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1.
Haemophilia ; 2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33550602

RESUMO

INTRODUCTION: Detection of early arthropathy is crucial for the management of haemophilia, but data on moderate haemophilia are limited. Therefore, we evaluated joint health and treatment modalities in Nordic patients with moderate haemophilia A (MHA) and B (MHB). AIM: To explore and compare the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) and Haemophilia Joint Health Score (HJHS) to detect early arthropathy in moderate haemophilia. METHODS: A cross-sectional, multicentre study covering Nordic patients with MHA and MHB. Arthropathy was evaluated by HEAD-US and HJHS 2.1. RESULTS: We assessed 693 joints in 118 patients. HEAD-US scores (medians [interquartile ranges]) were as follows: elbows 0 points (0-0), knees 0 (0-0) and ankles 0 (0-1). Respectively, by HJHS: elbows 0 (0-1), knees 0 (0-1) and ankles 0 (0-1). Cartilage (14%) and bone (13%) were most commonly affected by HEAD-US. Frequent HJHS findings were crepitus on motion in knees (39%), and loss of flexion (23%) and extension (13%) in ankles. HEAD-US correlated strongly with HJHS (elbows r = .70, knees r = .60 and ankles r = .65), but 24% had discordant scores. Joints with HJHS zero points, 5% captured HEAD-US ≥1 point. Moreover, 26% had HJHS findings without HEAD-US pathology. Notably, 31% of knees had crepitus on motion and normal HEAD-US. CONCLUSION: Overall, the joints attained low scores implying good joint health. HEAD-US correlated strongly with HJHS. In 5%, HEAD-US detected subclinical pathology. Crepitus on motion was frequently reported despite normal HEAD-US, thus not necessarily reflecting arthropathy. HEAD-US therefore improves the joint assessment in moderate haemophilia.

2.
Thromb Haemost ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33412597

RESUMO

BACKGROUND: Low levels of total C4b-binding protein (C4BPt), a circulating inhibitor of the classical/lectin complement pathways, were observed in patients with antiphospholipid antibodies (aPLs) and during warfarin treatment. OBJECTIVES: To investigate the associations between aPL and C4BPt in patients with persistently positive (++) aPL, with/without clinical manifestations and systemic lupus erythematosus (SLE), and in controls. Furthermore, we explored the impact of anticoagulation on C4BPt and in relation to complement activation. METHODS: In a cross-sectional design we investigated defined subgroups: primary (p) antiphospholipid syndrome (APS, N = 67), aPL++ individuals without clinical manifestations (aPL carriers, N = 15), SLE-aPL++ (N = 118, among them, secondary [s] APS, N = 56), aPL negative (-) SLE (SLE-aPL-, N = 291), and 322 controls. Clinical characteristics, including treatment, were tabulated. C4BPt was determined with a magnetic bead method. Complement proteins (C1q, C2, C3, C4, C3a, C3dg, sC5b-9, factor I [FI]) were measured. A mediation analysis was performed to decompose the total effect of aPL++ on C4BPt into the direct and indirect effects of aPL++ through warfarin. RESULTS: Overall, C4BPt is 20% decreased in aPL++ patients, regardless of SLE, APS, clinical manifestations, and aPL profile. C4BPt levels associate positively with complement proteins C1q, C2, C3, and C4, and negatively with complement activation product C3dg. In the SLE group, warfarin treatment contributes to approximately half of the C4BPt reduction (9%) CONCLUSION: Both aPLs and warfarin are associated with C4BPt reduction. Complement activation in aPL++ patients may partly be explained by impaired inhibition through depressed C4BPt levels. Further studies are needed to understand the clinical implications.

