| 1. |
- Ahmad, Abrar, et al.
(författare)
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Identification of polymorphisms in Apolipoprotein M gene and their relationship with risk of recurrent venous thromboembolism
- 2016
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 116:3, s. 41-432
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein M (ApoM) plasma levels have been reported to be associated with risk of venous thromboembolism (VTE) recurrence. However, the role of genetic alterations in the ApoM gene in VTE recurrence remains unknown. The aim of this study was to identify genetic aberrations in ApoM gene in VTE recurrence and their role in prediction of VTE recurrence in a prospective follow-up study of 1465 VTE patients. During follow-up, 156 (10.6 %) patients had VTE recurrence. First screening of whole ApoM gene was performed by Sanger's sequencing in selected age and sex matched non-recurrent and recurrent patients (n=95). In total six polymorphisms were identified and two polymorphisms (rs805297 and rs9404941) with minor allele frequency (MAF) ≥5 % were further genotyped in the whole cohort by Taqman PCR. ApoM rs805297 polymorphism was significantly associated with higher risk of VTE recurrence in males but not in females on both univariate (p= 0.038, hazard ratio = 1.72, confidence interval = 1.03-2.88) and on multivariate analysis adjusted with mild and severe thrombophilia, family history, location and acquired risk factors for VTE. However, ApoM rs9404941 polymorphism showed no significant association with risk of VTE recurrence in all patients as well as in different gender groups. Moreover, ApoM rs805297 and rs9404941 polymorphisms were not associated with the ApoM plasma levels. In conclusion, for the first time we have sequenced whole ApoM gene in VTE and identified six polymorphisms. ApoM rs805297 was significantly associated with higher risk of VTE recurrence in male but not in female patients.
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| 2. |
- Sundquist, Kristina, et al.
(författare)
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Plasminogen activator inhibitor-1 4G/5G polymorphism, factor V Leiden, prothrombin mutations and the risk of VTE recurrence.
- 2015
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 114:6, s. 1156-1164
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Tidskriftsartikel (refereegranskat)abstract
- Plasminogen-activator inhibitor (PAI)-1 is an important inhibitor of the plasminogen/plasmin system. PAI-1 levels are influenced by the 4G/5G polymorphism in the PAI-1 promoter. We investigated the relationship between the PAI-1 polymorphism and VTE recurrence, and its possible modification by factor V Leiden (FVL) and prothrombin (PTM) mutations. Patients (n=1,069) from the Malmö Thrombophilia Study were followed from discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of the study (maximum follow-up 9.8 years). One hundred twenty-seven patients (11.9 %) had VTE recurrence. PAI-1 was genotyped by TaqMan PCR. Cox regression analysis adjusted for age, sex and acquired risk factors of VTE showed no evidence of an association between PAI-1 genotype and risk of VTE recurrence in the study population as a whole. However, by including an interaction term in the analysis we showed that FVL but not PTM modified the effect of PAI-1 genotype: patients with the 4G allele plus FVL had a higher risk of VTE recurrence [hazard ratio (HR) =2.3, 95 % confidence interval (CI) =1.5-3.3] compared to patients with the 4G allele but no FVL (reference group) or FVL irrespective of PAI-1 genotype (HR=1.8, 95 % CI=1.3-2.5). Compared to reference group, 5G allele irrespective of FVL was associated with lower risk of VTE recurrence only when compared with 4G allele together with FVL. In conclusion, FVL has a modifying effect on PAI-1 polymorphism in relation to risk of VTE recurrence. The role of PAI-1 polymorphism as a risk factor of recurrent VTE may be FVL dependent.
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| 3. |
- Wang, Xiao, et al.
(författare)
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Diagnostic potential of plasma microRNA signatures in patients with deep-vein thrombosis
- 2016
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 116:2, s. 328-336
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Tidskriftsartikel (refereegranskat)abstract
- For excluding deep-vein thrombosis (DVT), a negative D-dimer and low clinical probability are used to rule out DVT. Circulating microR-NAs (miRNAs) are stably present in the plasma, serum and other body fluids. Their diagnostic function has been investigated in many diseases but not in DVT. The aims of present study were to assess the diagnostic ability of plasma miRNAs in DVT and to examine their correlation with known markers of hypercoagulability, such as D-dimer and APC-PCI complex. Plasma samples were obtained from 238 patients (aged 16-95 years) with suspected DVT included in a prospective multicentre management study (SCORE). We first performed miRNA screening of plasma samples from three plasma pools containing plasma from 12 patients with DVT and three plasma pools containing plasma from 12 patients without DVT using a microRNA Ready-to-use PCR Panel comprising 742 miRNA primer sets. Thirteen miRNAs that differentially expressed were further investigated by quantitative real-time (qRT)-PCR in the entire cohort. The plasma level of miR-424-5p (p=0.01) were significantly higher, whereas the levels of miR-136-5p (p=0.03) were significantly lower in DVT patients compared to patients without DVT. Receiver-operating characteristic curve analysis showed the area under the curve (AUC) values of 0.63 for miR-424-5p and 0.60 for miR-136-5p. The plasma level of miR-424-5p was associated with both D-dimer and APC-PCI complex levels (p<0.0001 and p=0.001, respectively). In conclusions, these findings indicate that certain miRNAs are associated with DVT and markers of hypercoagulability, though their diagnostic abilities are probably too low.
