RESUMEN
BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke. Acquired and inherited prothrombotic conditions are the most common risk factors for CVST. Sometimes, an etiology is not found. Wide utilization of next generation sequencing technologies in clinical practice may lead to identification of risk factors other than those classically associated with CVST. METHOD AND RESULTS: This retrospective clinical-laboratory observational study has a reference patient who presented with CVST as an adolescent. Work up for prothrombotic conditions showed high homocysteine level secondary to homozygosity for a common polymorphism, c.677 C > T in the methylenetetrahydrofolate reductase (MTHFR) gene. His older unaffected brother has a similar MTHFR genotype and high homocysteine. The whole exome sequencing revealed a likely pathogenic variant in the sodium voltage gated channel, alpha subunit 1(SCN1A) gene. CONCLUSION: CVST is a multifactorial disease. Prothrombotic conditions are the most common risk factors for CVST. High homocysteine due to the common MTHFR polymorphisms was previously attributed to various thrombotic conditions including CVST. Although high homocysteine due to MTHFR polymorphism may be a contributing factor, additional risk factors such as blood flow abnormalities during SCN1A related seizures may be needed for thrombosis.
Asunto(s)
Metilenotetrahidrofolato Reductasa (NADPH2) , Canal de Sodio Activado por Voltaje NAV1.1 , Trombosis de los Senos Intracraneales , Humanos , Trombosis de los Senos Intracraneales/genética , Masculino , Canal de Sodio Activado por Voltaje NAV1.1/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Adolescente , Estudios Retrospectivos , Predisposición Genética a la Enfermedad , Factores de Riesgo , Homocisteína/sangre , Secuenciación del Exoma/métodos , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
ABSTRACT: Cerebral venous sinus thrombosis (CVST) is an uncommon venous thromboembolic event accounting for <1% of strokes resulting in brain parenchymal injuries. JAK2V617F mutation, the most frequent driving mutation of myeloproliferative neoplasms, has been reported to be associated with worse clinical outcomes in patients with CVST. We investigated whether hematopoietic JAK2V617F expression predisposes to specific pathophysiological processes and/or worse prognosis after CVST. Using an in vivo mouse model of CVST, we analyzed clinical, biological, and imaging outcomes in mice with hematopoietic-restricted Jak2V617F expression, compared with wild-type Jak2 mice. In parallel, we studied a human cohort of JAK2V617F-positive or -negative CVST. Early after CVST, mice with hematopoietic Jak2V617F expression had increased adhesion of platelets and neutrophils in cerebral veins located in the vicinity of CVST. On day 1, Jak2V617F mice had a worse outcome characterized by significantly more frequent and severe intracranial hemorrhages (ICHs) and higher mortality rates. Peripheral neutrophil activation was enhanced, as indicated by higher circulating platelet-neutrophil aggregates, upregulated CD11b expression, and higher myeloperoxydase plasma level. Concurrently, immunohistological and brain homogenate analysis showed higher neutrophil infiltration and increased blood-brain barrier disruption. Similarly, patients with JAK2V617F-positive CVST tended to present higher thrombotic burden and had significantly higher systemic immune-inflammation index, a systemic thromboinflammatory marker, than patients who were JAK2V617F-negative. In mice with CVST, our study corroborates that Jak2V617F mutation leads to a specific pattern including increased thrombotic burden, ICH, and mortality. The exacerbated thromboinflammatory response, observed both in mice and patients positive for JAK2V617F, could contribute to hemorrhagic complications.
