RATIONALE FOR DEVELOPMENT OF LOW-MOLECULAR-WEIGHT HEPARINS AND THEIR CLINICAL POTENTIAL IN THE PREVENTION OF POSTOPERATIVE VENOUS THROMBOSIS

Interest in low-molecular-weight heparins (LMWHs) as potential antithrombotic agents was stimulated by two observations in the mid-1970s and early 1980s. The first was the finding that LMWH fractions prepared from unfractionated heparin (UFH) progressively lost their ability to prolong the activated partial thromboplastin time (APTT) while retaining their ability to inhibit Factor Xa. The second was the observation that LMWHs prepared by chemical depolarization of UFH are antithrombotic in experimental animal models but produce less microvascular bleeding in experimental models for an equivalent antithrombotic effect than the UFH from which they are derived. Subsequently, it was shown that LMWHs inhibit platelet function and impair vascular permeability less than standard heparin and that LMWHs have a longer biological half-life than standard heparin. A number of LMWHs have been evaluated in clinical trials in general and orthopedic surgery and in the treatment of venous thrombosis. LMWHs are highly effective in orthopedic surgery, where they appear to be more effective than standard heparin. LMWHs have also been shown to be either as effective or more effective than UFH in preventing postoperative thrombosis following general surgery. In preliminary studies, LMWHs appear to be as effective as standard heparin in the treatment of venous thrombosis, but larger studies are required using clinically relevant outcome measures.