McLean Discovers the Natural Anticoagulant Heparin Summary

  • Last updated on November 10, 2022

While studying cephalin in liver tissue, Jay McLean accidentally discovered the natural anticoagulant heparin.

Summary of Event

Jay McLean, a young medical student at The Johns Hopkins University, accidentally discovered the natural anticoagulant heparin in 1916 while working on a physiology research project for William H. Howell. McLean wished to become a surgeon with a strong basis in physiology, and he asked to be assigned a problem on which he could finish the research and publish the findings in a year. He specifically requested that he be allowed to work on the problem alone in order to prove to himself that he had the ability to accomplish such a complex task on his own. Heparin Anticoagulants Medicine;anticoagulants [kw]McLean Discovers the Natural Anticoagulant Heparin (Sept., 1915-Feb., 1916) [kw]Anticoagulant Heparin, McLean Discovers the Natural (Sept., 1915-Feb., 1916) [kw]Heparin, McLean Discovers the Natural Anticoagulant (Sept., 1915-Feb., 1916) Heparin Anticoagulants Medicine;anticoagulants [g]United States;Sept., 1915-Feb., 1916: McLean Discovers the Natural Anticoagulant Heparin[03820] [c]Health and medicine;Sept., 1915-Feb., 1916: McLean Discovers the Natural Anticoagulant Heparin[03820] [c]Science and technology;Sept., 1915-Feb., 1916: McLean Discovers the Natural Anticoagulant Heparin[03820] [c]Biology;Sept., 1915-Feb., 1916: McLean Discovers the Natural Anticoagulant Heparin[03820] McLean, Jay Howell, William H. Best, Charles Herbert

For more than thirty years, Howell had been studying the various aspects of the coagulation of blood. Blood;coagulation At the time, he was performing blood clotting experiments involving a substance known as cephalin. Cephalin Howell considered cephalin to be the thromboplastic substance of the body—that is, the substance that caused the blood to clot. The problem Howell assigned McLean was to develop a method to prepare cephalin in a highly purified form and to determine whether it enhanced the clotting process. The method of obtaining cephalin that Howell had previously employed involved the use of macerated brain tissue, which contains large amounts of cephalin. This brain tissue was dried on glass plates and then taken through a series of complex, time-consuming steps, using extraction by ether and alcohol precipitation to separate out the cephalin.

As McLean began work on his project, he also began taking an advanced course in German. While reading in the German chemical literature, he learned of work in Germany in which substances similar to cephalin were being extracted from heart and liver tissue. McLean suggested to Howell that it might be advantageous to use such organs in his experiments. Subsequently, he found that extracts from heart and liver tissue did indeed exhibit thromboplastic activity, but apparently the extracts were not pure cephalin. This was demonstrated by the fact that the precipitates from the heart and liver tissue had different appearances from the cephalin precipitate from brain tissue. McLean referred to the extract from the heart as “cuorin” and the extract from the liver as “heparphosphatid,” the terms used in the German literature.

In the course of his experiments, McLean also found that with time the thromboplastic activity of cephalin deteriorated in these tissues. It was while he was attempting to determine how long the thromboplastic activity lasted that McLean discovered that at a certain point, rather than simply failing to cause the blood to clot, the liver extract actually prevented the blood from clotting. McLean concluded that this inhibition of coagulation was the result of the substances mixed with the cephalin in the heparphosphatid extract.

As this discovery was not related to his assigned problem, McLean did not inform Howell immediately of what he had found. Instead, he repeated the experiment several times to prove that the conclusion was correct. When McLean informed Howell of his finding, Howell was understandably skeptical that McLean had discovered a naturally occurring anticoagulant. In order to convince Howell, McLean added some of his extract to the freshly drawn blood of a laboratory cat, and, as McLean predicted, the blood failed to clot. Even though Howell still was not totally convinced, he realized the importance of McLean’s work and decided to continue research on the project.

The first presentation concerning the anticoagulant delivered at a scientific meeting took place on February 19, 1916, before the Society of the Normal and Pathological Physiology at the University of Pennsylvania. In June, 1916, McLean submitted his work on the thromboplastic action of cephalin for publication in the American Journal of Physiology. Howell had discouraged McLean from mentioning the discovery of the anticoagulant substance, which McLean called heparphosphatid. In a letter to Canadian physiologist Charles Herbert Best, McLean stated that Howell did not think that he should include anything about the discovery of the anticoagulant in his paper; rather, it should be studied thoroughly and a separate paper written on it later. McLean argued that the finding was made during 1915-1916, and he believed that its discovery should be included as a record of the work done during that period. Howell finally agreed to permit its inclusion in the body of the paper. Further, in his letter to Best, McLean stated that Howell was very skeptical that he had found a true anticoagulant. This was because McLean was using a very weak solution of the anticoagulant, and it was only through very careful records and the systematic saving of little tubes and repetition that he was aware that he had an actual anticoagulant.

