Seby John, MD 

Inzitari D, Giusti B, Nencini P, Maria Gori AM, Nesi M, Palumbo V, et al. MMP9 Variation After Thrombolysis is Associated With Hemorrhagic Transformation of Lesion and Death. Stroke. 2013

Matrix Metalloproteinases (MMPs) are a family of > 20 zinc-dependent proteolytic enzymes that are thought to play a detrimental role in ischemic stroke. In this article, Inzitari and colleagues measured circulating blood levels of various MMPs and Tissue Inhibitors of Metalloproteinases (TIMPs) in patients with acute ischemic stroke, before and 24 hours after receiving intravenous tPA. Changes in the levels of MMPs/TIMPs were analyzed in patients who developed symptomatic intracerebral hemorrhage (ICH), death at 3-months, and those with poor outcomes at 3-months (mRS 3-6). After adjusting for clinical variables, they found that MMP9 among all MMPs was independently associated with death and symptomatic ICH. MMP9 changes also correlated with baseline, 24 hour and 7day NIHSS score.

This is the largest series on MMP measurements in acute ischemic stroke patients receiving IV tPA, and adds to experimental data on the role of MMPs. Recent studies have suggested that the adverse effects of tPA may be mediated by MMPs, which increases the blood-brain barrier permeability by degrading components of the extracellular matrix and tight junctions in endothelial cells, resulting in ICH. MMP9 is the most widely studied, and its levels significantly correlated with infarct volume, stroke severity, functional outcomes, ongoing brain ischemia and development of ICH post thrombolytic therapy.

Does the above literature have any research or practice implications? Can MMPs be used as diagnostic biomarkers for acute ischemic stroke? More importantly, can we use MMP levels to predict which patients might develop ICH after tPA administration? This is especially clinically relevant since tPA is the only FDA approved thrombolytic therapy for restoring blood flow in acute ischemic stroke. Combination therapies of intravenous tPA and anti-MMP agents might be a potential strategy to reduce or prevent hemorrhage associated with tPA, and maybe even extend the time window for thrombolysis. Inzitari et al hope that their study will encourage randomized trials of MMP9 antagonist co-administration with tPA.