Heparin is a highly-sulfated glycosaminoglycan of natural origin. It is also one of the oldest drugs still in widespread use: heparin, along with vitamin K antagonists, have been the main anticoagulant drugs for more than 70 years, as it has been used since the 1930s. Although it was first discovered almost a century ago, many years would have to pass until it could be mass produced and used as an anti-coagulant.
The Discovery and development of Heparin
Even today, there is still controversy regarding the credit of its discovery: initially attributed to the US physiologist William H. Howell (1860-1945), later authors credited the discovery of heparin to one of his alumnii, Jay McLean (1890-1957), who did research work under the guidance of Howell at the John Hopkins Medical School. In 1916-17, Jay McLean, then a second-year medicine student, was doing research work under the direction of Howell. McLean isolated a phosphatide (fat soluble compound) from canine liver cells with apparent in vitro anticoagulant properties that caused excess bleeding in experimental animals. However, McLean had to leave college in 1917 because of lack of money. One year later, in 1918, Howell and another of his alumnii, L. Emmett Holt Jr., developed another fat soluble anticoagulant apparently distinct from that isolated by McLean. Howell called it “heparin” (from the greek hepar, liver, after the tissue from which it was first isolated). After further research, they presented at the annual meeting of the American Physiological Society in 1922 an aqueous extraction protocol for isolating the newly discovered entity. In 1926, Howell presented further refinements to that protocol. The final result was a compound different from both the entities isolated by himself and Holt in 1918 and by McLean in 1916.
McLean’ initial discovery led some authors (at least until the early 1940s) to state that it was him, and not Howell, who did discover heparin, although indirectly. In fact, McLean himself claimed to have discovered heparin for years, although he waited to do so openly until Howell passed away. Unfortunately, McLean passed away in 1957 while writing his own version of the events (the unpublished paper would be published by Circulation magazine in 1959). Other authors claimed that McLean discovered a phospholipid with anticoagulant activity and not the polysaccharides later isolated by Howell and Emment. However, the latest research (Marcum 1992, 2000) tend to modify that statement, saying that a scientific discovery “is seldom made by an individual in isolation but often occurs in a community of scholars and their intellectual history or traditions”. The conclusion of Marcum and other authors was that, probably, the work of McLean changed the focus of Howell’s research, pointing him to the right direction where to investigate.
The compound refined by Howell and his colleagues began to be commercialized in 1924. However, clinical tests carried out at the Mayo clinic demonstrated that this preparation caused side effects such as headaches, fever and nausea. Nevertheless, heparin continued to be distributed commercially, although it was a difficult to obtain product that was not highly toxic, and therefore of little medical use.
Howell retired in 1931 and did not continued research on heparin. However, in other areas of the globe, there were other scientists working to produce a more refined heparin. In 1928, Canadian physiologist Charles Best (1899-1978; Nobel prize in 1923 for his discovery of insulin along with Frederick Banting) began to show interest in the production of heparin from the Toronto-based Connaught laboratories. By 1933, they had developed a first process to extract heparin from bovine liver. During their research, Best and his colleagues found out that liver, muscle and lung tissues contained the largest quantities of heparin and that the only “tissue” not containing significant quantities of heparin was blood itself. After several years of experiments to use heparin to treat thrombosis in dogs, in 1937 they had developed enough heparin to begin human trials. The development of secure, non-toxic heparin would be carried out in Canada in 1933-36. In April 1937 that newest form of heparin was first injected in a human patient, without secondary effects.
Also, in 1929, a Swedish scientist, Dr. Erik Jorpes, visited Best at Canada to observe the production process of insulin; he was also introduced to the heparin research. When he returned to the Karolinska Institut in Stokholm he tried to better purify heparin and thus avoid its side effects. Jorpes published the first conclusions of his research in 1935; by 1936, the Swedish company Vitrium AB was producing parenteral heparin for human use. By 1939, Jay McLean began to have success experimenting with the use of heparin (along with sulfapyridine) in the treatment of endocarditis and gangrene. Also, the same scientific team which developed heparin in Canada noted its potential use in the treatment of embolectomy, splenoctomy, grafts, and pulmonary embolism, since beginning research on heparin.
Connaught laboratories continued research on heparin in order to try to develop a protocol for mass-production. However, by the late 1940’s Moloney and Taylor had developed a method to cheaply produce large quantities of purified heparin. In the early 1950s, this discovery led Connaught laboratories to abandon the production of the compound they had pioneered. Since then, heparin has been safely used to prevent blood clotting in surgery patients, as well as to treat dialysis patients. There is only one exception: the heparin adulteration crisis of 2008, which affected thousands of people in eleven countries. The origin of the problem was finally found out to be the raw material processed in China from porcine intestine used in several batches of heparin imported by the US company Scientific Protein Laboratories. The crisis forced the withdrawal of entire batches of heparin distributed by Baxter and other companies. (For additional information on the Chinese heparin crisis, see our wikiheparin).