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Essentials Chronic kidney disease (CKD) is associated with procoagulant and inflammatory biomarkers. We studied the association of CKD and venous thromboembolism (VTE) in a case-cohort study. Factor VIII, D-dimer and C-reactive protein appeared to explain the association of CKD and VTE. Statin use was protective against VTE in those with and without CKD. SUMMARY: Background Chronic kidney disease (CKD) is associated with venous thromboembolism (VTE) risk via unknown mechanisms. Whether factors associated with reduced VTE risk in the general population might also be associated with reduced VTE risk in CKD patients is unknown. Objectives To determine whether thrombosis biomarkers attenuate VTE risk, and whether factors associated with reduced VTE risk are similarly effective in CKD patients. Methods Baseline biomarkers were measured in a cohort (294 VTE cases; 939 non-cases) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a nationwide prospective cohort study of 30 239 persons aged ≥45 years with 4.3 years of follow-up. The hazard ratio (HR) of VTE per 10 mL min-1 1.73 m-2 decrease in estimated glomerular filtration rate (eGFR), and the percentage attenuation of this HR by each biomarker, were calculated. Associations of protective factors (physical activity, lower body mass index [BMI], and aspirin, warfarin and statin use) with VTE were estimated in those with and without CKD. Results The HR for VTE with lower eGFR was 1.13 (95% confidence interval [CI] 1.02-1.25), and VTE risk was attenuated by 23% (95% CI 5-100) by D-dimer, by 100% (95% CI 50-100) by factor VIII, and by 15% (95% CI 2-84) by C-reactive protein. Normal BMI was associated with lower VTE risk in those without CKD (HR 0.47, 95% CI 0.32-0.70), but not in those with CKD (HR 1.07, 95% CI 0.51-2.22). Statin use, physical activity and warfarin use were associated with lower VTE risk in both groups. Conclusions Procoagulant and inflammatory biomarkers mediated the association of eGFR with VTE. Higher physical activity, statin use and warfarin use mitigated VTE risk in those with CKD and those without CKD, but normal BMI did not mitigate VTE risk in CKD patients.
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Embolia Pulmonar/etiología , Insuficiencia Renal Crónica/complicaciones , Tromboembolia Venosa/etiología , Trombosis de la Vena/etiología , Anciano , Anciano de 80 o más Años , Anticoagulantes/uso terapéutico , Biomarcadores , Proteína C-Reactiva/análisis , Creatinina/sangre , Ejercicio Físico , Factor VIII/análisis , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Tasa de Filtración Glomerular , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inflamación , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Embolia Pulmonar/epidemiología , Embolia Pulmonar/prevención & control , Insuficiencia Renal Crónica/sangre , Riesgo , Delgadez , Trombofilia/sangre , Trombofilia/tratamiento farmacológico , Trombofilia/etiología , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/prevención & control , Trombosis de la Vena/epidemiología , Trombosis de la Vena/prevención & controlRESUMEN
Essentials Cognitive disorders are increasing and vascular risk factors play a role in this. We performed a nested case control study of hemostasis biomarkers and cognitive impairment (CI). Higher baseline fibrinogen, factor VIII and D-dimer were related to incident CI over 3.5 years. Adjusted for other risk factors, 2+ abnormal markers (but not single ones) led to higher risk. SUMMARY: Background Vascular risk factors are associated with cognitive impairment, a condition that imposes a substantial public health burden. We hypothesized that hemostasis biomarkers related to vascular disease would be associated with the risk of incident cognitive impairment. Methods We performed a nested case-control study including 1082 participants with 3.5 years of follow-up in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a longitudinal cohort study of 30 239 black and white Americans aged ≥ 45 years. Participants were free of stroke or cognitive impairment at baseline. Baseline D-dimer, fibrinogen, factor VIII and protein C levels were measured in 495 cases who developed cognitive impairment during follow-up (based on abnormal scores on two or more of three cognitive tests) and 587 controls. Results Unadjusted odds ratios (ORs) for incident cognitive impairment were 1.32 (95% confidence interval [CI] 1.02-1.70) for D-dimer > 0.50 µg mL-1 , 1.83 (95% CI 1.24-2.71) for fibrinogen > 90th percentile, 1.63 (95% CI 1.11-2.38) for FVIII > 90th percentile, and 1.10 (95% CI 0.73-1.65) for protein C < 10th percentile. There were no differences in associations by race or region. Adjustment for demographic, vascular and health behavior risk factors attenuated these associations. However, having at least two elevated biomarkers was associated with incident cognitive impairment, with an adjusted OR of 1.73 (95% CI 1.10-2.69). Conclusion Elevated D-dimer, fibrinogen and FVIII levels were not associated with the occurrence of cognitive impairment after multivariable adjustment; however, having at least two abnormal biomarkers was associated with the occurrence of cognitive impairment, suggesting that the burden of these biomarkers is relevant.