Asunto(s)
Inflamación , Janus Quinasa 2 , Mutación , Trombosis de los Senos Intracraneales , Animales , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Ratones , Trombosis de los Senos Intracraneales/genética , Humanos , Pronóstico , Inflamación/genética , Modelos Animales de Enfermedad , Masculino , Femenino , Neutrófilos/metabolismoRESUMEN
BACKGROUND: Cerebral venous sinus thrombosis (CVST) is typically associated with a prothrombotic state of the blood, with its causative factors varying widely. Prior research has not reported the simultaneous occurrence of CVST and dural arteriovenous fistulas (DAVFs) as potentially resulting from genetic mutations. In this case report, we introduce a unique occurrence wherein a patient with a heterozygous mutation of the low-density lipoprotein receptor (LDLR) gene presented with CVST in conjunction with DAVFs. CASE: Presentation: A male patient, aged 51, sought treatment at our facility due to a consistent decline in cognitive functions accompanied by recurrent headaches. Comprehensive evaluations were administered, including neurological examinations, laboratory tests, magnetic resonance imaging, digital subtraction angiography, and whole exome sequencing. Digital subtraction angiography identified DAVFs in the patient's right sigmoid sinus and an occlusion within the left transverse sinus. The whole exome sequencing of blood samples pinpointed a heterozygous mutation in the LDLR gene (NM_000527:exon12:c.C1747T:p.H583Y). Following the confirmed diagnosis of CVST and DAVFs, the patient underwent anticoagulant therapy combined with endovascular procedures - these comprised embolization of the arteriovenous fistula in the right sigmoid sinus and balloon dilation with stent implantation in the left transverse sinus. A six-month follow-up indicated a significant abatement in the patient's symptoms. CONCLUSIONS: This report marks the first documented case of an LDLR gene mutation that could be associated with the onset of CVST and DAVFs. The mutation in the LDLR gene might foster a prothrombotic environment, facilitating the gradual emergence of CVST and the subsequent genesis of DAVFs.
Asunto(s)
Malformaciones Vasculares del Sistema Nervioso Central , Embolización Terapéutica , Trombosis de los Senos Intracraneales , Humanos , Masculino , Malformaciones Vasculares del Sistema Nervioso Central/complicaciones , Malformaciones Vasculares del Sistema Nervioso Central/diagnóstico por imagen , Malformaciones Vasculares del Sistema Nervioso Central/genética , Angiografía Cerebral , Senos Craneales , Embolización Terapéutica/métodos , Trombosis de los Senos Intracraneales/complicaciones , Trombosis de los Senos Intracraneales/diagnóstico por imagen , Trombosis de los Senos Intracraneales/genética , Persona de Mediana EdadRESUMEN
BACKGROUND: Dural venous sinus thrombosis (DVST) is an important cause of papilledema. Patients diagnosed with DVST should undergo work-up for underlying hypercoagulable state, including genetic causes. One important prothrombotic mutation is in the JAK2 gene, which is a driver of myeloproliferative neoplasms including polycythemia vera (PV). We aimed to determine the prevalence of JAK2 mutation in patients in presenting to neuro-ophthalmology clinic with DVST and papilledema. METHODS: Retrospective case series of patients seen in a tertiary neuro-ophthalmology practice who presented with papilledema due to DVST and were investigated for presence of JAK2 mutation. RESULTS: Four out of 15 patients with DVST (26%) were found to have JAK2 V617F mutation which led to subsequent diagnosis of PV in 2. One additional patient had a known diagnosis of essential thrombocytosis. We describe the clinical presentation of these four patients with papilledema and JAK2 mutation. CONCLUSIONS: A significant proportion of patients with papilledema secondary to DVST will harbor mutations in the JAK2 gene. Clinicians should be aware of this mutation as early testing will facilitate timely diagnosis and treatment of myeloproliferative disease to improve prognosis and reduce risk of recurrent thrombotic events.
Asunto(s)
Trastornos Mieloproliferativos , Papiledema , Policitemia Vera , Trombosis de los Senos Intracraneales , Humanos , Estudios Retrospectivos , Papiledema/genética , Janus Quinasa 2/genética , Policitemia Vera/diagnóstico , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/genética , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/genética , Mutación/genética , Trombosis de los Senos Intracraneales/diagnóstico por imagen , Trombosis de los Senos Intracraneales/genética , Trombosis de los Senos Intracraneales/complicacionesAsunto(s)
Policitemia Vera , Trombosis de los Senos Intracraneales , Trombocitemia Esencial , Humanos , Janus Quinasa 2/genética , Mutación , Policitemia Vera/complicaciones , Policitemia Vera/genética , Trombosis de los Senos Intracraneales/diagnóstico por imagen , Trombosis de los Senos Intracraneales/genéticaAsunto(s)
Deficiencia de Antitrombina III/genética , Antitrombina III/genética , Variación Genética/genética , Trombosis de los Senos Intracraneales/genética , Deficiencia de Antitrombina III/complicaciones , Deficiencia de Antitrombina III/diagnóstico por imagen , Niño , Humanos , Masculino , Linaje , Trombosis de los Senos Intracraneales/complicaciones , Trombosis de los Senos Intracraneales/diagnóstico por imagenAsunto(s)
