Abstract
Medical student Jay McLean was planning an academic surgical career. Deciding it would be too difficult to pursue laboratory research once he graduated, he took a 1-year break from his studies in 1915 and approached the author of his favourite physiology textbook, William Howell, at Johns Hopkins. After being assigned a project, and an office, consisting of ‘a sink and attached table drainboard with a shelf’, he set to work looking at thromboplastic substances in the body, initially in the brain and later in the liver. 1 While he discovered a great deal about thrombosis, unexpectedly he also found that some of his liver extracts had anticoagulant properties. His supervisor was initially so sceptical that this finding was left out of McLean’s original research paper. 2 But by the time McLean left to continue his medical studies, Howell had acknowledged the discovery and continued researching the anticoagulant substance now known as heparin.3 –5
Heparin is a large, complex, heterogeneous molecule. Found in mast cells in humans, and across a broad range of organisms, its biological purpose remains unclear although it is currently thought to play a role in cellular communication. 6 Studying it and isolating it has been difficult. Howell’s early work resulted in small-scale commercial production by Hynson, Westcott and Dunning in Baltimore in the 1920s, but this was never profitable for the company as it was too toxic for animal studies and could only be used in laboratory research. 7
Charles Best, Assistant Director at Connaught Laboratories in Toronto, worked extensively with liver extracts while refining insulin for human therapeutic use. He ‘visualized a similar advance in the heparin field’ and began significant research into heparin in the late 1920s. 8 As with insulin, subsequent work was a collaboration between researchers at Toronto University and Connaught Laboratories. 9 Further collaborative work began in Stockholm, under the direction of Swedish biochemist and medical practitioner Erik Jorpes. These laboratory researchers could see the potential clinical application of an effective anticoagulant in the prevention of thrombosis – they just needed a safe and reliable commercial product. Finally, clinical trials on the treatment of deep vein thrombosis (DVT) began in Sweden and Toronto in the mid-1930s with heparin from Kabi Vitrium AB and Connaught Laboratories, respectively.10,11
After these successful early trials, heparin quickly found many clinical applications, particularly once protamine was accidentally discovered to be an effective antidote in 1937. 12 Heparin was crucial to the development of cardiopulmonary bypass machines and the growth of cardiac surgery in the 1950s, as well as in dialysis. 13 From the outset it was used extensively as a treatment for DVT. At the Mariestad General Hospital in Sweden, heparin was given as DVT therapy from 1940, with the same protocol used for the next 18 years. Affected patients were given 15,000 units of heparin every 4 h in the daytime for 3 to 4 days, and mobilised as soon as swelling and tenderness resolved. 14 Despite widespread use for DVT, the first controlled trial demonstrating definitively that heparin prevented pulmonary embolism was not conducted until 1960.15,16 Incidentally, being the first drug to be prescribed regularly intravenously, heparin was also responsible for the early development of indwelling intravenous cannulas, with an early German example being first described as a ‘Heparin needle’.17,18
Prophylactic use of heparin for prevention of DVT following surgery, while often discussed, was not practical with intravenous therapy. In 1972, Kakkar and colleagues in London established the safety and efficacy of 5,000 units of subcutaneous heparin given at 12-h intervals for 7 days after major surgery. 4 This stimulated large multicentre trials and the widespread adoption of the practice. 19
Heparin (also known as unfractionated heparin or UFH) is a mix of molecules of varying molecular weight and clinical activity. Attempts to refine the commercial product by fractionation began in the 1970s with the goal of ‘tailoring heparins to perform highly specific clinical functions with maximum efficiency and minimal side effects’. 20 Unexplained thrombosis due to heparin therapy had been described in 1958 and, by the 1960s, improvements in blood film analysis had established that this was associated with a low platelet count (heparin-induced thrombocytopaenia or HIT syndrome).21,22 Since it was suspected this was immune-mediated, it was hoped that either a more refined product or a synthetic heparin would solve the problem. The first clinical trial of low-molecular-weight heparin (LMWH) took place in 1982, establishing that a once daily subcutaneous dose was sufficient for DVT prophylaxis, and associated with a lower post-operative bleeding risk. 23 It has been subsequently demonstrated that LMWH also has a lower incidence of HIT syndrome. Unfortunately, its targeted pharmacology means that it is not applicable in many areas of medicine, such as cardiopulmonary bypass. The only currently available synthetic product is fondaparinux, a synthetic pentasaccharide modelled on part of the heparin molecule. Released in 2002, it is used like LMWH, with proven efficacy in DVT prophylaxis and other clinical scenarios like acute coronary syndrome; theoretically is should not cause HIT syndrome since it does not interact with platelets.24,25
A robust, secure heparin supply chain is crucial to modern medical and surgical practice. Despite many advances in heparin manufacture, the world remains dependent on animal sources. These sources are extremely vulnerable. In the 1990s, global outbreaks of bovine spongiform encephalopathy effectively ended the production of heparin from bovine products and caused a temporary threat to supply. 26 Production then shifted to China, which currently supplies 80% of the world’s demand using porcine intestines from its pork industry. This makes supply precarious during periodic outbreaks of swine flu. There have also been problems with contamination, most notably in 2007 when there were several deaths in the United States and multiple adverse events worldwide; the reasons for and nature of the contamination remain controversial, but the product recall severely impacted supply. 27 New therapeutic uses for heparin are now increasing the need for this drug and exposing further vulnerabilities in the system. This was evident during the recent pandemic when the therapeutic benefits of heparin in the treatment of SARS-CoV-2 ramped up worldwide demand, while simultaneously closing meat packing works as hotbeds of viral transmission.
Heparin may be one of the oldest and most important drugs in modern medicine, however, as the title of a recent article suggested, the end of the story is not in sight. 16