3.
J Thromb Haemost ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33179380

RESUMO

BACKGROUND: Abdominal obesity has been shown to be a superior measure over overall obesity for detecting cardiovascular risk. OBJECTIVE: We conducted this study to compare the effects of overall and central obesity on VTE and to calculate population attributable fraction for obesity for VTE. METHODS: Body mass index (BMI) and waist circumference (WC) was used to represent overall and abdominal obesity, respectively. In the cohort study, we included 74,317 Swedish adults with anthropometric measures in 1997 and of whom 4332 were diagnosed with VTE until the end of 2017. A Mendelian randomization study was conducted to investigate causal associations of BMI, WC, and WC adjusted for BMI with VTE using data from FinnGen and UK Biobank study. Population attributable fraction was calculated for overall and abdominal obesity for VTE. RESULTS: In the cohort study, there were dose-response associations of BMI and WC with VTE. The association between BMI and VTE was attenuated largely after adjusting for WC. Among individuals with normal BMI, participants with substantially increased WC had 53% higher (HR 1.53; 95% CI, 1.28, 1.81) risk of VTE compared with those with normal WC. The causality of the association of WC adjusted for BMI with VTE was confirmed in MR analysis. The estimated population-attributable risk due to elevated BMI and WC were 12.4% (8.4%, 16.5%) and 23.7% (18.1%, 29.4%), respectively. CONCLUSIONS: WC might be a preferable indictor linking obesity to VTE. A large proportion of VTE cases can be prevented if the population maintained a healthy BMI and WC.

4.
Haemophilia ; 26(5): 891-897, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33021747

RESUMO

INTRODUCTION: The prevalence of arthropathy in moderate haemophilia A (MHA) and B (MHB) is not well known. AIM: We evaluated joint health in Nordic patients in relation to their treatment modality. METHODS: A cross-sectional, multicentre study covering MHA and MHB in Sweden, Finland and Norway. Arthropathy was evaluated by ultrasound (HEAD-US) and Haemophilia Joint Health Score (HJHS). RESULTS: We report on 145 patients: median age 28 years (IQR 13-52) and 61% MHA. Baseline factor VIII/factor IX activity (FVIII/FIX:C) was 2 IU/dL (median) (IQR 2-4): lower for MHB (2 IU/dL, IQR 1-2) than MHA (3 IU/dL, IQR 2-4) (P < .01). Eighty-five per cent of MHA and 73% MHB had a history of haemarthrosis (P = .07). Age at first joint bleed was lower for MHA (5 years [median], IQR 3-7) than MHB (7 years, IQR 5-12) (P = .01). Thirty-eight per cent received prophylaxis, started at median 10 years of age (IQR 4-24). Median joint bleeds and serious other bleeds during the last 12 months were both zero (IQR 0-1). Total HEAD-US captured 0/48 points (median) (IQR 0-2) and HJHS 4/120 points (IQR 1-10) with strong correlation between them (r = .72). FVIII/FIX: C ≤ 3 IU/dL was associated with higher HJHS (P = .04). Fifteen per cent had undergone orthopaedic surgery. CONCLUSION: The current joint health in Nordic moderate haemophilia patients was rather good, but a subgroup had severe arthropathy. FVIII/FIX: C ≤ 3 IU/dL and MHA were associated with a more severe bleeding phenotype. We suggest primary prophylaxis to all patients with FVIII/FIX:C ≤ 3 IU/dL.

5.
EBioMedicine ; 59: 102956, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32805626

RESUMO

BACKGROUND: Tumour necrosis factor (TNF) inhibitors are used in the treatment of certain autoimmune diseases but given the role of TNF in tumour biology and atherosclerosis, such therapies may influence the risk of cancer and cardiovascular disease. We conducted a Mendelian randomization study to explore whether TNF levels are causally related to cardiovascular disease and cancer. METHODS: Single-nucleotide polymorphisms associated with TNF levels at genome-wide significance were identified from a genome-wide association study of 30 912 European-ancestry individuals. Three TNF-associated single-nucleotide polymorphisms associated with higher risk of autoimmune diseases were used as instrumental variables. Summary-level data for 14 cardiovascular diseases, overall cancer and 14 site-specific cancers were obtained from UK Biobank and consortia. FINDINGS: Genetically-predicted TNF levels were positively associated with coronary artery disease (odds ratio (OR) 2.25; 95% confidence interval (CI) 1.50, 3.37) and ischaemic stroke (OR 2.27; 95% CI 1.50, 3.43), and inversely associated with overall cancer (OR 0.54; 95% CI 0.42, 0.69), breast cancer (OR 0.51; 95% CI 0.39, 0.67), and colorectal cancer (OR 0.20; 95% CI 0.09, 0.45). There were suggestive associations of TNF with venous thromboembolism (OR 2.18; 95% CI 1.32, 3.59), endometrial cancer (OR 0.25; 95% CI 0.07, 0.94), and lung cancer (OR 0.45; 95% CI 0.21, 0.94). INTERPRETATION: This study found evidence of causal associations of increased TNF levels with higher risk of common cardiovascular diseases and lower risk of overall and certain cancers.

