Arne Lauer

Anticoagulation With the Oral Direct Thrombin Inhibitor Dabigatran Does Not Enlarge Hematoma Volume in Experimental Intracerebral Hemorrhage

Background— The direct thrombin inhibitor dabigatran etexilate (DE) may constitute a future replacement of vitamin K antagonists for long-term anticoagulation. Whereas warfarin pretreatment is associated with greater hematoma expansion after intracerebral hemorrhage (ICH), it remains unclear what effect direct thrombin inhibitors would have. Using different experimental models of ICH, this study compared hematoma volume among DE-treated mice, warfarin-treated mice, and controls. Methods and Results— CD-1 mice were fed with DE or warfarin. Sham-treated mice served as controls. At the time point of ICH induction, DE mice revealed an increased activated partial thromboplastin time compared with controls (mean±SD 46.1±5.0 versus 18.0±1.5 seconds; P=0.022), whereas warfarin pretreatment resulted in a prothrombin time prolongation (51.4±17.9 versus 10.4±0.3 seconds; P<0.001). Twenty-four hours after collagenase-induced ICH formation, hematoma volume was 3.8±2.9 &mgr;L in controls, 4.8±2.7 &mgr;L in DE mice, and 14.5±11.8 &mgr;L in warfarin mice (n=16; Welch ANOVA between-group differences P=0.007; posthoc analysis with the Dunnett method: DE versus controls, P=0.899; warfarin versus controls, P<0.001; DE versus warfarin, P=0.001). In addition, a model of laser-induced cerebral microhemorrhage was applied, and the distances that red blood cells and blood plasma were pushed into the brain were quantified. Warfarin mice showed enlarged red blood cell and blood plasma diameters compared to controls, but no difference was found between DE mice and controls. Conclusions— In contrast with warfarin, pretreatment with DE did not increase hematoma volume in 2 different experimental models of ICH. In terms of safety, this observation may represent a potential advantage of anticoagulation with DE over warfarin.

Intracerebral haemorrhage associated with antithrombotic treatment: translational insights from experimental studies

Little is known about the pathophysiology of intracerebral haemorrhage that occurs during anticoagulant treatment. In observational studies, investigators have reported larger haematoma volumes and worse functional outcome in these patients than in those with intracerebral haemorrhage and a normal coagulation status. The need to prevent extensive haematoma enlargement by rapid reversal of the anticoagulation seems intuitive, although no evidence is available from randomised clinical trials. New oral anticoagulants, such as the direct thrombin inhibitor dabigatran and the factor Xa inhibitor rivaroxaban, have been approved recently; however, intracerebral haemorrhage during dabigatran or rivaroxaban anticoagulation has not been characterised, and whether anticoagulation reversal can be beneficial in this scenario is unknown. In a translational approach, new experimental models have been developed to study anticoagulation-associated intracerebral haemorrhage in more detail and to test treatment strategies. Vitamin k antagonists enlarge haematoma volumes and worsen functional outcome in animal models. Rapid reversal of anticoagulation in the experimental setting prevents prolonged haematoma expansion and improves outcome. The new oral anticoagulants increase intracerbral haemorrhage volumes less than does warfarin. Haemostatic approaches that have been used for vitamin k-associated intracerebral haemorrhage also seem to be effective in intracerebral haemorrhage associated with the new anticoagulants. These experimental studies are valuable for filling gaps in knowledge, but the results need careful translation into routine clinical practice.

Total Magnetic Resonance Imaging Burden of Small Vessel Disease in Cerebral Amyloid Angiopathy: An Imaging-Pathologic Study of Concept Validation

