RESUMO
BACKGROUND AND PURPOSE: Coma is an independent predictor of poor clinical outcomes in cerebral venous thrombosis (CVT). We aimed to describe the association of age, sex, and radiological characteristics of adult coma patients with CVT. METHODS: We used data from the international, multicentre prospective observational BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis) study. Only positively associated variables with coma with <10% missing data in univariate analysis were considered for the multivariate logistic regression model. RESULTS: Of the 596 adult patients with CVT (75.7% women), 53 (8.9%) patients suffered coma. Despite being a female-predominant disease, the prevalence of coma was higher among men than women (13.1% vs. 7.5%, p = 0.04). Transverse sinus thrombosis was least likely to be associated with coma (23.9% vs. 73.3%, p < 0.001). The prevalence of superior sagittal sinus thrombosis was higher among men than women in the coma sample (73.6% vs. 37.5%, p = 0.01). Men were significantly older than women, with a median (interquartile range) age of 51 (38.5-60) versus 40 (33-47) years in the coma (p = 0.04) and 44.5 (34-58) versus 37 (29-48) years in the non-coma sample (p < 0.001), respectively. Furthermore, an age- and superior sagittal sinus-adjusted multivariate logistic regression model found male sex (odds ratio = 1.8, 95% confidence interval [CI] = 1.0-3.4, p = 0.04) to be an independent predictor of coma in CVT, with an area under the receiver operating characteristic curve of 0.61 (95% CI = 0.52-0.68, p = 0.01). CONCLUSIONS: Although CVT is a female-predominant disease, men were older and nearly twice as likely to suffer from coma than women.
Assuntos
Coma , Humanos , Masculino , Feminino , Coma/etiologia , Coma/epidemiologia , Adulto , Pessoa de Meia-Idade , Trombose Intracraniana/epidemiologia , Trombose Intracraniana/complicações , Estudos Prospectivos , Trombose Venosa/epidemiologia , Trombose Venosa/complicações , Trombose dos Seios Intracranianos/epidemiologia , Trombose dos Seios Intracranianos/complicações , Fatores Sexuais , Fatores Etários , PrevalênciaRESUMO
OBJECTIVE: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. METHODS: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. RESULTS: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10-24 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10-16 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10-16 ) increased risk of CVT compared with individuals with blood group O. INTERPRETATION: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788.
Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Trombose Intracraniana/genética , Trombose Venosa/genética , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Trombofilia/genéticaRESUMO
Primary brain tumors are associated with an increased risk of pulmonary embolism (PE), particularly in the early post-operative period. The pathophysiological mechanisms of PE are poorly understood. This study aims to describe prospectively extracellular vesicles (EVs) levels and investigate whether or not their variations allow to identify patients at increased risk of post-operative PE. Consecutive meningioma or glioma patients candidate to tumor resection were included in the study if a pulmonary perfusion scan (Q-scan) performed before surgery ruled out PE. EVs derived from platelets (CD41+) or endothelial cells (CD144+), tissue factor-bearing EVs (CD142+) and their procoagulant subtype (annexin V+) were analyzed by flow cytometry before surgery (T0), within 24 h (T1), two (T2) and seven days (T7) after surgery. Q-scan was repeated at T2. Ninety-three patients with meningioma, 59 with glioma and 76 healthy controls were included in the study. CD142+ and annexin V+/CD142+ EVs were increased at T0 in meningioma and glioma patients compared to healthy controls. Twenty-nine meningioma (32%) and 16 glioma patients (27%) developed PE at T2. EVs levels were similar in meningioma patients with or without PE, whereas annexin V+ and annexin V+/CD142+ EVs were significantly higher at T1 and T2 in glioma patients with PE than in those without. Procoagulant EVs, particularly annexin V+/CD142+, increase after surgery and are more prevalent in glioma patients who developed PE after surgery than in those who did not.
