Prothrombogenic polymorphic variants of hemostatic and folate metabolism genes In patients with aseptic cerebral venous thrombosis

Cerebral venous sinus thrombosis (CVT) becomes the cause of stroke in less than 1% of patients. In 20-30% of patients, the cause of thrombosis remains unclear, and thrombosis is considered idiopathic. Inherited hypercoagulable conditions significantly increase the risk of CVT. The aim of the study was to evaluate the frequency of prothrombogenic polymorphic variants of hemostatic and methionine-homocysteine metabolism genes alleles and genotypes in patients with aseptic CVT. Fifty one patients aged 18–75 with aseptic CVT were examined. The control group included 36 healthy volunteers. Neuroimaging methods included brain MRI in standard modes (T1, T2, T2 d-f (FLAIR), DWI) and MR venosinusography. All patients were surveyed to identify carriers of prothrombogenic polymorphic variants of hemostatic and folate metabolism genes alleles and genotypes. Prothrombogenic polymorphic variants of hemostatic genes were detected in 94% of patients, and the variants of the methionine-homocysteine metabolism genes were observed in 86% of patients. The differences between distributions of alleles and genotypes 5G6754G of the PAI-1 gene, G103T of the FXIIIA1 gene, A66G of the MTRR gene, A2756G of the MTR gene in the group of patients with CVT and in the control group were significant. Allele 4G, genotypes 4G/4G and 5G/4G of 5G6754G polymorphism of the PAI-1 gene; allele T of G103Т polymorphism of the FXIIIA1 gene; allele G and genotype A/G of A66G polymorphism of the MTRR gene; allele G and genotype A/G of A2756G polymorphism of the MTR gene correlated with aseptic CVT. It was concluded that the gene polymorphisms 5G6754G (PAI-1), G103T (FXIIIA1), A66G (MTRR) and A2756G (MTR) carriage increased the risk of aseptic CVT and did not affect the thrombosis clinical manifestations.

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Brain MRI-findings in Ph - negative myeloproliferative disorders

Terapevticheskii arkhiv ◽

10.26442/00403660.2019.07.000329 ◽

2019 ◽

Vol 91 (7) ◽

pp. 29-34 ◽

Cited By ~ 2

Author(s):

M M Tanashyan ◽

A L Melikyan ◽

P I Kuznetsova ◽

A A Raskurazhev ◽

A A Shabalina ◽

...

Keyword(s):

Cerebrovascular Disease ◽

Sinus Thrombosis ◽

Cerebral Arteries ◽

Brain Mri ◽

Myeloproliferative Disorders ◽

Cerebral Venous Sinus Thrombosis ◽

Mri Findings ◽

Cerebral Lesions ◽

Cerebrovascular Pathology ◽

Underlying Mechanisms

Myeloproliferative disorders (MPD) are accompanied by a high proportion of thrombotic complications, which may lead to cerebrovascular disease (CVD). Aim. To describe MRI-findings in patients with Ph - negative MPD and evaluate any cerebrovascular disease. Materials and methods. We included 104 patients with Ph - negative MPD (age varied between 20 and 58) with clinical correlates of cerebrovascular pathology. Results. Brain MRI showed post - stroke lesions in 20% of patients (7 hemispheric infarcts due to thrombotic occlusion of one of the large cerebral arteries, 14 - cortical infarcts). 37 patients (36%) had vascular cerebral lesions. Cerebral venous sinus thrombosis occurred in 5 patients - in 7% (n=3) of patients with polycythemia vera and 5% (n=2) - in patients with essential thrombocythemia. The incidence of vascular cerebral lesions was associated with higher levels of the following: erythrocyte, platelet count, fibrinogen, and with the decrease in fibrinolytic activity, as well. Conclusion. The pioneering results of the study include the description and analysis of brain MRI-findings in patients with Ph - negative MPD. The underlying mechanisms of cerebrovascular pathology in these patients are associated with certain blood alterations (particularly, hemorheology) which present a major risk factor.

