Anticoagulant Treatment for Pediatric Infection-Related Cerebral Venous Thrombosis.

BACKGROUND: We aimed to describe the clinical presentation, risk of bleeding and recurrent thrombosis, and perioperative anticoagulant management of children with cerebral venous thrombosis (CVT) and an associated head or neck infection. METHODS: In this subgroup analysis of the EINSTEIN-Jr study, we included children with CVT and an associated head or neck infection who received therapeutic anticoagulants with either low-molecular-weight heparin (with or without subsequent vitamin K antagonists) or rivaroxaban for a period of 3 months. Analyses are descriptive. RESULTS: Of 74 included children, 59 (80%) had otomastoiditis, 21 (28%) a central nervous system infection, 18 (24%) sinusitis, and 9 (12%) another upper respiratory tract infection; 29 (39%) had infection of multiple regions of the head or neck. All 74 children received antibiotics and therapeutic anticoagulants; 41 (55%) underwent surgery, of whom 34 were diagnosed with CVT preoperatively. Anticoagulation was started before surgery in 12 children and interrupted 0-1 days prior to surgery. Anticoagulation was (re)started in all 34 children at a median of 1 day (interquartile range: 0-1) postoperatively, in therapeutic doses in 94%. Overall, one child (1%, 95% confidence interval: 0-7) had recurrent thrombosis, and one (1%, 95% confidence interval: 0-7) had major bleeding; neither was associated with surgery. At 3 months, no children had died, 3 (4%) had persistent focal neurologic deficits, and 2 (3%) had impaired vision. CONCLUSIONS: Children with CVT and an associated head or neck infection administered therapeutic anticoagulants generally had low risks of bleeding and thrombotic complications, including those who had surgical interventions with delay or interruption of anticoagulation.

Rivaroxaban for the treatment of cerebral venous thrombosis: a single-center experience.

The mainstay of cerebral venous thrombosis (CVT) treatment according to current guidelines is parenteral anticoagulation with unfractionated heparin or low-molecular-weight heparin followed by long-term oral anticoagulation with vitamin K antagonists. Direct oral anticoagulants (DOACs), including the factor Xa inhibitor rivaroxaban, are used occasionally off-label for CVT based on individual treatment plans. This publication sought to report our experience with rivaroxaban for the indication of CVT and to review the relevant literature data concerning this topic. We performed a single-center retrospective analysis including patients from our institution with the diagnosis of cerebral venous thrombosis treated with rivaroxaban. Among 12,500 stroke patients over an 11-year period, we identified 87 cases with a diagnosis of CVT (0.7%). As long-term anticoagulation, 80 of these patients were receiving vitamin K antagonists and seven were receiving DOACs, including six receiving rivaroxaban and one receiving apixaban. Of the six patients receiving rivaroxaban, at least 6 months of clinical follow-up data were available for five of them. Excellent clinical outcomes were obtained in four of these five cases (modified Rankin scale score: 0-1 points). No hemorrhagic events, recurrent thrombosis, or other relevant complications were recorded during the follow-up period. Despite our small study sample size, our positive results support that rivaroxaban may be a safe and effective treatment option for patients with CVT. Hopefully, ongoing randomized clinical trials will better clarify the role of rivaroxaban in the treatment of CVT so as to provide a more convenient and safer alternative to vitamin K antagonists in this context.

The Gliopeptide ODN, a Ligand for the Benzodiazepine Site of GABAA Receptors, Boosts Functional Recovery after Stroke.

Following stroke, the survival of neurons and their ability to reestablish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABAA receptors (GABAARs). Conversely, in the late phase, negative allosteric modulation of GABAAR can correct the suboptimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABAAR synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which makes it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in two different paradigms of experimental stroke in mice. Furthermore, we bring evidence that, during the subacute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity.SIGNIFICANCE STATEMENT Stroke remains a devastating clinical challenge because there is no efficient therapy to either minimize neuronal death with neuroprotective drugs or to enhance spontaneous recovery with neurorepair drugs. Around the brain damage, the peri-infarct cortex can be viewed as a reservoir of plasticity. However, the potential of wiring new circuits in these areas is restrained by a chronic excess of GABAergic inhibition. Here we show that an astrocyte-derived peptide, can be used as a delayed treatment, to safely correct cortical excitability and facilitate sensorimotor recovery after stroke.