Assuntos
Neoplasias Encefálicas , Vesículas Extracelulares , Glioma , Neoplasias Meníngeas , Meningioma , Embolia Pulmonar , Anexina A5 , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/cirurgia , Células Endoteliais , Glioma/complicações , Glioma/cirurgia , Humanos , Neoplasias Meníngeas/cirurgia , Meningioma/complicações , Meningioma/cirurgia , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Embolia Pulmonar/etiologiaRESUMO
In family studies, the risk for venous thromboembolism (VTE) in relatives with factor V Leiden (FVL) or G20210A prothrombin (PT20210A) gene polymorphisms may differ according to genotype and clinical presentation of the proband. To address this hypothesis, a retrospective cohort family study was carried out on 192 kindreds with at least one member with homozygous FVL or PT20210A, for a total of 886 relatives. The proband of the family was heterozygous in 68 and homozygous or with both polymorphisms in 124 kindreds. Twenty-three probands were asymptomatic, 11 had had arterial thrombosis, 7 obstetrical complications, and 151 venous thrombosis (122 VTE and 29 superficial vein thrombosis). The incidence of VTE (per 1000 patient-years) in relatives was higher when the proband had heterozygous rather than homozygous polymorphism (1.25 [95% confidence interval (CI), 0.73-1.91] vs 0.44 [0.19-0.78]) and when the proband had had VTE instead of other or no clinical manifestations (0.95 [0.57-1.42] vs 0.50 [0.19-0.96]). Compared with relatives belonging to kindreds with homozygous probands without VTE, the adjusted hazard ratio of VTE for relatives selected from kindreds with heterozygous probands with VTE was 4.14 (95% CI, 1.17-14.71). The genotype and clinical presentation of the proband influence the risk for VTE in relatives with FVL or PT20210A.
Assuntos
Fator V/genética , Protrombina/genética , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/genética , Adulto , Intervalo Livre de Doença , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Fatores de Risco , Tromboembolia Venosa/sangueRESUMO
BACKGROUND: Inconsistent data exists regarding the risk factors for bronchoalveolar lavage (BAL) positivity in lung donors, the incidence of donor-derived infections (DDI), and the effect of BAL positivity on lung transplant (LuTx) recipients' outcome. METHODS: A retrospective analysis was conducted on consecutive LuTx at a single center from January 2016 to December 2022. Donors' data, including characteristics, graft function and BAL samples were collected pre-procurement. Recipients underwent BAL before LuTx and about the 3rd, 7th and 14th day after LuTx. A DDI was defined as BAL positivity (bacterial growth ≥104 colony forming units) for identical bacterial species between donor and recipient. Recipients' pre-operative characteristics, intra-operative management, and post-operative outcomes were assessed. Two recipient cohorts were identified based on lung colonization status before undergoing LuTx. RESULTS: Out of 188 LuTx procedures performed, 169 were analyzed. Thirty-six percent of donors' BAL tested positive. Donors' characteristics and graft function at procurement were not associated with BAL positivity. Fourteen DDI were detected accounting for 23% of recipients receiving a graft with a positive BAL. Only among uncolonized recipients, receiving a graft with positive BAL is associated with higher likelihood of requiring invasive ventilation at 72 hours after LuTx on higher positive end-expiratory pressure levels having lower PaO2/FiO2, prolonged duration of mechanical ventilation and longer ICU stay. No difference in hospital length of stay was observed. CONCLUSIONS: Receiving a graft with a positive BAL, which is poorly predicted by donors' characteristics, carries the risk of developing a DDI and is associated to a worse early graft function among uncolonized recipients.
Assuntos
Líquido da Lavagem Broncoalveolar , Transplante de Pulmão , Doadores de Tecidos , Humanos , Masculino , Estudos Retrospectivos , Feminino , Fatores de Risco , Incidência , Adulto , Pessoa de Meia-Idade , Líquido da Lavagem Broncoalveolar/microbiologia , Lavagem Broncoalveolar/métodos , TransplantadosRESUMO
BACKGROUND AND OBJECTIVES: Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor XI (F11) and ABO gene interactions among patients with CVT. METHODS: Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified F11 and ABO genes with CVT status. RESULTS: We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, p = 0.08: sex: 71% male vs 68% female, p = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/F11 and rs8176645/ABO) had a 3.9 (95% CI 2.74-5.71, p = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, p = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/F11 increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, p = 2.00e15), compared with blood group-O combined with AA. DISCUSSION: Interactions between factor XI and ABO genes increase risk of CVT by 4- to 14-fold.