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Pulmonary involvements in systemic juvenile arthritis

10.21203/rs.3.rs-33776/v1 ◽

2020 ◽

Author(s):

Tingyan He ◽

Jiayun Ling ◽

Jun Yang

Keyword(s):

Sinus Thrombosis ◽

Drug Hypersensitivity ◽

Systemic Juvenile Idiopathic Arthritis ◽

Clinical Manifestations ◽

Cerebral Venous Sinus Thrombosis ◽

Chronic Inflammatory Disease ◽

Serum Cytokine ◽

Radiological Features ◽

Cytokine Levels ◽

To Receive

Abstract Background Systemic juvenile idiopathic arthritis (sJIA) is a chronic inflammatory disease of childhood. Pulmonary involvements in sJIA have been recently described. Herein, we assess unusual clinical and radiological features of patients with sJIA, and possible risk factors for pulmonary involvements in sJIA. Methods A total of thirty-nine patients with sJIA were retrospectively enrolled. Data extracted included demographics, medical history, clinical manifestations, laboratory results, serum cytokine levels, radiological findings, management, and prognosis. Results Macrophage activation syndrome (MAS) had been observed at the initial diagnosis or during disease flares in eleven patients (11/39, 28%). Cerebral venous sinus thrombosis was observed in one patient with paroxysmal headache during the MAS phase. Twenty-three patients demonstrated abnormal radiological features on chest Computed Tomography (CT). Only eleven patients had subtle respiratory symptoms with normal oxygen saturation. Eight patients had lung disease (LD) before biologic exposure. sJIA-LD occurred in another six patients after the introduction of tocilizumab. All these patients continued to receive tocilizumab therapy, and sJIA-LD was improved in twelve patients with complete resolution of pulmonary presentations, and partially relieved in two patients. Only one of the two patients with possible anaphylaxis to tocilizumab presented with LD. Severe sJIA-LD was found in two patients with trisomy 21 and Kabuki syndrome, respectively. Conclusions Pulmonary involvements are increasingly observed in children with sJIA. Possible high risks for sJIA-LD include the occurrence of MAS, some inherited diseases, and evidence of drug hypersensitivity. It is still a question of whether IL-1/IL-6 inhibitor exposure increases the risk of sJIA-LD. Vasculitis and thrombosis should be considered in sJIA during the MAS phase, particularly in patients with pulmonary involvements. Trial registration: Not applicable; this was a retrospective study.

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COVID-19 and cerebrovascular diseases: a comprehensive overview

Therapeutic Advances in Neurological Disorders ◽

10.1177/1756286420978004 ◽

2020 ◽

Vol 13 ◽

pp. 175628642097800

Author(s):

Georgios Tsivgoulis ◽

Lina Palaiodimou ◽

Ramin Zand ◽

Vasileios Arsenios Lioutas ◽

Christos Krogias ◽

...

Keyword(s):

Cerebrovascular Disease ◽

Clinical Laboratory ◽

Sinus Thrombosis ◽

Case Reports ◽

Cardiac Injury ◽

Clinical Manifestations ◽

Relevant Information ◽

Cerebral Venous Sinus Thrombosis ◽

Stroke Patients ◽

Comprehensive Overview

Neurological manifestations are not uncommon during infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A clear association has been reported between cerebrovascular disease and coronavirus disease 2019 (COVID-19). However, whether this association is causal or incidental is still unknown. In this narrative review, we sought to present the possible pathophysiological mechanisms linking COVID-19 and cerebrovascular disease, describe the stroke syndromes and their prognosis and discuss several clinical, radiological, and laboratory characteristics that may aid in the prompt recognition of cerebrovascular disease during COVID-19. A systematic literature search was conducted, and relevant information was abstracted. Angiotensin-converting enzyme-2 receptor dysregulation, uncontrollable immune reaction and inflammation, coagulopathy, COVID-19-associated cardiac injury with subsequent cardio-embolism, complications due to critical illness and prolonged hospitalization can all contribute as potential etiopathogenic mechanisms leading to diverse cerebrovascular clinical manifestations. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been described in case reports and cohorts of COVID-19 patients with a prevalence ranging between 0.5% and 5%. SARS-CoV-2-positive stroke patients have higher mortality rates, worse functional outcomes at discharge and longer duration of hospitalization as compared with SARS-CoV-2-negative stroke patients in different cohort studies. Specific demographic, clinical, laboratory and radiological characteristics may be used as ‘red flags’ to alarm clinicians in recognizing COVID-19-related stroke.

