Heparin as an injectable anticoagulant

In 1915 and 1916 Jay McLean, a medical student working in William Howell's laboratory at Johns Hopkins, found that some of his liver extracts slowed clotting. Howell was so skeptical at first that the finding was left out of McLean's paper, but he went on to study the anticoagulant now known as heparin. For two decades the substance resisted clinical use because the available extracts were too impure and too toxic. Howell's heparin, made in small amounts by Hynson, Westcott and Dunning of Baltimore in the 1920s, was too toxic even for animal studies and was used only in the laboratory.

The purification problem was solved in Toronto and in Stockholm. Charles Best, already known for his role in the insulin work of 1921, began heparin research in the late 1920s at Connaught Laboratories and the University of Toronto, and his team developed a standardized, purified preparation from beef liver and later from beef lung. The main steps involved removing toxic contaminants and ensuring consistent potency, expressed in standardized units. Gordon Murray, a surgeon at Toronto General Hospital, began using this preparation in patients in the mid-1930s, first for venous thrombosis and then for more complex vascular problems. Murray and colleagues from Best's group published their results in Surgery in 1937. In Sweden, Erik Jorpes worked with heparin made by the firm Kabi, and the surgeon Clarence Crafoord reported postoperative heparin to prevent thrombosis the same year.

In 1937 Erwin Chargaff and a colleague found, by accident, that protamine reverses heparin. From the outset heparin was used widely to treat deep vein thrombosis; at the Mariestad General Hospital in Sweden, patients received the same heparin protocol from 1940 for 18 years. Heparin made possible the heart-lung bypass circuit that John Gibbon and others developed for open cardiac surgery in the 1950s, and hemodialysis circuits needed it as well.

Heparin's mechanism was clarified over subsequent decades. It binds antithrombin III and accelerates its inhibition of thrombin and factor Xa by orders of magnitude, so patients with hereditary antithrombin deficiency can be resistant to it. The first clinical trial of low-molecular-weight heparin, in 1982, showed that a single daily subcutaneous dose prevented deep vein thrombosis after surgery with less bleeding. These smaller heparins act mainly on factor Xa and cause heparin-induced thrombocytopenia less often.

Unfractionated heparin is still used where rapid onset, short half-life, and reversal with protamine are required, including cardiopulmonary bypass, acute coronary syndromes, and bridging during procedures. Low-molecular-weight heparin cannot replace it in bypass circuits, and the only synthetic product, the pentasaccharide fondaparinux, copies just part of the heparin molecule.