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Negro o Afroamericano/psicología , Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/etnología , Cognición , Factor VIII/análisis , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Fibrinógeno/análisis , Hemostasis , Población Blanca/psicología , Biomarcadores/sangre , Estudios de Casos y Controles , Trastornos del Conocimiento/diagnóstico , Femenino , Disparidades en el Estado de Salud , Humanos , Incidencia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Estados Unidos/epidemiología , Regulación hacia ArribaRESUMEN
BACKGROUND: Upper extremity deep vein thrombosis (UEDVT) is an increasingly recognized complication in medical inpatients, with few data available regarding the incidence, risk factors and association with central venous catheter (CVC) use. METHODS: Between 2002 and 2009 all cases of hospital-acquired venous thromboembolism (VTE) at a university hospital were frequency matched 1 : 2 to non-cases without VTE by admission year and medical service. Records were abstracted to identify, characterize and assess risk factors for UEDVT. Weighted logistic regression was used to calculate odds ratios (ORs) for UEDVT associated with use of a CVC, adjusting for known VTE risk factors. RESULTS: Two hundred and ninety-nine cases of VTE complicated 64 034 admissions to medical services (4.6 per 1000 admissions). UEDVT constituted 51% (91/180) of all deep vein thrombosis (DVT), for an incidence of 1.4 per 1000 admissions (95% confidence interval [CI], 0.8-1.7). There were 247 CVCs placed per 1000 admissions (95% CI, 203-292). The use of a CVC was associated with a 14.0-fold increased risk of UEDVT (95% CI, 5.9-33.2), but was not associated with a significantly increased risk of PE (OR, 1.3; 95% CI, 0.8-2.1). Peripherally inserted central catheters had a higher OR for UEDVT (OR, 13.0; 95% CI, 6.1-27.6) than centrally inserted central venous catheters (CICC) (OR, 3.4; 95% CI, 1.7-6.8). CONCLUSION: UEDVT is a relevant complication affecting medical inpatients, accounting for half of hospital-acquired DVTs. Use of CVCs was strongly associated with risk of UEDVT.
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Cateterismo Venoso Central/efectos adversos , Catéteres Venosos Centrales/efectos adversos , Pacientes Internos , Tromboembolia/etiología , Trombosis Venosa Profunda de la Extremidad Superior/etiología , Anciano , Estudios de Casos y Controles , Cateterismo Venoso Central/instrumentación , Femenino , Hospitales Universitarios , Humanos , Incidencia , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , Tromboembolia/diagnóstico , Factores de Tiempo , Trombosis Venosa Profunda de la Extremidad Superior/diagnóstico , VermontRESUMEN
The inflammatory response to healing in venous thrombosis might cause vein damage and post-thrombotic syndrome. Inflammation may also be involved in venous insufficiency apart from deep-vein thrombosis. We studied the association of inflammation markers with venous insufficiency in a general population sample. We characterised 2,404 men and women in a general population cohort for peripheral venous disease and its severity using physical exam, symptom assessment, and venous ultrasound. Inflammation markers, C-reactive protein (CRP), fibrinogen, interleukin 1-beta (IL-1-beta), IL-8, IL-10, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant-1 (MCP-1) and vascular endothelial cell growth factor (VEGF) were compared in 352 case participants with peripheral venous disease and 352 controls with no venous abnormalities frequency matched to cases by age, sex and race. Associations were also evaluated including a subset of 108 cases of severe venous disease, as previously defined. Odds ratios (95% CI), for peripheral venous disease for biomarkers in the top quartile (adjusting for age, race, sex, body mass index and history of venous thrombosis) were 1.8 (1.1-3.0), 1.6 (1.0-2.5) and 1.5 (0.9-2.3) for CRP, fibrinogen and IL-10, respectively. Associations were larger considering cases of severe venous disease, with odds ratios for these three analytes of 2.6 (1.2-5.9), 3.1 (1.3-7.3) and 2.2 (1.1-4.4), and for IL-8: 2.4 (1.1-5.2). There was no association of IL-1-beta, ICAM-1, VCAM-1, E-selectin, MCP-1 or VEGF with overall cases or severe venous disease. In conclusion, a subset of inflammation markers were associated with increased risk of peripheral venous disease, suggesting potential therapeutic targets for treatment.
