While studying cephalin in liver tissue, Jay McLean accidentally discovered the natural anticoagulant heparin.
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.
For more than thirty years, Howell had been studying the various aspects of the coagulation of blood.
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,
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
The first clinical trials with heparin were conducted by E. C. Mason
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.
-
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. -
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. -
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. -
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. -
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.
Discovery of Human Blood Groups
Carrel Rejoins Severed Blood Vessels
Crile Performs the First Direct Blood Transfusion
Gibbon Develops the Heart-Lung Machine