6.
Thromb Haemost ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32791533

RESUMO

BACKGROUND: Factor VIII (FVIII) activity (FVIII:C) can be measured by different methods including one-stage clotting assays (OSAs) and chromogenic assays (CSAs). Discrepancy between FVIII:C assays is known and associated with genetic variations causing mild and moderate hemophilia A (HA). We aimed to study the discrepancy phenomenon and to identify associated genetic alterations. Further, we investigated if hemostatic global assays could discriminate the group with discrepant FVIII:C from them. METHODS: The study contained plasma samples from 45 patients with HA (PwHA) from Hemophilia Centers in Stockholm, Sweden, and Belgrade, Serbia. We measured FVIII:C with OSA and CSA, sequenced the F8 gene, and performed two global hemostatic assays; endogenous thrombin potential and overall hemostatic potential. RESULTS: Nineteen of 45 PwHA had a more than twofold higher FVIII:C using OSA compared to CSA and were considered discrepant. Thirty-four causal mutations were detected, where of five had not previously been associated with assay discrepancy. These novel mutations were p.Tyr25Cys, p.Phe698Leu, p.Met699Leu, p.Ile1698Thr, and Ala2070Val. We found no difference between discrepant and nondiscrepant cases with either of the global assays. CONCLUSION: There was a discrepancy between FVIII:C assays in almost half of the PwHA, which for some could lead to missed HA diagnoses or misclassification of severity. Genotyping confirmed that mutations associated with FVIII:C discrepancy cluster in the A domains of F8, and five mutations not previously associated with FVIII:C discrepancy was identified. Global hemostatic assays did not contribute to distinguish assay discrepancy in PwHA.

7.
Nutrients ; 11(12)2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31817859

RESUMO

Whether circulating fatty acids (FAs) play a causal role in the development of cardiovascular disease (CVD) remains unclear. We conducted a Mendelian randomisation study to explore the associations between plasma phospholipid FA levels and 15 CVDs. Summary-level data from the CARDIoGRAMplusC4D, MEGASTROKE, and Atrial Fibrillation consortia and UK Biobank were used. Sixteen single-nucleotide polymorphisms (SNPs) associated with ten plasma FAs were used as instrumental variables. SNPs in or close to the FADS1 gene were associated with most FAs. We performed a secondary analysis of the association between a functional variant (rs174547) in FADS1, which encodes ?5-desaturase (a key enzyme in the endogenous FA synthesis), and CVD. Genetic predisposition to higher plasma α-linolenic, linoleic, and oleic acid levels was associated with lower odds of large-artery stroke and venous thromboembolism, whereas higher arachidonic and stearic acid levels were associated with higher odds of these two CVDs. The associations were driven by SNPs in or close to FADS1. In the secondary analysis, the minor allele of rs174547 in FADS1 was associated with significantly lower odds of any ischemic stroke, large-artery stroke, and venous thromboembolism and showed suggestive evidence of inverse association with coronary artery disease, abdominal aortic aneurysm and aortic valve stenosis. Genetically higher plasma α-linolenic, linoleic, and oleic acid levels are inversely associated with large-artery stroke and venous thromboembolism, whereas arachidonic and stearic acid levels are positively associated with these CVDs. The associations were driven by FADS1, which was also associated with other CVDs.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Ácidos Graxos Dessaturases/genética , Ácidos Graxos/sangue , Fosfolipídeos/sangue , Alelos , Ácido Araquidônico/sangue , Doenças Cardiovasculares/classificação , Análise de Dados , Predisposição Genética para Doença , Humanos , Ácido Linoleico/sangue , Análise da Randomização Mendeliana , Razão de Chances , Ácido Oleico/sangue , Polimorfismo de Nucleotídeo Único , Fatores de Proteção , Fatores de Risco , Ácidos Esteáricos/sangue , Ácido alfa-Linoleico/sangue
8.
Thromb Res ; 178: 34-40, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30959280