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Proteína C-Reactiva/metabolismo , Citocinas/metabolismo , Fibrinógeno/metabolismo , Enfermedades Vasculares Periféricas/diagnóstico , Venas/metabolismo , Anciano , Biomarcadores/metabolismo , California , Quimiocina CCL2/metabolismo , Progresión de la Enfermedad , Selectina E/metabolismo , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Persona de Mediana Edad , Enfermedades Vasculares Periféricas/inmunología , Grupos de Población , Molécula 1 de Adhesión Celular Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Venas/patologíaRESUMEN
BACKGROUND: Normal protein C (PC) plasma levels range widely in the general population. Factors influencing normal PC levels are thought to influence the risk of venous thrombosis. Little is known about the underlying genetic variants. OBJECTIVES: We performed a genome scan of normal PC levels to identify genes that regulate normal PC levels. PATIENTS/METHODS: We performed a variance components linkage analysis for normal PC levels in 275 individuals from a single, large family. We then sequenced candidate genes under the identified linkage peak in eight family members: four with high and four with low, but normal, PC levels. For variants showing a difference in carriers between those with high and low PC levels, we re-evaluated linkage in the 275 family members conditional on the measured genotype effect. Genotype-specific mean PC levels were determined using likelihood analysis. Findings were replicated in the Leiden Thrombophilia Study (LETS). RESULTS: We identified a quantitative trait locus at chromosome 5q14.1 affecting normal PC plasma level variability. Next-generation sequencing of 113 candidate genes under the linkage peak revealed four SNPs in BHMT2, ACOT12, SSBP2 and XRCC4, which significantly increased PC levels in our thrombophilic family, but not in LETS. CONCLUSIONS: We identified four genes at chromosome 5q14.1 that might influence normal PC levels. BHMT2 seems the most likely candidate to regulate PC levels via homocysteine, a competitive inhibitor to thrombin. Failure to replicate our findings in LETS might be due to differences between the studies in genetic background and linkage disequilibrium patterns.
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Polimorfismo de Nucleótido Simple , Proteína C/metabolismo , Estudios de Casos y Controles , Ligamiento Genético , Humanos , Proteína C/genéticaRESUMEN
BACKGROUND: We sought to define the risk factors present at admission for venous thromboembolism (VTE) in medical inpatients and develop a risk model for clinical use. METHODS: Between January 2002 and June 2009, 299 cases of hospital-acquired VTE were frequency matched to 601 controls. Records were abstracted using a standard form for characteristics of the thrombosis, medical conditions and other risk factors. Weighted logistic regression and survey methods were used to develop a risk model for hospital-acquired VTE that was validated by bootstrapping. RESULTS: VTE complicated 4.6 per 1000 admissions. Two risk assessment models were developed, one using laboratory data available at admission (Model 1) and the other excluding laboratory data (Model 2). Model 1 consisted of the following risk factors (points): history of congestive heart failure (5), history of inflammatory disease (4), fracture in the past 3 months (3), history of VTE (2), history of cancer in the past 12 months (1), tachycardia (2), respiratory dysfunction (1), white cell count ≥ 11 × 10(9) /L (1), and platelet count ≥ 350 × 10(9) /L (1). Model 2 was similar, except respiratory dysfunction had 2 points and white cell and platelet counts were removed. The c-statistic for Model 1 was 0.73 (95% CI 0.70, 0.77) and for Model 2 0.71 (95% CI 0.68, 0.75). CONCLUSIONS: We present a VTE risk assessment model for use in medical inpatients. The score is simple and relies on information known at the time of admission and typically collected in all medical inpatients. External validation is needed.