Rivaroxaban for the treatment of cerebral venous thrombosis.

BACKGROUND: New Oral Anticoagulants (NOACs) such as Rivaroxaban are introduced as alternatives to conventional vitamin-K antagonists in the long-term treatment of thrombotic events due to their lower bleeding risk. There is a lack of evidence on the effectiveness and safety of Rivaroxaban in Cerebral venous thrombosis (CVT). This study aims to assess the effectiveness and bleeding risk of Rivaroxaban in comparison with Warfarin for the treatment of CVT. MATERIALS AND METHODS: 36 patients with diagnosis of CVT were included. Clinical and background information was assessed on admission and patients were followed for at least 12 months. Measured outcomes were modified Rankin Scale (mRS), evidence of recanalization on contrast-enhanced Brain MR venography (MRV) and major or minor bleeding. Patients were divided into two groups according to the type of oral anticoagulant (Rivaroxaban vs Warfarin). Groups were compared in terms of final outcomes and side effects. RESULT: Overall, 13 (36.11%) patients received Warfarin and 23 (63.89%) received Rivaroxaban. Optimal mRS score (0-1) was attained in 9 of 10 (90%) of patients treated with Rivaroxaban and 19 of 22 (86.36%) of patients received Warfarin. MRV showed complete or partial recanalization in 12 of 14 (85.71%) patients treated with Rivaroxaban and all patients in the Warfarin group. There was no significant difference between the two groups in terms of major and minor hemorrhage. CONCLUSION: Rivaroxaban holds promise for the treatment of CVT.

[Complex management of type 2 heparin-induced thrombocytopenia in patients with major bleeding tendency: two case report]. / Prise en charge de la thrombopénie induite par l'héparine immuno-allergique de type 2 au travers de deux cas cliniques chez des patients à risque hémorragique majeur.

Type 2 heparin-induced thrombocytopenia (HIT 2) is a rare pro-thrombotic disorder occurring in patients treated with heparin. It is defined as a clinical-biological syndrome associating the sudden onset of a thrombocytopenia, characterized by a drop of more than 50% of the initial platelet count, and thrombosis. We report two cases of HIT 2 occurring in patients with major bleeding tendency. The first HIT occurred in a patient whose management, in accordance with current guidelines, made it possible to control the thrombocytopenia and the anticoagulation despite the complexity of adapting and monitoring treatments in the context of recent cerebral hemorrhage. The second refers to an autoimmune HIT, which occurred in a patient whose management required the use of alternative therapies to the standard treatments suggested for HIT 2, to correct the severe refractory thrombocytopenia.

[Efficacy and safety of Shenxiong Glucose Injection in treatment of cerebral thrombosis:systematic review and Meta-analysis].

