Milestones in Anticoagulant Drugs
An article on antithrombotic therapy by Jack Hirsh, MD, and these accompanying milestones were published in December 2008 as part of the special ASH anniversary brochure, 50 Years in Hematology: Research That Revolutionized Patient Care.
|Heparin is discovered in dog liver by a team from The Johns Hopkins University in Baltimore, MD.
|Scientists purify heparin and produce enough pure material for clinical use.
|A U.S. clinical scientist shows that heparin requires a plasma factor (now known as antithrombin or AT) for its anticoagulant action.
|The mechanism of the interaction between heparin and AT is explained by scientists from Harvard University and from the University of Uppsala.
|Cattle in the northern U.S. and Canada are dying from a bleeding disease caused by a substance in moldy sweet clover.
|A Danish scientist discovers that dietary vitamin K is necessary to prevent bleeding.
|Researchers at the University of Wisconsin identify the substance in moldy clover as dicumarol. Over the next several years, warfarin, a related compound, is made in this laboratory.
|Dicumarol is first given to patients at the Mayo Clinic.
|Clinical studies with warfarin begin in the U.S., and the drug is approved for clinical use in 1954.
|The mechanism of action of vitamin K is explained by scientists who discover that warfarin's anticoagulant effect is caused by interference with the action of vitamin K.
Low-Molecular-Weight Heparin (LMWH)
|Researchers begin work on LMWH.
|The first clinical studies of LMWH are performed in the mid-1980s and show that LMWH is effective for preventing venous thrombosis in high-risk patients.
|LMWH can now be administered safely in an out-of-hospital setting.
|Scientists determine the structure of the high-affinity binding site on heparin and soon after demonstrate that this high-affinity site is a pentasaccharide (five-sugar unit) with a unique structure.
|The pentasaccharide is synthesized, and, over the ensuing two decades, the synthetic compound is developed into a drug for clinical use.
|Multicenter clinical trials show that fondaparinux is an effective antithrombotic drug.