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Pacientes Internos , Trombosis de la Vena/epidemiología , Humanos , Medición de RiesgoRESUMEN
BACKGROUND: Previously, we found increased clot-lysis time (CLT), as measured with a plasma-based assay, to increase the risk of venous thrombosis in two population-based case-control studies. The genes influencing CLT are as yet unknown. PATIENTS/METHODS: We tested CLT as risk factor for venous thrombosis in Kindred Vermont II (n = 346), a pedigree suffering from a high thrombosis risk, partially attributable to a type I protein C deficiency. Furthermore, we tested for quantitative trait loci (QTLs) for CLT, using variance component linkage analysis. RESULTS: Protein C-deficient family members had shorter CLTs than non-deficient members (median CLT 67 min vs. 75 min). One standard deviation increase in CLT increased the risk of venous thrombosis 2.4-fold in non-deficient family members. Protein C deficiency without elevated CLT increased the risk 6.9-fold. Combining both risk factors yielded a 27.8-fold increased risk. The heritability of CLT was 42-52%. We found suggestive evidence of linkage on chromosome 11 (62 cM), partly explained by the prothrombin 20210A mutation, and on chromosome 13 (52 cM). Thrombin-activatable fibrinolysis inhibitor genotypes did not explain the variation in CLT. CONCLUSION: Hypofibrinolysis appears to increase thrombosis risk in this family, especially in combination with protein C deficiency. Protein C deficiency is associated with short CLT. CLT is partly genetically regulated. Suggestive QTLs were found on chromosomes 11 and 13.
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Fibrinólisis/genética , Genoma Humano/fisiología , Deficiencia de Proteína C/fisiopatología , Trombosis/genética , Pruebas de Coagulación Sanguínea , Carboxipeptidasa B2/genética , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 13 , Familia , Ligamiento Genético , Humanos , Mutación , Deficiencia de Proteína C/genética , Protrombina/genética , Sitios de Carácter CuantitativoRESUMEN
The valve sinuses of the deep venous system are frequent sites of venous thrombus initiation. We previously reported that, in comparison with the non-valvular lumenal endothelium, the valve sinus endothelium had decreased expression of von Willebrand factor (vWF) and increased expression of endothelial protein C receptor (EPCR) and thrombomodulin (TM), suggesting alteration in the procoagulant/anticoagulant balance. We hypothesized that increased stasis in the deeper recesses of the venous valves would be associated with a gradient of increased thromboresistance. Expression of EPCR, TM, and vWF was analyzed via quantitative confocal immunofluorescence in residual saphenous veins collected following coronary artery bypass procedures. In agreement with our hypothesis, endothelial expression of vWF in the valve sinus decreased from the uppermost to the deepest region of the valve sinus. In contrast to our hypothesis, EPCR expression decreased from the uppermost to the deepest region of the valve sinus (p < 0.001) and TM expression remained unchanged throughout the valve sinus. Comparison of the non-valvular lumenal endothelium with the valve sinus endothelium demonstrated significantly decreased vWF expression (p < 0.001) in the valvular sinus consistent with our previous report; however, we did not observe statistically significant differences in EPCR or TM expression in this comparison. In addition, remarkable inter-individual variation in expression of these three proteins was also observed. These findings suggest that the genesis of these observations is more complex than predicted by our initial hypothesis, likely due, at least in part, to the complex rheology of the valvular sinus microenvironment.