Assuntos
Sistema ABO de Grupos Sanguíneos , Fator XI , Humanos , Sistema ABO de Grupos Sanguíneos/genética , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Fator XI/genética , Trombose Venosa/genética , Trombose Intracraniana/genética , Epistasia Genética/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , GalactosiltransferasesRESUMO
Background: Cerebral venous thrombosis (CVT) is an uncommon cause of stroke in young adults. We aimed to determine the impact of age, gender and risk factors (including sex-specific) on CVT onset. Methods: We used data from the BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis), a multicentre multinational prospective observational study on CVT. Composite factors analysis (CFA) was performed to determine the impact on the age of CVT onset in males and females. Results: A total of 1309 CVT patients (75.3% females) aged ⩾18 years were recruited. The overall median (IQR-interquartile range) age for males and females was 46 (35-58) years and 37 (28-47) years (p < 0.001), respectively. However, the presence of antibiotic-requiring sepsis (p = 0.03, 95% CI 27-47 years) among males and gender-specific risk factors like pregnancy (p < 0.001, 95% CI 29-34 years), puerperium (p < 0.001, 95% CI 26-34 years) and oral contraceptive use (p < 0.001, 95% CI 33-36 years) were significantly associated with earlier onset of CVT among females. CFA demonstrated a significantly earlier onset of CVT in females, ~12 years younger, in those with multiple (⩾1) compared to '0' risk factors (p < 0.001, 95% CI 32-35 years). Conclusions: Women suffer CVT 9 years earlier in comparison to men. Female patients with multiple (⩾1) risk factors suffer CVT ~12 years earlier compared to those with no identifiable risk factors.
Assuntos
Trombose Intracraniana , Trombose Venosa , Masculino , Gravidez , Adulto Jovem , Humanos , Feminino , Idoso , Pessoa de Meia-Idade , Trombose Venosa/epidemiologia , Idade de Início , Trombose Intracraniana/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: The clinical course of cerebral sinus-venous thrombosis (CSVT) is largely unknown because prospective studies with a long follow-up and with the goal to assess thrombosis recurrence rate and predisposing factors for recurrence are lacking. METHODS AND RESULTS: One hundred forty-five patients with a first CSVT were followed up for a median of 6 years after discontinuation of anticoagulant treatment. End points were recurrent CSVT or other clinical manifestations of venous thromboembolism. CSVT recurred in 5 patients (3%) and other manifestations of venous thromboembolism (deep vein thrombosis of the lower limbs or pulmonary embolism) were seen in 10 additional patients (7%), for a recurrence rate of 2.03 per 100 person-years (95% confidence interval, 1.16 to 3.14) for all manifestations of venous thromboembolism and 0.53 per 100 person-years (95% confidence interval, 0.16 to 1.10) for CSVT. Nearly half of the recurrences occurred within the first year after discontinuation of anticoagulant therapy. Risk factors for recurrent venous thrombosis were male sex (adjusted hazard ratio, 9.66; 95% confidence interval, 2.86 to 32.7) and, for thromboses other than CSVT, severe thrombophilia resulting from antithrombin, protein C, protein S deficiency, anti-phospholipid antibodies, or combined abnormalities (adjusted hazard ratio, 4.71; 95% confidence interval, 1.34 to 16.5). CONCLUSIONS: The risk of recurrent CSVT is low and is higher in the first year after discontinuation of anticoagulant treatment and among men. Mild thrombophilia abnormalities are not associated with recurrent CSVT, but severe thrombophilia entails an increased risk of deep vein thrombosis of the lower limbs or pulmonary embolism.
Assuntos
Trombose dos Seios Intracranianos/diagnóstico , Anticoagulantes , Feminino , Seguimentos , Humanos , Extremidade Inferior , Masculino , Prognóstico , Embolia Pulmonar , Recidiva , Risco , Fatores de Risco , Fatores Sexuais , Trombose dos Seios Intracranianos/complicações , Trombose dos Seios Intracranianos/etiologia , Trombofilia , Trombose VenosaRESUMO
BACKGROUND: Cerebral vein thrombosis (CVT) is a rare, life-threatening disease affecting one adult per 100,000 per year. Genetic risk factors are deficiencies of the natural anticoagulant proteins antithrombin, protein C, protein S or single nucleotide polymorphisms such as factor V Leiden and prothrombin 20210A. In 20% of patients, the cause of CVT remains unknown. AIM: To identify novel genetic risk factors for CVT using targeted next-generation DNA sequencing (NGS). METHODS: We investigated 171 CVT patients and 298 healthy controls. Patients were selected using the following criteria: objective diagnosis of CVT, no active cancer. We performed targeted NGS analysis of the protein-coding regions of 734 candidate genes related to hemostasis and inflammation, 150 ancestry informative markers and 28 thrombosis-associated variants. RESULTS: We identified 3723 common and low frequency variants with minor allele frequency (MAF) >1% in 590 genes. Single variant association testing using logistic regression analysis identified rs8176719 insertion/deletion (indel) variant in the ABO gene associated with CVT (age and sex adjusted OR 2.03; 95% CI 1.52-2.73; Pâ¯=â¯2.07â¯×â¯10-6; Bonferroni Pâ¯=â¯0.008). In addition, we identified 8839 rare variants (MAFâ¯≤â¯1%) in 723 genes. Gene-based association analysis of these rare variants using a burden test revealed only a tentative association of non-coding variants located in the F8 locus with CVT. CONCLUSION: Targeted NGS identified a common indel variant rs8176719 in the ABO gene. Gene-based tests of association failed to reveal genomic loci with a cumulative burden of rare variants associated with CVT.
