Assuntos
Infarto Cerebral , Trombose Intracraniana , Imageamento por Ressonância Magnética , Trombose Venosa , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Trombose Venosa/patologia , Trombose Intracraniana/patologia , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/metabolismo , Adulto Jovem , Infarto Cerebral/patologia , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Cefaleia/etiologia , Córtex Cerebral/patologia , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/diagnóstico por imagem , Diagnóstico Diferencial , Lobo Temporal/patologia , Lobo Temporal/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/patologia , Convulsões/etiologia , Edema Encefálico/patologia , Lobo Frontal/patologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/irrigação sanguíneaRESUMO
Cerebral venous thrombosis (CVT) is a neurovascular disease with recently increasing incidence. Aseptic inflammatory responses play an important role in the pathology of CVT. Recent studies report that neutrophil extracellular traps (NETs) are major triggers of thrombosis and inflammation in stroke, but their effect on brain injury in CVT requires further validation. In this study, two CVT animal models were used to simulate superior sagittal sinus thrombosis and cortical vein thrombosis. The effects of brain tissue infiltration of NETs and the molecular mechanisms associated with NET formation were deeply explored in combination with proteomics, histology, and serology. The results showed that the cortical vein thrombosis model could be combined with more severe blood-brain barrier (BBB) disruption and showed more severe cerebral hemorrhage. Decreased Sirtuin 1 (SIRT1) expression promotes high mobility group box 1 (HMGB1) acetylation, causing increased cytosolic translocation and extracellular release, and HMGB1 can promote NET formation and recruitment. In addition, corticocerebral accumulation of NETs contributes to BBB damage. This establishes a vicious cycle between BBB damage and NET accumulation. SIRT1 mediated-HMGB1 deacetylation may play a critical role in attenuating BBB damage following CVT. This study employed a combined validation using models of venous sinus thrombosis and cortical vein thrombosis to investigate the deacetylation role of SIRT1, aiming to offer new insights into the pathological mechanisms of brain injury following CVT.
Assuntos
Barreira Hematoencefálica , Armadilhas Extracelulares , Proteína HMGB1 , Sirtuína 1 , Animais , Masculino , Ratos , Acetilação , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Armadilhas Extracelulares/metabolismo , Proteína HMGB1/metabolismo , Trombose Intracraniana/metabolismo , Trombose Intracraniana/patologia , Neutrófilos/metabolismo , Ratos Sprague-Dawley , Sirtuína 1/metabolismo , Trombose Venosa/metabolismo , Trombose Venosa/patologiaRESUMO
BACKGROUND AND PURPOSE: Perviousness is the differential attenuation on CT of an intracranial arterial occlusive thrombus before and after IV contrast administration. While perviousness/permeability has been shown to be related to various clinical outcomes and reflects histopathologic composition, it remains unclear whether perviousness is also associated with differences in proteomic composition. MATERIALS AND METHODS: Retrieved clots from 59 patients were evaluated with quantitative mass spectrometry. Proteomic differences between high-perviousness (≥11 HU) and low-perviousness (<11 HU) clots were investigated. Perviousness as a continuous variable was also correlated with protein abundance. Last, an ex vivo lysis assay was performed to investigate the differential susceptibility to tPA, deoxyribonuclease, and ADAMTS13 thrombolysis as a function of perviousness. RESULTS: In total, 2790 distinct proteins were identified. Thrombus perviousness was associated with distinct proteomic features, including depletion of the macrophage marker CD14 (P = .039, z = 1.176) and hemoglobin subunit ζ (P = .046, z = 1.68) in pervious clots. Additionally, proteins involved in platelet cytoskeleton remodeling (tropomyosin α-3-chain) and granule secretion/aggregation (synaptotagmin-like protein 4/FC region receptor II-a) were associated with increasing perviousness (P < .006), among numerous other proteins. Monocyte/macrophage-associated proteins (apoptosis-associated specklike protein containing a CARD/SAMHD1) were also depleted in pervious emboli (P < .002). Ex vivo lysis indicated that pervious clots were more susceptible to ADAMTS13-augmented tPA thrombolysis compared with impervious clots (P < .05), though without differences in deoxyribonuclease digestion. CONCLUSIONS: Thrombus perviousness is associated with complex proteomic features, including differential abundance of platelet-related proteins in highly permeable clots with monocyte/macrophage depletion. This association may help to explain why highly pervious thrombi were also found more susceptible to ADAMTS13-augmented thrombolysis.
