RESUMO
Periprocedural antithrombotic management with glycoprotein IIb/IIIa inhibitors (GPI) for intracranial artery stenting is still controversial. We sought to assess the safety and efficacy of prophylactic tirofiban infusion for acute intracranial intraprocedural stent thrombosis in routine clinical practice. From January 2013 to December 2019, consecutive patients treated with endovascular stenting for symptomatic intracranial atherosclerotic stenosis (ICAS) were identified and dichotomized by whether tirofiban was used. The efficacy and safety outcomes were compared by propensity score matching. A total of 160 consecutive patients in the tirofiban group and 177 patients in the non-tirofiban group were enrolled. Propensity score matching analysis selected 236 matched patients. One acute intraprocedural stent thrombosis (AIST) occurred in patients receiving prophylactic tirofiban, while 8 in the non-tirofiban group. The incidence of AIST in the tirofiban group was significantly lower than that in the non-tirofiban group (0.8% vs 6.8%, P = 0.039). The periprocedural ischemic events (8.5% vs 5.1%, P = 0.424), periprocedural intracranial hemorrhage (4.2% vs 0.8%, P = 0.219) and 30-day total mortality (3.4% vs 0%, P = 0.125) were not statistically different between the two groups. Compared with conventional stenting angioplasty without tirofiban, tirofiban prophylactic infusion can lower the incidence of AIST, without increasing the risk of periprocedural intracranial hemorrhage and 30-day total mortality. However, there is no superiority in reducing periprocedural ischemic events. The current study adds more important insights to the available clinical evidence on the use of tirofiban during stenting of ICAS.
Assuntos
Procedimentos Endovasculares/efeitos adversos , Arteriosclerose Intracraniana/terapia , Inibidores da Agregação Plaquetária/administração & dosagem , Tirofibana/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioplastia , Feminino , Humanos , Trombose Intracraniana/prevenção & controle , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos Retrospectivos , Stents/efeitos adversos , Tirofibana/efeitos adversos , Resultado do TratamentoRESUMO
RATIONALE: Hereditary Protein C (PC) deficiency is a rare genetic disorder caused by PROC gene mutation. In this article, we report a case of PC deficiency in a Chinese family due to a novel PROC gene mutation. STUDY SUBJECT: The proband presented with recurrent cerebral infarction over the course of the previous 3âyears. He was admitted to the hospital due to signs of mental retardation. DIAGNOSES: Physical examination, laboratory tests, and magnetic resonance imaging demonstrated that the proband had a manifestation of PC deficiency that included acute cerebral infarction. DNA sequencing analysis revealed a missense variant, c.1015Gâ>âA (p.V339âM from valine to methionine) in exon 9 of the PROC gene. In addition, Sanger sequencing confirmed that the proband's son was heterozygous for the same variant. Therefore, the PROC gene mutation was transmitted in an autosomal dominant inheritance manner. INTERVENTIONS: The patient was treated with a daily dosage of Warfarin (3.5âmg) and was scheduled to undergo regular blood coagulation tests. OUTCOMES: At the 3-month follow-up appointment, the patient showed improvements in his overall health condition. LESSONS: We identified a novel missense mutation in the PROC gene in a Chinese family which caused a decrease in the PC antigen level and recurrent cerebral infarction.
Assuntos
Povo Asiático/genética , Deficiência de Proteína C/genética , Proteína C/genética , Anticoagulantes/uso terapêutico , Angiografia Cerebral , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/genética , Infarto Cerebral/prevenção & controle , Imagem de Difusão por Ressonância Magnética , Genes Dominantes , Humanos , Trombose Intracraniana/genética , Trombose Intracraniana/prevenção & controle , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Deficiência de Proteína C/complicações , Recidiva , Varfarina/uso terapêuticoRESUMO
We herein report a case involving a 32-year-old Japanese man with recurrent cerebral venous thrombosis due to hereditary protein C deficiency. He was admitted to our hospital with impaired consciousness. Brain magnetic resonance imaging demonstrated high intensities diffusely along the bilateral sulci and magnetic resonance venography revealed left transverse sinus and superior sagittal sinus stenoses. His father had a history of cerebral infarction and venous thrombosis. The protein C activity level examined by chromogenic synthetic substrate assay was markedly reduced. He was diagnosed with protein C deficiency, and a genetic analysis revealed a heterozygous mutation at exon 3 c.199G>A,p.Glu67Lys on the protein C gene. Four months later, at his second admission, he had transient aphasia, and his protein C activity was under 10%. We switched warfarin to the direct oral anticoagulants edoxaban. He remains fully recovered with no adverse events after the administration of edoxaban for a year. Direct oral anticoagulants may be a new tool for treating cerebral venous thrombosis due to hereditary protein C deficiency.