IMPORTANCE Cerebral amyloid angiopathy (CAA) is characteristically associated with magnetic resonance imaging (MRI) biomarkers of small vessel brain injury, including strictly lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. Although these neuroimaging markers reflect distinct pathophysiologic aspects in CAA, no studies to date have combined these structural imaging features to gauge total brain small vessel disease burden in CAA. OBJECTIVES To investigate whether a composite score can be developed to capture the total brain MRI burden of small vessel disease in CAA and to explore whether this score contributes independent and complementary information about CAA severity, defined as intracerebral hemorrhage during life or bleeding-related neuropathologic changes. DESIGN, SETTING, AND PARTICIPANTS This retrospective, cross-sectional study examined a single-center neuropathologic CAA cohort of eligible patients from the Massachusetts General Hospital from January 1, 1997, through December 31, 2012. Data analysis was performed from January 2, 2015, to January 9, 2016. Patients with pathologic evidence of CAA (ie, any presence of CAA from routinely collected brain biopsy specimen, biopsy specimen at hematoma evacuation, or autopsy) and available brain MRI sequences of adequate quality, including T2-weighted, T2*-weighted gradient-recalled echo, and/or susceptibility-weighted imaging and fluid-attenuated inversion recovery sequences, were considered for the study. MAIN OUTCOMES AND MEASURES Brain MRIs were rated for lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. All 4 MRI lesions were incorporated into a prespecified ordinal total small vessel disease score, ranging from 0 to 6 points. Associations with severity of CAA-associated vasculopathic changes (fibrinoid necrosis and concentric splitting of the wall), clinical presentation, number of intracerebral hemorrhages, and other imaging markers not included in the score were explored using logistic and ordinal regression. RESULTS In total, 105 patients with pathologically defined CAA were included: 52 with autopsies, 22 with brain biopsy specimens, and 31 with pathologic samples from hematoma evacuations. The mean (range) age of the patients was 73 (71-74) years, and 55 (52.4%) were women. In multivariable ordinal regression analysis, severity of CAA-associated vasculopathic changes (odds ratio, 2.40; 95% CI, 1.06-5.45; P = .04) and CAA presentation with symptomatic intracerebral hemorrhage (odds ratio, 2.23; 95% CI, 1.07-4.64; P = .03) were independently associated with the total MRI small vessel disease score. The score was associated with small, acute, diffusion-weighted imaging lesions and posterior white matter hyperintensities in adjusted analyses. CONCLUSIONS AND RELEVANCE This study provides evidence of concept validity of a total MRI small vessel disease score in CAA. After further validation, this approach can be potentially used in prospective clinical studies.

Cortical superficial siderosis predicts early recurrent lobar hemorrhage

Objective: To identify predictors of early lobar intracerebral hemorrhage (ICH) recurrence, defined as a new ICH within 6 months of the index event, in patients with cerebral amyloid angiopathy (CAA). Methods: Participants were consecutive survivors (age ≥55 years) of spontaneous symptomatic probable or possible CAA-related lobar ICH according to the Boston criteria, drawn from an ongoing single-center cohort study. Neuroimaging markers ascertained in CT or MRI included focal (≤3 sulci) or disseminated (>3 sulci) cortical superficial siderosis (cSS), acute convexity subarachnoid hemorrhage (cSAH), cerebral microbleeds, white matter hyperintensities burden and location, and baseline ICH volume. Participants were followed prospectively for recurrent symptomatic ICH. Cox proportional hazards models were used to identify predictors of early recurrent ICH adjusting for potential confounders. Results: A total of 292 patients were enrolled. Twenty-one patients (7%) had early recurrent ICH. Of these, 24% had disseminated cSS on MRI and 19% had cSAH on CT scan. In univariable analysis, the presence of disseminated cSS, cSAH, and history of previous ICH were predictors of early recurrent ICH (p < 0.05 for all comparisons). After adjusting for age and history of previous ICH, disseminated cSS on MRI and cSAH on CT were independent predictors of early recurrent ICH (hazard ratio [HR] 3.92, 95% confidence interval [CI] 1.38–11.17, p = 0.011, and HR 3.48, 95% CI 1.13–10.73, p = 0.030, respectively). Conclusions: Disseminated cSS on MRI and cSAH on CT are independent imaging markers of increased risk for early recurrent ICH. These markers may provide additional insights into the mechanisms of ICH recurrence in patients with CAA.

Warfarin pretreatment reduces cell death and MMP-9 activity in experimental intracerebral hemorrhage.