To systematically evaluate the efficacy and safety of Shenxiong Glucose Injection in the treatment of cerebral thrombosis.Randomized controlled trials( RCTs) of Shenxiong Glucose Injection for cerebral thrombosis were screened out by searching CNKI,Wan Fang,VIP,Sino Med,Cochrane Library,PubMed,EMbase,and Web of Science in a systematic way,and the Meta-analysis on finally included studies was conducted by using Handbook 5. 1 evaluation criteria and tools and Rev Man 5. 3 software. GRADE system( GRADE pro 3. 6. 1) was used to grade the evidence quality of key outcome indicators. A total of 25 studies were included,with a total sample size of 2 286 cases,1 144 in the experimental group and 1 142 in the control group. The results of Meta-analysis showed that the total effective rate of Shenxiong Glucose Injection combined with ozagrel in the treatment of cerebral thrombosis was better than that of ozagrel alone( RR = 1. 26,95%CI [1. 20,1. 32],P<0. 000 01); the total effective rate of conventional treatment plus Shenxiong Glucose Injection and ozagrel for cerebral thrombosis was better than that of conventional treatment combined with ozagrel( RR = 1. 26,95%CI [1. 09,1. 46],P = 0. 002). In addition,Shenxiong Glucose Injection combined with ozagrel could reduce the incidence of adverse reactions( RR = 0. 38,95%CI [0. 24,0. 60],P < 0. 000 1),improve the neurological impairment( MD14 d=-7. 19,95% CI[-9. 16,-5. 22],P< 0. 000 1; MD30 d=-5. 34,95% CI [-5. 85,-4. 83],P < 0. 000 1; MD42 d=-7. 03,95% CI [-7. 79,-6. 28],P<0. 000 01; MD60 d=-6. 18,95%CI [-6. 55,-5. 81],P< 0. 000 01; MD90 d=-4. 90,95% CI [-5. 74,-4. 06],P<0. 000 01),and improve activities of daily living( ADL)( MD = 15. 00,95%CI [12. 20,17. 80],P<0. 000 01). The mortality was only included in one study,and the sample size was small,requiring to be further verified by a large sample size. The adverse reactions mainly included lung infection,skin pruritus,gastrointestinal reaction and so on,all of which could be tolerated or disappeared without affecting the treatment. Based on the available data and methods,Shenxiong Glucose Injection combined with ozagrel for cerebral thrombosis could improve the total effective rate,neurological impairment,and ability of daily living,with no serious adverse reactions. The evidence quality level of GRADE system was low in the evaluation of total effective rate,mortality and incidence of adverse reactions.However,the quality of the included researches was not high,requiring rigorously designed and internationally standardized clinical trials with a large sample size to improve the quality of evidence.

Cerebral Venous Thrombosis after Red Blood Cell Transfusion for the Treatment of Iron Deficiency Anemia.

A 57-year-old male presented with generalized seizure who received red blood cell (RBC) transfusion for the treatment of iron deficiency anemia (IDA). Neuroradiological findings revealed cerebral venous thrombosis (CVT) on the left frontal vein. He received anticoagulants, anticonvulsants, and iron supplements. He discharged without any neurological deficit. It should be noted that RBC transfusion might increase the risk of CVT in patients with IDA.

Deep Venous Thrombosis with Decreased Cerebral Blood Flow to the Thalamus was Completely Restored by Factor Xa Inhibitor.

BACKGROUND: Cerebral venous thrombosis is rare and an uncommon cause of stroke and has diverse etiologies and varied clinical presentations. Here, we report 2 cases of deep cerebral venous thrombosis. CASE DESCRIPTION: A 64-year-old woman presented with cerebral venous thrombosis due to a hypercoagulable state associated with ovarian tumor. On initial fluid-attenuated inversion recovery and diffusion-weighted imaging, there was a diffuse high-intensity lesion in the bilateral thalamus. Computed tomography angiography showed occlusion of the straight sinus, vein of Galen, and internal cerebral vein. Single-photon emission computed tomography showed decreased cerebral blood flow in the bilateral thalamus. After 3 weeks of factor Xa inhibitor therapy, the patient's consciousness gradually improved and eventually became clear enough to leave the hospital. She had no neurological deficit. Another patient was a 47-year-old man who presented with splitting headache and drowsiness. Magnetic resonance venography confirmed deep thrombosis of the vein of Galen. He completely recovered after 4 weeks of factor Xa inhibitor therapy. CONCLUSIONS: This study reports on 2 rare cases of decreased cerebral blood flow in the bilateral thalamus on single-photon emission computed tomography, which improved following the administration of factor Xa inhibitor.

Toward a scientific understanding of the effectiveness, material basis and prescription compatibility of a Chinese herbal formula Dan-hong injection.

Since traditional Chinese medicine (TCM) is a complex mixture of multiple components, the application of methodologies for evaluating single-components Western medicine in TCM studies may have certain limitations. Appropriate strategies that recognize the integrality of TCM and connect to TCM theories remain to be developed. Here we use multiple unique approaches to study the scientific connotation of a TCM formula Dan-hong injection (DHI) without undermining its prescription integrity. The blood circulation improving and healing promoting effects of DHI were assessed by a qi stagnation blood stasis rat model and a mouse model of laser irradiation induced cerebral microvascular thrombosis. By UFLC-PDA-Triple Q-TOF-MS/MS and relevance analysis between chemical characters and biological effects, 82 chemical constituents and nine core components, whose blood circulation promoting effects were found comparable to that of whole DHI, were successfully identified. What's more, the rationality of DHI prescription compatibility could be reflected not only in the maximum efficacy of the original ratio, but also in the interactions of compounds from different ingredient herbs, such as complementary activities and facilitating tissues distribution. This study provides scientific evidences in explanation of the clinical benefits of DHI, and also gives a good demonstration for the comprehensive evaluation of other TCM.