Assuntos
Inibidores do Fator Xa/administração & dosagem , Trombose Intracraniana/prevenção & controle , Mutação , Proteína C/genética , Piridinas/administração & dosagem , Tiazóis/administração & dosagem , Trombose Venosa/prevenção & controle , Administração Oral , Adulto , Substituição de Medicamentos , Heterozigoto , Humanos , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/etiologia , Masculino , Deficiência de Proteína C/complicações , Deficiência de Proteína C/diagnóstico , Deficiência de Proteína C/tratamento farmacológico , Deficiência de Proteína C/genética , Recidiva , Resultado do Tratamento , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/etiologiaAssuntos
Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/etiologia , Infarto/diagnóstico por imagem , Infarto/etiologia , Trombose Intracraniana/diagnóstico por imagem , Nefropatias/diagnóstico por imagem , Rim/irrigação sanguínea , Púrpura Trombocitopênica Trombótica/diagnóstico por imagem , Trombose/diagnóstico por imagem , Trombose/etiologia , Recusa do Paciente ao Tratamento , Proteína ADAMTS13/deficiência , Proteína ADAMTS13/genética , Dor Abdominal/etiologia , Infarto Cerebral/prevenção & controle , Criança , Feminino , Humanos , Infarto/prevenção & controle , Trombose Intracraniana/etiologia , Trombose Intracraniana/prevenção & controle , Nefropatias/etiologia , Nefropatias/prevenção & controle , Imageamento por Ressonância Magnética , Mutação , Púrpura Trombocitopênica Trombótica/complicações , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/imunologia , Trombose/prevenção & controle , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND AND PURPOSE: There is a paucity of data regarding antiplatelet management strategies in the setting of stent-assisted coiling/flow diversion for ruptured intracranial aneurysms. This study aimed to identify current challenges in antiplatelet management during stent-assisted coiling/flow diversion for ruptured intracranial aneurysms and to outline possible antiplatelet management strategies. MATERIALS AND METHODS: The modified DELPHI approach with an on-line questionnaire was sent in several iterations to an international, multidisciplinary panel of 15 neurointerventionalists. The first round consisted of open-ended questions, followed by closed-ended questions in the subsequent rounds. Responses were analyzed in an anonymous fashion and summarized in the final manuscript draft. The statement received endorsement from the World Federation of Interventional and Therapeutic Neuroradiology, the Japanese Society for Neuroendovascular Therapy, and the Chinese Neurosurgical Society. RESULTS: Data were collected from December 9, 2019, to March 13, 2020. Panel members achieved consensus that platelet function testing may not be necessary and that antiplatelet management for stent-assisted coiling and flow diversion of ruptured intracranial aneurysms can follow the same principles. Preprocedural placement of a ventricular drain was thought to be beneficial in cases with a high risk of hydrocephalus. A periprocedural dual, intravenous, antiplatelet regimen with aspirin and a glycoprotein IIb/IIIa inhibitor was preferred as a standard approach. The panel agreed that intravenous medication can be converted to oral aspirin and an oral P2Y12 inhibitor within 24 hours after the procedure. CONCLUSIONS: More and better data on antiplatelet management of patients with ruptured intracranial aneurysms undergoing stent-assisted coiling or flow diversion are urgently needed. Panel members in this DELPHI consensus study preferred a periprocedural dual-antiplatelet regimen with aspirin and a glycoprotein IIb/IIIa inhibitor.