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Cerebral Venous Sinus Thrombosis Associated with COVID-19: A Case Series and Literature Review

10.21203/rs.3.rs-115097/v1 ◽

2020 ◽

Author(s):

Vahid Reza Ostovan ◽

Razieh Foroughi ◽

Mahtab Rostami ◽

Mostafa Almasi-Dooghaee ◽

Manouchehr Esmaili ◽

...

Keyword(s):

Sinus Thrombosis ◽

Clinical Manifestations ◽

Case Series ◽

Cerebral Venous Sinus Thrombosis ◽

Hemorrhagic Transformation ◽

Venous Sinus ◽

Teaching Hospitals ◽

Venous Sinus Thrombosis ◽

North West ◽

Confirmatory Tests

Abstract Background: Since the COVID-19 pandemic, several cases of cerebral venous sinus thrombosis (CVST) have been reported in SARS-CoV-2 infected individuals. This study provides a series of patients with CVST and SARS-CoV-2 infection.Methods: Consecutive patients with documented SARS-CoV-2 infection, as well as clinical and radiological characteristics of CVST, were reported from three teaching hospitals in the South West, North West, and the center of Iran from June to July 2020. We also searched the abstract archives until the end of August 2020 and gathered 28 reported cases. The diagnostic criteria for SARS-CoV-2 infection were determined according to SARS-CoV-2 detection in oropharyngeal or nasopharyngeal samples in clinically suspected patients. Demographics, main COVID-19 symptoms, confirmatory tests for SARS-CoV-2 infection diagnosis, the interval between the diagnosis of SARS-CoV-2 infection and CVST, clinical and radiological features of CVST, therapeutic strategies, CVST outcomes, rate of hemorrhagic transformation, and mortality rate were investigated.Results: Six patients (aged 31 to 62 years old) with confirmed CVST and SARS-CoV-2 infection were admitted to our centers. Four patients had no respiratory symptoms of SARS-CoV-2 infection. Five out of six patients developed the clinical manifestations of CVST and SARS-CoV-2 infection simultaneously. Three patients had known predisposing factors for CVST. Despite receiving CVST and SARS-CoV-2 infection treatments, four out of six patients passed away.Conclusions: The role of SARS-CoV-2 as a “cause” versus an “additive contributor” remains to be elucidated. Practitioners should be aware of the possibility of CVST in SARS-CoV-2 infection.

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Prothrombotic immune thrombocytopenia after COVID-19 vaccine

Blood ◽

10.1182/blood.2021011958 ◽

2021 ◽

Author(s):

Andreas Tiede ◽

Ulrich J Sachs ◽

Andreas Czwalinna ◽

Sonja Werwitzke ◽

Rolf Bikker ◽

...

Keyword(s):