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| 4. |
- Zöller, Bengt, et al.
(författare)
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Age-and sex-specific seasonal variation of venous thromboembolism in patients with and without family history: a nationwide family study in Sweden.
- 2013
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 110:6, s. 1164-1171
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Tidskriftsartikel (refereegranskat)abstract
- Seasonal variation in venous thromboembolism (VTE) risk in individuals with familial predisposition to VTE has not been explored. This nationwide study aimed to determine whether there are age- and sex-specific seasonal differences in risk of hospitalisation of VTE among individuals with and without a family history of VTE. The Swedish Multi-Generation Register was linked to Hospital Discharge Register data for the period 1964-2010. Seasonal variation in first VTE events in 1987-2010 for individuals with and without a family history of VTE (siblings or parents) was determined by several independent methods. Stratified analyses were performed according to age, sex, and VTE subtype (pulmonary embolism [PE] or deep venous thrombosis [DVT]). Seasonal variation in VTE incidence, mostly with a peak during the winter, was observed in both sexes in individuals with and without family history with overall peak-to-low ratios (PLRs) of 1.15 and 1.21, respectively. The peak day was December 25 and February 1 for those with and without a family history of VTE, respectively. Seasonal variation was strongest among individuals aged >50 years. Among individuals aged 0-25 years with a family history, the peak for VTE was in July (PLR = 1.20). Significant seasonal variation was observed for PE and DVT with the exception of DVT among those with a family history (PLR = 1.01). In conclusion, our data support the presence of a modest seasonal variation of VTE among individuals with and without a family history of VTE. However, young age and family history may modify and attenuate the effect of season on VTE.
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| 5. |
- Zöller, Bengt, et al.
(författare)
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Association of Short-Term Mortality of Venous Thromboembolism with Family History of Venous Thromboembolism and Charlson Comorbidity Index
- 2019
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 119:1, s. 48-55
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Tidskriftsartikel (refereegranskat)abstract
- Studies on short-term prognosis of venous thromboembolism (VTE) that take family history of VTE and Charlson Comorbidity Index (CCI) into account are sparse. The aim was to investigate the importance of family history of VTE and CCI for short-term mortality after a first episode of VTE. Using Swedish medical databases, we conducted a 90-day nationwide cohort study of 41,700 Swedish born patients with a first-time VTE (July 2005-August 2012). Patients diagnosed with VTE and prescribed anticoagulant treatment were included. Mortality hazard ratios (HRs) with 95% confidence intervals (CIs) were determined with Cox regression. Patients with first-degree (sibling/parent) family history of VTE (n = 11,405, 27.4%) had significantly lower CCI than those without family history. Independent risk factors for 90-day mortality in the adjusted model were: female sex (HR = 1.19, 95% CI: 1.09-1.29), increasing age (HR = 1.02, 95% CI: 1.01-1.02 per year), pulmonary embolism (HR = 1.21, 95% CI: 1.11-1.32) or combined pulmonary embolism and deep venous thrombosis (HR = 1.60, 95% CI: 1.27-2.01) compared with deep venous thrombosis, CCI = 1 (HR = 2.93, 95% CI: 2.32-3.72), CCI = 2 (HR = 8.65, 95% CI: 7.16-10.46) or CCI = 3 (HR = 22.25, 95% CI: 18.73-26.44) compared with CCI = 0. Having one or two or more affected first-degree relatives with VTE was associated with lower mortality, HR = 0.83 (95% CI: 0.74-0.92) and HR = 0.65 (95% CI: 0.51-0.85), respectively. The mortality rate was 0.70% in patients with a CCI of zero. In receiver operating characteristic (ROC) analysis, the area under the ROC curve for CCI was 0.84 (0.83-0.95). Family history of VTE is associated with lower mortality while CCI is a strong predictor for short-term mortality in VTE. Co-morbidities are important for risk assessment of VTE.
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| 6. |
- Zöller, Bengt, et al.
(författare)
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Determination of age-specific and sex-specific familial risks for the different manifestations of venous thromboembolism: A nationwide family study in Sweden.
