Antithrombotics

Upon vascular injury, the coagulation system is activated thrombocytes and fibrin molecules coalesce into a plug that seals the defect and halts bleeding (hemostasis). Unnecessary formation of an intravascular clot—a thrombosis—can be life-threatening. 

If the clot forms on an atheromatous plaque in a coronary artery, myocardial infarction is imminent a thrombus in a deep leg vein can be dislodged and carried into a lung artery and can cause pulmonary embolism. 

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D, H W Hoeffken, D Crosse, J Stuerzebecher, P D Martin, B F P Edwards and W Bode 1992. Refined 2.3 Angstroms X-Ray Crystal Structure of Bovine Thrombin Complexes Formed witli he 3 Benzamidine and Arginine-Based Thrombin Inhibitors NAPAP, 4-TAPAP and MQPA A Starting Point for Improving Antithrombotics. Journal of Molecular Biology 226 1085-1099. 

The therapeutic iadication (TI) is antithrombotic, unless otherwise noted. Tl is antithrombotic and sudden heariugloss. 

Itazigrel (137) is an antithrombotic compound because of its inhibition of platelet aggregation induced by collagen. It is synthe.sizcd froin l-bromo-l-(4-methoxy)benzoyl-4-methoxytol-uene (135) by reaction in the usual way with triflucffothioacetamide (136) to give itazigrel 471. 

Fondaparinux, the factor Xa-binding pentasaccharide (Arixtra, MW 1,728 Da), is prepared synthetically, unlike UFH, LMWH and danaparoid, which are obtained from animal sources. Despite only inactivating free factor Xa, clinical trials indicate that fondaparinux is an effective antithrombotic agent, both for venous thromboembolism prophylaxis and treatment, as well as for acute coronary syndrome and ST elevation myocardial infarction [4]. 

Prevention of DVT and PE (antithrombotic prophylaxis) is another common indication for UFH, LMWH or coumarin, especially following surgery or immobilizing trauma. Fondaparinux is approved for prevention of DVT and PE after hip and knee surgery, and following abdominal surgery. 

The PDE3 inhibitor, cilostazol, has been used as an antithrombotic agent and is currently being used in patients being treated for intermittent claudication. Cilostazol is also used for the prevention of restenosis after treatments such as angioplasty. Another PDE3 selective inhibitor, milrinone, has been used in the treatment of congestive heart failure. Milrinone also has been shown to increase the conductance of the CFTR transporter in vitro. 

Albers GW, Amarenco R Easton JD, Sacco RL, Teal R. Antithrombotic and thrombol3ftic therapy for ischemic stroke The seventh ACCR Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 126 483S-512S. 

Fibrinolytic agents have prothrombotic properties as well. The plasmin generated by thrombolysis leads to the production of thrombin, which is a potent platelet activator and converts fibrinogen to fibrin. Indeed, studies have shown early reocclusion in as many as 17% of the patients treated with lAT and 34% of the patients treated with IV rt-PA. Therefore, a strong rationale exists for the adjuvant use of antithrombotic agents. 

Dipyridamole exerts its effect by inhibition of platelet phosphodiesterase E5, increasing cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP). By inhibiting its uptake and metabolism by erythrocytes, dipyridamole also increases the availability of adenosine within blood vessels, promoting inhibition of platelet aggregation and local vasodilatation. " Dipyridamole may also inhibit cAMP phosphodiesterase in platelets, which further increases cAMP levels and may enhance endothelial nitric oxide production, contributing to its antithrombotic effect. Existing trials of dipyridamole in stroke have focused on secondary prevention and will be discussed briefly. 

Early Recurrence Rates in Cardioembolic Stroke The primary rationale for acute antithrombotic therapy in cardioembolic stroke, including that associated with AF, is prevention of early recurrence secondary to further embolism. 

Antithrombotic Treatment of Acute Stroke Due to Large Artery Atherosclerosis... 

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