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Direct thrombin inhibitors:

Dr Mohammed Abdelsattar Direct thrombin inhibitors

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Mechanism of action of thrombin: thrombin acts to convert factor XI to XIa , VIII to VIIIa , V to Va , fibrinogen to fibrin , and XIII to XIIIa .

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Thrombin bound to thrombomodulin activates protein C, an inhibitor of the coagulation cascade.

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Thrombin inhibitors are anticoagulants that bind to and inhibit the activity of thrombin therefore prevent blood clot formation . Thrombin inhibitors inactivate free thrombin and also the thrombin that is bound to fibrin. Thrombin has many important functions in the clotting pathway, so it is a good target for anticoagulants drugs.

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Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants bind directly to thrombin and do not require a cofactor such as antithrombin to exert their effect

Recombinant hirudins: lepirudin and desirudin:

Recombinant hirudins : lepirudin and desirudin derivatives of hirudin , a peptide originally isolated from the salivary glands

lepirudin :

lepirudin have the highest affinity for thrombin Lepirudin is licensed for the anticoagulation in patients with heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease intravenous infusion lepirudin is renally excreted, dose adjustments are required in patients with renal impairment dose adjustment based on aPTT is required during treatment


Desirudin subcutaneously administered DTI approved by the ( FDA) for postoperative prevention of V eno thrombo embolism in patients undergoing elective hip replacement surgery However , desirudin was associated with an increased incidence of major bleeding events


Argatroban Argatroban is licensed in the United States for the prophylaxis or treatment of thrombosis in patients with HIT and for anticoagulation in patients with a history of HIT or at risk of HIT undergoing PCI . hepatically metabolized and dose adjustments are necessary in patients with hepatic but not renal impairment. dosing is titrated to maintain an aPTT of 1.5–3 times that of baseline


Argatroban CONTRAINDICATIONS patients with overt major bleeding, or in patients hypersensitive to this product or any of its components .


Bivalirudin thrombin inhibition activity nearly 800 times weaker than that of hirudin the binding of bivalirudin to thrombin is reversible because once bound, it is slowly cleaved by thrombin so it is only transiently inhibited and the enzymatic activity of the thrombin site is restored . contribute to its decreased bleeding risk and improved safety profile when compared with r- hirudins


Bivalirudin INDICATIONS AND USAGE an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). an anticoagulant in patients undergoing percutaneous coronary intervention (PCI). patients with, or at risk of, HIT/HITTS undergoing PCI .


Bivalirudin contraindicated in patients with severe renal impairment active major bleeding Hypersensitivity The Bivalirudin Angioplasty Study showed that bivalirudin had a better efficacy in preventing these primary outcomes as well as a lower bleeding rate when compared with UFH in over 4000 patients undergoing PTCA for unstable or post-infarct angina

Oral Direct Thrombin Inhibitors:

Oral Direct Thrombin Inhibitors The newest oral DTIs under investigation include dabigatran Dabigatran received FDA approval in October 2010 for the indication of thrombosis prevention in nonvalvular AF prodrug that is converted in the liver through esterases to the active compound, dabigatran , which is a competitive, direct and reversible inhibitor of thrombin

Oral Direct Thrombin Inhibitors:

Oral Direct Thrombin Inhibitors DOSAGE AND ADMINISTRATION Recommended Dose For patients with creatinine clearance ( CrCl ) >30 mL/min, the recommended dose of PRADAXA is 150 mg taken orally, twice daily , with or without food. For patients with severe renal impairment ( CrCl 15-30 mL/min), the recommended dose of PRADAXA is 75 mg twice daily .

Oral Direct Thrombin Inhibitors:

Oral Direct Thrombin Inhibitors Converting from or to Warfarin When converting patients from warfarin therapy to PRADAXA, discontinue warfarin and start PRADAXA when the international normalized ratio (INR) is below 2.0.


Conclusions These newer anticoagulants offer several advantages over the traditional agents: direct inhibition of free and clot-bound thrombin, lack of required co-factors, a more predictable anticoagulant response, inhibition of thrombin-induced platelet aggregation and absence of immune-mediated thrombocytopenia. Currently , four parenteral DTIs are available in the United States, each licensed for a specific indication


sources Articles from British Journal of Clinical Pharmacology

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