ADN/genética , Janus Quinasa 2/genética , Mutación , Nervio Óptico/patología , Papiledema/etiología , Trombosis de los Senos Intracraneales/complicaciones , Análisis Mutacional de ADN , Humanos , Janus Quinasa 2/metabolismo , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Papiledema/diagnóstico , Papiledema/fisiopatología , Trombosis de los Senos Intracraneales/diagnóstico , Trombosis de los Senos Intracraneales/genética , Campos Visuales/fisiologíaRESUMEN
Cerebral venous sinus thrombosis (CVST) is more common in women than in men, possibly due to gender-specific risk factors in young adults. The purpose of this study was to investigate whether the clinical and radiological findings, other risk factors, and clinical course of CVST associated with pregnancy and puerperium differ from those of other CVST cases. We retrospectively reviewed patients diagnosed with CVST in our hospital between September 2007 and December 2019. The risk factors, clinical and radiological characteristics, and follow-up data for female patients with CVST were compared between cases associated with pregnancy and puerperium with those of other cases. A total of 50 female patients with CVST were included in the study. Twenty-four (48%) cases occurred during pregnancy and puerperium. The mean age of the pregnant or puerperal patients was lower than that of the other patients (p = 0.007). There was no significant difference between the groups in terms of clinical and neuroradiological findings or presence of any additional risk factors including hereditary thrombophilia. There was also no difference in terms of in-hospital mortality rates and modified Rankin Scale (mRS) scores at 6 months between the groups. The clinical presentation of CVST and the frequencies of the presence of other risk factors including genetic thrombophilia in pregnant and puerperal patients were similar to those of non-pregnant female patients. Screening for additional risk factors, especially genetic thrombophilia, should therefore not be neglected in CVST occurring during pregnancy and puerperium.
Asunto(s)
Senos Craneales/diagnóstico por imagen , Periodo Posparto/fisiología , Complicaciones del Embarazo/diagnóstico por imagen , Trombosis de los Senos Intracraneales/diagnóstico por imagen , Adulto , Senos Craneales/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Embarazo , Complicaciones del Embarazo/genética , Complicaciones del Embarazo/fisiopatología , Estudios Retrospectivos , Trombosis de los Senos Intracraneales/genética , Trombosis de los Senos Intracraneales/fisiopatologíaRESUMEN
OBJECTIVE: To analyse the frequency and characteristics of the Janus kinase 2 (JAK2) V617F mutation in patients with cerebral venous sinus thrombosis (CVST) with thrombocytosis. METHODS: The study enrolled CVST patients with thrombocytosis that had undergone JAK2 V617F mutation detection to determine the frequency of the JAK2 V617F mutation in this cohort. Correlations between patient demographics, whole blood cell counts, targeted sequencing results and JAK2 V617F mutation status were determined. RESULTS: A total of 23 patients were enrolled in the study: 11 (47.8%) with the JAK2 V617F mutation and 12 (52.2%) without the JAK2 V617F mutation. The mean platelet count was significantly higher in patients with the JAK2 V617F mutation than in patients without the mutation (478.1 ± 107.4 × 109/l versus 374.4 ± 54.1 × 109/l, respectively). There were no significant differences in age, sex, white blood cell count or haemoglobin level between the two groups. Other than single nucleotide polymorphisms, no hot-spot mutations associated with myeloid tumours other than the JAK2 V617F mutation were detected in four CVST patients that underwent targeted sequencing. CONCLUSION: The JAK2 V617F mutation was frequently detected in CVST patients with thrombocytosis and it was associated with higher platelet counts.
Asunto(s)
Janus Quinasa 2 , Trastornos Mieloproliferativos , Trombosis de los Senos Intracraneales , Trombocitosis , Humanos , Janus Quinasa 2/genética , Mutación , Trombosis de los Senos Intracraneales/diagnóstico por imagen , Trombosis de los Senos Intracraneales/genética , Trombocitosis/complicaciones , Trombocitosis/genéticaRESUMEN
Cerebral venous sinus thrombosis (CVST) combined with intracerebral hemorrhage(ICH) is a special subgroup, and whether intrasinus thrombolysis (IST) or mechanical thrombectomy (MT) therapy should be carried out is controversial because of previous hemorrhage and possible delayed hemorrhage.The aim of this study was to analyze the safety and effectiveness of endovascular treatment of CVST with ICH and further discuss the treatment strategy. This is a retrospective study of 56 cases admitted from January 2010 to June 2019 diagnosed with CVST combined with ICH, and all were treated with endovascular treatment including IST with or without MT. We reviewed the clinical, radiological, and outcome data of all patients. The percentage of cases that showed complete and partial recanalization were 67.8% and 26.9% after endovascular treatment. ICH exacerbation occurred in 5 cases during thrombolysis. The percentage of cases with good outcome was 87.5% at discharge. 51 cases were followed up at sixth month. 49 cases had a mRS score of 0-2,and 2 cases had a mRS score of 3-4 at sixth month.Our data suggest that endovascular treatment may improve clinical and radiological outcome in most patients of CVST with ICH, but confirmation in prospective, controlled studies is warranted.
