The leading cause of death and disability in high-income countries is thromboembolic disease, and its prevalence is sharply increasing in middle- and low-income countries as well (1). Anticoagulants are used to alter arterial and venous thromboembolic events. Heparin and warfarin are the mainstays of anticoagulation therapy. For decades, these drugs have been collectively used for hemostasis. The usage is elaborately seen pre-operatively, perioperatively, and post-operatively in a roll.
Anticoagulant therapy is extensively used in prosthetic valves, cardiac surgeries, prophylaxis, pregnancy, arrhythmia, etc. Though heparin is one of the oldest drugs discovered, it remains prominent even today. These two drugs were discovered in the 20th century and have a very interesting story behind them.
Heparin was the first and oldest anticoagulant to be discovered. In 1916, a medical student named Jay McLean was working under a Physiologist named William Henry Howell at John Hopkins Hospital. Howell's main interest was anticoagulation, where he believed that the balance between a clotting inhibitor (termed antithrombin) and a procoagulant (termed thromboplastin) controls blood clotting (2). He hypothesized that the liberation of cephalin, named so due to its initial extraction from canine brain cells, from platelets and white blood cells counteracted antithrombin, thereby enabling the activation of prothrombin with the assistance of calcium (3). McLean was then assigned by Howell to examine the chemical purity of the cephalin and demonstrate that cephalin is what accounts for the procoagulant activity. McLean extracted phosphatides from the canine liver, which showcased the properties of anticoagulants in vitro and led to excessive bleeding in experimental animals. However, he went to Baltimore to research phosphatides under Richard Mills Pearce. At Hopkin's, Howell and another medical student, L. Emmett Holt Jr., had isolated a fat-soluble anticoagulant and termed it ‘’heparin,’’ which was coined by Howell (3).
In 1922, at the American Physiological Society's annual meeting, he presented a method for isolating heparin using an aqueous extraction. He later improved this protocol and named the water-soluble carbohydrate glucuronic acid at the 12th International Physiological Congress in 1926. He correctly stated that this was a different compound from those discovered by McLean in 1916 and by himself and Holt in 1918 (3).
A physiologist and physician named Charles Best, who previously worked on insulin, took the initiative to bring heparin to the bedside. He started this program in 1928 and continued working until 1937, when he made the first publication on the application of heparin for thrombus prevention in dogs, in which heparin prevented the formation of thrombus in veins traumatized by mechanical or chemical intervention (4).
On April 16, 1937, the first use of heparin was done when a solution of heparin in saline was passed into the brachial artery which resulted in clotting time during the two-hour infusion (2). Since then, heparin has been used in various ways, especially in cardiac surgery, where the dose of heparin can be reversed by the antidote dose of protamine.
A common oral anticoagulant used around the world is warfarin. This drug was encountered in the 1920s on the prairies of Canada and the Northern Plains of America. Earlier on, cattle in the area were dying of internal bleeding without an apparent cause. During this time, the economy was hit by the Great Depression, and due to scarcity, cattle and sheep grazed on sweet clover hay. The hemorrhaging happens when the climate is damp and the hay is molded. Usually, they disposed of the hay, but due to the economic conditions, the farmers could not afford replacement fodder. Hence, it led to a hemorrhagic disease that became known as 'sweet clover disease' (5). Frank W. Schofield and Lee M. Roderick, two local veterinary surgeons, demonstrated that this disease is reversible by removing moldy hay or by transfusing fresh blood into the bleeding animal (6). A ‘plasma prothrombin defect’ was termed by Roderick to be the acquired coagulation disorder as a cause (7). In spite of the cautions, this disease continued for a decade. In agony, Ed Carlson, a Wisconsin farmer, drove his dead cow to a scientist named Karl Link, a biochemist. On arrival, Ed showed Karl a milk can of unclotted blood. Karl and his colleagues devised a fresh in-vitro clotting test utilizing rabbit plasma, which was utilized to facilitate the chemical separation of substances discovered in the hay. After 6 years, Link finally crystallized the substance, which was proved to be 3,3′-methylene-bis[4-hydroxycoumarin] and termed dicoumarol (8) (9). In 1945, dicoumarol was used as a rodenticide. Despite this, Link worked through a list of 150 variations of coumarin, of which number 42 was found to be particularly potent, and an active component 'warfarin' was born. The name 'warfarin' was derived from the acronym 'WARF' which stands for Wisconsin Alumni Research Foundation whereas 'arin' signifies the link with coumarin. In 1948, it was sold as a rodenticide. During the year 1951, a US Army inductee attempted suicide with multiple doses of warfarin but fully recovered by using the Vitamin K injection for reserve. This sparked interest in the therapeutic use of warfarin and led to the popularity of this particular drug. Due to its high water solubility and oral bioavailability, warfarin proved more potent than dicoumarol. Hence, it was approved for humans in 1954. Followed by a heart attack in 1955, President Dwight Eisenhower received warfarin. Despite being rat poison, what was beneficial for a war hero and the President of the United States must be excellent for everyone, as Duxbury and Poller pointed out in this statement (10).
The evolution of anticoagulants has led to their use in life-altering procedures. Some have failed in initial trials, while others have had encouraging results. The drugs are tested for clinical effectiveness during their extensive studies. It’s been almost 100 years since heparin and warfarin were discovered, respectively, and they remain potent and worthwhile.
Bibliography
(1) Mannucci PM, Franchini M. Old and new anticoagulant drugs. Ann Med. 2011;43:116–23.4
(2) Douglas Wardrop, David Keeling. The story of the discovery of heparin and warfarin. BJHaem. 22 April 2008;141:pg 757-763
(3) Howell, W.H. (1912), The factors concerned in the process of the clotting of blood. Therapeutic Gazette, 36, 95–98
(4) Murray, D.W.G., Jaques, L.B., Perrett, T.S. & Best, C.H. (1937) Heparin and the thrombosis of veins following injury. Surgery, 2, 163–187.
(5) Gregory B. Lim., Warfarin: from rat poison to clinical use. Nature Reviews Cardiology (2017).
(6) Schofield, F.W. (1924) The cause of a new disease in cattle stimulating hemorrhagic septicaemia and blackleg. Journal of the American Veterinary Medicine Association, 64, 553–575.
(7) Roderick, L.M. (1929) The pathology of sweet clover disease in cattle. Journal of the American Veterinary Medicine Association, 74, 314–325.
(8) Campbell, H.A. & Link, K.P. (1941) Studies on the hemorrhagic sweet clover disease. IV. The isolation and crystallization of the hemorrhagic agent. Journal of Biological Chemistry, 138, 21–33.
(9) Campbell, H.A., Roberts, W.L., Smith, W.K. & Link, K.P. (1940) Studies on the hemorrhagic sweet clover disease. I. The preparation of hemorrhagic concentrates. Journal of Biological Chemistry, 136, 47–55.
(10) Duxbury, B.M. & Poller, L. (2001) The oral anticoagulant saga: past, present, and future. Clinical and Applied Thrombosis/Hemostasis, 7, 269–275