Healthy Donor ◽

Immune Thrombocytopenia ◽

Sinus Thrombosis ◽

Clinical Manifestations ◽

Cerebral Venous Sinus Thrombosis ◽

Dependent Manner ◽

Thromboembolic Events ◽

Platelet Factor ◽

Vein Thrombosis ◽

Heparin Anticoagulation

We report five cases of prothrombotic immune thrombocytopenia after exposure to the ChAdOx1 vaccine (AZD1222, Vaxzevria) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients presented 5 to 11 days after first vaccination. The spectrum of clinical manifestations included cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), arterial cerebral thromboembolism, and thrombotic microangiopathy (TMA). All patients had thrombocytopenia and markedly elevated D-Dimer. Autoantibodies against platelet factor 4 (PF4) were detected in all patients although they had never been exposed to heparin. Immunoglobulin from patient sera bound to healthy donor platelets in an AZD1222-dependant manner, suppressed by heparin. Aggregation of healthy donor platelets by patient sera was demonstrated in the presence of buffer or AZD1222 and was also suppressed by heparin. Anticoagulation alone or in combination with eculizumab or intravenous immunoglobulin (IVIG) resolved the pathology in three patients. Two patients had thromboembolic events despite anticoagulation at a time when platelets were increasing after IVIG. In summary, an unexpected autoimmune prothrombotic disorder is described after vaccination with AZD1222. It is characterized by thrombocytopenia and anti-PF4 antibodies binding to platelets in AZD1222-dependent manner. Initial clinical experience suggests a risk of unusual and severe thromboembolic events.

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Potential value of the calibrated automated thrombogram in patients after a cerebral venous sinus thrombosis; an exploratory study

Thrombosis Journal ◽

10.1186/s12959-021-00335-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Myrthe M. van der Bruggen ◽

Bram Kremers ◽

Rene van Oerle ◽

Robert J. van Oostenbrugge ◽

Hugo ten Cate

Keyword(s):

Sinus Thrombosis ◽

Venous Blood ◽

Lag Time ◽

Peak Height ◽

Cerebral Venous Sinus Thrombosis ◽

Venous Sinus ◽

Control Group ◽

Venous Sinus Thrombosis ◽

Cat Assay ◽

Long Time

Abstract Background Cerebral venous sinus thrombosis (CVST) is a relatively rare, but potentially lethal condition. In approximately 15% of the patients, the cause of CVST remains unclear. Conventional clotting tests such as prothrombin time and activated partial thromboplastin time are not sensitive enough to detect prothrombotic conditions nor mild haemostatic abnormalities. The calibrated automated thrombogram (CAT) is a physiological function test that might be able to detect minor aberrations in haemostasis. Therefore, we aimed to detect the presence of a prothrombotic state in patients who endured idiopathic CVST with the CAT assay. Methods Five adult patients with an idiopathic, radiologically proven CVST that had been admitted during the past 3 years were included in this study. The control group consisted of five age/gender matched healthy volunteers. Exclusion criteria were known haematological disorders, malignancy (current/past) or hormonal and anticoagulant therapy recipients. We obtained venous blood samples from all participants following cessation of anticoagulation. Using the CAT assay, we determined lag time, normalized endogenous thrombin potential (ETP), ETP reduction and normalized peak height. In addition, prothrombin concentrations were determined. Results We found no significant differences in lag time (4.7 min [4.5–4.9] vs 5.3 min [3.7–5.7], p = 0.691), normalized ETP (142% [124–148] vs 124% [88–138], p = 0.222), ETP reduction (29% [26–35] vs 28% [24–58], p > 0.999), and normalized peak height (155% [153–175] vs 137 [94–154], p = 0.056) between patients and their age/gender matched controls. In addition, prothrombin concentrations did not significantly differ between patients and controls (120% [105–132] vs 127% [87–139], p > 0.999). Conclusion Reasons for absent overt hypercoagulability within this study population may be the small patient sample, long time since the event (e.g. 3 years) and avoidance of acquired risk factors like oral contraception. Given the fact that CVST is a serious condition with a more than negligible risk of venous thrombosis event recurrence, exclusion of clinically relevant hypercoagulability remains a challenging topic to further study at the acute and later time points, particularly in patients with idiopathic CVST.