Asunto(s)
Hemorragia Cerebral/terapia , Trombolisis Mecánica/métodos , Trombosis de los Senos Intracraneales/terapia , Trombectomía/métodos , Terapia Trombolítica/métodos , Adolescente , Adulto , Hemorragia Cerebral/diagnóstico por imagen , Terapia Combinada , Femenino , Fibrinolíticos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Trombosis de los Senos Intracraneales/diagnóstico por imagen , Trombosis de los Senos Intracraneales/genética , Trombosis de los Senos Intracraneales/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
The plasminogen activator inhibitor-1 (PAI-1) 4G/4G homozygous genotype represents a genetic thrombophilia that has been associated with enhanced risk of arterial and venous thrombotic events. The optimal anticoagulation strategy for PAI-1 4G homozygous patients is unclear. Herein we present a case of a patient with PAI-1 4G/4G homozygosity who was placed on dabigatran after developing cerebral venous sinus thrombosis (CVST), but who then suffered an acute myocardial infarction several weeks later. We seek to highlight the relationship between the PAI-1 4G/4G genotype and risk of CVST, as well as discuss our management strategy in the aftermath of dabigatran failure.
Asunto(s)
Hemostasis/genética , Homocigoto , Infarto del Miocardio/genética , Inhibidor 1 de Activador Plasminogénico/genética , Trombosis de los Senos Intracraneales/genética , Adulto , Anticoagulantes/uso terapéutico , Antitrombinas/uso terapéutico , Dabigatrán/uso terapéutico , Sustitución de Medicamentos , Predisposición Genética a la Enfermedad , Hemostasis/efectos de los fármacos , Heparina/uso terapéutico , Humanos , Masculino , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/tratamiento farmacológico , Fenotipo , Trombosis de los Senos Intracraneales/diagnóstico por imagen , Trombosis de los Senos Intracraneales/tratamiento farmacológico , Factores de Tiempo , Insuficiencia del Tratamiento , Warfarina/uso terapéuticoRESUMEN
We report on a 14-year-old girl presenting with an acute headache syndrome that developed after intake of contraceptive drug. Laboratory values showed a homozygous mutation of factor V Leiden and we treated her initially with heparin, then with coumadin. There were no complications during the course of treatment. Interestingly, the initial headache responded well to therapy with sumatriptan, so it is assumed as a first manifestaion of migraine and this delayed the actually diagnosis. Imaging studies showed extensive cerebral venous sinus thrombosis. However, the patient had no focal deficits.