Assuntos
Aneurisma Roto/terapia , Procedimentos Endovasculares , Aneurisma Intracraniano/terapia , Trombose Intracraniana/prevenção & controle , Inibidores da Agregação Plaquetária/uso terapêutico , Adulto , Consenso , Técnica Delphi , Embolização Terapêutica/efeitos adversos , Embolização Terapêutica/instrumentação , Embolização Terapêutica/métodos , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Procedimentos Endovasculares/métodos , Feminino , Humanos , Trombose Intracraniana/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , StentsRESUMO
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
To determine the prevalence of the V617F Janus Kinase 2 (JAK2) mutation in patients with thrombosis without other biological signs of underlying myeloproliferative neoplasm (MPN) and identify associated risk factors for thrombosis. Over a 10-year period, data were collected from patients with thrombotic events and who had also been screened for the V617F JAK2 mutation. Patients with signs of underlying MPN, such as haematocrit levels ≥ 50% and/or platelet counts ≥ 450 × 109/L and/or splanchnic thrombosis were excluded from the study. Of 340 patients fulfilling inclusion criteria, JAK2 mutation was found in 9 (2.65%), the allele burden being at least 2% in 4 (1.1%). Upon follow-up, MPN was diagnosed in the latter 4. Univariate analysis of the whole cohort showed that age (54 ± 15 vs. 64 ± 13, p = 0.027), platelet count (317 ± 111 vs. 255 ± 75, p = 0.017), C-reactive protein level > 5 mg/L (OR 7.29, p = 0.014), and splenomegaly (OR 54.5, p = 0.0002) were significantly associated with JAK2 mutation. There was also a trend for an increased risk of cerebral venous thrombosis (OR 6.54, p = 0.064). Logistic regression confirmed a significant association between splenomegaly and JAK2 mutation (OR 43.15 [95%CI, 3.05-610.95], p = 0.0054). The V617F JAK2 mutation is rarely found in patients with thrombotic events without overt MPN. Splenomegaly, however, is a statistically and clinically relevant indicator of a potential JAK2 mutation in patients with non-splanchnic thrombotic events. Such patients should require further assessment and a close follow-up.
Assuntos
Trombose Intracraniana , Janus Quinase 2/genética , Transtornos Mieloproliferativos , Esplenomegalia/diagnóstico por imagem , Trombose , Proteína C-Reativa/análise , Estudos de Coortes , Feminino , França/epidemiologia , Predisposição Genética para Doença , Humanos , Trombose Intracraniana/etiologia , Trombose Intracraniana/prevenção & controle , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/classificação , Transtornos Mieloproliferativos/epidemiologia , Transtornos Mieloproliferativos/genética , Contagem de Plaquetas/métodos , Prevalência , Medição de Risco , Fatores de Risco , Trombose/sangue , Trombose/epidemiologia , Trombose/genética , Trombose/fisiopatologia , Trombose VenosaRESUMO
Patients with atrial fibrillation who undergo percutaneous coronary intervention are at increased risk for both coronary and cerebral thrombotic events. As a result, antithrombotic therapy for this patient population continues to pose a significant challenge. In this review, we discuss the development of warfarin triple therapy as the standard of care in the last century, the transition to dual therapy with warfarin and a P2Y12 inhibitor, the advent of NOACs, recent clinical trials, and new regimens with a NOAC and a P2Y12 inhibitor. We also discuss our current clinical practice, based on the available data.
Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/complicações , Trombose Coronária/prevenção & controle , Trombose Intracraniana/prevenção & controle , Anticoagulantes/efeitos adversos , Aspirina/administração & dosagem , Cardiologia/tendências , Trombose Coronária/etiologia , Quimioterapia Combinada/efeitos adversos , Humanos , Trombose Intracraniana/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Varfarina/administração & dosagemRESUMO
Background and Purpose- Patients with intracerebral hemorrhage (ICH) and atrial fibrillation (AF) are at risk for ischemic events. While risk calculators (CHA2DS2-VASc and HAS-BLED) have been validated to assess risk for ischemic stroke and major bleeding in AF patients, decisions about anticoagulation must consider the net clinical benefit of anticoagulation. Furthermore, stroke and bleeding risk are highly correlated, making decisions more difficult. Methods- We examined patients in the GERFHS III study (Genetic and Environmental Risk Factors for Hemorrhagic Stroke)-a population-based retrospective study of spontaneous ICH patients without a structural or traumatic cause in the Greater Cincinnati/Northern Kentucky region between July 2008 and December 2012. CHA2DS2-VASc and HAS-B(L)ED (minus L because labile international normalized ratio was unavailable) scores were calculated for ICH patients with AF. Using a Markov state transition model, we estimated net clinical benefit of anticoagulation relative to no treatment in quality-adjusted life years (QALYs). We defined minimal clinically relevant benefit as 0.1 QALYs. Results- Among 1186 cases of spontaneous ICH, 95 cases had AF and met our survival criteria. Within 1 year, 8 of 95 (8%) would be expected to have a major bleeding event on anticoagulation, and 5 of 95 (5%) of patients would be expected to have an ischemic stroke off anticoagulation. Sixty-eight of 95 (71%) patients would have higher risk for major bleeding than for ischemic stroke. Anticoagulation with directly acting anticoagulants would result in no clinically significant gain or loss in 73%. Roughly 12% would gain >0.1 QALYs, and 15% would lose >0.1 QALYs. Among patients receiving aspirin, most have no significant net clinical benefit or loss. Overall, anticoagulation of the entire cohort would result in an aggregate loss of 0.92 QALYs. Conclusions- Our analysis suggests that universal anticoagulation after ICH would be associated with a net loss of QALY. Additional factors should be considered before anticoagulating patients with AF after ICH. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00930280.
Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/etiologia , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Hemorragia Cerebral/complicações , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Coeficiente Internacional Normatizado , Trombose Intracraniana/prevenção & controle , Masculino , Pessoa de Meia-Idade , Resultados Negativos , Anos de Vida Ajustados por Qualidade de Vida , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Microthrombosis after subarachnoid hemorrhage has an adverse effect on prognosis. Milk fat globule-epidermal growth factor 8 promotes phagocytosis of phagocytic cells and may reduce microthrombosis. This study investigated the effects of recombinant human milk fat globule-epidermal growth factor 8 on microthrombosis and neurological function after subarachnoid hemorrhage. METHODS: Rats subarachnoid hemorrhage model was induced by intravascular puncture method. Western blot was performed to measure the expression of endogenous milk fat globule-epidermal growth factor 8 after subarachnoid hemorrhage. Microthrombosis was quantified by microthrombi count using immunohistochemistry and immunofluorescence. The neuroprotective effect of recombinant human milk fat globule-epidermal growth factor 8 administration was evaluated by modified Garcia score, beam balance, Rotarod test, and Morris water maze. RESULTS: Endogenous milk fat globule-epidermal growth factor 8 protein level increased after subarachnoid hemorrhage. Microthrombosis was significantly increased in subarachnoid hemorrhage rats brain, while recombinant human milk fat globule-epidermal growth factor 8 dramatically reduced microthrombosis as well as improve short- and long- term neurobehavior after subarachnoid hemorrhage. CONCLUSIONS: Recombinant human milk fat globule-epidermal growth factor 8 reduces microthrombosis and improves neurological function after subarachnoid hemorrhage, which may be an effective strategy for treating subarachnoid hemorrhage.