Assuntos
Isquemia Encefálica , Trombose Intracraniana , AVC Isquêmico , Acidente Vascular Cerebral , Trombose , Humanos , Acidente Vascular Cerebral/patologia , Proteômica , Trombose Intracraniana/patologia , Trombose/patologia , Terapia Trombolítica , Desoxirribonucleases , Isquemia Encefálica/patologia , Proteína ADAMTS13RESUMO
Cerebrovascular diseases represent a leading cause of disability, morbidity, and death worldwide. In the last decade, the advances in endovascular procedures have not only improved acute ischemic stroke care but also conceded a thorough analysis of patients' thrombi. Although early anatomopathological and immunohistochemical analyses have provided valuable insights into thrombus composition and its correlation with radiological features, response to reperfusion therapies, and stroke etiology, these results have been inconclusive so far. Recent studies applied single- or multi-omic approaches-such as proteomics, metabolomics, transcriptomics, or a combination of these-to investigate clot composition and stroke mechanisms, showing high predictive power. Particularly, one pilot studies showed that combined deep phenotyping of stroke thrombi may be superior to classic clinical predictors in defining stroke mechanisms. Small sample sizes, varying methodologies, and lack of adjustments for potential confounders still represent roadblocks to generalizing these findings. However, these techniques hold the potential to better investigate stroke-related thrombogenesis and select secondary prevention strategies, and to prompt the discovery of novel biomarkers and therapeutic targets. In this review, we summarize the most recent findings, overview current strengths and limitations, and present future perspectives in the field.
Assuntos
Isquemia Encefálica , Transtornos Cerebrovasculares , Trombose Intracraniana , AVC Isquêmico , Acidente Vascular Cerebral , Trombose , Humanos , Isquemia Encefálica/patologia , AVC Isquêmico/complicações , Acidente Vascular Cerebral/terapia , Transtornos Cerebrovasculares/complicações , Trombose/patologia , Trombectomia/efeitos adversos , Trombose Intracraniana/patologiaRESUMO
Thrombus components are dynamically influenced by local blood flow and blood immune cells. After a large-vessel occlusion stroke, changes in the cerebral thrombus are unclear. Here we assessed a total of 206 cerebral thrombi from patients with ischemic stroke undergoing endovascular thrombectomy. The thrombi were categorized by time to reperfusion of <4 h (T4), 4-8 h (T4-8), and >8 h (T8). The cellular compositions in thrombus were analyzed, and relevant clinical features were compared. Both white blood cells and neutrophils were increased and then decreased in thrombus with time to reperfusion, which were positively correlated with those in peripheral blood. The neutrophil extracellular trap (NET) content in thrombus was correlated with the degree of neurological impairment of patients. Moreover, with prolonged time to reperfusion, the patients showed a trend of better collateral grade, which was associated with a lower NET content in the thrombus. In conclusion, the present results reveal the relationship between time-related endovascular immune response and clinical symptoms post-stroke from the perspective of thrombus and peripheral blood. The time-related pathological changes of cerebral thrombus may not be the direct cause for the difficulty in thrombolysis and thrombectomy. A low NET content in thrombi indicates excellent collateral flow, which suggests that treatments targeting NETs in thrombi might be beneficial for early neurological protection.
Assuntos
Trombose Intracraniana , AVC Isquêmico , Acidente Vascular Cerebral , Trombose , Humanos , Trombose Intracraniana/etiologia , Trombose Intracraniana/patologia , Leucócitos/patologia , Acidente Vascular Cerebral/patologia , Trombectomia/métodos , Trombose/patologiaRESUMO
Ischemic stroke is among the leading causes of disability and death worldwide. In acute ischemic stroke, successful recanalization of occluded vessels is the primary therapeutic aim, but even if it is achieved, not all patients benefit. Although blockade of platelet aggregation did not prevent infarct progression, cerebral thrombosis as cause of secondary infarct growth has remained a matter of debate. As cerebral thrombi are frequently observed after experimental stroke, a thrombus-induced impairment of the brain microcirculation is considered to contribute to tissue damage. Here, we combine the model of transient middle cerebral artery occlusion (tMCAO) with light sheet fluorescence microscopy and immunohistochemistry of brain slices to investigate the kinetics of thrombus formation and infarct progression. Our data reveal that tissue damage already peaks after 8 h of reperfusion following 60 min MCAO, while cerebral thrombi are only observed at later time points. Thus, cerebral thrombosis is not causative for secondary infarct growth during ischemic stroke.
