Hemorrhagic transformation following ischemic stroke: Significance, causes, and relationship to therapy and treatment

Abstract

Hemorrhagic transformation (HT) is a frequent consequence of ischemic stroke that becomes more prevalent after thrombolytic therapy. Despite concerns about safety parameters, thrombolytic drugs remain the first course of action available to clinicians for stroke management. However, recent efforts in preclinical studies have attempted to discover other drugs that can lessen the risk of hemorrhage associated with thrombolytic administration. This review focuses on three classes of pharmacologic agents that have shown some promise in animal models of stroke, and can thus be considered as possible candidates for coadministration with thrombolytics in the treatment of stroke. These include the following: 1) spin trap agents, such as alpha-phenyl-N-t-butylnitrone (PBN) that scavenge free radicals; 2) matrix metalloproteinase (MMP) inhibitors, such as BB-94, that prevent membrane and vessel remodeling following ischemia; and 3) the novel glycoprotein (GP) IIb/IIIa platelet receptor antagonist SM-20302. Although these drugs affect different mechanisms, the common denominator seemed to be their effectiveness in reducing the incidence of hemorrhage in response to thrombolytic infusion following an embolic stroke.

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

“…MMP-9 and MMP-3 inhibitors decrease HT produced by tPA. 123 Batimastat (BB-94) is a board spectrum MMP inhibitor that reduces tPA-related HT in rats. Minocycline inhibits MMP-9 and microglia and reduces tPA-related HT in rats.…”

Crystal Structure of the Michaelis Complex between Tissue-type Plasminogen Activator and Plasminogen Activators Inhibitor-1

“…It is administered intravenously to improve blood flow by dissolving clots and to maintain patency of blood vessels. However, the tPA treatment for ischemic strokes has a short therapeutic window (Ͻ3 h within occlusion) and the high incidence of post-treatment complications, including intracerebral hemorrhage (55,56), leading to its limited clinical use (only 3-8% of patients eligible for such therapy) (3,4,57). Newer generation of recombinant tPA is being continuously developed (2).…”

A novel approach to screening for new neuroprotective compounds for the treatment of stroke

“…Despite the significant advances that have been made in understanding the pathophysiology of cerebral ischemia on the cellular and molecular level, only one drug, recombinant tissue-type plasminogen activator (rt-PA), is approved by the FDA for use in patients with ischemic stroke (Green and Shuaib, 2006). Unfortunately, the utilization of rt-PA is limited by its short time window of efficacy and its potential to cause intracerebral hemorrhage (NINDS rt-PA trial) (Lapchak, 2002a;Lapchak, 2002b;Lyden and Zivin, 1993). Thus, there is a critical need for additional safe and effective treatments for stroke.…”