Assuntos
Antígenos de Superfície/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Fibrinolíticos/administração & dosagem , Trombose Intracraniana/prevenção & controle , Proteínas do Leite/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Antígenos de Superfície/metabolismo , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Trombose Intracraniana/sangue , Trombose Intracraniana/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas do Leite/metabolismo , Atividade Motora/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/fisiopatologia , Fatores de TempoRESUMO
AIMS: To understand the different influences of statins on the incidence rate of each stroke subtype in association with low-density lipoprotein (LDL) cholesterol levels, we performed a post hoc analysis on the data from the Japan Statin Treatment Against Recurrent Stroke (J-STARS) study. METHODS: Subjects (n=1,578) were divided into three groups according to their mean postrandomized LDL cholesterol level (ï¼100, 100-120, and ≥ 120 mg/dL) until the last observation before the event or the end of follow-up. A Cox proportional hazard model for time to events was used for calculating adjusted hazard ratios, 95% confidence intervals, and the trend tests. RESULTS: The event rates for atherothrombotic stroke did not decrease in accordance with the postrandomized LDL cholesterol level subgroups of either the control or the pravastatin group (p=0.15 and 0.33 for the trend, respectively). In the control group, however, no atherothrombotic stroke event was observed in the subgroup of the low postrandomized LDL cholesterol level (less than 100 mg/dL). The event rates for atherothrombotic stroke were lower in the middle postrandomized LDL cholesterol level subgroup (100-120 mg/dL) of the pravastatin group than that of the control group. The event rates for lacunar stroke decreased in the lower postrandomized LDL cholesterol level subgroup of the control group but not of the pravastatin group (p=0.004 and 0.06 for the trend, respectively). CONCLUSIONS: Statins showed different influences on the risks of atherothromobotic and lacunar stroke according to postrandomized LDL cholesterol levels.
Assuntos
Infarto Cerebral , LDL-Colesterol/sangue , Trombose Intracraniana , Pravastatina/uso terapêutico , Acidente Vascular Cerebral Lacunar , Infarto Cerebral/sangue , Infarto Cerebral/etiologia , Infarto Cerebral/prevenção & controle , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Trombose Intracraniana/sangue , Trombose Intracraniana/diagnóstico , Trombose Intracraniana/epidemiologia , Trombose Intracraniana/prevenção & controle , Japão , Masculino , Pessoa de Meia-Idade , Medição de Risco/estatística & dados numéricos , Prevenção Secundária/métodos , Acidente Vascular Cerebral Lacunar/sangue , Acidente Vascular Cerebral Lacunar/diagnóstico , Acidente Vascular Cerebral Lacunar/epidemiologia , Acidente Vascular Cerebral Lacunar/prevenção & controleAssuntos
Monofosfato de Adenosina/análogos & derivados , Aneurisma Intracraniano/cirurgia , Trombose Intracraniana/prevenção & controle , Inibidores da Agregação Plaquetária/uso terapêutico , Stents , Monofosfato de Adenosina/uso terapêutico , Aspirina/uso terapêutico , Encéfalo/cirurgia , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
(3ß,5α,16α,20S)-4,4,14-trimethyl-3,20-bis(methylamino)-9,19-cyclopregnan-16-ol-dihydrochloride (JLX001), a derivative of cyclovirobuxine D (CVB-D), is a novel compound from synthesis. This study aims to confirm the therapeutic effect of JLX001 on cerebral ischemia and researchits antiplatelet and antithrombosis activities via thromboxane (TXA2)/phospholipase C-ß-3(PLCß3)/protein kinase C (PKC) pathway suppression. The therapeutic effects of JLX001 was evaluated by infarct sizes, brain edema and neurological scores in Sprague-Dawley (SD) rats with middle cerebral artery occlusion (MCAO). Brain TXA2 and prostacyclin (PGI2) were measured by enzyme-linked immunosorbentassay (ELISA). P-PLCß3and activated PKC were detected by immunohistochemical method. Adenosine diphosphate (ADP) or 9, 11-dieoxy-11α, 9α-epoxymethanoeprostaglandin F2α (U46619) was used as platelet agonist in the in vivo and in vitro platelet aggregation experiments. Clotting time and bleeding time were determined. Besides, two whole-animal experiments including arteriovenous shunt thrombosis and pulmonary thromboembolism model were conducted. Results showed that JLX001 treatment markedly alleviated cerebral infarcts, edema, and neurological scores in permanent middle cerebral artery occlusion (pMCAO) rats. Brain TXA2 level, p-PLCß3and activated PKC were decreased, while PGI2level had no significant change. Besides, JLX001 inhibited platelet aggregation induced by ADP or U46619 and exhibited anti-coagulation effects with a minor bleeding risk. In the two whole-animal experiments, JLX001 inhibited thrombus formation. In summary, JLX001 attenuates cerebral ischemia injury and the underlying mechanisms relate to inhibiting platelet activation and thrombus formation via TXA2/PLCß3/PKC pathway suppression.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/prevenção & controle , Trombose Intracraniana/prevenção & controle , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Aspirina/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Edema Encefálico/sangue , Edema Encefálico/patologia , Edema Encefálico/prevenção & controle , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Epoprostenol/metabolismo , Feminino , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Trombose Intracraniana/sangue , Trombose Intracraniana/enzimologia , Trombose Intracraniana/patologia , Masculino , Camundongos Endogâmicos ICR , Fosfolipase C beta/metabolismo , Inibidores da Agregação Plaquetária/uso terapêutico , Proteína Quinase C/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Tromboxano A2/metabolismo , Triterpenos/uso terapêuticoRESUMO