Effect of Melilotus officinalis extract on the apoptosis of brain tissues by altering cerebral thrombosis and inflammatory mediators in acute cerebral ischemia.

Present investigation evaluates the protective effect of Melilotus officinalis (MO) extract on the brain tissues in acute cerebral ischemia. Acute cerebral ischemia was induced by occlusion of carotid artery and rats with cerebral ischemia were treated with MO (100, 250 & 500mg/kg) for the duration of three days. Cerebral ischemia was confirmed by estimating infract volume and neurological deficit score. Moreover biochemical parameters in plasma such as 6-keto-PGF1α and TXB2 and concentration of cytokine, oxidative stress, apoptosis ratio and protein expressions of Bcl2 & Bax were estimated in the brain tissues. It was observed that treatment with MO significantly (p<0.01) decreases the infract volume and neurological deficit score than negative control group. There was significant decrease (p<0.01) in the oxidative stress and cytokine in the brain tissues and increase in the plasma concentration of 6-keto-PGF1α in MO treated group of rats compared to negative control group. Plasma concentration of TXB 2 was significantly enhanced in MO treated group compared to negative control group of rats. It was also found that treatment with MO ameliorates the apoptosis induced by cerebral ischemia. Present study concludes that MO ameliorates apoptosis of brain tissues in cerebral ischemic rats by decreasing cerebral thrombosis, oxidative stress and inflammatory mediators.

Rutin improves functional outcome via reducing the elevated matrix metalloproteinase-9 level in a photothrombotic focal ischemic model of rats.

BACKGROUND: Blood-brain barrier (BBB) disruption mediated by proteases plays a pivotal role in neural tissue damage after acute ischemic stroke. In an animal stroke model, the activation of matrix metalloproteinases (MMPs), especially MMP-9, was significantly increased and it showed potential association with blood-brain barrier (BBB) disruption and cerebral edema. Theoretically, it is expected that early blockade of expression and activation of MMP-9 after ischemic stroke provides neuroprotective effects from secondary neural tissue damage. This study was aimed to determine the ability of rutin to influence MMP-9 expression, activity and BBB disruption using a photothrombotic focal ischemic model in rats. METHODS: Adult male Sprague-Dawley rats, weighing between 250 and 300 g (aged 8 weeks) received focal cerebral ischemia by photothrombosis using Rose Bengal (RB) and cold light. Injured animals were divided into two groups; one group received 50mg/kg of rutin intraperitoneally, starting 1h after injury and at 12h intervals for 3 days, while animals in the control group received weight-adjusted doses of saline vehicle over the same period. In each group, the expressions and activities of MMP-9 were assessed by Western blot and gelatin zymography at 6, 24, 48, and 72 h after photothrombotic insult. The effects of rutin on BBB disruption and functional outcomes were also determined. RESULTS: Western blot and zymographic analysis showed up-regulated MMP-9 expression and activity in the ischemic cortex. The expression and activity of MMP-9 were significantly elevated at 6h after photothrombotic insult, which remained up-regulated for at least until 72 h after injury. In the rutin-treated group, MMP-9 expression and activity were significantly attenuated at 6, 24, and 48 h compared to the control group. Relative to the control group, BBB permeability was significantly reduced in the rutin-treated group. The results of the rotarod test revealed that rutin treatment significantly improved functional outcomes. CONCLUSIONS: Rutin treatment starting 1h after injury attenuated BBB disruption during photothrombotic focal ischemia, which was partly, at least, achieved through inhibitory effects on MMP-9 expression and activity. The results of this study suggest that rutin might be useful in clinical trials aimed to improve the outcome of patients suffering from acute ischemic stroke.

