|Year : 2017 | Volume
| Issue : 4 | Page : 198-200
The Story of Heparin
Consultant Vascular Surgeon, Department of Vascular Surgery, Sundaram Medical Foundation, Chennai, Tamil Nadu, India
|Date of Web Publication||31-Oct-2017|
Consultant Vascular Surgeon, Department of Vascular Surgery, Sundaram Medical Foundation, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Subramanian S. The Story of Heparin. Indian J Vasc Endovasc Surg 2017;4:198-200
Heparin is one of the oldest drugs to be used, having celebrated 100 years of its discovery in 2016. Its discovery and further developments to make it safe for human use in the first half of the 20th century laid the foundation for the fields of cardiac and vascular surgery, hemodialysis, and organ transplantation. Indeed, without heparin, we would not be where we are today.
Heparin has been replaced by low molecular weight heparins, fondaparinux, and direct oral anticoagulants in a large proportion of clinical use today. In spite of this, however, it continues to hold sway as the primary drug for intra-operative anticoagulation and hemodialysis. It is in this context that it is vital to look back at the discovery and development of one of the most vital drugs in modern medicine.
The story of the discovery of heparin is a saga of intrigue, controversy, and towering personalities with a tragic twist of contrasting claims of credit. It is also a reminder of how basic science research has been key to the advancement of clinical medicine. The story itself revolves around key personalities and goes through phases of initial discovery, development of heparin forin vitro use, its refinement for human use, clinical application, and further knowledge of its structure and composition.
| Discovery to Commercial Availability For In Vitro Use|| |
The key players
Jay Mclean (1890–1957) - Surgeon from Baltimore, USA who is credited with the discovery of heparin as the 2nd year medical student.
“The discovery of heparin came as a result of my determination to accomplish something by my own ability.”
William Henry Howell (1860–1945) - Eminent Physiologist, Professor of Physiology, Johns Hopkins University. Studied and contributed to knowledge of the Physiology of coagulation for greater than half a century.
“Investigators by nature are men who cannot refrain from following out their ideas. They are driven constantly to such work by interest or by irritation. Either stimulus is sufficient. I fancy that among our greatest investigators it is the irritative impulse that predominates.”
Mclean had a troubled childhood, losing his father at the age of 4 years and being brought up by a stepfather with meager means. Earning sufficient money at odd jobs, he managed to spend his 2nd year at medical school doing a research project on “thromboplastic property of cephalin” under William H Howell, the renowned physiologist at John Hopkins University. The study was aimed at identifying the nature and active ingredient of cephalin, known as a procoagulant extract from brain tissue. Mclean managed to complete the study months ahead of time and went on to study properties of similar extracts from heart and liver, named cuorin and heparphosphatid, respectively. These were thought to have a procoagulant effect. Mclean found, on the contrary, that the heparphosphatid extracts from liver had a significant anticoagulant effect on the blood. Although an antithrombin was postulated to exist to keep the blood fluid, this was the first time it was demonstrated in the laboratory. The importance of this discovery was lost on Mclean who devoted only five lines on this as part of his paper on “The Thromboplastic action of Cephalin” published in the American Journal of Physiology in June 1916. He moved on to Philadelphia where he continued research on cephalin and its thromboplastic properties. This would mark the beginning of a long time of oblivion for Mclean from the research world into anticoagulants.
William H Howell joined Johns Hopkins University as a pupil of H Newell Martin, Professor of biology in 1879. He published his thesis on “The origin of fibrin formed in the coagulation of blood” in December 1884. By 1910, he had published more than a dozen papers on coagulation of blood and became an eminent authority on the subject. At that time, there was no clarity on the existence of a natural anticoagulant in the human body; although, there were other examples in nature such as hirudin (from leech). Howell proposed that there was a hirudin like anticoagulant in the human blood, even naming it antithrombin.
Mclean's discovery opened up new frontiers in the search for an anticoagulant. Howell along with another medical student, L. Emmett Holt Jr. worked further on Mclean's Phosphatid extracts and described purification methods working on an ether extraction technique. He named this “Antiprothrombin” in 1917 and coined the term “Heparin” in 1918 to denote its origin from the liver.