BACKGROUND: Cerebral sinovenous thrombosis (CSVT) is a rare, yet important complication of acute lymphoblastic leukemia (ALL) therapy, associated with significant morbidity and mortality. Paucity of data from India prompted us to report our experience with CSVT over a period of 17 years. MATERIALS AND METHODS: This is a retrospective analysis of 500 consecutive ALL patients, below 18 year of age, treated between January 1998 and December 2014, who developed symptomatic CVST. RESULTS: Seven of the 467 eligible patients developed symptomatic CVST with an incidence of 1.5% (7/467). Six of the CVST events, occurred during induction and 1 during reinduction. Median time to symptoms was 21 days (range, 2 to 27 d) from first exposure to L-asparaginase therapy. Management included low-molecular-weight heparin (enoxaparin sodium) at a dose of 1 mg/kg twice a day for at least 3 months along with supportive care. There were 2 thrombosis-attributable deaths. The remaining patients tolerated rechallenge with L-asparaginase uneventfully during reinduction, under cover of heparin prophylaxis. Complete neurological recovery was observed in all surviving patients. CONCLUSIONS: Incidence of symptomatic L-asparaginase associated CSVT during ALL treatment was 1.5% with high case fatality rate (28%). It is noteworthy that full neurological recovery is likely in surviving patients, and rechallenge with L-asparaginase is safe with heparin prophylaxis. Currently available screening methods are not practically implementable in resource-limited settings.
Assuntos
Asparaginase/efeitos adversos , Trombose Intracraniana/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adolescente , Anticoagulantes/uso terapêutico , Antineoplásicos/uso terapêutico , Asparaginase/uso terapêutico , Criança , Pré-Escolar , Enoxaparina/uso terapêutico , Feminino , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Incidência , Índia , Trombose Intracraniana/mortalidade , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Indução de Remissão/métodos , Estudos RetrospectivosRESUMO
Adverse cardiovascular effects of particulate air pollution persist even at lower concentrations than those of the current air quality limit. Therefore, identification of safe and effective measures against particle-induced cardiovascular toxicity is needed. Nootkatone is a sesquiterpenoid in grapefruit with diverse bioactivities including anti-inflammatory and antioxidant effects. However, its protective effect on the cardiovascular injury induced by diesel exhaust particles (DEPs) has not been studied before. We assessed the possible protective effect of nootkatone (90 mg/kg) administered by gavage 1 h before intratracheal instillation of DEPs (30 µg/mouse). Twenty-four hours after the intratracheal administration of DEPs, various thrombotic and cardiac parameters were assessed. Nootkatone inhibited the prothrombotic effect induced by DEPs in pial arterioles and venules in vivo and platelet aggregation in whole blood in vitro. Also, nootkatone prevented the shortening of activated partial thromboplastin time and prothrombin time induced by DEPs. Nootkatone inhibited the increase of plasma concentration of fibrinogen, plasminogen activator inhibitor-1, interleukin-6, and lipid peroxidation induced by DEPs. Immunohistochemically, hearts showed an analogous increase in glutathione and nuclear factor erythroid-derived 2-like 2 expression by cardiac myocytes and endothelial cells after DEP exposure, and these effects were enhanced in mice treated with nootkatone + DEPs. Likewise, heme oxygenase-1 was increased in mice treated with nootkatone + DEPs compared with those treated with DEPs or nootkatone + saline. The DNA damage caused by DEPs was prevented by nootkatoone pretreatment. In conclusion, nootkatoone alleviates DEP-induced thrombogenicity and systemic and cardiac oxidative stress and DNA damage, at least partly, through nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 activation. NEW & NOTEWORTHY Nootkatoone, a sesquiterpenoid found in grapefruit, alleviates the thrombogenicity and systemic and cardiac oxidative stress and DNA damage in mice exposed to diesel exhaust particles. Nootkatone-induced boosting of nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 levels in the heart of mice exposed to diesel exhaust particles suggests that its protective effect is, at least partly, mediated through nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 activation.