Assuntos
Encéfalo/irrigação sanguínea , Infarto da Artéria Cerebral Média/complicações , Trombose Intracraniana/etiologia , Ataque Isquêmico Transitório/complicações , AVC Isquêmico/complicações , Traumatismo por Reperfusão/etiologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/patologia , Trombose Intracraniana/patologia , Ataque Isquêmico Transitório/patologia , AVC Isquêmico/patologia , Cinética , Masculino , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/patologiaRESUMO
High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7% (IQR 0.6-6.2%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke.
Assuntos
Plaquetas/patologia , Isquemia Encefálica/patologia , Proteína HMGB1/metabolismo , Trombose Intracraniana/patologia , Neutrófilos/patologia , Tromboembolia/patologia , Plaquetas/metabolismo , Isquemia Encefálica/metabolismo , Humanos , Trombose Intracraniana/metabolismo , Neutrófilos/metabolismo , Tromboembolia/metabolismoRESUMO
OBJECTIVE: The aim of the present study was to determine whether there is a correlation between thrombotic pathology and prognosis of endovascular treatment (EVT) for acute ischemic stroke (AIS). METHODS: Thrombi were taken from 58 patients with cerebral ischemic thrombosis who were consecutively selected for EVT for AIS. The collected thrombi then underwent hematoxylin-eosin staining for pathological examinations to determine the red blood cell (RBC) ratio and fibrin/platelet components. The patients were divided into the following three groups according to their proportions of RBCs in thrombi: RBC-rich group (RBC ratio ≥ 70%), mixed group (RBC ratio at 31-69%), and fibrin/platelet-rich group (RBC ratio ≤ 30%). Prognosis was classified into good (0-2 points on modified Rankin scale [mRS] at postoperative 90 days) and poor (3-6 points on mRS at postoperative 90 days). Correlational analysis was performed between thrombotic pathology and prognosis of EVT for AIS. RESULTS: Among all patients, the distributions were as follows: 18.96% (11/58) patients in the RBC-rich group, 63.79% (37/58) patients in the mixed group, and 17.24% (10/58) patients in the fibrin/platelet-rich group. In addition, 43.10% (25/58) of the patients had good prognosis and 56.90% (33/58) had poor prognosis.There was no statistically significant difference between the good prognosis and the poor prognosis in the RBC-rich group, the mixed group, and the fibrin/platelet-rich group (P=0.713, 0.829, 0.748).Multivariate logistic regression analysis to explored the association between RBC-rich group and good prognosis while adjusting for other baseline prognostic factors (age, ASPECTS, NIHSS score, and PRT and intravenous alteplase-bridging therapy). Compared to the fibrin/platelet-rich group, the odds ratio(OR) of achieving good prognosis was 0.60 (Pâ¯=â¯0.592) for the mixed group and ORâ¯=â¯0.74 (Pâ¯=â¯0.793) for the RBC-rich group.Notably, age was found to be negatively associated with good prognosis (ORâ¯=â¯0.91, Pâ¯=â¯0.013). The ASPECTS score was found to be positively associated with good prognosis (ORâ¯=â¯2.01, Pâ¯=â¯0.002). Alteplase bridging was associated with a marginally significant positive association with good prognosis (ORâ¯=â¯4.23, Pâ¯=â¯0.083). CONCLUSIONS: No correlation was found between thrombotic pathology and prognosis of EVT for AIS. Good prognosis after endovascular treatment was associated with low age, high ASPECTS at admission, and alteplase bridging.
