Direct Thrombin Inhibitors

George A Fritsma

doi:10.29074/ascls.17.2.118

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

George A Fritsma, MS MT(ASCP)⇑
1. is the UAB Coagulation Service Coordinator at the University of Alabama at Birmingham, Birmingham AL

Address for correspondence: George A Fritsma MS MT(ASCP), Department of Pathology, 619 South 19th Street, West Pavilion, P230, University of Alabama at Birmingham, Birmingham AL 35233. gfritsma{at}path.uab.edu

Extract

DIRECT THROMBIN INHIBITORS The direct thrombin inhibitors (DTIs) argatroban, hirudin, and ximelagatran form the newest class of anticoagulants.

Unlike heparin, which depends on antithrombin (AT) to inhibit thrombin activity, and unlike Coumadin®, a vitamin K antagonist that attenuates thrombin production by reducing the activity of coagulation factors II, VII, IX, and X, the DTIs neutralize thrombin directly by occupying its catalytic or its fibrinogen binding sites or both.

In clinical trials most DTIs match or exceed the clinical efficacy of heparin and Coumadin while creating no additional hemorrhagic risk. They require little laboratory monitoring, and when monitoring is necessary, the partial thromboplastin time (PTT) or the ecarin clotting time (ECT, snake venom derived) are used.¹ The activated clotting time (ACT) may also be used during heart surgery or percutaneous cardiac interventions (PCI).

The DTIs provide crucial alternatives for patients with heparin-induced thrombocytopenia with thrombosis (HIT) and are beginning to replace heparin and Coumadin in other prophylactic and therapeutic applications.²

Thrombin Injuries to veins or arteries expose subendothelial collagen and tissue factor and release von Willebrand factor. The collagen and von Willebrand factor combine to activate platelets, releasing platelet-stored coagulation factors, while tissue factor activates the coagulation mechanism to generate the protease thrombin from prothrombin (Figure 1).³ Thrombin activates additional platelets, activates factor V, VIII, and XI, cleaves fibrinogen to form fibrin polymer, triggers the protein C control protein pathway, activates thrombin activated fibrinolysis inhibitor (TAFI), triggers inflammation, and stimulates cellular proliferation (Figure 2).⁴ Thrombin binds to fibrin polymer in clots…

ABBREVIATIONS: ACT = activated clotting time; AT = antithrombin; DTI = direct thrombin inhibitor; EC = endothelial cell; ECT = ecarin clotting time; HIT = heparin-induced thrombocytopenia; INR = international normalized ratio; LMWH = low molecular weight heparin; PCI = percutaneous cardiac interventions; PT = prothrombin time; PTT = partial thromboplastin time; TAFI = thrombin activated fibrinolysis inhibitor; TF = tissue factor; UFH = unfractionated heparin.