Assuntos
Antioxidantes/farmacologia , Plaquetas/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Fibrinolíticos/farmacologia , Trombose Intracraniana/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos/farmacologia , Emissões de Veículos , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/metabolismo , Plaquetas/patologia , Modelos Animais de Doenças , Feminino , Heme Oxigenase-1/metabolismo , Exposição por Inalação , Trombose Intracraniana/sangue , Trombose Intracraniana/induzido quimicamente , Trombose Intracraniana/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Sesquiterpenos PolicíclicosRESUMO
Cerebral venous thrombosis (CVT) is a severe multifactorial condition with various clinical manifestations that may include headache, papilledema, seizures, focal deficits, coma and death. The mortality rate of untreated CVT is up to 50%, but it drops to 10% when CVT is properly treated. Prevention of CVT is feasible through healthy lifestyle, genetic counseling, molecular genetic analysis for common thrombophilia-related mutations, and prophylactic anticoagulative medication.
Assuntos
Predisposição Genética para Doença/genética , Trombose Intracraniana/genética , Mutação , Trombofilia/genética , Adulto , Saúde da Família , Feminino , Humanos , Trombose Intracraniana/etiologia , Trombose Intracraniana/prevenção & controle , Masculino , Linhagem , Fatores de Risco , Trombofilia/complicações , Trombofilia/prevenção & controle , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Pregnancy is associated with increased risk of venous thrombotic events, including cerebral venous thrombosis. We aimed to study the complications and outcome of subsequent pregnancies in women with previous cerebral venous thrombosis. METHODS: Follow-up study of women with acute cerebral venous thrombosis at childbearing age included in a previously described cohort (International Study of Cerebral Vein and Dural Sinus Thrombosis). Patients were interviewed by local neurologists to assess rate of venous thrombotic events, pregnancy outcomes, and antithrombotic prophylaxis during subsequent pregnancies. RESULTS: A total of 119 women were included, with a median follow-up of 14 years. Eighty-two new pregnancies occurred in 47 women. In 83% (68 of 82), some form of antithrombotic prophylaxis was given during at least 1 trimester of pregnancy or puerperium. Venous thrombotic events occurred in 3 pregnancies, including 1 recurrent cerebral venous thrombosis. Two of the 3 women were on prophylactic low-molecular-weight heparin at the time of the event. Outcomes of pregnancies were 51 full-term newborns, 9 preterm births, 2 stillbirths, and 20 abortions (14 spontaneous). CONCLUSIONS: In women with prior cerebral venous thrombosis, recurrent venous thrombotic events during subsequent pregnancies are infrequent.