Little is known about the pathophysiology of oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH). We compared hematoma volume, number of terminal deoxynucleotidyl dUTP nick-end labeling (TUNEL)-positive cells (indicating cell death), MMP-9 levels, and perilesional edema formation between warfarin-treated mice and controls. Intracerebral hemorrhage was induced by an injection of collagenase into the right striatum. Twenty-four hours later, hematoma volume was measured using a photometric hemoglobin assay. Cell death was quantified using TUNEL staining. MMP-9 levels were determined by zymography, and edema formation was assessed via the wet–dry method. Warfarin increased hematoma volume by 2.6-fold. The absolute number of TUNEL-positive cells in the perihematomal zone was lower in warfarin-treated animals (300.5 ± 39.8 cells/mm2) than in controls (430.5 ± 38.9 cells/mm2; p = 0.034), despite the larger bleeding volume. MMP-9 levels were reduced in anticoagulated mice as compared to controls (p = 0.018). Perilesional edema formation was absent in warfarin mice and modestly present in controls. Our results suggest differences in the pathophysiology of OAC-ICH compared to intracerebral hemorrhage occurring under normal coagulation. A likely explanation is that thrombin, a strong inductor of apoptotic cell death and blood–brain barrier disruption, is produced to a lesser extent in OAC-ICH. In humans, however, we assume that the detrimental effects of a larger hematoma volume in OAC-ICH by far outweigh potential protective effects of thrombin deficiency.

Antiplatelet pretreatment does not increase hematoma volume in experimental intracerebral hemorrhage

While oral anticoagulants are associated with greater hematoma expansion and higher mortality rates in patients with intracerebral hemorrhage (ICH), there is ongoing discussion whether pretreatment with antiplatelet drugs also worsens prognosis. Using an experimental model of ICH, we investigated the effects of antiplatelet pretreatment on hematoma volume and functional outcome. CD-1 mice were treated with acetyl-salicylic acid (ASA, 60 mg/kg per 24 hours), clopidogrel (22.5 mg/kg per 24 hours), or both (ASA + clopidogrel) through drinking water for 3 days (n = 20 per group). Thereafter, platelet aggregation was found to be significantly reduced. Untreated mice and mice pretreated with warfarin served as controls. A stereotactic injection of collagenase into the right striatum was used to induce ICH. Twenty-four hours after ICH induction, hematoma volume was measured to be 15.0 ± 4.4 µL in controls, 14.1 ± 5.3 µL in ASA mice, 16.8 ± 5.1 µL in clopidogrel mice, and 16.4 ± 5.1 µL in ASA + clopidogrel animals. These differences were not statistically significant. However, mice pretreated with warfarin revealed largely increased hematoma volumes (25.0 ± 7.4 µL versus controls, P = 0.001). Neurologic outcome was not different between antiplatelet-pretreated animals and untreated controls. Our results suggest that plasmatic coagulation rather than platelet function is the most critical element for preventing hematoma expansion in acute ICH. Future therapeutic strategies may take these findings into account.

Statins in Intracerebral Hemorrhage

While statins play an indisputable role in primary and secondary prevention of ischemic cardiovascular and cerebrovascular disease, a concern exists regarding a possible association between low lipoprotein levels and statin use on the risk of intracerebral hemorrhage (ICH). While these data may incline physicians to discontinue statins after ICH, an increasing amount of preclinical and clinical evidence suggests that statins might have a beneficial effect on outcome and recovery in this context that goes beyond lipid lowering effects. Different etiologies of ICH and the related risk of recurrence should also be taken into account when deciding about statin use/avoidance in patients with high risk of ICH. The problem is compounded by paucity of data from randomized controlled trials and well-designed prospective observational studies. This review will discuss the existing evidence on potential interactions between statins and risk of ICH as well as outcomes in order to provide practical recommendations for clinical decision-making.

Imaging of Contrast Medium Extravasation in Anticoagulation-Associated Intracerebral Hemorrhage With Dual-Energy Computed Tomography

Background and Purpose— Contrast medium extravasation (CE) in intracerebral hemorrhage (ICH) is a marker of ongoing bleeding and a predictor of hematoma expansion. The aims of the study were to establish an ICH model in which CE can be quantified, characterized in ICH during warfarin and dabigatran anticoagulation, and to evaluate effects of prothrombin complex concentrates on CE in warfarin-associated ICH. Methods— CD1-mice were pretreated orally with warfarin, dabigatran, or vehicle. Prothrombin complex concentrates were administered in a subgroup of warfarin-treated mice. ICH was induced by stereotactic injection of collagenase VIIs into the right striatum. Contrast agent (350 &mgr;L Isovue 370 mg/mL) was injected intravenously after ICH induction (2–3.5 hours). Thirty minutes later, mice were euthanized, and CE was measured by quantifying the iodine content in the hematoma using dual-energy computed tomography. Results— The optimal time point for contrast injection was found to be 3 hours after ICH induction, allowing detection of both an increase and a decrease of CE using dual-energy computed tomography. CE was higher in the warfarin group compared with the controls (P=0.002). There was no significant difference in CE between dabigatran-treated mice and controls. CE was higher in the sham-treated warfarin group than in the prothrombin complex concentrates–treated warfarin group (P<0.001). Conclusions— Dual-energy computed tomography allows quantifying CE, as a marker of ongoing bleeding, in a model of anticoagulation-associated ICH. Dabigatran induces less CE in ICH than warfarin and consequently reduces risks of hematoma expansion. This constitutes a potential safety advantage of dabigatran over warfarin. Nevertheless, in case of warfarin anticoagulation, prothrombin complex concentrates reduce this side effect.

