Thrombin-specific inhibitors directly diminish
thrombin-induced coagulation and cellular activities without the side effects of
heparin.
Hirudin is the most potent natural
thrombin-specific inhibitor. Recombinant
hirudins (such as
desirudin) have been shown to be effective in the treatment of
heparin-induced
thrombocytopenia (HIT) and in the prevention of thrombotic complications after hip or knee surgery. The application of recombinant
hirudin has been limited mainly by hemorrhagic complications. Synthetic
thrombin-specific inhibitors, including
oligopeptides, tripeptides and non-
peptide low molecular weight (LMW)
thrombin inhibitors, have been designed according to their interactions with the active sites of
thrombin.
Bivalirudin (an anti-
thrombin oligopeptide) has been approved for preventing
thrombosis in
unstable angina patients following angioplasty in adjunct to
aspirin. Argotroban (a tripeptide
thrombin inhibitor) has been used for the treatment of HIT, peripheral and cerebral thrombotic diseases. The benefit of using
thrombin-specific inhibitors alone in acute
myocardial infarction or
unstable angina remains uncertain. A number of LMW
thrombin-specific inhibitors have been developed. Some of them can be administrated orally, and cause less increase in bleeding time than other
thrombin inhibitors. The efficacy, safety, stability and oral bioavailability of the
thrombin inhibitors may be considerably improved through structural optimization. Most of the LMW
thrombin inhibitors are currently being tested in animal models or at early stages of clinical trials. In this review, we will present an overview of recent advances in
thrombin-specific inhibitors.