Assuntos
Plaquetas/patologia , Procedimentos Endovasculares , Eritrócitos/patologia , Trombose Intracraniana/terapia , AVC Isquêmico/terapia , Fatores Etários , Idoso , Plaquetas/química , Avaliação da Deficiência , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Feminino , Fibrina/análise , Fibrinolíticos/uso terapêutico , Humanos , Trombose Intracraniana/sangue , Trombose Intracraniana/patologia , AVC Isquêmico/sangue , AVC Isquêmico/patologia , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Stents , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do TratamentoRESUMO
Primary hemostasis consists in the activation of platelets, which spread on the exposed extracellular matrix at the injured vessel surface. Secondary hemostasis, the coagulation cascade, generates a fibrin clot in which activated platelets and other blood cells get trapped. Active platelet-dependent clot retraction reduces the clot volume by extruding the serum. Thus, the clot architecture changes with time of contraction, which may have an important impact on the healing process and the dissolution of the clot, but the precise physiological role of clot retraction is still not completely understood. Since platelets are the only actors to develop force for the retraction of the clot, their distribution within the clot should influence the final clot architecture. We analyzed platelet distributions in intracoronary thrombi and observed that platelets and fibrin co-accumulate in the periphery of retracting clots in vivo. A computational mechanical model suggests that asymmetric forces are responsible for a different contractile behavior of platelets in the periphery versus the clot center, which in turn leads to an uneven distribution of platelets and fibrin fibers within the clot. We developed an in vitro clot retraction assay that reproduces the in vivo observations and follows the prediction of the computational model. Our findings suggest a new active role of platelet contraction in forming a tight fibrin- and platelet-rich boundary layer on the free surface of fibrin clots.
Assuntos
Coagulação Sanguínea , Plaquetas/química , Fibrina/química , Trombose Intracraniana/patologia , Modelos Estatísticos , Fenômenos Biomecânicos , Plaquetas/patologia , Retração do Coágulo , Simulação por Computador , Fibrina/ultraestrutura , Humanos , Trombose Intracraniana/cirurgia , Intervenção Coronária Percutânea/métodosRESUMO
ABSTRACT: As of August 23, 2020, the 2019 novel coronavirus disease (COVID-19) has infected more than 23,518,340 people and caused more than 810,492 deaths worldwide including 4,717 deaths in China. We present a case of a 53-year-old woman who was admitted to the hospital because of dry coughs and high fever on January 26, 2020, in Wuhan, China. She was not tested for SARS-CoV-2 RNA until on hospital day 11 (illness day 21) because of a significant shortage of test kits at the local hospital. Then, her test was positive for COVID-19 on hospital day 20. Despite intensive medical treatments, she developed respiratory failure with secondary bacterial infection and expired on hospital day 23 (3 days after she was tested positive for SARS-CoV-2 RNA). A systemic autopsy examination, including immunohistochemistry and ultrastructural studies, demonstrates that SARS-CoV-2 can infect multiple organs with profound adverse effect on the immune system, and the lung pathology is characterized by diffuse alveolar damage. Extrapulmonary SARS-CoV-2 RNA was detected in several organs postmortem. The detailed pathological features are described. In addition, this report highlights the value of forensic autopsy in studying SARS-CoV-2 infection and the importance of clinicopathological correlation in better understanding the pathogenesis of COVID-19.
Assuntos
COVID-19/diagnóstico , Autopsia , Epiglotite/patologia , Feminino , Fibroblastos/patologia , Humanos , Infarto/patologia , Trombose Intracraniana/patologia , Rim/irrigação sanguínea , Rim/patologia , Pulmão/patologia , Linfonodos/patologia , Linfócitos/patologia , Pessoa de Meia-Idade , Miócitos Cardíacos/patologia , Miofibroblastos/patologia , Necrose , RNA Viral/análise , Infarto do Baço/patologia , Hemorragia Subaracnóidea/patologia , Tromboembolia/patologia , Trombose/patologia , Tireoidite Autoimune/patologia , Bexiga Urinária/patologiaRESUMO
AIMS: Cerebral venous thrombosis (CVT) is a rare but severe complication of bacterial meningitis. The histopathological features of CVT in meningitis patients have not been described. MATERIALS AND METHODS: We studied histopathology findings of brain autopsy material from 2 patients with bacterial meningitis complicated by CVT and compared findings with those in 3 CVT patients without meningitis and 1 patient with bacterial meningitis without CVT. The histological slides were re-evaluated and assessed for the presence of thrombosis, cerebral venous sinus mural inflammation and bleeding, inflammation at the thrombosis attachment point, endothelial abnormalities, and the presence of bacteria. RESULTS: The 2 patients who died of bacterial meningitis complicated by CVT showed multifocal deep intramural inflammation in the cerebral venous sinus, whereas this was absent in patients with only bacterial meningitis or CVT. Bacteria were identified within the intramural inflammation and thrombus. CONCLUSION: We observed bacterial invasion causing multifocal deep intramural inflammation and venous wall disintegration as CVT in pneumococcal meningitis.