Assuntos
Veias Cerebrais/patologia , Trombose Intracraniana/genética , Sistema ABO de Grupos Sanguíneos/genética , Adulto , Estudos de Casos e Controles , Veias Cerebrais/metabolismo , Feminino , Frequência do Gene , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação INDEL , Trombose Intracraniana/patologia , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodosRESUMO
BACKGROUND: The role of thrombophilic and cardiovascular risk factors in different manifestations of retinal vein occlusion (RVO), i.e., central or branch RVO, and at different ages is still debated. AIMS: To evaluate the association between thrombophilic and cardiovascular risk factors and the risk of RVO (overall, separately for central and branch RVO, and at different ages). METHODS: Case-control study on 313 patients with a first objectively-confirmed RVO (216 central and 97 branch RVO) and 415 healthy individuals. RESULTS: Antithrombin, protein C or protein S deficiency (adjusted odds ratio [95%CI]: 15.60 [2.01-121]; p=0.009), hyperhomocysteinemia (HHCy; 3.22 [1.38-7.49]; p=0.007), high factor VIII (FVIII) levels (3.08 [1.20-7.89]; p=0.019), factor V Leiden (2.93 [0.97-8.86]; p=0.058) and the presence of at least one cardiovascular risk factor (1.79 [1.00-3.23]; p=0.050) were associated with an increased risk of branch RVO. The association was weaker for central RVO, and limited to HHCy (2.15 [1.09-4.24]; p=0.027) and high FVIII (1.99 [0.90-4.42]; p=0.091). For HHCy, high FVIII and cardiovascular risk factors the association with the risk of RVO was stronger at an age>50years (3.41[1.29-8.99], p=0.013; 2.57[1.00-6.68], p=0.050; and 2.03[1.16-3.56], p=0.013, respectively) than ≤50years (1.93[0.85-4.36], p=0.114; 1.67[0.54-5.12], p=0.371; and 1.22[0.73-2.03], p=0.454, respectively), whereas classic inherited thrombophilia (antithrombin, protein C or protein S deficiencies, factor V Leiden and prothrombin G20210A mutation) was slightly more prevalent at an age≤50years (1.62 [0.76-3.45], p=0.210) than >50years (1.11[0.44-2.79], p=0.833). CONCLUSIONS: Thrombophilic and cardiovascular risk factors are associated with RVO, particularly branch RVO. The risk of RVO associated with HHCy, high FVIII and cardiovascular risk factors is higher at an older age.
Assuntos
Doenças Cardiovasculares/complicações , Oclusão da Veia Retiniana/sangue , Oclusão da Veia Retiniana/complicações , Trombofilia/complicações , Adulto , Fatores Etários , Idoso , Antitrombinas/sangue , Estudos de Casos e Controles , Fator V/análise , Fator VIII/análise , Feminino , Humanos , Hiper-Homocisteinemia/complicações , Itália , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Fatores de RiscoRESUMO
BACKGROUND: Red cell distribution width (RDW) is a marker of cardiovascular diseases and venous thromboembolism, but its role in cerebral vein thrombosis (CVT) is unknown. AIMS: To investigate whether high values of RDW are associated with an increased risk of CVT. METHODS: A case-control study of CVT patients (≥18years-old) referred to our center contrasted with healthy individuals. Odds ratios (ORs) were calculated for RDW values >90th percentile by multivariable logistic regression and adjusted for demographic characteristics, hemorheological parameters, renal function, fibrinogen and CRP. Quartiles based on the distribution of RDW values were used in an additional model to assess a dose-response relationship. The risk of CVT associated with the combined presence of high RDW and either thrombophilia abnormalities or oral contraceptive use was also estimated. RESULTS: 143 cases (median age 36years, 18-79) and 352 controls (42years, 18-80) were investigated. RDW values >90th percentile (>14.6%) were associated with an increased risk of CVT (OR 2.44, 95% CI 1.39-4.28). The association remained after further adjustment for hemorheological parameters (OR 3.73, 95% CI 1.72-8.09), inflammatory markers (OR 3.77, 95% CI 1.72-8.25) and renal function (OR 3.62, 95% CI 1.53-8.55). The risk appeared restricted to these extreme levels (>14.6%), as there was no graded association between values of RDW and CVT risk over quartiles. There was a synergistic effect on the risk of CVT for the combination of high RDW and thrombophilia abnormalities (OR 33.20, 95% CI 6.95-158.55) or oral contraceptive use (OR 37.99, 95% CI 8.78-164.45). CONCLUSIONS: Values of RDW >90th percentile are associated with CVT.