RESUMO

Venous thromboembolism (VTE) affects approximately 1 per 1000 persons annually. Although patients are increasingly treated with direct oral anticoagulants, many patients continue to be anticoagulated with vitamin K antagonists (VKA). The most important adverse events during VKA treatment, bleeding and the risk of recurrent VTE, are difficult to predict. Global haemostatic assays, such as thrombin generation assays and the viscoelastic whole blood tests thromboelastography (TEG) and thromboelastometry (ROTEM), allow a comprehensive assessment of haemostasis and could potentially predict such side effects. In the present study we compared results from thrombin generation (Calibrated Automated Thrombogram and Innovance ETP assays) and TEG and ROTEM in 84 warfarin-treated patients with primary or recurrent VTE and 87 healthy controls. VKA treatment lead to lagtime prolongation and a lower overall thrombin production, which correlated strongly with INR (Pearson r = 0.89 and r = -0.85, respectively). The reduced thrombin generation of VKA-treated patients was accurately reflected by tissue-factor activated ROTEM (EXTEM) clotting time prolongation (vs. CAT lagtime, r = 0.87). Clot strength or clot formation kinetics were only weakly affected by thrombin generation. Intrinsic pathway activated TEG or ROTEM (INTEM) were not sensitive to the reduced thrombin generation. In conclusion, patients anticoagulated with VKA after VTE showed a reduced plasma thrombin generation that was accurately reflected by tissue factor activated ROTEM. ROTEM provided additional information to thrombin generation, including clot formation kinetics and strength.


Assuntos
Anticoagulantes/uso terapêutico , Tromboelastografia/métodos , Varfarina/uso terapêutico , Anticoagulantes/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Varfarina/farmacologia
9.
Blood ; 130(15): 1706-1712, 2017 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-28835439

RESUMO

There is uncertainty regarding the effectiveness and occurrence of thromboembolic events in patients treated with prothrombin complex concentrates (PCCs) for the management of major bleeding events (MBEs) on rivaroxaban or apixaban. We investigated the effectiveness of PCCs given for the management of MBEs in patients on rivaroxaban or apixaban. Between 1 January 2014 and 1 October 2016, we prospectively included patients on rivaroxaban or apixaban treated with PCCs for the management of MBEs. The effectiveness of PCCs was assessed by using the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria for the assessment of the effectiveness of major bleeding management. The safety outcomes were thromboembolic events and all-cause mortality within 30 days after treatment with PCCs. A total of 84 patients received PCCs for the reversal of rivaroxaban or apixaban due to a MBE. PCCs were given at a median (interquartile range) dose of 2000 IU (1500-2000 IU). Intracranial hemorrhage (ICH) was the most common site of bleeding requiring reversal (n = 59; 70.2%), followed by gastrointestinal bleeding in 13 (15.5%) patients. Management with PCCs was assessed as effective in 58 (69.1%) patients and ineffective in 26 (30.9%) patients. Most patients with ineffective hemostasis with PCCs had ICH (n = 16; 61.5%). Two patients developed an ischemic stroke, occurring 5 and 10 days after treatment with PCC. Twenty-seven (32%) patients died within 30 days after a MBE. The administration of PCCs for the management of MBEs associated with rivaroxaban or apixaban is effective in most cases and is associated with a low risk of thromboembolism. Our findings are limited by the absence of a control group in the study.


Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Hemorragia/tratamento farmacológico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Rivaroxabana/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Fatores de Coagulação Sanguínea/efeitos adversos , Estudos de Coortes , Demografia , Feminino , Hemorragia/mortalidade , Humanos , Masculino , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Rivaroxabana/efeitos adversos , Tromboembolia/induzido quimicamente , Resultado do Tratamento
10.
Thromb Haemost ; 117(8): 1528-1533, 2017 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-28692107

RESUMO

Von Willebrand disease (VWD) is the most common bleeding disorder, but no bedside tests specific for Von Willebrand factor are available. The objective of this study was to evaluate the diagnostic accuracy of whole blood ristocetin-induced platelet aggregometry (WB-RIPA) in VWD. WB-RIPA was performed in VWD patients (n=100) and healthy controls (n=17) using the Multiplate® platelet impedance aggregometry platform. The diagnostic properties of the test were described as sensitivity/specificity, positive and negative predictive value, and ROC area under the curve (AUC). Patients with VWD had impaired platelet aggregation by WB-RIPA. At a cut-off of 98 U, the test sensitivity and specificity of WB-RIPA for VWD was 0.95 and 0.53. A cut-off of 60 U provided a specificity of 1.00 with reduced sensitivity of 0.76. All patients with type 3 VWD and >90 % of patients with type 2 VWD were accurately distinguished from the controls. Incorrect classifications were attributable to patients with type 1 VWD, showing partly overlapping WB-RIPA results with healthy controls. Remarkably, these patients had lower bleeding scores and higher VWF activity than other type 1 VWD patients. Overall, WB-RIPA discriminated VWD patients from healthy controls accurately with a ROC AUC of 0.94. These results show that WB-RIPA is a promising diagnostic test for VWD, especially when timely results are required. Depending on the chosen test threshold, WB-RIPA could be clinically used as a rule out test, or to suggest patients in whom further testing for VWD is warranted.


Assuntos
Agregação Plaquetária , Testes de Função Plaquetária , Testes Imediatos , Ristocetina/farmacologia , Doença de von Willebrand Tipo 1/diagnóstico , Doença de von Willebrand Tipo 2/diagnóstico , Doença de von Willebrand Tipo 3/diagnóstico , Adulto , Área Sob a Curva , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos Testes , Fatores de Tempo , Fluxo de Trabalho , Doença de von Willebrand Tipo 1/sangue , Doença de von Willebrand Tipo 2/sangue , Doença de von Willebrand Tipo 3/sangue
11.
Thromb Res ; 158: 168-173, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28669410

RESUMO

BACKGROUND: Thrombosis and complement activation are pathogenic features of antiphospholipid syndrome (APS). Their molecular link is Plasma carboxypeptidase-B, also known as thrombin activatable fibrinolysis inhibitor (TAFIa), which plays a dual role: anti-fibrinolytic, by cleaving carboxyl-terminal lysine residues from partially degraded fibrin, and anti-inflammatory, by downregulating complement anaphylatoxins C3a and C5a. AIM: To investigate the levels of TAFI (proenzyme) and TAFIa (active enzyme) in relation to complement activation, fibrin clot permeability and fibrinolytic function in clinical and immunological subsets of 52 APS patients and 15 controls. RESULTS: TAFI (p<0.001), TAFIa (p<0.05) and complement factor C5a (p<0.001) were increased, while fibrin permeability (p<0.01) was decreased and clot lysis time (CLT) was prolonged (p<0.05) in APS patients compared to controls. Furthermore, TAFIa was increased (p<0.01) in samples from APS patients affected by arterial thrombosis compared to other APS-phenotypes. Positive associations were found between TAFI and age, fibrinogen and C5a, and between TAFIa and age, fibrinogen and thrombomodulin. CONCLUSION: TAFI and TAFIa levels were increased in patients with APS as a potential response to complement activation. Interestingly, TAFI activation was associated with arterial thrombotic APS manifestations. Thus, TAFIa may be considered a novel biomarker for arterial thrombosis in APS.