Assuntos
Trombose Intracraniana/etiologia , Trombose Intracraniana/patologia , Meningite Pneumocócica/complicações , Trombose Venosa/etiologia , Trombose Venosa/patologia , Feminino , Humanos , Masculino , Meningite Pneumocócica/patologia , Pessoa de Meia-IdadeRESUMO
ABSTRACT: We report a case of a sudden death of a 23-year-old man with a history of ulcerative colitis and primary sclerosing cholangitis due to cerebral vascular thrombosis. He was found supine in bed with no signs of trauma or drug use. Three days before being found, he had complained of fever and excessive diarrhea. At autopsy, the brain was markedly edematous with diffuse subarachnoid hemorrhage over the left cerebral hemisphere. The vessels at the base of the brain were unremarkable, and there was no significant hemorrhage over the inferior surfaces. On sectioning, clotted blood was identified in the left frontal lobe and lateral ventricles. Microscopically, the left cerebral hemisphere showed extensive intraparenchymal hemorrhage, necrosis, and numerous thrombosed leptomeningeal vessels. Sections of the transverse and descending colon showed changes consistent with the history of ulcerative colitis.Cerebral venous and sinus thrombosis represents approximately 1% of all strokes and is a known rare complication associated with inflammatory bowel disease (IBD). Symptoms of cerebral venous thrombosis are highly variable and may manifest as headache, focal neurological deficits, seizure, or encephalopathy. In addition to acquired hypercoagulability risk factors patients develop during active disease flares (eg, dehydration), studies suggest that IBD itself represents an independent risk factor for thrombosis. It is important for the forensic pathologist to consider thrombotic complications, particularly those in the cerebral venous system, as potential manifestations of known or undiagnosed IBD.
Assuntos
Colangite Esclerosante/complicações , Colite Ulcerativa/complicações , Morte Súbita/etiologia , Trombose Intracraniana/patologia , Adulto , Hemorragia Cerebral/patologia , Humanos , Masculino , Hemorragia Subaracnóidea/patologiaRESUMO
Loss of cognitive function with aging is a complex and poorly understood process. Recently, clinical research has linked the occurrence of cortical microinfarcts to cognitive decline. Cortical microinfarcts form following the occlusion of penetrating vessels and are considered to be restricted to the proximity of the occluded vessel. Whether and how such local events propagate and affect remote brain regions remain unknown. To this end, we combined histological analysis and longitudinal diffusion tensor imaging (DTI), following the targeted-photothrombotic occlusion of single cortical penetrating vessels. Occlusions resulted in distant tissue reorganization across the mouse brain. This remodeling co-occurred with the formation of a microglia/macrophage migratory path along subcortical white matter tracts, reaching the contralateral hemisphere through the corpus callosum and leaving a microstructural signature detected by DTI-tractography. CX3CR1-deficient mice exhibited shorter trail lengths, differential remodeling, and only ipsilateral white matter tract changes. We concluded that microinfarcts lead to brain-wide remodeling in a microglial CX3CR1-dependent manner.
Assuntos
Infarto Encefálico/patologia , Macrófagos/patologia , Microglia/patologia , Substância Branca/patologia , Animais , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/genética , Receptor 1 de Quimiocina CX3C/genética , Movimento Celular , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/genética , Trombose Intracraniana/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vias Neurais/diagnóstico por imagem , Vias Neurais/patologia , Substância Branca/diagnóstico por imagemRESUMO
INTRODUCTION: Pial arteriovenous fistula (PAVF) is a rare intracranial vascular disease, and its presentation with a huge tumor-resembling thrombus is rarer. PATIENT CONCERNS: A 38-year-old female patient presented with a sudden left-side motor disorder and loss of consciousness. The patient was otherwise in good health and had no history of hypertension or diabetes. During the physical examination, she appeared lethargic and manifested left limb paralysis with level zero muscle strength and a positive pathological reflex. DIAGNOSES: Because imaging failed to rule out a tumor stroke, an intracranial lesion resection was performed immediately. Because the lesion was considered to be a vascular structure, digital subtraction angiography was undertaken before the surgery, and PAVF was diagnosed. INTERVENTIONS: Endovascular embolization was conducted, followed by PAVF and hematoma resection. OUTCOMES: At the 3-month follow up, her left limb muscle strength was level 4, and she could live on her own (Modified Rankin Scale score =â2). CONCLUSIONS: It is noteworthy that PAVF with a large thrombus may appear as a tumor in the initial diagnosis, and therefore it is necessary to perform an intracranial vascular examination in patients with tumor stroke symptoms.
