Prediction of Hemorrhagic Transformation After Thrombolytic Therapy of Clot Embolism

Abstract

Background and Purpose-Thrombolytic treatment of stroke carries the risk of hemorrhagic transformation. Therefore, the potential of MRI for prediction of recombinant tissue plasminogen activator (rtPA)-induced bleeding is explored to identify patients in whom rtPA treatment may provoke such complications. Methods-Spontaneously hypertensive rats (SHR) (nϭ9) were submitted to middle cerebral artery (MCA) clot embolism, followed 3 hours later by intra-arterial infusion of 10 mg/kg rtPA. Untreated SHR (nϭ9) were infused with saline. MRI imaging was performed before treatment and included apparent diffusion coefficient (ADC), T2, and perfusion mapping and contrast enhancement with gadolinium-DTPA. The distribution of intracerebral hemorrhages was studied 3 days later by histological staining. Results-Clot embolism led to the rapid decline of ADC in the territory of the occluded artery. Tissue lesion volume derived from ADC imaging increased by 155Ϯ69% in the untreated animals and by 168Ϯ87% in the treated animals (PϭNS), determined on the histological sections after 3 days. This same lesion growth in both groups indicated absence of therapeutic effect after 3-hour treatment delay. Hemorrhagic transformations were significantly more frequent in treated SHR (PϽ0.05). In untreated rats, hemorrhages were found in the border zone of the ischemic territory; in treated animals, hemorrhagic transformations occurred in the ischemic core region. rtPA-induced hemorrhages were predicted by a disturbance of the blood-brain barrier in 3 of 4 animals before treatment by Gd-DTPA contrast enhancement but not by ADC, T2, or perfusion imaging. The region of contrast enhancement colocalized with subsequent bleeding in these animals. Conclusions-The disturbance of blood-brain barrier but not of other MR parameters allows risk assessment for hemorrhagic transformation induced by subsequent thrombolytic treatment.

Oxygen Therapy Reduces Secondary Hemorrhage after Thrombolysis in Thromboembolic Cerebral Ischemia

“…Topographic analysis of multimodal MRI showed that more than 95% of the hypointense T2* signal 24 hours after tMCAO was located within the area of intense postcontrast enhancement on T1w images at 2.5 hours after tMCAO. This is in accordance with previous experimental and clinical findings that early appearance of a circumscribed contrast enhancement on T1w shows tissue at risk for subsequent secondary hemorrhage (Kastrup et al, 2008;Neumann-Haefelin et al, 2002). Although an attenuation of postischemic BBB permeability in animals treated with NBO or HBO has been reported earlier (Liu et al, 2009;Qin et al, 2007;Veltkamp et al, 2005a), it was unclear as to whether this reflected a specific protective effect on cerebral microvessels or was proportional to overall parenchymal protection.…”

Hemorrhagic Transformation of Ischemic Stroke: Prediction with CT Perfusion

“…The median NIHSS score at presentation was 15 (interquartile range, [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The mean time from stroke symptom onset to CT scanning was 125 minutes Ϯ 46.…”

“…Comparisons among the small number of patients with hemorrhage did not reveal significant differences in PS between the hemorrhagic infarction and parenchymal hematoma groups. However, the importance of the HT subtypes is being debated (15,(17)(18)(19). Results of a recent study demonstrated that hemorrhagic infarction is not necessarily benign and is associated with a worse clinical outcome compared with that of patients without hemorrhage (16).…”

“…Because even small degrees of hemorrhage may be detrimental, it may be desirable to identify those patients who are more likely to have HT before administering TPA. Disruption of the blood-brain barrier (BBB) integrity, considered focal to the development of HT, has been demonstrated in animal models (18,19) as an increase in the permeability-surface area product (PS); however, it has not yet been fully elucidated in humans.…”

Acute blood–brain barrier opening in experimentally induced focal cerebral ischemia is preferentially identified by quantitative magnetization transfer imaging

“…To illustrate this risk, the probability of symptomatic HT increases significantly during the first 36 h after stroke onset in patients receiving rt-PA (6.4% vs. 0.6% in placebo-treated patients), and 61% of the patients with symptomatic HT die within 3 months (1). Studies performed using animal stroke models show similar findings with increased risk of HT associated with thrombolytics (2)(3)(4)(5). In view of these complications with thrombolytic therapy, it is important to develop diagnostic imaging techniques that reliably identify tissue regions that are prone to HT and to obtain such data when deciding on a treatment protocol.…”