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Antígenos CD/biosíntesis , Endotelio Vascular/metabolismo , Receptores de Superficie Celular/biosíntesis , Trombomodulina/biosíntesis , Válvulas Venosas/metabolismo , Factor de von Willebrand/biosíntesis , Receptor de Proteína C Endotelial , Expresión Génica , Variación Genética , Humanos , Vena Safena/metabolismo , Trombomodulina/metabolismo , Factor de von Willebrand/metabolismoRESUMEN
BACKGROUND: Obesity is a risk factor for venous disease. We tested the associations between adipokines and the presence and severity of venous disease. METHODS: Participants for this analysis were drawn from a cohort of 2408 employees and retirees of a university in San Diego who were examined for venous disease using duplex ultrasonography. From this cohort, a case-control study sample of all 352 subjects with venous disease and 352 age-, sex- and race-matched subjects without venous disease were included in this analysis. All subjects completed health history questionnaires, had a physical examination with anthropometric measurements and had venous blood analyzed for adipokines. RESULTS: After adjustment for age, sex and race, those with venous disease had significantly higher levels of body mass index (BMI), leptin and interleukin-6. Levels of resistin and tumor necrosis factor-alpha were also higher but of borderline significance (0.05 < P < 0.10). Compared with the lowest tertile and with adjustment for age, sex, race and BMI, the 2nd and 3rd tertiles of resistin (odds ratios, 1.9 and 1.7, respectively), leptin (1.7 and 1.7) and tumor necrosis factor-alpha (1.4 and 1.7) were associated with increasing severity of venous disease. Conversely, a 5 kg m⻲ increment in BMI was associated with a higher odds ratio (1.5) for venous disease, which was independent of the adipokines included in this study. CONCLUSIONS: Both obesity and adipokines are significantly associated with venous disease. These associations appear to be independent of each other, suggesting potentially different pathways to venous disease.
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Adipoquinas/metabolismo , Extremidad Inferior/irrigación sanguínea , Enfermedades Vasculares/metabolismo , Anciano , Índice de Masa Corporal , California , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Interleucina-6/metabolismo , Leptina/metabolismo , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Oportunidad Relativa , Resistina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ultrasonografía/métodos , Enfermedades Vasculares/terapiaRESUMEN
BACKGROUND: Clinically silent deep vein thrombosis (DVT) is common and may cause chronic venous disease that resembles post-thrombotic syndrome. OBJECTIVE: We evaluated whether peripheral venous disease in a general population shares risk factors with DVT. METHODS: In an established cohort of 2404 men and women, the San Diego Population Study, peripheral venous disease was evaluated using physical examination, symptom assessment and venous ultrasound. We performed a case-control study including 308 cases in four hierarchical groups by severity and 346 controls without venous abnormalities, frequency matched to cases by 10-year age group, race and gender. Cases and controls had no prior history of venous thrombosis. Hemostatic risk factors were measured in cases and controls. RESULTS: Accounting for age, obesity and family history of leg ulcer, odds ratios (ORs) of venous disease for elevated factor VIII, von Willebrand factor (VWF), D-dimer and for factor V Leiden were 1.4 (95% CI 0.9-2.1), 1.5 (CI 1.0-2.3), 1.7 (CI 1.1-2.8) and 1.1 (CI 0.5-2.4), respectively. These associations were larger for the two most severe case groups; ORs 2.0 (CI 1.0-3.8), 1.7 (CI 0.9-3.3), 2.7 (CI 1.2-6.1) and 2.3 (CI 0.8-7.1). Each hemostatic factor was also associated with severity of venous disease, for example elevated D-dimer was associated with a 2.2-fold increased odds of being in one higher severity case group. Prothrombin 20210A was not associated with venous disease. CONCLUSIONS: DVT risk factors are associated with presence and severity of peripheral venous disease. Results support a hypothesis that peripheral venous disease may sometimes be post-thrombotic syndrome as a result of a previous unrecognized DVT.
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Enfermedades Vasculares Periféricas/diagnóstico , Enfermedades Vasculares Periféricas/epidemiología , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/epidemiología , Factores de Edad , Anciano , California , Estudios de Casos y Controles , Factor V/genética , Femenino , Predisposición Genética a la Enfermedad , Hemostasis , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Protrombina/genética , Factores de RiesgoRESUMEN
BACKGROUND: Evidence found in the literature for a strong correlation between coagulation factors suggests that single genes might influence the plasma concentrations of multiple coagulation factors (i.e. pleiotropically acting genes). OBJECTIVE: To determine whether there is a genetic basis for the correlation among coagulation factors by assessing the heritability of interrelated coagulation factors. PATIENTS/METHODS: We performed principal components analysis, and subsequently variance components analysis, to estimate the heritability of principal components of coagulation factors in family members of a large French-Canadian kindred. RESULTS: Four clusters were identified by principal components analysis in 200 family members who did not carry the protein C 3363C mutation. Cluster 1 consisted of prothrombin, factor VII (FVII), FIX, FX and protein S; cluster 2 consisted of FV, FIX, protein C and tissue factor pathway inhibitor; cluster 3 consisted of FVIII and von Willebrand factor; and cluster 4 consisted of antithrombin, protein C and FVII. The heritability of the principal components estimated by variance components analysis was, respectively, 37%, 100%, 37%, and 37%. CONCLUSION: Our findings support the hypothesis that genes can influence plasma levels of interrelated coagulation factors.
