Thus, clinical effectiveness of
heparin is an expression of its close relationship to the vessel wall.