Assuntos
Anticoncepcionais Orais/efeitos adversos , Índices de Eritrócitos , Trombose dos Seios Intracranianos/sangue , Trombose Venosa/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Coagulação Sanguínea , Estudos de Casos e Controles , Feminino , Humanos , Testes de Função Renal , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Adulto JovemRESUMO
INTRODUCTION: Oral contraceptive (OC) use increases the risk of venous thromboembolism (VTE), but the effect of duration of use remains to be elucidated. PATIENTS AND METHODS: This case-control study was aimed to investigate the duration of OC use on the risk of VTE according to women age, periods of use, prevalence of other risk factors and the role of thrombophilia abnormalities. Seven-hundred patients and 209 controls who used OC were stratified into short users (≤1year), long users (1 to 5years), and very long users (>5years). RESULTS AND CONCLUSIONS: Compared to non-users, the odds ratio (OR) for VTE was 9.0 (95% CI 6.9-12.2) in short, 6.5 (95% CI 4.8-83.7) in long and 5.9 (95% CI 4.4-8.1) in very long users. The risk of VTE in short users was highest in women ≤30years and in the first year of use (OR 13.1, 95% CI 7.7-22.4) and decreased afterward (OR 7.7, 95% CI 5.0-11.9). This trend was not observed in women >30years. Compared to non-carriers and non-users, a joint effect of thrombophilia abnormalities and OC use on VTE risk was observed particularly in short users (OR 62.2, 95% CI 29.8-129.6), but also afterward (OR 25.4, 95% CI 16.5-39.2). Other transient risk factors for VTE were present in 25% of very long and 16% of short users. In conclusion, the risk of VTE in OC users decreases over time only before 30years and in first users. Thrombophilia abnormalities strongly interact with the duration of OC use in determining VTE.
Assuntos
Anticoncepcionais Orais/efeitos adversos , Tromboembolia Venosa/induzido quimicamente , Adolescente , Adulto , Estudos de Casos e Controles , Anticoncepcionais Orais/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Trombofilia/complicações , Tromboembolia Venosa/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Deep vein thrombosis (DVT) genetic predisposition is partially known. OBJECTIVES: This study aimed at assessing the functional impact of nine ADAMTS13 single nucleotide variants (SNVs) previously reported to be associated as a group with DVT in a burden test and the individual association of selected variants with DVT risk in two replication studies. METHODS: Wild-type and mutant recombinant ADAMTS13 were transiently expressed in HEK293 cells. Antigen and activity of recombinant ADAMTS13 were measured by ELISA and FRETS-VWF73 assays, respectively. The replication studies were performed in an Italian case-control study (Milan study; 298/298 patients/controls) using a next-generation sequencing approach and in a Dutch case-control study (MEGA study; 4306/4887 patients/controls) by TaqMan assays. RESULTS: In vitro results showed reduced ADAMTS13 activity for three SNVs (p.Val154Ile [15%; 95% confidence interval [CI] 14-16], p.Asp187His [19%; 95%[CI] 17-21], p.Arg421Cys [24%; 95%[CI] 22-26]) similar to reduced plasma ADAMTS13 levels of patients carriers for these SNVs. Therefore these three SNVs were interrogated for risk association. The first replication study identified 3 heterozygous carriers (2 cases, 1 control) of p.Arg421Cys (odds ratio [OR] 2, 95%[CI] 0.18-22.25). The second replication study identified 2 heterozygous carriers (1 case, 1 control) of p.Asp187His ([OR] 1.14, 95%[CI] 0.07-18.15) and 10 heterozygous carriers (4 cases, 6 controls) of p.Arg421Cys ([OR] 0.76, 95%[CI] 0.21-2.68). CONCLUSIONS: Three SNVs (p.Val154Ile, p.Asp187His and p.Arg421Cys) showed reduced ex vivo and in vitro ADAMTS13 levels. However, the low frequency of these variants makes it difficult to confirm their association with DVT.