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Factores de Coagulación Sanguínea/genética , Adolescente , Adulto , Anciano , Preescolar , Humanos , Lactante , Persona de Mediana Edad , Familia de Multigenes , Mutación , Proteína C/genética , Protrombina/genética , RadioinmunoensayoRESUMEN
BACKGROUND: Thrombophilia is a frequent medical condition associated with symptomatic deep vein thrombosis (DVT). Unlike other clinical risk factors associated with DVT, such as surgery, thrombophilia has not been demonstrated to be associated with asymptomatic venous thrombotic events. Our aim was to search for asymptomatic sequelae of DVT in a protein C (PC)-deficient family. METHODS: We studied 228 individuals from a large kindred with PC deficiency and performed a systematic ultrasound examination. RESULTS: Among the 203 patients without a known history of venous thrombosis we found seven patients with abnormalities indicative of prior asymptomatic thrombosis: six (7.4%) in the PC-deficient group (n = 81) and only one (0.8%) in the non-deficient group (n = 122). The relative risk for these sequelae associated with PC deficiency was 9.0 (95% CI: 1.1-73.7). CONCLUSIONS: These data suggest that chronic venous abnormalities are frequently present and that thrombotic events in asymptomatic individuals with familial PC deficiency may be underestimated.
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Deficiencia de Proteína C/complicaciones , Deficiencia de Proteína C/diagnóstico , Trombosis de la Vena/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Salud de la Familia , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Proteína C/genética , Embolia Pulmonar/complicaciones , Embolia Pulmonar/diagnóstico , Riesgo , Trombofilia/complicaciones , Trombofilia/diagnóstico , Trombosis , Ultrasonografía , Trombosis de la Vena/diagnósticoRESUMEN
Kindred Vermont II has a high frequency of venous thrombosis, occurring primarily in pedigree members with type I protein C deficiency due to a 3363 inserted (Ins) C mutation in exon 6 of the protein C gene. However, only a subset of 3363 InsC carriers have suffered thrombotic episodes, suggesting that the increased risk of thrombosis results upon the co-occurrence of 3363 InsC with a second, unknown, thrombophilic mutation that segregates independently within the pedigree. To test this hypothesis and to localize the co-occurring gene, we performed a genome scan of venous thrombosis in Kindred Vermont II. Non-parametric linkage statistics identified three potential gene locations, on chromosomes 11q23 (nominal P < 0.0001), 18p11.2-q11.2 (P < 0.0007), and 10p12 (P < 0.0003), supporting the presence of at least one additional thrombophilic mutation in the pedigree. Identification of the unknown mutation(s) promises to reveal a new genetic risk factor for thrombophilia, contribute to our understanding of the blood clotting mechanism, and expand our knowledge of the diversity of oligogenic disease.
