Before, during, and after: An Argument for Safety and Improved Outcome of Thrombolysis in Acute Ischemic Stroke with Direct Oral Anticoagulant Treatment

Abstract

Direct oral anticoagulants are the primary stroke prevention option in patients with atrial fibrillation. Anticoagulant use before stroke, however, might inhibit clinician comfort with thrombolysis if a stroke does occur. Resuming anticoagulants after ischemic stroke is also problematic for fear of hemorrhage. We describe extensive literature showing that thrombolysis is safe after stroke with direct anticoagulant use. Early reinstitution of direct anticoagulant treatment is associated with lower risk of embolic recurrence and lower hemorrhage risk. The use of direct anticoagulants before, during, and after thrombolysis appears to be safe and is likely to promote improved outcomes after ischemic stroke. ANN NEUROL 2024;96:871-886.

Figure 1:. Simplified coagulation cascade emphasizing differing mechanism of warfarin, heparin, direct thrombin inhibitors and factor Xa inhibitors.

Vitamin K antagonists such as warfarin inhibit the production of all vitamin K dependent clotting factors, including Factors II (aka prothrombin), VII, IX and X. In contrast, direct thrombin inhibitors such as argatroban and dabigatran bind directly to activated Factor IIa (thrombin) and prevent its activation of fibrinogen to fibrin. Factor Xa inhibitors reduce the activation of Factor II to Factor IIa, which also results in reduced production of fibrin. Created with BioRender.com.

Figure 2:. Examples of asymptomatic hemorrhagic transformation after ischemic stroke.

A moderately large ischemic stroke is seen on a Fluid Attenuated Inversion Recovery (FLAIR) sequence (A), while susceptibility weighted imaging reveals a moderate amount of subsequent hemorrhage (B). Very small lesions on FLAIR (C) and (E, arrow) can result in small hemorrhage (D) or a microbleed (F, arrow).

Figure 3:. Neurovascular unit after ischemia and reperfusion.

The neurovascular unit consists of endothelial cells, pericytes, astrocytic foot processes, and extracellular matrix. After ischemia and reperfusion pericytes contract and endothelial cells swell. An inflammatory response activates a host of proteases, platelets, and promotes microvascular thrombosis. With time these changes promote oxidative stress that leads to neuronal and glial cell death. NO: nitric oxide. TNF-α: tissue necrosis factor alpha. IL-1β: interleukin 1 beta. IL-6: interleukin 6. ROS: reactive oxygen species. Tregs: regulatory T cells. CD4: cluster of differentiation 4. LFA-1: lymphocyte function associated antigen 1. ICAM-1: intercellular adhesion molecule 1. RBC: red blood cell. Author’s figure reprinted with permission of Hindawi Scientific Journals.

Figure 4:. Thrombin inhibitors reduce thrombin cytotoxicity to promote tissue survival.

Thrombin, a serine protease, cleaves the extracellular peptide sequence of the PAR1 G-protein coupled receptor, resulting in cytotoxicity. Among other effects, damage to the endothelial cells results in BBB failure, vasogenic edema and hemorrhage. Neurons and astrocytes are damaged directly via their own PAR1 receptors. Reduced thrombin activity in brain, either via direct thrombin inhibitors (argatroban, dabigatran) or indirectly by Factor Xa inhibitors (not illustrated) block cytotoxicity to preserve BBB integrity and promote cell survival. PAR1: protease activated receptor 1. TRAP: thrombin receptor activating peptide. q/11, i/o, and 12/13 are G protein subunits that transduce PAR1 activation. Created with BioRender.com.