Review of stroke thrombolytics

Abstract

The cornerstone of acute ischemic stroke treatment relies on rapid clearance of an offending thrombus in the cerebrovascular system. There are various drugs and different methods of assessment to select patients more likely to respond to treatment. Current clinical guidelines recommend the administration of intravenous alteplase (following a brain noncontract CT to exclude hemorrhage) within 4.5 hours of stroke onset. Because of the short therapeutic time window, the risk of hemorrhage, and relatively limited efficacy of alteplase for large clot burden, research is ongoing to find more effective and safer reperfusion therapy, as well as focussing on refinement of patient selection for acute reperfusion treatment. Studies using advanced imaging (incorporating perfusion CT or diffusion/perfusion MRI) may allow us to use thrombolytics, or possibly endovascular therapy, in an extended time window. Recent clinical trials have suggested that Tenecteplase, used in conjunction with advanced imaging selection, resulted in more effective reperfusion than alteplase, which translated into increased clinical benefit. Studies using Desmoteplase have suggested its potential benefit in a sub-group of patients with large artery occlusion and salveageable tissue, in an extended time window. Other ways to improve acute reperfusion approaches are being actively explored, including endovascular therapy, and the enhancement of thrombolysis by ultrasound insonation of the clot (sono-thrombolysis).

Keywords: Ischemic stroke; Stroke trials; Thrombolysis.

Figure 1

Clinical imaging of the (infarct) core and penumbra in two hyperacute stroke patients with proximal M1 middle cerebral artery territory occlusion. The right column shows the core (red) and penumbra (green) which are derived from the cerebral blood flow map (left column) and delay time map (middle column). The top patient one has a very large acute core (red) and very little penumbra (green). Their total core volume exceeded 70 mL and the patient had a poor outcome from thrombolysis - which was entirely predictable due to the large core. This illustrates the concept of 'futile reperfusion' where reperfusion will not help the patient and possibly it may even harm them. Patient two on the bottom row has a very large acute penumbra (green) and small core (red) and clearly will benefit substantially from thrombolysis (should it be effective at opening the vessel).

Figure 2

The coagulation process. The intrinsic pathway involves activation of components from within the vasculature (activation of Factor IX by Factor IXa). The extrinsic pathway is the principal initiating pathway for in vivo blood coagulation. The pathway involves the exposure of Tissue Factor (TF), a glycoprotein, and phospholipids to blood, these components are from the surface membranes of fibroblasts that are within and around blood vessels. TF and phospholipids, when exposed to blood, interact with Factor VIIa to convert Factor IX to Factor IXa (from the intrinsic system). Factori VIIIa is then formed from interactions between Factor IX and phospholipids. Factor VIIIa and Factor X then combine to form Factor Xa. Factor Xa then interacts with phospholipids to form Factor Va and a "prothombinase". This is the stage where the intrinsic and extrinsic pathways converge and form the common pathway. Prothombinase the uses feedback mechanism for Factor VIIIa and Factor XIa as a check to ensure that coagulation is still required, and if so, forms a thrombin. Thrombolytic drugs have action of factor XIII to break the fibrin crosslinks.

Figure 3

The molecular structure of alteplase.

Figure 4

Molecular structure of tenecteplase.