Assuntos
Veias Cerebrais , Fibrinolíticos/administração & dosagem , Heparina de Baixo Peso Molecular/administração & dosagem , Trombose Intracraniana/prevenção & controle , Complicações Cardiovasculares na Gravidez/prevenção & controle , Resultado da Gravidez , Adulto , Feminino , Seguimentos , Humanos , Trombose Intracraniana/epidemiologia , Trombose Intracraniana/fisiopatologia , Gravidez , Complicações Cardiovasculares na Gravidez/epidemiologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , RecidivaRESUMO
BACKGROUND: Survivors of stroke due to intracerebral haemorrhage (ICH) are at risk of thromboembolism. Antithrombotic (antiplatelet or anticoagulant) treatments may lower the risk of thromboembolism after ICH, but they may increase the risks of bleeding. OBJECTIVES: To determine the overall effectiveness and safety of antithrombotic drugs for people with ICH. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (24 March 2017). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL: the Cochrane Library 2017, Issue 3), MEDLINE Ovid (from 1948 to March 2017), Embase Ovid (from 1980 to March 2017), and online registries of clinical trials (8 March 2017). We also screened the reference lists of included trials for additional, potentially relevant studies. SELECTION CRITERIA: We selected all randomised controlled trials (RCTs) of any antithrombotic treatment after ICH. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data. We converted categorical estimates of effect to the risk ratio (RR) or odds ratio (OR), as appropriate. We divided our analyses into short- and long-term treatment, and used fixed-effect modelling for meta-analyses. Three review authors independently assessed the included RCTs for risks of bias and we created a 'Summary of findings' table using GRADE. MAIN RESULTS: We included two RCTs with a total of 121 participants. Both RCTs were of short-term parenteral anticoagulation early after ICH: one tested heparin and the other enoxaparin. The risk of bias in the included RCTs was generally unclear or low, with the exception of blinding of participants and personnel, which was not done. The included RCTs did not report our chosen primary outcome (a composite outcome of all serious vascular events including ischaemic stroke, myocardial infarction, other major ischaemic event, ICH, major extracerebral haemorrhage, and vascular death). Parenteral anticoagulation did not cause a statistically significant difference in case fatality (RR 1.25, 95% confidence interval (CI) 0.38 to 4.07 in one RCT involving 46 participants, low-quality evidence), ICH, or major extracerebral haemorrhage (no detected events in one RCT involving 75 participants, low-quality evidence), growth of ICH (RR 1.64, 95% CI 0.51 to 5.29 in two RCTs involving 121 participants, low-quality evidence), deep vein thrombosis (RR 0.99, 95% CI 0.49 to 1.96 in two RCTs involving 121 participants, low quality evidence), or major ischaemic events (RR 0.54, 95% CI 0.23 to 1.28 in two RCTs involving 121 participants, low quality evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs to support or discourage the use of antithrombotic treatment after ICH. RCTs comparing starting versus avoiding antiplatelet or anticoagulant drugs after ICH appear justified and are needed in clinical practice.
Assuntos
Hemorragia Cerebral/complicações , Enoxaparina/uso terapêutico , Fibrinolíticos/uso terapêutico , Heparina/uso terapêutico , Trombose Intracraniana/prevenção & controle , Acidente Vascular Cerebral/tratamento farmacológico , Hemorragia Cerebral/mortalidade , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/etiologia , Trombose Venosa/epidemiologiaRESUMO
OBJECTIVES: Cerebral malperfusion for patients with acute type A aortic dissection (AAAD) remains an unsolved problem. The present study aimed to evaluate our management of cerebral perfusion and identify predictors of perioperative cerebral malperfusion in patients undergoing surgical repair of AAAD. METHODS: Between January 2004 and December 2015, 137 consecutive patients with AAAD underwent aortic replacement at Tsuchiya General Hospital. The status of the dissected supra-aortic branch vessels (SABVs) was classified as patent or thrombosis by preoperative computed tomographic angiography. Intraoperative cerebral perfusion was monitored by transcutaneous carotid echo and regional oxygen saturation. In cases with neurological symptoms or cerebral malperfusion, quick cerebral perfusion was immediately started using a quick cutdown technique. We assessed clinical outcomes, including mortality and complications, and analysed predictors of early mortality and cerebral malperfusion. RESULTS: The early mortality rate was 8.0%. Postoperative cerebral injury was observed in 4 patients (2.9%). Nineteen patients had perioperative cerebral malperfusion. There were no postoperative cerebral injuries in the patients in whom intraoperative cerebral malperfusion was corrected. Multivariable analysis revealed that preoperative shock (odds ratio [OR] 22.60, P < 0.0001) and extension of dissection to the abdominal aorta (OR 9.31, P = 0.0064) were significant risk factors for early mortality. Preoperative neurological symptoms (OR 12.40, P = 0.0006) and partial or complete thrombosis of the SABV (OR 64.10, P < 0.0001) were identified as independent predictors of perioperative cerebral malperfusion. CONCLUSIONS: Perioperative cerebral perfusion should be carefully managed, especially in the patients with preoperative neurological symptoms or partial or complete thrombosis of the SABV.