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HISTORICAL ARTICLE
JOURNAL ARTICLE
PORTRAIT
A century of heparin: past, present and future.
Journal of Thrombosis and Haemostasis : JTH 2016 December
Heparin was discovered around 1922 by Howell (Baltimore) and was further developed by the teams of Best (Toronto) and Jorpes (Stockholm). Kakkar (London) propagated its routine use for the prevention of postoperative thrombosis from 1971 onwards. The discovery of low molecular weight heparins (1976, Johnson, London) and their development in the subsequent years led to the present arsenal of clinically useful drugs. In 1976, three teams independently found that a specific structure in heparin binds tightly to antithrombin. This enabled the teams of Lindahl (Stockholm) and Casu (Milan) to determine the pentasaccharide structure responsible for this binding and Petitou, from the Choay team (Paris), to synthesize it (1983). It was found (Olson and others) that heparin facilitates the interaction between antithrombin and a clotting enzyme by allosteric changes in the antithrombin (important for factor Xa) and by facilitating the approach of the enzyme to antithrombin via its "sliding" along the heparin molecule (important for thrombin). Antithrombin action therefore requires a minimum length of seven sugar units next to the pentasaccharide whereas anti-factor Xa action does not. The effect of heparin is almost entirely due to anti-thrombin action (B≐guin), so anti-factor Xa activity does not reflect the concentration of anticoagulant heparin. The anticoagulant effect is poorly reflected by the activated partial thromboplastin time. Because present clinical use is based on the latter tests, it is not generally known that the individual response to heparin shows an extremely wide variation. Individualization of heparin dosage is likely to improve clinical results.
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