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Genómica/métodos , Deficiencia de Proteína C/genética , Trombofilia/genética , Trombosis de la Vena/genética , Adolescente , Adulto , Anciano , Mapeo Cromosómico , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 11 , Salud de la Familia , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Deficiencia de Proteína C/complicaciones , Trombofilia/complicaciones , Trombosis de la Vena/etiologíaRESUMEN
BACKGROUND: Earlier studies found strong support for a genetic basis for regulation of coagulation factor levels and measures of a prethrombotic state (d-dimer, prothrombin fragment 1.2). OBJECTIVES: Estimation of how much of the variation in the levels of coagulation factors and measures of a prethrombotic state, including measures of protein C activation and inactivation, could be attributed to heritability and household effect. PATIENTS AND METHODS: Blood samples were collected from 330 members of a large kindred of French-Canadian origin with type I protein C deficiency. Heritability and common household effect were estimated for plasma concentrations of prothrombin, factor (F)V, factor VIII, factor (F)IX, fibrinogen, von Willebrand factor (VWF), antithrombin, protein C, protein S, protein Z, protein Z-dependent protease inhibitor (ZPI), fibrinopeptide A (FPA), protein C activation peptide (PCP), activated protein C-protein C inhibitor complex (APC-PCI), activated protein C-alpha1-antitrypsin complex (APC-alpha1AT), prothrombin fragment 1.2 (F1.2) and d-dimer, using the variance component method in sequential oligo-genic linkage analysis routines (SOLAR). RESULTS: The highest heritability was found for measures of thrombin activity (PCP and FPA). High estimates were also found for prothrombin, FV, FIX, protein C, protein Z, ZPI, APC-PCI and APC-alpha1AT. An important influence of shared household effect on phenotypic variation was found for VWF, antithrombin, protein S and F1.2. CONCLUSIONS: We found strong evidence for the heritability of single coagulation factors and measures of a prethrombotic state. Hemostatic markers with statistically significant heritability constitute potential targets for the identification of novel genes involved in the control of quantitative trait loci.
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Factores de Coagulación Sanguínea/genética , Deficiencia de Proteína C/genética , Trombofilia/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Factores de Coagulación Sanguínea/análisis , Proteínas Sanguíneas/análisis , Niño , Preescolar , Composición Familiar , Salud de la Familia , Femenino , Ligamiento Genético , Humanos , Lactante , Patrón de Herencia , Masculino , Persona de Mediana Edad , Fenotipo , Deficiencia de Proteína C/sangreRESUMEN
Recently, high levels of coagulation factor (F)VIII, FIX and FXI have been associated with an increased risk of venous thrombosis. For several coagulation factors a substantial hereditary component was found. If regulatory genes are located outside the clotting factor genes, they may regulate the levels of several proteins in the coagulation system. Thus levels would then cluster in individuals. The aim of the present study was to assess the inter-relation among levels of the pro- and anticoagulant proteins in the coagulation cascade. We also investigated the relation between the coagulation factors and d-dimer levels (marker of coagulation activity). All analyses were performed in healthy subjects, the control population of the Leiden Thrombophilia Study (LETS), to eliminate the influence of a prior thrombosis on the interpretation of the results (n = 466). Using principal-components analysis, a method intended to explain relationships among several correlated variables, we found a clustering between the vitamin K-dependent factors (prothrombin, VII, IX, X) and FXI and FXII. FV and FVIII clustered with fibrinogen and d-dimer. FXIII remained relatively independent of the other factors. Adding the anticoagulant factors to the analysis resulted in minor changes in the clustering pattern. The anticoagulant factors clustered together. We found relatively independent clusters within the group of pro- and anticoagulant factors, which may suggest that the genetic basis for high or low levels of factors in the coagulation system may, at least partly, lie outside the genes coding for these factors.
Asunto(s)
Factores de Coagulación Sanguínea/análisis , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Adolescente , Adulto , Anciano , Coagulación Sanguínea , Inhibidores de Factor de Coagulación Sanguínea/análisis , Análisis por Conglomerados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Componente PrincipalRESUMEN
Genetic evidence from a large Vermont kindred indicates that an unknown gene promotes thrombosis when inherited in conjunction with type I protein C deficiency. Cyclooxygenase-1 [prostaglandin H synthase 1 gene (PTGS1)] was tested as a plausible candidate for the unknown gene because of its role in primary hemostasis. The complete sequence of PTGS1 (25 638 nucleotides) was determined from a 37 kb human genomic cosmid clone to characterize intronic regions and subsequently to allow the search for mutations by direct sequencing of genomic DNA. Northern blot analysis confirms usage of a newly described distal poly-adenylation signal. Short tandem repeat (STR) sequences found in intron 2 and the 3' flanking region were developed as new genetic markers for PTGS1. The position of PTGS1 was refined on the CHLC chromosome 9 linkage map using the new markers scored in four Centre d'Etude du Polymorphisme Humain families and multipoint linkage analysis. Direct sequencing of DNA from members of the Vermont kindred led to the discovery of two new single nucleotide polymorphisms (SNPs) that give rise to non-conservative amino acid changes in the signal peptide (Arg(8) to Trp and Pro(17) to Leu) of cyclooxygenase-1. Linkage analysis of the SNP and STR markers indicated that PTGS1 is not the interacting gene associated with an increased incidence of thrombosis in the Vermont kindred.