Assuntos
Proteína ADAMTS13/genética , Polimorfismo de Nucleotídeo Único , Trombose Venosa/genética , Proteína ADAMTS13/análise , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MasculinoRESUMO
BACKGROUND: We investigated the coagulation system in patients during extracorporeal membrane oxygenation (ECMO) initiated for respiratory failure and the influence of the ECMO circuit on coagulation tests; we compared different coagulation tests for monitoring unfractionated heparin (UH) therapy; we investigated whether or not coagulation parameters were predictive of bleeding during ECMO. METHODS: Pilot study on twelve consecutive adult patients admitted at our general ICU for acute respiratory failure and placed on ECMO from November 2011 to October 2012. Coagulation tests were performed before ECMO start and daily, including day of circuit change and day of circuit removal. UH was monitored with activated partial thromboplastin time (APTT) ratio, at a therapeutic range of 1.5-2.0. RESULTS: We observed no effect of ECMO circuit on coagulation parameters measured pre- and postlung, but platelet count decreased significantly over time (-82x10(3)/mmc, 95%CI 40-123). APTT showed a correlation with antifactor Xa activity, whereas other global coagulation tests such as activated clotting time, thromboelastography and endogenous thrombin potential did not. Major bleeding occurred in three patients but no difference in any coagulation parameter was observed between them and those who did not bleed. CONCLUSIONS: This pilot study shows that ECMO initiated for respiratory support in adults does not change coagulation parameters. Over time a statistically significant reduction of platelet count was observed, possibly due to consumption within the circuit, consumption microangiopathy or the underlying patients' diseases. Although APTT was appropriate to monitor UH, major bleedings occurred and a lower therapeutic range may be advisable.
Assuntos
Oxigenação por Membrana Extracorpórea/métodos , Hemostasia , Respiração Artificial/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes , Coagulação Sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Doença Pulmonar Obstrutiva Crônica/terapia , Síndrome do Desconforto Respiratório/terapia , Insuficiência Respiratória/sangue , Insuficiência Respiratória/terapiaRESUMO
Rare mutations in PROC, PROS1 or SERPINC1 as well as common variants in F5, F2, F11 and SERPINC1 have been identified as risk factors for deep vein thrombosis (DVT). To identify novel genetic risk factors for DVT, we have developed and applied next-generation DNA sequencing (NGS) of the coding area of hemostatic and proinflammatory genes. Using this strategy, we previously identified a single nucleotide variant (SNV) rs6050 in the FGA gene and novel, rare SNVs in the ADAMTS13 gene associated with DVT. To identify novel coding variants in the genetic predisposition to DVT, we applied NGS analysis of the coding area of 186 hemostatic and proinflammatory genes in 94 DVT cases and 98 controls and we identified 18 variants with putative role in DVT. A group of 585 Italian idiopathic DVT patients and 550 healthy controls was used to genotype all the 18 risk-associated variants identified by NGS. Replication study in the Italian population identified the rs2232710 variant in the protein Z-dependent protease inhibitor (ZPI) gene to be associated with an increased risk of DVT (OR 2.74; 95% CI 1.33-5.65; P = 0.0045; Bonferroni P = 0.081). However, the rs2232710 SNV showed no association with DVT in two Dutch replication cohorts the LETS study (454 patients and 451 controls) and the MEGA study (3799 patients and 4399 controls), indicating that the rs2232710 variant is not a risk factor for DVT.