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A Case Report of Cerebral Venous Sinus Thrombosis in Palestine: The Importance of Rapid Diagnosis and Treatment of CVST

Journal of Clinical Review & Case Reports ◽

10.33140/jcrc.04.06.06 ◽

2019 ◽

Vol 4 (6) ◽

Keyword(s):

Case Report ◽

Sinus Thrombosis ◽

Brain Mri ◽

Transverse Sinus ◽

Cerebral Venous Sinus Thrombosis ◽

Venous Sinus ◽

Successful Outcome ◽

Venous Sinus Thrombosis ◽

Brain Ct ◽

First Case

Cerebral venous sinus thrombosis (CVST) is an often under-diagnosed, life-threatening condition. We report the first case of CVST in Palestine of a 39-year-old female who presented with a history of loss of consciousness preceded by severe vertigo and headache. Brain CT scan without contrast was done, in which no abnormality was detected. Further Brain MRI and MRV studies with contrast showed thrombosis of left transverse sinus with extension to left sigmoid sinus and left jugular vein. The patient was anticoagulated and admitted to the ICU for regular monitoring and frequent brain CT scans to rule out hemorrhagic transformation. The patient made a full recovery. Lab and molecular studies were carried out as an outpatient to investigate the etiology of this presentation. The aim of this case report is to demonstrate the importance of early detection and treatment of CVST for a successful outcome.

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Non-contrast computed tomography in the diagnosis of cerebral venous sinus thrombosis

Radiology and Oncology ◽

10.1515/raon-2016-0026 ◽

2016 ◽

Vol 50 (3) ◽

pp. 263-268 ◽

Cited By ~ 8

Author(s):

Jernej Avsenik ◽

Janja Pretnar Oblak ◽

Katarina Surlan Popovic

Keyword(s):

Computed Tomography ◽

Sensitivity And Specificity ◽

Sinus Thrombosis ◽

Clinical Signs ◽

Area Under The Curve ◽

Cerebral Venous Sinus Thrombosis ◽

Venous Sinus ◽

Control Group ◽

Emergency Setting ◽

Venous Sinus Thrombosis

Abstract Background The aim of the study was to investigate the sensitivity and specificity of non-contrast computed tomography (NCCT) in the diagnosis of cerebral venous sinus thrombosis (CVST). Methods. Screening our neurological department database, we identified 53 patients who were admitted to neurological emergency department with clinical signs of CVST. Two independent observers assessed the NCCT scans for the presence of CVST. CT venography and/or MR venography were used as a reference standard. Interobserver agreement between the two readers was assessed using Kappa statistic. Attenuation inside the cerebral venous sinuses was measured and compared between the patient and the control group. Results CVST was confirmed in 13 patients. Sensitivity and specificity of NCCT for overall presence of CVST were 100% and 83%, respectively, with Kappa value of 0.72 (a good agreement between observers). The attenuation values between CVST patients and control group were significantly different (73.4 ± 14.12 HU vs. 58.1 ± 7.58 HU; p = 0.000). The ROC analysis showed an area under the curve (AUC) of 0.916 (95% CI, 0.827 – 1.00) and an optimal cutoff value of 64 HU, leading to a sensitivity of 85% and specificity of 87%. Conclusions NCCT as a first-line investigation has a high value for diagnosis of CVST in the emergency setting. The additional measurement of the sinus attenuation may improve the diagnostic value of the examination.

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Evaluation of polymorphic variants in apoptotic genes and their role in susceptibility and clinical progression to systemic lupus erythematosus

Lupus ◽

10.1177/0961203316678671 ◽

2016 ◽

Vol 26 (7) ◽

pp. 746-755 ◽

Cited By ~ 7

Author(s):

N Glesse ◽

P Vianna ◽

L M G Paim ◽

M C C Matte ◽

A K K Aguiar ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Protective Factor ◽