Further work by Howell and Holt led to refinements in the extraction protocol. In 1923, an aqueous extraction protocol was described, and commercial production was started by a Baltimore company, Hynson, Westcott, and Dunning. This preparation was mainly used for laboratory purposes. Clinical usage was limited to an additive during blood transfusion which was accompanied by severe toxic reactions and hence, stopped. Till the early 1930s, this was the heparin available commercially with no further advancements toward clinical use. Professor Howell retired from his position at Johns Hopkins in 1931 and did no further work on heparin.
Till the 1940s, Professor Howell was considered as the discoverer of heparin in the scientific community. Although he did acknowledge the role of Mclean in the first couple of his articles, further publications did not. Mclean's relative oblivion from the anticoagulation research circles did not help his cause. In the 1940s, Mclean began a sustained campaign attempting to reclaim his place as the discoverer of heparin through a series of lectures and letters to Charles Best in Toronto. His role was eventually recognized close to and after his death in 1959 with his obituary crediting him as the “discoverer of heparin” and a plaque in Johns Hopkins acknowledging his role in association with Professor Howell. He left behind an unfinished article on his story of the “Discovery of Heparin” published in Circulation 1959.
| The Clinical Use of Heparin|| |
The key players
Charles Herbert Best (1899–1978) – Professor of Physiology in Toronto, famous for his work on Insulin. Led the team that produced a purified, nontoxic form of heparin that would set the tone for its clinical use.
Gordon Murray (1894–1976) – Surgeon at Toronto, famous for his contributions to general, orthopedic, vascular and cardiac surgery, and hemodialysis. Established the clinical role of heparin in vascular surgical operations and hemodialysis.
J. Eric Jorpes (1894–1973) – Biochemist at Karolinska Institute, Stockholm, Sweden. Identified the chemical structure of heparin and described its use in thrombotic disorders.
Charles Best recognized the need for better extraction methods for purified heparin and to reduce its toxic effects. In 1928, he established a team at the Connaught Laboratories, Toronto with Arthur Charles and David Scott to work on the extraction and purification of heparin. Their initial work with dog liver as the source was discouraging. They then began to use bovine liver and after 4 years, published a series of articles in 1933 detailing an extraction process for crude heparin from bovine liver, extrahepatic sources of heparin and a purification protocol for heparin. By 1936, they had established bovine lung as a more reliable and cheaper source of heparin for commercial production. They were also able to produce a crystallized sodium salt of heparin which was potent and nontoxic.
The next steps were to realize the clinical benefits of heparin. Gordon Murray was an established vascular surgeon by then and realized the enormous need for an anticoagulant.
In laboratory studies initially, he clearly demonstrated the efficacy of heparin in preventing coagulation in damaged arteries and veins. He then described great success in clinical use during vascular surgical procedures and for treatment of venous thromboembolism. By the late 1930s, he had introduced heparin as a mainstay in vascular surgery opening up a new era in the growth of the specialty.
At around the same time, great progress was being made in Stockholm. Eric Jorpes, a Swedish biochemist, had traveled to Toronto to learn about heparin. He did pioneering work and is credited with isolating the chemical structure of heparin. In 1936, he described heparin as being composed of uronic acid and glucosamine with a high percentage of ester sulfate. He further described its location within mast cells and identified the sulfated amino group of glucosamine as being vital to its biologic activity. Together with Clarence Crafoord, the legendary Swedish cardiothoracic surgeon, he outlined the role of heparin in clinical use for the prevention of postoperative thrombosis and in the treatment of venous thrombosis.
Further work over the decades has been concentrated on improving the techniques toward the synthesis of heparin and in isolating the specific structures responsible for its anticoagulation properties. Heparin continues to be synthesized from animal tissue, mostly from porcine intestine. Research into its active structural moiety eventually led to the development of low molecular weight heparins by enzymatic cleavage of heparin and the synthetic production of its pentasaccharide, Fondaparinux. These changed its adverse reaction profile, ease of administration, and need for monitoring. Further research continues into its production by bioengineering methods to maintain safety and purity and to reduce dependence on animal tissue.
More than a century after it was discovered, heparin continues to play a vital role in clinical medicine. Although the controversies with credit for its discovery will probably never be settled, it would be appropriate to salute the vision, knowledge and skill of each of the stalwarts without whose contribution, the specialty of vascular surgery would never have developed.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
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