Assuntos
Polimorfismo de Nucleotídeo Único , Serpinas/genética , Trombose Venosa/genética , Estudos de Casos e Controles , HumanosRESUMO
INTRODUCTION: Cerebral venous thrombosis (CVT) is a rare cerebrovascular condition accounting for <1% of all stroke cases and mainly affects young adults. Its genetic aetiology is not clearly elucidated. METHODS AND ANALYSIS: To better understand the genetic basis of CVT, we have established an international biobank of CVT cases, Biorepository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) which aims to recruit highly phenotyped cases initially of European descent and later from other populations. To date we have recruited 745 CVT cases from 12 research centres. As an initial step, the consortium plans to undertake a genome-wide association analysis of CVT using the Illumina Infinium HumanCoreExome BeadChip to assess the association and impact of common and low-frequency genetic variants on CVT risk by using a case-control study design. Replication will be performed to confirm putative findings. Furthermore, we aim to identify interactions of genetic variants with several environmental and comorbidity factors which will likely contribute to improve the understanding of the biological mechanisms underlying this complex disease. ETHICS AND DISSEMINATION: BEAST meets all ethical standards set by local institutional review boards for each of the participating sites. The research outcomes will be published in international peer-reviewed open-access journals with high impact and visibility. The results will be presented at national and international meetings to highlight the contributions into improving the understanding of the mechanisms underlying this uncommon but important disease. This international DNA repository will become an important resource for investigators in the field of haematological and vascular disorders.
Assuntos
Predisposição Genética para Doença , Trombose Intracraniana/genética , Trombose Venosa/genética , Adulto , Estudos de Casos e Controles , Fator V/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Protrombina/genética , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: An association between high red cell distribution width (RDW) and venous thromboembolism (VTE) has been observed. However, it is not known whether this association differs within various manifestations of VTE, nor if there is an interaction between RDW and thrombophilia abnormalities on the risk of VTE. AIMS: To investigate whether RDW is a marker of the risk of VTE; to identify subgroups of patients in which the association between RDW and VTE is stronger; to investigate a possible interaction between RDW and thrombophilia abnormalities. METHODS: Case-control study on 730 patients with a first objectively-confirmed VTE episode (300 unprovoked and 430 provoked) consecutively referred to our Center between 2007 and 2013, and 352 healthy controls. Blood was taken for a thrombophilia work-up and a complete blood count, including RDW, at least three months after VTE. RESULTS: Individuals with RDW above the 90(th) percentile (>14.6%) had a 2.5-fold increased risk of VTE compared to those with RDW ≤90(th) percentile, independently of age, sex, body mass index, other hematological variables and renal function (adjusted odds ratio: 2.52 [95%CI:1.42-4.47]). The risk was similar for unprovoked and provoked VTE, and slightly higher in patients with pulmonary embolism (adjusted odds ratio 3.19 [95%CI:1.68-6.09]) than in those with deep vein thrombosis alone (2.29 [95%CI:1.22-4.30]). No interaction between high RDW and thrombophilia abnormalities on the risk of VTE was observed. CONCLUSION: Our findings confirm RDW as an independent and easily available marker for stratification of the risk of VTE.
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Contagem de Eritrócitos/estatística & dados numéricos , Índices de Eritrócitos , Trombofilia/sangue , Trombofilia/epidemiologia , Tromboembolia Venosa/sangue , Tromboembolia Venosa/epidemiologia , Biomarcadores/sangue , Causalidade , Tamanho Celular , Comorbidade , Eritrócitos/patologia , Feminino , Humanos , Incidência , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e Especificidade , Tromboembolia Venosa/diagnósticoRESUMO
BACKGROUND: Sudden sensorineural hearing loss (ISSHL) is idiopathic in 85% of cases and cochlear micro-thrombosis has been hypothesized as pathogenic mechanism. The role of thrombophilia and cardiovascular risk factors in ISSHL is controversial and whether these risk factors influence the clinical outcome of ISSHL is unknown. METHODS: and patients To investigate the role of thrombophilia and cardiovascular risk factors in ISSHL and to evaluate their influence on clinical outcome of the disease, 118 patients with a first episode of ISSHL and 415 healthy controls were investigated. Thrombophilia screening included measurements of antithrombin, protein C, protein S, factor V Leiden, prothrombin G20210A, antiphospholipid antibodies, fibrinogen, factor VIII and homocysteine. RESULTS: Deficiencies of antithrombin, protein C or S taken together, high factor VIII and hyperhomocysteinemia were significantly associated with ISSHL (OR [95%CI]: 7.55 [1.05-54.47], 2.91 [1.31-6.44] and 2.69 [1.09-6.62], respectively), whereas no association was found with the remaining thrombophilia markers. A 2-fold increased risk of poor clinical outcome was observed for every 5 µmol/L increase of fasting homocysteine levels (adjusted OR [95%CI]) 2.13 [1.02-4.44]) until levels of approximately 15 µmol/L, then the risk increased slowly. Cardiovascular risk factors (arterial hypertension, hyperlipidemia, diabetes and smoking) were associated with an increased risk of ISSHL (OR [95%CI] 1.88 [1.17-3.03]) and with a poor clinical outcome (OR [95%CI] 2.22 [0.93-5.26]). CONCLUSIONS: Hyperhomocysteinemia, high factor VIII and, with more uncertainty, deficiencies of antithrombin, protein C or S and cardiovascular risk factors increase the risk of ISSHL. Hyperhomocysteinemia and cardiovascular risk factors are associated with a poor clinical outcome of ISSHL.