After McLean left The Johns Hopkins University, Howell, working with Emmett Holt, Holt, Emmett continued McLean’s work. Howell and Holt, after evaluating many variations of McLean’s methods, developed a technique that yielded a reliable preparation of the anticoagulant. In their publication in the American Journal of Physiology submitted in October, 1918, Howell and Holt first introduced the word “heparin” for the heparphosphatid that McLean had discovered. In this article, they also described how heparin could be prepared from lymph glands as well as from heart and liver. They described the antagonism between heparin and cephalin in the clotting mechanism. Howell later published papers, in 1922 and 1925, describing the preparation of heparin in a more purified form. In 1928, he published a detailed paper on the chemical and physiological reactions of heparin.

Meanwhile, Best, working at the University of Toronto, had been concerned with the preparation of insulin for administration to diabetic patients; after learning of Howell’s work, he recognized the potential clinical applications of heparin. Realizing that clinical trials of heparin must be preceded by extensive work on its chemical preparation, Best organized a group of scientists to study its chemistry and physiology. From 1928 through 1936, the University of Toronto researchers made numerous discoveries concerning heparin. Working under the direction of Best, David Scott Scott, David and Arthur Charles Charles, Arthur discovered that heparin could be extracted from beef lung, a much less expensive source. These investigators also developed methods of purifying, concentrating, and standardizing heparin. During this period it was demonstrated also that heparin is an effective anticoagulant in dogs.

Significance

The first clinical trials with heparin were conducted by E. C. Mason Mason, E. C. in 1924 and Howell in 1928 in blood transfusion studies. These trials were largely unsuccessful because of the undesirable reactions in the patients. As soon as a purified, concentrated form of heparin became available in 1935, Gordon Murray Murray, Gordon began clinical trials in Toronto. His results, published in 1937, clearly indicated that treatment with heparin could prevent some types of clinical thrombosis. The availability of heparin also made possible a large number of experimental studies. These resulted in the first exchange transfusion in 1938 and the development of the artificial kidney in 1944.

In the 1940’s, researchers began large-scale clinical experiments with anticoagulant therapy in the United States, Sweden, and Switzerland. These experiments involved heparin treatment of medical conditions such as leg thrombosis, thrombophlebitis of deep veins, and pulmonary embolism. The success of these studies firmly established the use of heparin in medical practice. It was not until 1966, however, that studies were done to demonstrate the use of heparin in the prevention of postoperative thrombosis, a frequent cause of complications and mortality following surgery. In a study by J. G. Scharnoff, patients receiving small doses of heparin subcutaneously prior to surgery had a lower incidence of thromboemboli. This study did not have proper controls, however, so the results were not widely accepted as valid, but beginning in the early 1970’s numerous other studies demonstrated conclusively the benefit of prophylactic administration of heparin.

Heparin plays an important role in both treatment and prevention of thrombosis, but its use can have drawbacks. Clotting is a natural protective mechanism of the body, and its inhibition by heparin can lead to excessive bleeding. Heparin-associated complications are not uncommon. A 1977 study by J. Porter found heparin use to be the most frequent cause of drug-related deaths of hospitalized patients.

Heparin also has uses in medical science beyond treatment and prevention of thrombosis. It makes possible the maintenance of blood circulation outside the body, which is necessary in heart surgery and in renal dialysis. Heparin is used also to prevent clotting in devices implanted in veins for the intermittent injection of medication or the withdrawal of blood for laboratory testing. Heparin Anticoagulants Medicine;anticoagulants

Further Reading
  • citation-type="booksimple"

    xlink:type="simple">Best, Charles H. “Preparation of Heparin and Its Use in the First Clinical Cases.” Circulation 19 (January, 1959): 79-86. Very interesting article, written as part of a historical symposium on anticoagulants, gives a historical perspective by one of the early investigators of heparin. Includes excerpts from McLean’s and Howell’s letters and makes reference to other early investigators of heparin.
  • citation-type="booksimple"

    xlink:type="simple">Howell, William H., and Emmett Holt. “Two New Factors in Blood Coagulation—Heparin and Pro-antithrombin.” American Journal of Physiology 47 (1918): 328-341. A technical article in which Howell expands McLean’s work and first introduces the term “heparin.” Also describes other factors involved in the coagulation process and correctly identifies the role of heparin in preventing intravascular coagulation.
  • citation-type="booksimple"

    xlink:type="simple">McLean, Jay. “The Thromboplastic Action of Cephalin.” American Journal of Physiology 41 (1916): 250-257. The article in which McLean first reported his discovery of the natural anticoagulant. Provides considerable insight into the extent and complexity of McLean’s work. Written in fairly technical language.
  • citation-type="booksimple"

    xlink:type="simple">Triplett, Douglas A., ed. “Heparin: Clinical Use and Laboratory Monitoring.” In Laboratory Evaluation of Coagulation. Chicago: American Society of Clinical Pathologists Press, 1982. Provides a thorough and accessible description of heparin’s biochemistry, biological actions, and clinical applications. Includes references.
  • citation-type="booksimple"

    xlink:type="simple">Wintrobe, Maxwell M. Hematology, the Blossoming of a Science: A Story of Inspiration and Effort. Philadelphia: Lea & Febiger, 1985. A very impressive work that covers the historical development of the study of blood. Valuable for anyone interested in the history of medicine.

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