Non-selective calcium channel blocker bepridil decreases secondary pathology in mice after photothrombotic cortical lesion.

Experimental studies have identified a complex link between neurodegeneration, ß-amyloid (Aß) and calcium homeostasis. Here we asked whether early phase ß-amyloid pathology in transgenic hAPPSL mice exaggerates the ischemic lesion and remote secondary pathology in the thalamus, and whether a non-selective calcium channel blocker reduces these pathologies. Transgenic hAPPSL (n = 33) and non-transgenic (n = 30) male mice (4-5 months) were subjected to unilateral cortical photothrombosis and treated with the non-selective calcium channel blocker bepridil (50 mg/kg, p.o., once a day) or vehicle for 28 days, starting administration 2 days after the operation. Animals were then perfused for histological analysis of infarct size, Aß and calcium accumulation in the thalamus. Cortical photothrombosis resulted in a small infarct, which was associated with atypical Aß and calcium accumulation in the ipsilateral thalamus. Transgenic mice had significantly smaller infarct volumes than non-transgenic littermates (P<0.05) and ischemia-induced rodent Aß accumulation in the thalamus was lower in transgenic mice compared to non-transgenic mice (P<0.01). Bepridil decreased calcium load in the thalamus (P<0.01). The present data suggest less pronounced primary and secondary pathology in hAPPSL transgenic mice after ischemic cortical injury. Bepridil particularly decreased calcium pathology in the thalamus following ischemia.

Melatonin reduced the elevated matrix metalloproteinase-9 level in a rat photothrombotic stroke model.

BACKGROUND: The accumulation of toxic free radicals plays a pivotal role in the early molecular cascades of blood-brain barrier (BBB) disruption mediated by matrix metalloproteinases (MMPs) activation in ischemic stroke. Theoretically, it is expected that early blockade of activation of MMPs may provide protective effects from secondary neural tissue damage. The present study was designed to determine the ability of melatonin to influence MMP-9 activity and BBB disruption, in a focal ischemia rat model induced by photothrombosis. METHODS: Adult, male, 8-week Sprague-Dawley rats weighing 230-300 g received focal cerebral ischemia by photothrombosis using Rose Bengal (RB). The injured animals were divided into two groups. One group received 50mg/kg of melatonin intraperitoneally, starting 1h after injury and at 12h intervals for 3 days. The control group received weight-adjusted doses of saline vehicle. In each group, MMP-9 expression and activity were assessed by Western blot and gelatin zymography, respectively, at various times. The effects of melatonin on BBB disruption and brain edema were also determined. RESULTS: MMP-9 activity and expression were significantly elevated at 24h in the ischemic cortex, which remained up-regulated at least until 72 h after injury. Melatonin treatment significantly attenuated MMP-9 activity and expression at 24, 48, and 72 h after ischemic injury. Relative to control group, BBB permeability was significantly reduced in the melatonin-treated group. The water content was decreased by melatonin treatment, although there was no statistically significant difference. CONCLUSIONS: Melatonin treatment starting 1h after injury attenuated BBB disruption during focal ischemia, which is at least partly due to inhibition of MMP-9 activity. Melatonin might have a potential role in clinical trials aimed to improve the outcome of patients suffering cerebral ischemia.

[Effects of rhubarb aglycone combined with thrombolysis on brain microvascular basement membrane impairment in rats with thrombus-occluded cerebral ischemia].

