Mechanisms of Fibrinolysis-Associated Hemorrhagic Transformation

Zoppo, Gregory J. del; Okada, Yasushi; Hamann, Gerhard F.; Fitridge, Robert; Pessin, Michael S.

doi:10.1007/978-4-431-68459-6_30

Cited by 5 publications

(3 citation statements)

References 52 publications

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“…22 All PH and late HI patients in our series were hypertensives, and many were diabetics. MMP-9 proteolytic activity easily could undermine the integrity of a weakened arterial wall.…”

Section: Discussionmentioning

confidence: 71%

Matrix Metalloproteinase Expression Is Related to Hemorrhagic Transformation After Cardioembolic Stroke

Montaner

Álvarez-Sabín

Molina

et al. 2001

Stroke

276

217

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Background and Purpose-In animal models of cerebral ischemia, matrix metalloproteinase (MMP) expression was significantly increased and related to blood-brain barrier disruption, edema formation, and hemorrhagic transformation (HT). MMP inhibitors reduce HT after embolic ischemia in tissue-type plasminogen activator-treated animals. We aimed to determine the relationship between MMPs and HT after human ischemic stroke. Methods-Serial MMP-2 and MMP-9 determinations were performed by means of ELISA in 39 cardioembolic strokes in the middle cerebral artery territory. Hemorrhagic events were classified according to clinical and CT criteria (hemorrhagic infarction [HI] and parenchymal hematoma [PH]). HT was evaluated on CT at 48 hours (early HT) and again between day 5 and 7 (late HT). Results-HT was present in 41% of the patients (43.75% early HI, 25% early PH and 31.25% late HI). MMP-2 values were within normal range and were unrelated to HT. Increased expression of MMP-9 (normal range Ͻ97 ng/mL) was found among patients with and without HT (159.3Ϯ82 versus 143.9Ϯ112.6 ng/mL; Pϭ0.64). According to HT subtypes, the highest baseline MMP-9 levels corresponded to patients with late HI (240.4Ϯ111.2 versus 102.5Ϯ76.7 ng/mL for all other patients, Pϭ0.002). Baseline MMP-9 was the only variable associated with late HI in the multiple logistic regression model (OR 9; CI 1.46, 55.24; Pϭ0.010). Peak of MMP-9 at the 24-hour time point (250.6 ng/mL) was found before appearance of PH. Conclusions-MMPs are involved in some subtypes of HT after human cardioembolic stroke. Baseline MMP-9 level predicts late HI and a 24-hour peak precedes early PH. Key Words: cerebral ischemia Ⅲ embolism, cerebral Ⅲ hematoma, parenchymal Ⅲ hemorrhagic stroke Ⅲ matrix metalloproteinase H emorrhagic transformation (HT) is a feared event that may follow ischemic stroke. Thrombolytic therapy has been shown to be beneficial for acute stroke, although this therapy increases risk of HT. 1 Therefore, identification of the underlying mechanisms of this complication is critical to improvement of the safety profile of thrombolytic agents for stroke treatment.Matrix metalloproteinases (MMPs) belong to a family of zinc-binding proteolytic enzymes that normally remodel the extracellular matrix. 2 MMP-2 and MMP-9 specifically attack type IV collagen, laminin, and fibronectin, the major components of the basal lamina around cerebral blood vessels. 3 In animal models of cerebral ischemia, MMP expression was increased significantly and related to blood-brain barrier disruption, edema formation, and HT. 4,5 However, whether HT in humans also is related to MMP action remains unknown.We hypothesize that after MMPs degrade ECM components of the basal lamina, blood elements may extravasate, which leads to HT. In the present exploratory study, we aimed to correlate the expression of MMPs after human cardioembolic stroke with the appearance of different subtypes of HT. Subjects and Methods Study PopulationFrom June 1999 through March 2000, we studied prospectively consecut...

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“…22 All PH and late HI patients in our series were hypertensives, and many were diabetics. MMP-9 proteolytic activity easily could undermine the integrity of a weakened arterial wall.…”

Section: Discussionmentioning

confidence: 71%

Matrix Metalloproteinase Expression Is Related to Hemorrhagic Transformation After Cardioembolic Stroke

Montaner

Álvarez-Sabín

Molina

et al. 2001

Stroke

276

217

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“…110-113 The distinguishing features are the rapid extravasation of blood leading to the compression of contiguous and adjacent tissues with loss of neurological function 30110 It is, so far, conjectural whether the processes leading to the development of coagula in the ischaemic zone begin with the microvascular events that lead to haemorrhagic infarction,33 34 52 however, vascular disintegration would seem to be necessary.…”

Section: Barrier Loss and Haemorrhagic Transformationmentioning

confidence: 99%

Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke

Zoppo

Kummer

Hamann³

1998

Journal of Neurology, Neurosurgery & Psychiatry

232

176

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“…Hemorrhagic transformation seems tied to alterations in the integrity of the basal lamina. In clinical preparations and certain experimental models, PH has also been attributed to the impact of systemic blood pressure, the downstream movement of thromboemboli, or rupture of larger injured vessels which may have undergone degenerative changes (15,16,26). The distinguishing features are the rapid extravasation of blood leading to the compression of adjacent tissues with subsequent loss of neurological function (15).…”

Section: Microvascular Damage and Hemorrhagic Transformationmentioning

confidence: 99%

Hemorrhagic Transformation of Cerebral Infarction – Possible Mechanisms

Hamann¹,

Zoppo²,

Kummer³

1999

Thromb Haemost

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SummaryTo analyse the risk/benefit of cerebral thrombolysis the role of hemorrhagic transformation, either as clinically silent hemorrhagic infarction or disastreous parenchymal hemorrhage, is crucial. Thrombolysis in acute ischemic stroke increases the risk of severe, life-threatening hemorrhagic complications by up to 10 times compared to controls. In this paper, previous proposed concepts for the development of intracerebral hemorrhage and hemorrhagic transformation are presented. The role of the cerebral microvasculature will be emphasized. In experimental focal cerebral ischemia a significant loss of basal lamina components of the cerebral microvessels has been demonstrated. This loss in vessel wall integrity is associated with the development of petechial hemorrhage. The mechanisms for this microvascular damage may include plasmin-generated laminin degradation, matrix metalloproteinases activation, transmigration of leukocytes through the vessel wall, and other processes. We propose that attenuation of the microvascular integrity loss with subsequent reduction in hemorrhage is theoretically possible 1) by an improvement in the definition of an individual time window of therapy (by means of imaging techniques), 2) by a biochemical quantification of the basal lamina damage to avoid dangerous interventions, and 3) by pharmacological strategies to protect the basal lamina during thrombolysis.

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Mechanisms of Fibrinolysis-Associated Hemorrhagic Transformation

Cited by 5 publications

References 52 publications

Matrix Metalloproteinase Expression Is Related to Hemorrhagic Transformation After Cardioembolic Stroke

Matrix Metalloproteinase Expression Is Related to Hemorrhagic Transformation After Cardioembolic Stroke

Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke

Hemorrhagic Transformation of Cerebral Infarction – Possible Mechanisms

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