Assuntos
Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Carboxipeptidase B2/sangue , Carboxipeptidase B2/imunologia , Adulto , Ativação do Complemento , Complemento C5a/imunologia , Feminino , Fibrina/imunologia , Fibrina/metabolismo , Humanos , Masculino , Tromboplastina/imunologia
12.
Blood ; 128(23): e59-e66, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27742707

RESUMO

There is a clear clinical need for high-specificity plasma biomarkers for predicting risk of venous thromboembolism (VTE), but thus far, such markers have remained elusive. Utilizing affinity reagents from the Human Protein Atlas project and multiplexed immuoassays, we extensively analyzed plasma samples from 2 individual studies to identify candidate protein markers associated with VTE risk. We screened plasma samples from 88 VTE cases and 85 matched controls, collected as part of the Swedish "Venous Thromboembolism Biomarker Study," using suspension bead arrays composed of 755 antibodies targeting 408 candidate proteins. We identified significant associations between VTE occurrence and plasma levels of human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1), von Willebrand factor (VWF), glutathione peroxidase 3 (GPX3), and platelet-derived growth factor ß (PDGFB). For replication, we profiled plasma samples of 580 cases and 589 controls from the French FARIVE study. These results confirmed the association of VWF and PDGFB with VTE after correction for multiple testing, whereas only weak trends were observed for HIVEP1 and GPX3. Although plasma levels of VWF and PDGFB correlated modestly (ρ ∼ 0.30) with each other, they were independently associated with VTE risk in a joint model in FARIVE (VWF P < .001; PDGFB P = .002). PDGFΒ was verified as the target of the capture antibody by immunocapture mass spectrometry and sandwich enzyme-linked immunosorbent assay. In conclusion, we demonstrate that high-throughput affinity plasma proteomic profiling is a valuable research strategy to identify potential candidate biomarkers for thrombosis-related disorders, and our study suggests a novel association of PDGFB plasma levels with VTE.


Assuntos
Proteômica , Proteínas Proto-Oncogênicas c-sis/sangue , Tromboembolia Venosa/sangue , Biomarcadores/sangue , Proteínas de Ligação a DNA/sangue , Feminino , Glutationa Peroxidase/sangue , Humanos , Masculino , Fatores de Risco , Fatores de Transcrição/sangue , Fator de von Willebrand/metabolismo
13.
Thromb Haemost ; 115(2): 406-14, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26423325

RESUMO

Genetic associations for the reoccurrence of venous thromboembolism (VTE) are not well described. Our aim was to investigate if common genetic variants, previously found to contribute to the prediction of first time thrombosis in women, were associated with risk of recurrence. The Thromboembolism Hormone Study (TEHS) is a Swedish nationwide case-control study (2002-2009). A cohort of 1,010 women with first time VTE was followed up until a recurrent event, death or November 2011. The genetic variants in F5 rs6025, F2 rs1799963, ABO rs514659, FGG rs2066865, F11 rs2289252, PROC rs1799810 and KNG1 rs710446 were assessed together with clinical variables. Recurrence rate was calculated as the number of events over the accumulated patient-time. Cumulative recurrence was calculated by Kaplan-Meier curve. Cox proportional-hazard model was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between groups. A total of 101 recurrent events occurred during a mean follow-up time of five years. The overall recurrence rate was 20 per 1,000 person-years (95% CI; 16-24). The recurrence rate was highest in women with unprovoked first event and obesity. Carriers of the risk alleles of F5 rs6025 (HR=1.7 (95% CI; 1.1-2.6)) and F11 rs2289252 (HR=1.8 (95% CI; 1.1-3.0)) had significantly higher rates of recurrence compared to non-carriers. The cumulative recurrence was 2.5-fold larger in carriers of both F5 rs6025 and F11 rs2289252 than in non-carriers at five years follow-up. In conclusion, F5 rs6025 and F11 rs2289252 contributed to the risk of recurrent VTE and the combination is of potential clinical relevance for risk prediction.


Assuntos
Fator V/genética , Fator XI/genética , Tromboembolia Venosa/sangue , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Fator V/metabolismo , Fator XI/metabolismo , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Estudos Prospectivos , Recidiva , Fatores de Risco , Suécia , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/genética
14.
Thromb Res ; 134(2): 426-32, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24745723

RESUMO

INTRODUCTION: We investigated whether genetic variations robustly associated with coronary artery disease are also associated with risk of venous thromboembolism in a well-defined, female case-control study (n=2753) from Sweden. MATERIALS AND METHODS: 39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in genome-wide association studies were identified in a literature search and genotyped in the ThromboEmbolism Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression. RESULTS: Only rs579459 in the ABO locus demonstrated a significant association with VTE. A tentative association between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts (total n=7181). CONCLUSIONS: It appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE.