Asunto(s)
Trombosis de los Senos Intracraneales , Adolescente , Diagnóstico Tardío , Factor V/genética , Femenino , Heparina/uso terapéutico , Humanos , Trastornos Migrañosos/diagnóstico , Mutación , Trombosis de los Senos Intracraneales/diagnóstico , Trombosis de los Senos Intracraneales/tratamiento farmacológico , Trombosis de los Senos Intracraneales/genética , Sumatriptán/uso terapéutico , Warfarina/uso terapéuticoAsunto(s)
Eliminación de Gen , Trombosis Intracraneal/genética , Deficiencia de Proteína C/genética , Proteína C/genética , Trombosis de los Senos Intracraneales/genética , Bioensayo , Niño , Humanos , Trombosis Intracraneal/metabolismo , Trombosis Intracraneal/patología , Masculino , Pronóstico , Proteína C/metabolismo , Deficiencia de Proteína C/metabolismo , Deficiencia de Proteína C/patología , Análisis de Secuencia de ADN , Trombosis de los Senos Intracraneales/metabolismo , Trombosis de los Senos Intracraneales/patologíaRESUMEN
Essentials Sinus thrombosis may play a crucial role in development of dural arteriovenous fistula (DAVF). Little is known about the association between gene polymorphism and the development of DAVF. MMP-2-1306 C/T showed a higher prevalence rate in DAVF cases with sinus thrombosis. MMP-2-1306C/T polymorphism is likely a potential risk factor for sinus thrombosis in DAVF. SUMMARY: Background Dural arteriovenous fistula (DAVF) is a rare but important cerebrovascular disorder in adults. Little is known about the molecular genetic pathogenesis underlying DAVF development. Objectives To investigate the associations of gene polymorphisms and DAVF. Materials and Methods By the use of real-time PCR genotyping, seven single-nucleotide polymorphisms (SNPs) of angiogenesis-related genes were analyzed in 72 DAVF patients. Pertinent clinical and imaging data were subgrouped on the basis of location (cavernous sinus versus lateral sinus), lesions (single versus multiple), cerebral venous reflux (CVR) grading (Borden I versus Borden II/III), and sinus thrombosis (with versus without). Results We found that individuals carrying the polymorphic allele of matrix metalloproteinase (MMP)-2-1306 C/T (rs243865) had a significantly increased risk of sinus thrombosis in DAVF (odds ratio 6.2; 95% confidence interval 1.7-22.9). There was a weak difference in associations of tissue inhibitor of metalloproteinase (TIMP)-2 (rs2277698) gene polymorphism and DAVF patients subgrouped by CVR grading. Conclusions These preliminary results indicate that MMP-2-1306 C/T, but not MMP-9, TIMP-1, TIMP-2, and vascular endothelial growth factor A SNP variants, is a risk factor for the development of sinus thrombosis in DAVF patients.
Asunto(s)
Malformaciones Vasculares del Sistema Nervioso Central/genética , Metaloproteinasa 2 de la Matriz/genética , Polimorfismo de Nucleótido Simple , Trombosis de los Senos Intracraneales/genética , Anciano , Angiografía de Substracción Digital , Malformaciones Vasculares del Sistema Nervioso Central/diagnóstico por imagen , Malformaciones Vasculares del Sistema Nervioso Central/enzimología , Angiografía Cerebral/métodos , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fenotipo , Medición de Riesgo , Factores de Riesgo , Trombosis de los Senos Intracraneales/diagnóstico por imagen , Trombosis de los Senos Intracraneales/enzimologíaRESUMEN
Turan Ö, Anuk-Ince D, Olcay L, Sezer T, Gülleroglu K, Yilmaz-Çelik Z, Ecevit A. Neonatal cerebral sinovenous thrombosis: Two cases, two different gene polymorphisms and risk factors. Turk J Pediatr 2017; 59: 71-75. Cerebral sinovenous thrombosis (CSVT) is a rare disease in the neonatal period and also the greatest risk of neonatal mortality and morbidity. In this report, we presented two cases with CSVT and different risk factors. One of these cases had methylenetetrahydrofolate reductase (MTHFR) C677T homozygous polymorphism and the other case had both MTHFR A1298C homozygous polymorphism, plasminogen activator inhibitor-1 (PAI-1) 4G/ 5G polymorphism and elevated lipoprotein a. Early diagnosis and prompt initiation of therapy of neonatal CSVT may prevent neonatal mortality and poor long-term neurodevelopmental outcomes.
Asunto(s)
Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Inhibidor 1 de Activador Plasminogénico/genética , Trombosis de los Senos Intracraneales/genética , Femenino , Heparina de Bajo-Peso-Molecular/uso terapéutico , Homocigoto , Humanos , Recién Nacido , Masculino , Polimorfismo Genético , Factores de Riesgo , Trombosis de los Senos Intracraneales/tratamiento farmacológico , Trombosis de los Senos Intracraneales/etiologíaRESUMEN
The prevalence of protein S (PS) deficiency in Asian patients with venous thromboembolism is around 8-30%, higher than that in Caucasian populations. The present study reports the genotypes (including one novel mutation) and phenotypes of children with PS deficiency at a tertiary care institute. A total of six patients were included, three with arterial ischemic stroke, two with cerebral venous sinus thrombosis, and one with deep vein thrombosis. PS mutations were identified in four patients: p.R355C, p.G336D, p.E67A, and p.N188KfsX9. p.N188KfsX9 is a novel mutation with less than 20% PS activity noted in heterozygotes.