OBJECTIVE: To explore the protective effects of rhubarb aglycone combined with urokinase (UK) thrombolysis on brain microvascular basement membrane impairment in rats with thrombus-occluded cerebral ischemia by regulating the expression of IgG, CoLIV and LN in rats brain, by which the level of injury of brain microvascular basement membrane could be detected. METHOD: Rats were randomly divided into sham-operated, model, thrombolysis, rhubarb aglycone and combination (rhubarb aglycone combined with thrombolysis) groups. Moreover, rats in model, thrombolysis, rhubarb aglycone and combination groups were randomly divided into 3, 6, and 9 h groups respectively. Model of thrombus-occluded cerebral ischemia was duplicated by using the combination of rats' auto-thrombus with inserting the nylon thread. Rats were administrated with thrombolysis therapy through artery at 3, 6, and 9 h after cerebral ischemia. At 24 h of administration through artery, intracranial hemorrhage ratio (ICHR) and mortality of rats were observed, and then the brain of rats was taken. In the study, expression of IgG, CoLIV and LN in rats brain were measured. RESULT: Thrombolysis at 9 h of cerebral ischemia made rats mortality and BHR increase, administration of combined therapy could make them decrease. Expression of IgG level in rats brain of 9 h and 6 h model groups increased, while CoLIV and LN expression decreased significantly. In each administration 9 h group, IgG level was lower, and CoLIV and LN were higher, such changes appeared significantly in rhubarb aglycone and association groups. CONCLUSION: Brain microvascular basement membrane impairment could be caused by the therapy of delayed thrombolysis, which made the mortality and BHR increase. Rhubarb aglycone combined with the therapy of thrombolysis could perform the protective effects on brain microvascular basement membrane and then decrease the ICHR and mortality caused by thrombolysis after cerebral ischemia.

Deep cerebral vein thrombosis associated with iron deficiency anaemia in adults.

Cerebral venous thrombosis (CVT) is rare and has a wide spectrum of symptoms, therefore it is difficult to diagnose. Thrombosis of the deep cerebral veins occurs very rarely: it has been reported that approximately 6% of patients with CVT have deep CVT, and the prognosis for patients with this condition is poor. CVT has been reported in association with dehydration, a hypercoagulable state, mastoiditis, tumour invasion of a venous sinus, use of oral contraceptives, pregnancy, puerperium, head trauma, vasculitis, and intracranial and systemic infections. However, in the literature, there are few reported cases of CVT in association with iron deficiency anaemia, especially in adults. We present here two patients with bilateral thalamic and basal ganglionic lesions due to thrombosis of the deep cerebral veins. Both of our patients had severe hypochromic microcytic anaemia due to iron deficiency, and both had a good prognosis after 2 months.

Fibrinolytic treatment for acute ischaemic stroke.

Ischaemic stroke is a leading cause of death and disability in the US. At present, intravenous administration of tissue plasminogen activator within 3 h of symptom onset is the only proven effective treatment for patients with acute ischaemic stroke. Unfortunately, most treated patients do not make a functional recovery and very few patients presenting with acute stroke qualify for intravenous tissue plasminogen activator therapy. The focus of current research is to extend the therapeutic window for intervention beyond 3 h, and to improve the outcome of treated patients. The purpose of the present paper is to describe the current state of affairs for intravenous plasminogen activators, and to review recently published research. Agents and strategies under investigation include the intra-arterial delivery of plasminogen activators or antiplatelet agents, as well as combined intravenous/intra-arterial protocols.

Systemic hemostasis with recombinant-activated factor VII followed by local thrombolysis with recombinant tissue plasminogen activator in intraventricular hemorrhage.

INTRODUCTION: A 51-year-old woman on warfarin thromboprophylaxis for transient ischemic attacks developed sudden onset nausea, vomiting, and decreased mental status, rapidly becoming comatose. Head computed tomography (CT) showed intracerebral hemorrhage, extending into all ventricular chambers, and acute obstructive hematocephalus requiring urgent ventricular drainage. CT angiogram showed no evidence of an aneurysm or vascular malformation. METHODS: The pretreatment international normalized ratio (INR) of 4.9 was rapidly corrected with recombinant activated factor VII and an external ventricular drain was placed. Despite accurate positioning, the ventriculostomy thrombosed and became nonfunctional. Recombinant tissue plasminogen activator was given intraventricularly and resulted in partial ventricular decompression within 24 hours, with dramatic improvement in the patient's level of consciousness. RESULTS: Repeated intraventricular fibrinolysis resulted in further reduction of the intraventricular hematoma within a few days and a good patient outcome. The patient did not require permanent ventricular shunt. CONCLUSION: To our knowledge, this is the first reported case of combined systemic enhancement of hemostasis and local fibrinolysis as a life-saving measure in intracranial hemorrhage.