Assuntos
Doença da Artéria Coronariana/genética , Tromboembolia Venosa/genética , Sistema ABO de Grupos Sanguíneos/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Loci Gênicos , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Fatores de Risco , Adulto Jovem
15.
Thromb Res ; 133(5): 936-44, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24630645

RESUMO

OBJECTIVE: The antiphospholipid syndrome (APS) is defined by persistent antiphospholipid antibodies together with thrombosis and/or pregnancy morbidity. We investigated the tightness of fibrin clot and fibrinolytic function in plasma samples from APS patients compared with two control groups. MATERIAL AND METHODS: APS patients (n=49), healthy controls (HC) (n=19) and warfarin-treated nonAPS thrombosis controls (nonAPS-TC) (n=39) were investigated. Fibrin permeability was assessed as the permeability coefficient (Ks) by a flow measurement technique. Additionally, clot density and fibrinolytic function was analysed by a turbidimetric clotting and lysis assay. Fibrin structure was visualised using scanning electron microscopy. Finally, the number of cell-derived microparticles (MPs) in the samples were correlated to fibrin permeability RESULTS AND CONCLUSIONS: The Ks value was lower in samples from APS-patients compared to HC and nonAPS-TC (p<0.0001 for both) indicating a less permeable fibrin clot in APS patients. Scanning electron microscopy images confirmed compact fibrin with smaller intrinsic pores and thinner fibers in samples from APS patients as compared to HC. Prolonged fibrinolysis (clot lysis) times were present in the subgroup of APS patients with previous arterial thrombosis (n=15) as compared to HC and to nonAPS-TC (all p-values<0.05). In conclusion, tighter fibrin clots were formed in plasma from APS patients compared with healthy controls and warfarin treated patients with thrombosis of "nonAPS origin". This new observation presents a possible mechanism contributing to the thrombotic predisposition of APS patients. Impaired fibrinolysis, selectively present among APS patients with previous arterial thrombosis, may further aggravate the pro-thrombotic state in this APS subgroup.


Assuntos
Síndrome Antifosfolipídica/sangue , Fibrina/metabolismo , Fibrinólise/fisiologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/sangue
16.
Arterioscler Thromb Vasc Biol ; 32(8): 2008-16, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22701019

RESUMO

OBJECTIVE: Elevated plasma levels of coagulation factor XI (FXI) are implicated in the pathogenesis of venous thromboembolism and ischemic stroke, and polymorphisms in the F11 gene are associated both with risk of venous thromboembolism and an elevated plasma FXI level. METHODS AND RESULTS: Here, we report the first hypothesis-free genome-wide genetic analysis of plasma FXI levels. Two genome-wide significant loci were detected in the family-based Genetic Analysis of Idiopathic Thrombophilia 1 cohort: one located in the kininogen 1 gene (KNG1) (rs710446; P=7.98 × 10(-10)) and one located in the structural F11 gene (rs4241824; P=1.16 × 10(-8)). Both associations were replicated in a second population-based Swedish cohort. A significant effect on KNG1 mRNA expression was also seen for the 2 most robustly FXI-associated single nucleotide polymorphisms located in KNG1. Furthermore, both KNG1 single nucleotide polymorphisms were associated with activated partial thromboplastin time, suggesting that FXI may be the main mechanistic pathway by which KNG1 and F11 influence activated partial thromboplastin time and risk of thrombosis. CONCLUSIONS: These findings contribute to the emerging molecular basis of venous thromboembolism and, more importantly, help in understanding the biological regulation of a phenotype that has proved to have promising therapeutic properties in relation to thrombosis.


Assuntos
Fator XI/análise , Estudo de Associação Genômica Ampla , Cininogênios/genética , Tempo de Tromboplastina Parcial , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Mapeamento Cromossômico , Fator XI/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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