- 2011
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 106:1, s. 102-112
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Tidskriftsartikel (refereegranskat)abstract
- This nationwide study aimed to determine whether differences exist in age-specific and sex-specific familial risks for pulmonary embolism (PE), venous thrombosis of the lower limbs (VT) and other forms of venous thromboembolism (OVTE) among offspring, siblings and spouses of affected individuals. The Swedish Multi-Generation Register was linked to the Hospital Discharge Register data for the period 1987-2007. Standardised incidence ratios (SIRs) were calculated for individuals whose relatives were hospitalised for venous thromboembolism (VTE), as determined by the International Classification of Diseases (ICD), and those whose relatives were unaffected by VTE. The total number of hospitalised VTE patients was 45,362. All VTE patients were categorised as PE, VT or OVTE according to ICD at first hospitalisation. For example, the parental SIRs for PE, VT and OVTE in offspring at age 10-19 years were 2.89 (95% CI 1.48-5.06), 4.99 (95% CI 3.22-6.10) and 3.89 (95% CI 2.51-5.75), respectively. The low spousal risks of PE (1.08; 95% CI 1.02-1.13), VT (1.06; 95% CI 1.011.12) and OVTE (1.07; 95% CI 1.00-1.15) suggest the familial risks to be largely genetic. In both men and women, familial relative risks were increased for all the different manifestations of VTE with the exception of those older than 70 years. Familial history is a risk indicator in both sexes, and is potentially useful for clinical risk assessment for the different manifestations of VTE.
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| 7. |
- Zöller, Bengt, et al.
(författare)
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Familial risk of venous thromboembolism in first-, second- and third-degree relatives: a nationwide family study in Sweden.
- 2013
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 109:3, s. 458-463
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Tidskriftsartikel (refereegranskat)abstract
- Venous thromboembolism (VTE) clusters in families, but the familial risk of VTE has only been determined in first-degree relatives. This nationwide study aimed to determine the familial risk of VTE in first-, second- and third-degree relatives of affected individuals. The Swedish Multi-Generation Register was linked to Hospital Discharge Register data for the period 1987-2009. This was a case-cohort study. Odds ratios (ORs) for VTE were calculated for individuals whose relatives were hospitalised for VTE, as determined by the International Classification of Diseases (ICD), and those whose relatives were unaffected by VTE. The familial OR for VTE was 2.49 in siblings (95% confidence interval [CI] 2.40-2.58), 2.65 in children (2.50-2.80), 2.09 in parents (2.03-2.15), 1.52 in maternal half-siblings (1.26-1.85), 2.34 in paternal half-siblings (2.00-2.73), 1.69 in nieces/nephews (1.57-1.82), 1.47 in cousins (1.33-1.64), and 1.14 in spouses of individuals diagnosed with VTE (1.09-1.18). Familial clustering was stronger at young ages. The familial transmission was slightly stronger for males compared with females but was only significant for siblings 1.13 (1.05-1.22) and parents 1.11 (1.05-1.78) of probands. The present data showing an increased VTE risk among not only first-degree relatives but also second- and third-degree relatives indicate that the genetic component of the familial clustering of VTE is strong. Family history is a potentially useful genetic surrogate marker for clinical VTE risk assessment, even in second- and third degree-relatives.
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| 8. |
- Zöller, Bengt, et al.
(författare)
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Family history of venous thromboembolism as a risk factor and genetic research tool.
- 2015
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 114:5, s. 890-900
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Tidskriftsartikel (refereegranskat)abstract
- Familial clustering of venous thromboembolism (VTE) was described as far back as 1905 by Briggs. Although Egeberg discovered inherited deficiency of antithrombin in 1965, it was not until Dahlbäck discovered resistance to activated protein C in 1993 that it became clear that genetic factors are common risk factors of VTE. Several genes have been linked to familial aggregation of VTE and genome-wide association studies have found several novel gene loci. Still, it has been estimated that much of the heritability for VTE remains to be discovered. Family history (FH) of VTE is therefore still important to determine whether a patient has an increased genetic risk of VTE. FH has the potential to represent the sum of effects and interactions between environmental and genetic factors. In this article the design, methodology, results, clinical and genetic implications of FH studies of VTE are reviewed. FH in first-degree relatives (siblings and/or parents) is associated with a 2-3 times increased familial relative risk (FRR). However, the FRR is dependent on age, number of affected relatives, and presentation of VTE (provoked/unprovoked). Especially high familial risks are observed in individuals with two or more affected siblings (FFR> 50). However, the familial risk for recurrent VTE is much lower or non-significant. Moreover, FH of VTE appears mainly to be important for venous diseases (i. e. VTE and varicose veins). The familial associations with other diseases are weaker. In conclusion, FH of VTE is an important research tool and a clinically potential useful risk factor for VTE.
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