Discovery and Purification of Heparin

MILESTONES

A transmission electron micrograph of an activated mast cell releasing granules containing heparin and histamine. Science Photo Library /Alamy Stock Photo

MILESTONE 1 Discovery and purification of heparin

Heparin was the first anticoagulant agent In 1922, Howell described an aqueous was used in a human for the first time: a saline to be discovered and isolated for medical extraction protocol and, in 1926, refined solution of heparin infused into the brachial use, and is one of the oldest drugs still to be this protocol and identified a water-soluble artery resulted in a significantly increased in widespread clinical use. Indeed, heparin polysaccharide anticoagulant, which he also clotting time, with no toxic adverse effects. remains on the WHO Model List of Essential termed ‘heparin’ (despite being different from A Swedish physiologist Erik Jorpes had vis- Medicines — the safest and most effective the compounds previously isolated in 1916 ited Best in Canada in 1929 and then returned medicines needed in a health-care system. and 1918). to the Karolinska Institute in Stockholm. In Heparin is a naturally occurring glycos- 1935, Jorpes published his research into the aminoglycan produced in the body by baso- heparin infused into structure of heparin, which allowed a Swedish phils and mast cells (image). The substance company to begin commercial production of was identified a centenary ago, although the brachial artery resulted heparin for intravenous use. By 1949, Peter who should be credited with the discovery in a significantly increased Moloney and Edith Taylor had patented a remains controversial. clotting time method to produce heparin with a high yield In 1916, Jay McLean was a second-year and at a low cost, which established the medical student working with the physiolo- widespread availability and use of the drug. gist William Henry Howell at Johns Hopkins This water-soluble heparin was commer- Before the 1940s, Howell was widely cred- Medical School in Baltimore, Maryland, USA. cially produced, but contained impurities ited with the discovery of heparin, although The pair were initially working on cephalin, that caused adverse effects such as headaches, Best and many others contributed to its devel- thought to be a procoagulant substance fevers, and nausea, which limited its medicinal opment into a clinically usable product. In that neutralized antithrombin and thereby use. Howell retired in 1931, and died in 1945. 1963, a plaque was unveiled at Johns Hopkins allowed the activation of prothrombin, In 1929, Charles Best (famous for being a University to commemorate Jay McLean MD leading to clotting. co-discover of insulin with fellow Canadian (1890–1957), “in recognition of his major con- After this work, McLean extracted fat- Sir Frederick Banting) working with graduate tribution to the discovery of heparin in 1916 as soluble compounds called phosphatides from student Arthur Charles decided to try to a second-year medical student in collaboration dog liver that seemed to have anticoagulant purify heparin further to reduce or eliminate with Professor William H. Howell”. properties in vitro, and which produced the adverse effects, and to demonstrate its Gregory B. Lim, excessive bleeding when given to experi- utility in the prevention of thrombus for- Chief Editor, Nature Reviews Cardiology mental animals. McLean then moved to the mation. In 1933, Arthur Charles and senior University of Pennsylvania and continued his colleague David Scott published a series of ORIGINAL ARTICLES Howell, W. H. & Holt, E. Two new factors research into cephalins. three papers outlining a protocol for isolating in blood coagulation – heparin and pro-antithrombin. Am. J. Physiol. 47, 328–341 (1918) | Charles, A. F. & Scott, D. A. Studies Nevertheless, work on anticoagulants a crude preparation of heparin from bovine on heparin: I. The preparation of heparin. J. Biol. Chem. 102, continued in the Howell laboratories. In 1918, liver, an analysis of extrahepatic tissues in 425–429 (1933) | Charles, A. F. & Scott, D. A. Studies on heparin: together with medical student L. Emmett which heparin could be identified, and a II. Heparin in various tissues. J. Biol. Chem. 102, 431–435 (1933) | Charles, A. F. & Scott, D. A. Studies on heparin. III. The Holt Jr, Howell isolated another fat-soluble protocol for purifying heparin. purification of heparin. J. Biol. Chem. 102,437–448 (1933) | anticoagulant, distinct from the one previ- In 1937, Best and colleagues published Murray, D. W. G. et al. Heparin and the thrombosis of veins following injury. Surgery 2, 163–187 (1937) | Jorpes, E. The ously isolated by McLean. Howell coined their observations that heparin prevented chemistry of heparin. Biochem. J. 29, 1817–1830 (1935). the name ‘heparin’ for this type of substance thrombus formation in dogs whose veins had FURTHER READING Wardrop, D. & Keeling, D. The story of (derived from the Greek for ‘liver’, from which undergone mechanical or chemical trauma. the discovery of heparin and warfarin. Br. J. Haematol. 141, 757–763 (2008) it was first isolated). On 16 April 1937, the purified form of heparin