Thrombin is a serine protease protein that plays a central role in blood coagulation. It converts soluble fibrinogen into insoluble strands of fibrin and activates platelets, ultimately leading to the formation of blood clots or thrombi. Dysregulated thrombin activity has been implicated in a number of thrombotic disorders such as deep vein thrombosis, pulmonary embolism, myocardial infarction and stroke. Traditional anticoagulant drugs used to combat these conditions like heparin and warfarin inhibit upstream factors in the coagulation cascade, resulting in relatively indirect and variable inhibition of thrombin. This has led researchers to develop novel direct thrombin inhibitors which allow more effective and precise management of thrombotic diseases. In this article, we discuss the emergence of thrombin inhibitors as an important class of anticoagulants.

Direct Thrombin Inhibitors
Direct thrombin inhibitors are small organic molecules that bind directly to thrombin's active site and catalytically block its proteolytic activity. They act rapidly to halt clot formation and dissolution by directly inhibiting one of the key enzymes of coagulation. Some of the major direct thrombin inhibitors approved for clinical use include hirudin, argatroban, dabigatran and bivalirudin. These drugs have favorable pharmacological properties compared to indirect anticoagulants like heparin. They demonstrate dose-dependent, predictable anticoagulant response without the need for coagulation monitoring. This makes them suitable for various indications requiring short or long-term anticoagulation.

Fondaparinux and Idraparinux
Anticoagulant pentasaccharide drugs like fondaparinux and idraparinux augment antithrombin's natural ability to inhibit thrombin and factor Xa. While not direct thrombin inhibitors per se, their selective and potent indirect anti-Xa and anti-IIa activities make them safe and effective as prophylactic anticoagulants for various clinical indications. Fondaparinux is commonly used for post-operative venous thromboembolism prevention and has better efficacy than enoxaparin. Idraparinux is a long acting injectable under development for the same applications.

Bivalirudin and Argatroban
Bivalirudin is a synthetic 20 amino acid polypeptide modeled after hirudin. It has selective direct thrombin inhibiting activity with no anti-FXa effect. This makes it safer for uses where FXa inhibition needs to be avoided, like in patients with heparin-induced thrombocytopenia on cardiopulmonary bypass surgery. Argatroban is a direct thrombin inhibitor developed based on L-arginine. It is an injectable anticoagulant useful for anticoagulating patients with heparin resistance or allergy. Both bivalirudin and argatroban are good alternatives when indirect anticoagulants cannot be used.

Pharmacological Advantages
Direct thrombin inhibitors eliminate the need for monitoring associated variables like vitamin K levels, clotting factor levels or platelet counts as seen with indirect anticoagulants. Their fast onset and short half-life permits precise dosing for peri-operative use. Besides, direct thrombin inhibitors are insensitive to platelet responsiveness variations unlike heparin and overcome heparin resistance issues seen in few patients. Additionally, complications linked to food and drug interactions inherent to vitamin K antagonists do not arise with these newer anticoagulants.

Future Directions
Novel direct thrombin inhibitor classes are under active investigation including specific serine protease inhibitors, peptidomimetics, monoclonal antibody-based binders and allosteric inhibitors targeting substrate recognition pockets. Combination therapies employing thrombin inhibitors along with anti-factor Xa agents show potential for optimizing anticoagulation benefit and reducing risk of recurrence. Selective thrombin imaging probes also aid improved elucidation of procoagulant mechanisms in disease states. It remains to be seen whether further optimization yields improved oral agents with sustained ultra-long half-lives suitable for once-weekly dosing regimens.

Conclusion
In this article, we discussed how direct thrombin inhibitors overcome limitations of traditional indirect anticoagulants and established their role as an important class of novel anticoagulants. Both parenteral and oral forms are utilized effectively for prophylaxis and treatment of venous thromboembolism, atrial fibrillation and arterial thrombotic disorders. Their predictable dose response characteristics provide advantages over other previous mainstay anticoagulants. Direct thrombin inhibitors thus represent a significant paradigm shift with ongoing refinement