Vascular Surgery Chronicles: Pioneers of Hepar

Elsevier Global Medical News

The ready availability of nearly unlimited quantities of biologically based drugs such as heparin is something that is taken for granted nowadays. But it is within the memory of living generations that having enough heparin for experimental studies, much less for clinical use, was an impossibility.

'first it was necessary to determine the effect of the heparin ... in the dogs which were to be used for the thrombosis test. ... after three weeks of testing and as i was about to use a very large dose, i received a phone call from dr. best's office to drop whatever i was doing and come over immediately. when i arrived, dr. best asked what i had been doing. i showed him my record book. he said "that's all very well jacques, but do realize you have used up the world's supply of heparin?" '  --l. b. jacques, d.sc., reflecting on his days as a student assistant with dr. best and dr. murray in the early days of heparin research (j. ortho. med. 1993;8:139-48).

Hirudin, the first anticoagulation substance ever isolated, is just over 100 years old. It was first obtained from the medicinal leech in 1905. By 1912, Dr. William Henry Howell discovered that there was a substance similar to hirudin in human and other mammalian blood plasma.

It was not until 1916, however, that Dr. Jay McLean working in Dr. Howell's laboratory at Johns Hopkins University, Baltimore, reported his partial isolation of heparin. Dr. Howell and Dr. McLean performed animal studies, but were unable to proceed beyond preliminary clinical experiments because of its toxicity.

In 1929 Dr. Charles Herbert Best (the codiscoverer of insulin with Dr. Frederick Banting) and his colleagues, chemists Dr. Arthur F. Charles and Dr. David. A. Scott at the Connaught Laboratories at the University of Toronto, began the work that led to the production of a crystalline, barium salt of heparin from beef liver that was 100 times more potent than the original crude extract and was free of toxic side effects such that it could be used in large doses in numerous animal experiments leading to clinical trials.

By 1932, Dr. Best and Dr. Gordon D. W. Murray at the Toronto laboratories and Toronto General Hospital were investigating the use of heparin in dogs as "a prophylactic in those conditions which lead to postoperative pulmonary embolism, and as an adjuvant in those operations based upon blood vessels in which the outcome has been so doubtful, because of the tendency of thrombosis to occur at the site of the operation," they reported.

Blood vessel work prior to this time was primarily the province of physiologists, and not clinicians, because "blood flow in the operated vessels failed in a few hours, blocked by the formation of a thrombus and clot. A few hours was sufficient time for a physiological experiment which was completed in one working day, but [was] of no value for the treatment of patients," according to L. B. Jacques, D. Sc., a student of Dr. Murray's who was instrumental in the early research.

In 1938, Dr. Murray and Dr. Best reported on the method of "regional heparinization" which they developed in dogs. Heparin was injected "into an artery proximal to a suture line to affect the clotting time locally in that vessel and in the blood returning from that extremity, but not to change the clotting time of the whole blood stream."

Dr. Murray would go on to become the first surgeon to make use of the drug in human trials, beginning in May 1935, having the advantage of being located at the world's best source of heparin. However, similar work was being carried out by Dr. J. Erik Jorpes, Dr. Clarence Crafoord, and others in Stockholm, using heparin prepared in the manner developed by Dr. Best and his colleagues.

By 1940 Dr. Murray was using heparin not just to prevent deep vein thrombosis and pulmonary embolism, but as an intraoperative adjunct to vascular surgery where he found it greatly improved arterial patency after arterial repair.

More Information 1. Heparin: The Contributions of William Henry Howell. (Circulation 1984;69:1198-203). 2. Preparation of Heparin and Its Use in the First Clinical Cases. (Circulation 1959;19:79-86).