Assuntos
Fístula Arteriovenosa/diagnóstico por imagem , Fístula Arteriovenosa/patologia , Pia-Máter/irrigação sanguínea , Pia-Máter/diagnóstico por imagem , Adulto , Angiografia Digital , Feminino , Hematoma Subdural Intracraniano/diagnóstico por imagem , Hematoma Subdural Intracraniano/patologia , Humanos , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/patologia , Imageamento por Ressonância Magnética , Pia-Máter/patologia , Tomografia Computadorizada por Raios XRESUMO
Previously, we reported that phospholipase D1 (PLD1) and PLD2 inhibition by selective PLD1 and PLD2 inhibitors could prevent platelet aggregation in humans, but not in mice. Moreover, only the PLD1 inhibitor, but not PLD2 inhibitor, could effectively prevent thrombus formation in mice, indicating that PLD might play different roles in platelet function in humans and mice. Although PLD1 and PLD2 were reported to be implicated in thrombotic events, the role of PLD in mice remains not completely clear. Here, we investigated the role of PLD1 and PLD2 in acute pulmonary thrombosis and transient middle cerebral artery occlusion-induced brain injury in mice. The data revealed that inhibition of PLD1, but not of PLD2, could partially prevent pulmonary thrombosis-induced death. Moreover, concurrent PLD1 and PLD2 inhibition could considerably increase survival rate. Likewise, inhibition of PLD1, but not PLD2, partially improved ischemic stroke and concurrent inhibition of PLD1, and PLD2 exhibited a relatively better protection against ischemic stroke, as evidenced by the infarct size, brain edema, modified neurological severity score, rotarod test, and the open field test. In conclusion, PLD1 might play a more important role than PLD2, and both PLD1 and PLD2 could act synergistically or have partially redundant functions in regulating thrombosis-relevant events.
Assuntos
Trombose Intracraniana/enzimologia , AVC Isquêmico/enzimologia , Fosfolipase D/metabolismo , Animais , Trombose Intracraniana/patologia , AVC Isquêmico/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICRRESUMO
We report a 50-year-old man who developed fatal brainstem infarction five days after traumatic cervical vertebral artery dissection (CVAD). Autopsy revealed multiple fresh infarcts in the territory of the vertebrobasilar system. No thrombus was found in the infarct lesions. The cervical vertebral artery (CVA) showed severe atherosclerotic stenosis extending to the proximal half of the left side, similar stenosis at the origin on the right side, fresh thrombotic occlusion extending to the proximal half of the right side, and multiple dissections in the distal foraminal segments on both sides. In the distal half of the basilar artery (BA) and the origin of the right posterior cerebral artery (PCA), the lumen was extensively filled with fresh thrombus. Although an intricate mixture of white and red thrombi filled the lumen at the origin of the right PCA, the white thrombus gradually appeared at the periphery whereas the red thrombus occupied the central and more proximal part of the BA. We confirm that cerebral infarction associated with CVAD is due not only to emboli originating from the dislodged thrombus at sites of arterial dissection, as reported previously, but also to newly formed thrombus in the cerebral arteries caused by impaired blood flow, as was seen in the present case.