Clinical Imaging Factors Associated With Infarct Progression in Patients With Ischemic Stroke During Transfer for Mechanical Thrombectomy

Importance When transferred from a referring hospital (RH) to a thrombectomy-capable stroke center (TCSC), patients with initially favorable imaging profiles (Alberta Stroke Program Early CT Score [ASPECTS] ≥6) often demonstrate infarct progression significant enough to make them ineligible for mechanical thrombectomy at arrival. In rapidly evolving stroke care networks, the question of the need for vascular imaging at the RHs remains unsolved, resulting in an important amount of futile transfers for thrombectomy. Objective To examine the clinical imaging factors associated with unfavorable imaging profile evolution for thrombectomy in patients with ischemic stroke initially transferred to non-TCSCs. Design, Setting, and Participants Data from patients transferred from 1 of 30 RHs in our regional stroke network and presenting at our TCSC from January 1, 2010, to January 1, 2016, were retrospectively analyzed. Consecutive patients with acute ischemic stroke initially admitted to a non–thrombectomy-capable RH and transferred to our center for which a RH computed tomography (CT) and a CT angiography (CTA) at arrival were available for review. Main Outcomes and Measures ASPECTS were evaluated. The adequacy of leptomeningeal collateral blood flow was rated as no or poor, decreased, adequate, or augmented per the adapted Maas scale. The main outcome was an ASPECTS decay, defined as an initial ASPECTS of 6 or higher worsening between RH and TCSC CTs to a score of less than 6 (making the patient less likely to derive clinical benefit from thrombectomy at arrival). Results A total of 316 patients were included in the analysis (mean [SD] age, 70.3 [14.2] years; 137 [43.4%] female). In multivariable models, higher National Institutes of Health Stroke Score, lower baseline ASPECTSs, and no or poor collateral blood vessel status were associated with ASPECTS decay, with collateral blood vessel status demonstrating the highest adjusted odds ratio of 5.14 (95% CI, 2.20-12.70; P < .001). Similar results were found after stratification by vessel occlusion level. Conclusions and Relevance In patients with ischemic stroke transferred for thrombectomy, poor collateral blood flow and stroke clinical severity are the main determinants of ASPECTS decay. Our findings suggest that in certain subgroups vascular imaging, including collateral assessment, can play a crucial role in determining the benefits of transfer for thrombectomy.

Translational insights into traumatic brain injury occurring during dabigatran or warfarin anticoagulation.

To date, only limited data are available on the effects of pretreatment with novel oral anticoagulants in the event of traumatic brain injury (TBI). We determined intracerebral hemorrhage volume and functional outcome in a standardized TBI model in mice treated with warfarin or dabigatran. Additionally, we investigated whether excess concentrations of dabigatran could increase bleeding and whether this was preventable by using prothrombin complex concentrate (PCC). C57 mice were treated orally with warfarin or dabigatran; sham-treated mice served as controls. Effective anticoagulation was verified by measurement of international normalized ratio and diluted thrombin time, and TBI was induced by controlled cortical impact (CCI). Twenty-four hours after CCI, intracerebral hemorrhage volume was larger in warfarin-pretreated mice than in controls (10.1 ± 4.9 vs 4.1 ± 1.7 μL; analysis of variance post hoc P = 0.001), but no difference was found between controls and dabigatran-pretreated mice (5.3 ± 1.5 μL). PCC applied 30 minutes after CCI did not reliably reduce intracerebral hemorrhage induced by excess dabigatran concentration compared with saline (10.4 ± 11.2 vs 8.7 ± 7.1 μL). Our data suggest pathophysiological differences in TBI occurring during warfarin and dabigatran anticoagulation. The reduced hemorrhage formation under dabigatran therapy could present a safety advantage compared with warfarin. An excess dabigatran concentration, however, can increase hemorrhage.