Clinical Manifestations ◽

Immunological Tolerance ◽

Control Group ◽

Systemic Lupus ◽

Autoantibody Production ◽

Wide Range ◽

Polymorphic Variants

Background Systemic lupus erythematosus (SLE) is an autoimmune disease marked by the disruption of the immune homeostasis. Patients exhibit a wide range of clinical manifestations, and environmental and genetic factors are involved in SLE pathogenesis. Evidence suggests that abnormalities in the cellular and molecular events that coordinate apoptosis may favour the generation of autoantigens involved in autoimmunity. In this way, the apoptotic deregulation may be affected by polymorphic variants in apoptotic-related genes. Methods We analyzed FAS, FASL, BCL-2 and BAX polymorphisms in order to correlate to SLE susceptibility and clinical features. A total of 427 SLE patients from the Hospital de Clínicas de Porto Alegre and 543 controls from southern Brazil were evaluated. Results We observed higher frequencies of the FASL –844CC genotype and –844C allele, as well as of the FASL-844C/IVS2nt-124A haplotype in African-derived SLE patients when compared to controls ( P < 0.001). FASL –844C, which is related to high FasL expression, could contribute to increased apoptosis and to the breakdown of immunological tolerance, favouring autoantibody production and inflammation. On the other hand, the BAX –248GA genotype and the –248A allele , related to low protein expression, were observed as a protective factor against SLE in this same population. The rate of apoptosis and cell death was evaluated in peripheral lymphocytes, and SLE patients presented a higher percentage of dead lymphocytes (CD3+Annexin V+ 7-AAD+) compared to the control group. Conclusion Our data support a role for apoptosis in SLE susceptibility.

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Association of Polymorphic Variants of Brain-Derived Neurotrophic Factor Gene (Bdnf Rs6265) and Glutamate Transporter Gene of the Second Type (Slc1a2 Rs4354668) with the Course of Multiple Sclerosis in Patients Living in Tomsk Region

Annals of the Russian academy of medical sciences ◽

10.15690/vramn1069 ◽

2019 ◽

Vol 74 (1) ◽

pp. 14-19

Author(s):

Semkina A. AnastasiIa ◽

Diana Z. Osmanova ◽

Valentina M. Alifirova ◽

Marina A. Titova ◽

Ekaterina S. Koroleva ◽

...

Keyword(s):

Multiple Sclerosis ◽

Clinical Manifestations ◽

Glutamate Transporter ◽

Control Group ◽

Transporter Gene ◽

Tomsk Region ◽

Polymorphic Variants ◽

The Moment ◽

Glutamate Transporter Gene ◽

Bdnf Rs6265

Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that affects people of working age and ultimately leads to disability. This disease is of polygenic origin. The role of factors related to the pathogenesis of the disease and affecting both neuroinflammation and remyelination is studied. Aims: Our goal was to investigate the association of single nucleotide polymorphisms BDNF rs6265 and SLC1A2 rs4354668 with the risk of occurrence, clinical manifestations and the course of MS.Materials and methods: The study included 302 patients with MS, 268 healthy volunteers were enrolled in a control group. The obtained blood was used for DNA extraction by standard phenol-chloroform method. The identification of allelic variants of genes SLC1A2 (rs4354668) and BDNF (rs6265) was performed by polymerase chain reaction.Results: When comparing the frequencies of genotypes and alleles of polymorphic variants of BDNF and SLC1A2 genes between the groups of MS patients and the control group, no statistically significant differences were revealed. Comparison of genotype and allele frequencies of patients depending on sex, age of onset of the disease also did not reveal statistically significant differences. The study of the association of polymorphic variant of the gene BDNF (rs6265) with clinical manifestations of the disease revealed the association of genotype CC with oculomotor and trigeminal disorders at the onset of the disease (F=7, p=0.017). The study of the polymorphic variant rs4354668 of the glutamate transporter gene SLC1A2 revealed the association of allele G with an earlier (within 5 years from the moment of debut) transition of the disease to the stage of secondary progression, despite the therapy with DMT (χ2=5.940; p=0.010; OR 1.58; 95% CI 1.09−2.29). Homozygous genotype of TT (χ2=6.393; p=0.041; OR 0.50; 95% CI 0.28−0.88) and allele T (χ2=5.940; p=0.010; OR 0.63; 95% CI 0.44−0.92) of the polymorphism rs4354668 of the glutamate transporter gene SLC1A2 are significantly more common in the group of patients with late transition (15 years or more from the moment of debut) to the secondary progressive course.Conclusions: In our study we revealed the relationship of the studied polymorphic variants of genes with clinical signs at the onset of the disease and with the clinical manifestations of MS in patients living in the Tomsk region.

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