Assuntos
Infarto Cerebral/patologia , Trombose Intracraniana/patologia , Procedimentos Neurocirúrgicos/efeitos adversos , Dissecação da Artéria Vertebral/patologia , Infarto Cerebral/etiologia , Vértebras Cervicais/patologia , Humanos , Trombose Intracraniana/etiologia , Masculino , Pessoa de Meia-Idade , Dissecação da Artéria Vertebral/etiologiaRESUMO
Epigenetic processes play important roles in brain responses to ischemic injury. We studied effects of photothrombotic stroke (PTS, a model of ischemic stroke) on the intracellular level and cellular localization of histone deacetylases HDAC3, HDAC4 and HDAC6 in the rat brain cortex, and tested the potential neuroprotector ability of their inhibitors. The background level of HDAC3, HDAC4 and HDAC6 in the rat cerebral cortex was relatively low. HDAC3 localized in the nuclei of some neurons and few astrocytes. HDAC4 was found in the neuronal cytoplasm. After PTS, their levels in penumbra did not change, but HDAC4 appeared in the nuclei of some cells. Its level in the cytoplasmic, but not nuclear fraction of penumbra decreased at 24, but not 4 h after PTS. HDAC6 was upregulated in neurons and astrocytes in the PTS-induced penumbra, especially in the nuclear fraction. Unlike HDAC3 and HDAC4, HDAC6 co-localized with TUNEL-positive apoptotic cells. Inhibitory analysis confirmed the involvement of HDAC6, but not HDAC3 and HDAC4 in neurodegeneration. HDAC6 inhibitor HPOB, HDAC2/8 inhibitor α-phenyl tropolone, and non-specific histone deacetylase inhibitor sodium valproate, but not HDAC3 inhibitor BRD3308, or HDAC4 inhibitor LMK235, decreased PTS-induced infarction volume in the mouse brain, reduced apoptosis, and recovered the motor behavior. HPOB also restored PTS-impaired acetylation of α-tubulin. α-phenyl tropolone restored acetylation of histone H4 in penumbra cells. These results suggest that histone deacetylases HDAC6 and HDAC2 are the possible molecular targets for anti-ischemic therapy, and their inhibitors α-phenyl tropolone, HBOP and sodium valproate can be considered as promising neuroprotectors.
Assuntos
Córtex Cerebral/enzimologia , Desacetilase 6 de Histona/biossíntese , Inibidores de Histona Desacetilases/farmacologia , Trombose Intracraniana/enzimologia , Acidente Vascular Cerebral/enzimologia , Tropolona/farmacologia , Ácido Valproico/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Expressão Gênica , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/biossíntese , Trombose Intracraniana/patologia , Trombose Intracraniana/prevenção & controle , Lasers Semicondutores/efeitos adversos , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/prevenção & controle , Tropolona/uso terapêutico , Ácido Valproico/uso terapêuticoRESUMO
Importance: To date, only uncontrolled studies have evaluated the efficacy and safety of endovascular treatment (EVT) in patients with cerebral venous thrombosis (CVT), leading to the lack of recommendations on EVT for CVT. Objective: To evaluate the efficacy and safety of EVT in patients with a severe form of CVT. Design, Setting, and Participants: TO-ACT (Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis) was a multicenter, open-label, blinded end point, randomized clinical trial conducted in 8 hospitals in 3 countries (the Netherlands, China, and Portugal). Patients were recruited from September 2011 to October 2016, and follow-up began in March 2012 and was completed in December 2017. Adult patients with radiologically confirmed CVT who had at least 1 risk factor for a poor outcome (mental status disorder, coma state, intracerebral hemorrhage, or thrombosis of the deep venous system) were included. Data were analyzed according to the intention-to-treat principle from March 2018 to February 2019. The trial was halted after the first interim analysis for reasons of futility. Interventions: Patients were randomized to receive either EVT with standard medical care (intervention group) or guideline-based standard medical care only (control group). The EVT consisted of mechanical thrombectomy, local intrasinus application of alteplase or urokinase, or a combination of both strategies. Patients in the intervention group underwent EVT as soon as possible but no later than 24 hours after randomization. Main Outcomes and Measures: Primary end point was the proportion of patients with a good outcome at 12 months (recovered without a disability; modified Rankin Scale [mRS] score of 0-1). Secondary end points were the proportion of patients with an mRS score of 0 to 1 at 6 months and an mRS score of 0 to 2 at 6 and 12 months, outcome on the mRS across the ordinal continuum at 12 months, recanalization rate, and surgical interventions in relation to CVT. Safety end points included symptomatic intracranial hemorrhage. Results: Of the 67 patients enrolled and randomized, 33 (49%) were randomized to the intervention group and 34 (51%) were randomized to the control group. Patients in the intervention group vs those in the control group were slightly older (median [interquartile range (IQR)] age, 43 [33-50] years vs 38 [23-48] years) and comprised fewer women (23 women [70%] vs 27 women [79%]). The median (IQR) baseline National Institutes of Health Stroke Scale score was 12 (7-20) in the EVT group and 12 (5-20) in the standard care group. At the 12-month follow-up, 22 intervention patients (67%) had an mRS score of 0 to 1 compared with 23 control patients (68%) (relative risk ratio, 0.99; 95% CI, 0.71-1.38). Mortality was not statistically significantly higher in the EVT group (12% [n = 4] vs 3% [n = 1]; P = .20). The frequency of symptomatic intracerebral hemorrhage was not statistically significantly lower in the intervention group (3% [n = 1] vs 9% [n = 3]; P = .61). Conclusions and Relevance: The TO-ACT trial showed that EVT with standard medical care did not appear to improve functional outcome of patients with CVT. Given the small sample size, the possibility exists that future studies will demonstrate better recovery rates after EVT for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT01204333.
