Milestone |
Milestone 1 (1916–1937)
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Heparin was serendipitously discovered by Jay McLean and William Henry Howell working at Johns Hopkins Medical School; the anticoagulant was subsequently purified for clinical use by Charles Best and colleagues. Read more.
Milestone 2 (1940–1978)
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Warfarin is a derivative of coumarin (a naturally occurring substance in sweet clover) that was developed by Karl Link and colleagues and originally marketed as a rodenticide, but subsequently adopted for clinical use as an anticoagulant. Read more.
Animation
This animation illustrates the history and development of warfarin, and its evolution from rat poison to widespread clinical anticoagulant drug.
Nobel Prize (1943)
The Nobel Prize in Physiology or Medicine is awarded jointly to Danish biochemist and physiologist Henrik Dam (pictured left) “for his discovery of vitamin K” and American biochemist Edward Adelbert Doisy (pictured right) “for his discovery of the chemical nature of vitamin K”. The new vitamin was found to have a role in coagulation and received the letter K because the discoveries were reported in a German journal, which called it the Koagulationsvitamin.
Milestone 3 (1947–1960)
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The combination of heparin and a vitamin K antagonist is found in randomized, controlled clinical trials to be an effective treatment for acute pulmonary embolism. Read more.
Milestone 4 (1975-1978)
L. Marshall/Macmillan Publishers Limited
In a large series of clinical trials and meta-analyses, low doses of heparin are shown to be effective in reducing the incidence of postoperative venous thromboembolism. Read more.
Milestone 5 (1979–1982)
S. Fenwick/Macmillan Publishers Limited
Low-dose heparin is found to be ineffective in preventing recurrent venous thrombosis, but higher doses are an effective alternative to warfarin for secondary prophylaxis. Read more.
Milestone 6 (1983–1995)
S. Fenwick/Macmillan Publishers Limited
Control of vitamin K antagonists including warfarin is markedly improved by standardizing laboratory monitoring by replacing the prothrombin ratio with the international normalized ratio. Read more.
Audio
Listen to Professor Jack Hirsh discuss his involvement in anticoagulant research, including the development of the international normalized ratio.
Milestone 7 (1996-1997)
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Studies show that low-molecular-weight heparin can be safely administered in a fixed or weight-adjusted dose without the need for monitoring, leading to convenient, out-of-hospital treatment of thrombosis. Read more.
Audio
Listen to Professor Harry Büller discuss clinical trials on the prevention and treatment of thrombosis and how medical practice has evolved.
Milestone 8 (2001-2006)
Alamy Stock Photo
The demonstration that the synthetic pentasaccharide fondaparinux is effective for the prevention and treatment of venous thrombosis indicates that factor Xa is a good target for antithrombotic therapy. Read more.
Animation
This animation illustrates the clotting factors involved in thrombus formation, and how these factors can be pharmacologically targeted using heparin, warfarin, and direct thrombin and factor Xa inhibitors for clinical anticoagulation.
Poster
Macmillan Publishers Limited
This poster displays the various classes of anticoagulant drugs that are used to prevent and treat venous and arterial thrombosis. Download the poster (3.2 MB).
Milestone 9 (2003)
Brian Jackson/Alamy Stock Photo
The development of ximelagatran provided the proof of principle that a specific oral thrombin inhibitor is safe and effective in a variety of thrombotic disorders, setting the stage for the introduction of a new class of oral thrombin and factor Xa inhibitors. Read more.
Milestone 10 (2007–2014)
S.Fenwick/Macmillan Publishers Limited/
Scott Camazine/Alamy Stock Photo
Randomized trials with the direct thrombin and factor Xa inhibitors show that these non-vitamin K antagonist oral anticoagulants (NOACs) given in fixed doses are as safe and effective as warfarin in prevention and treatment of venous thromboembolism and in stroke prevention in atrial fibrillation. Read more.
Focus issue
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This Focus issue features four Review articles in which experts discuss clinical trial data on oral direct thrombin and factor Xa inhibitors as alternatives to vitamin K antagonists in various clinical settings. Read more.
Milestone 11 (2011)
Andrey Sevostianov/Alamy Stock Photo
A long-standing uncertainty in the field of anticoagulation is the optimal duration of treatment for venous thrombosis, and the careful balance between antithrombotic benefit and bleeding risk. Read more.
Review
In this Review, Mehran and colleagues discuss the overall clinical effect of non-vitamin K antagonist oral anticoagulants, which is a balance between ischaemic benefit and bleeding risk. Read more.
Milestone 12 (2013)
S. Fenwick/Macmillan Publishers Limited
The incidence of device-induced thrombosis (for example by catheters or cardiac prosthetic valves) highlights the need for more-targeted anticoagulants to prevent thrombosis on prosthetic surfaces. Read more.
Audio
Listen to Professor Jeffrey Weitz discuss the ongoing challenges in anticoagulant therapy and the developments that are on the horizon.
Milestone 13 (2015-2017)
Laurel/Alamy Stock Photo
Antidotes for the non-vitamin K antagonist oral anticoagulants (NOACs) are undergoing development and regulatory approval, and will allow rapid reversal of NOAC effects in emergency settings. Read more.
Review
In this Review, Levy and colleagues describe the mechanism of action of the NOAC-reversal strategies, and provide guidance on potential indications and management strategies for reversal. Read more.
Milestone 14 (2017)
V. Summersby/Macmillan Publishers Limited
The COMPASS trial shows that the combination of low-dose rivaroxaban and aspirin is more effective than aspirin alone in reducing cardiovascular outcomes in patients with stable atherosclerotic vascular disease. Read more.