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Perda Auditiva Neurossensorial/sangue , Perda Auditiva Neurossensorial/epidemiologia , Hiper-Homocisteinemia/complicações , Trombofilia/complicações , Adulto , Testes de Coagulação Sanguínea , Fator V/análise , Fator VIII/análise , Feminino , Humanos , Hiper-Homocisteinemia/sangue , Masculino , Pessoa de Meia-Idade , Proteína C/análise , Proteína S/análise , Protrombina/análise , Fatores de Risco , Trombofilia/sangueRESUMO
Among the so called antiphospholipid (aPL) antibodies Lupus Anticoagulant (LAC) is considered the strongest risk factor for thromboembolic events. In individuals without a previous thromboembolic event (carriers), LAC is a risk factor when associated with the presence of anticardiolipin (aCL) and aß2-Glycoprotein I (aß2GPI) antibodies. On the other hand, data on carriers of isolated LAC positivity are sparse and inconclusive. The aim of this study was to prospectively determine the incidence of thrombosis in a cohort of carriers of isolated LAC positivity. One-hundred seventy-nine carriers of LAC confirmed twelve weeks apart and in a reference laboratory were studied. During a total follow up of 552 person-years, there were seven thromboembolic events (1.3% person-y). All the seven patients had at least one adjunctive major risk factor for thrombosis. The cumulative incidence of thromboembolic events was 3.1% (95% CI 0.6-5.6) after 2years, and 5.9% (95% CI 1.2-10.6) after 5 and 10years. On a multivariate regression analysis considering age, sex, autoimmune disease, risk factors for arterial and venous thrombosis, use of aspirin, only age was found to be an independent predictor of thromboembolic events (HR=1.1, 95% CI 1.0-1.2, p=0.02). These data might be relevant in clinical practice and underline the importance of differentiating LAC carriers in terms of isolated positivity or positivity associated with the presence of antibodies to aCL and ß2-glycoprotein I.
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Inibidor de Coagulação do Lúpus/imunologia , Tromboembolia/sangue , Trombose/imunologia , beta 2-Glicoproteína I/imunologia , Adulto , Idoso , Anticorpos , Anticorpos Anticardiolipina/sangue , Feminino , Humanos , Incidência , Inibidor de Coagulação do Lúpus/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Fatores de Risco , Tromboembolia/epidemiologia , Trombose/sangue , Fatores de Tempo , Resultado do Tratamento , beta 2-Glicoproteína I/sangueRESUMO
Venous thromboembolism (VTE), i.e., deep vein thrombosis and pulmonary embolism, are among the main causes of morbidity and mortality in pregnancy with an estimated incidence of 1 per thousand women years. Recommendations on antithrombotic prophylaxis are weak. The aim of the "Pregnancy Health-care Program" (PHP) was to evaluate the individual risk of VTE in a cohort of pregnant women, and manage them with the aim of reducing the rate of VTE. The study was conducted from Jan 2008 to Dec 2010 in the hospital and obstetrical outclinics in Cremona, Italy, and included 1,787 pregnant women who received clinical observation (n = 1,197), above-knee compression stockings (n = 437) or compression stockings and low-molecular-weight heparin (LMWH) (n = 85) depending on their individual VTE risk, evaluated with a risk score (0.5-3.0) derived from the relative risk estimates of a number of risk factors. Visits were scheduled at the end of each trimester and at hospital discharge after delivery. No VTE occurred, but one superficial vein thrombosis was observed 3 days after vaginal delivery in a woman who received clinical observation (0.6 per thousand). No bleeding was observed in LMWH users. The PHP based on stratification of individual VTE risk resulted in a low incidence of VTE events.