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Anticoagulantes/farmacologia , Veias Cerebrais/patologia , Fibrinolíticos/farmacologia , Trombose Intracraniana/tratamento farmacológico , Trombólise Mecânica , Avaliação de Resultados em Cuidados de Saúde , Adulto , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Veias Cerebrais/diagnóstico por imagem , Terapia Combinada , Feminino , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Seguimentos , Humanos , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/patologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Método Simples-Cego , Ativador de Plasminogênio Tecidual/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/farmacologia , Adulto JovemRESUMO
Patent foramen ovale (PFO) is implicated in the pathogenesis of different clinical syndromes in which it plays variable roles. In 2017 and 2018, four randomized clinical trials were published, allowing for the clarification of certain issues pertaining to cryptogenic stroke. Recently, eight European scientific societies collaborated to the writing of an interdisciplinary international position paper on PFO and cryptogenic stroke, based upon best available evidence, with the aim of defining the principles needed to guide decision making. Nonetheless, a tailored approach is not suitably addressed by standard position documents, considering that decisions about optimal management of PFO patients with left circulation thromboembolism are often challenging, mostly due to comorbidities and complex clinical scenarios.A panel of Italian cardiology experts gathered under the auspices of the Italian Society of Interventional Cardiology (SICI-GISE) for comprehensive discussion and consensus development, with the aim of providing practical recommendations, for both clinical and interventional cardiologists, regarding optimal management of PFO in patients with cerebral or systemic thromboembolism. In this position paper, various clinical scenarios in patients with and without high-risk PFO features are presented and discussed, including PFO patients with associated conditions (e.g. hypercoagulable states, deep vein thrombosis/pulmonary embolism, short runs of atrial fibrillation), and special subsets (e.g. patients with risk factors for atrial fibrillation, patients aged ≥65 years, patients who refused percutaneous PFO closure), with the Panel's recommendations being provided for each scenario.
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Forame Oval Patente/terapia , Trombose Intracraniana/complicações , Tromboembolia/complicações , Cardiologia , Tomada de Decisões , Humanos , Trombose Intracraniana/patologia , Itália , Fatores de Risco , Tromboembolia/patologiaRESUMO
BACKGROUND AND PURPOSE: Detailed insight into the composition of thrombi retrieved from patients with ischemic stroke by mechanical thrombectomy might improve pathophysiologic understanding and therapy. Thus, this study searched for links between histologic thrombus composition and stroke subtypes and mechanical thrombectomy results. MATERIALS AND METHODS: Thrombi from 85 patients who had undergone mechanical thrombectomy for acute ischemic stroke between December 2016 and March 2018 were studied retrospectively. Thrombi were examined histologically. Preinterventional imaging features, stroke subtypes, and interventional parameters were re-analyzed. Statistical analysis was performed with the Kruskal-Wallis test, Mann-Whitney U test, or Spearman correlation as appropriate. RESULTS: Cardioembolic thrombi had a higher percentage of macrophages and a tendency toward more platelets than thrombi of large-artery atherosclerotic stenosis (P = .021 and .003) or the embolic stroke of undetermined source (P = .037 and .099) subtype. Thrombi prone to fragmentation required the combined use of contact aspiration and stent retrieval (P = .021) and were associated with an increased number of retrieving maneuvers (P = .001), longer procedural times (P = .001), and a higher lymphocyte content (P = .035). CONCLUSIONS: We interpreted the higher macrophage and platelet content in cardioembolic thrombi compared with large-artery atherosclerotic stenosis or embolic stroke of undetermined source thrombi as an indication that the latter type might be derived from an atherosclerotic plaque rather than from an undetermined cardiac source. The extent of thrombus fragmentation was associated with a more challenging mechanical thrombectomy and a higher lymphocyte content of the thrombi. Thus, thrombus fragmentation not only might be caused by the recanalization procedure but also might be a feature of a lymphocyte-rich, difficult-to-retrieve subgroup of thrombi.