Asunto(s)
Ligamiento Genético , Isoenzimas/genética , Prostaglandina-Endoperóxido Sintasas/genética , Trombosis/genética , Secuencia de Bases , Ciclooxigenasa 1 , Análisis Mutacional de ADN , Salud de la Familia , Marcadores Genéticos , Humanos , Proteínas de la Membrana , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Deficiencia de Proteína C/genética , Señales de Clasificación de Proteína/genética , Análisis de Secuencia de ADNRESUMEN
We have previously reported that the 3363 inserted (Ins) C mutation in exon 6 of the protein C gene was present in four unrelated French patients and in four French Canadian families with type I protein C deficiency as well as in a large Vermont protein C deficient kindred of French Canadian origin. The present study was designed to investigate the likelihood of the existence of a founder effect for this mutation in protein C deficient individuals of French origin living in France, Quebec and Vermont. In order to demonstrate a possible founder effect for the 3363 InsC mutation, we have previously constructed a high-resolution genetic map to locate several highly polymorphic markers close to the protein C locus. Thereafter, the markers D2S347, D2S2339, D2S383, D2S2271 and D2S2215 were genotyped in 117 heterozygotes from France (n = 7), Quebec (n = 36) or Vermont (n = 74). The allelic frequency distribution of these five markers was also determined in fifty control French Canadian subjects and thirty-two unaffected members of the Vermont kindred with normal protein C levels and compared with their frequency in our cohort of heterozygotes. Our data suggest that patients from Quebec and Vermont carry a common haplotype at the protein C locus. Moreover, in order to study the evolutionary history of the 3363 InsC mutation, we traced back the ascending genealogy of one proband in each of the families with this mutation. These results showed that the 3363 InsC mutation was most probably introduced in North America by a couple of French settlers who established themselves in 1669 on Isle d'Orleans located near Quebec City. All heterozygotes for the 3363 InsC mutation living in North America are related to these founders within 10 generations. Thus, these families afford a unique opportunity to evaluate the role of the protein C system in thrombophilia due to the high degree of linkage disequilibrium at the protein C gene, which in essence holds that variable more constant than in a more heterogeneous population.
Asunto(s)
Efecto Fundador , Mutagénesis Insercional , Proteína C/genética , Trombofilia/genética , Consanguinidad , Emigración e Inmigración/historia , Exones/genética , Femenino , Francia/epidemiología , Francia/etnología , Heterocigoto , Historia del Siglo XVII , Humanos , Masculino , Repeticiones de Microsatélite , Linaje , Quebec/etnología , Sistema de Registros , Trombofilia/epidemiología , Trombofilia/historia , Vermont/epidemiologíaRESUMEN
The incomplete penetrance of thrombosis in familial protein C deficiency suggests disease occurs when this deficit is combined with additional abnormalities in the hemostatic system. The pattern of inherited thrombophilia in the Vermont II kindred, which is affected by a clinically dominant type I protein C deficiency, provides strong evidence for a second unidentified gene that segregates independently of protein C deficiency and increases susceptibility to thrombosis. To test the second gene hypothesis, thirty-four candidate genes for proteins involved in hemostasis or inflammation were tested as the unknown defect, using highly polymorphic short tandem repeat (STR) markers in an informative subset (n = 31) of the kindred. The genes considered are; alpha-fibrinogen, beta-fibrinogen, gamma-fibrinogen, prothrombin, tissue factor, factor V, protein S, complement component 4 binding protein, factor XI, factor XII, factor XIIIa, factor XIIIb, histidine rich glycoprotein, high molecular weight kininogen, kallikrein, von Willebrands factor, platelet factor 4, thrombospondin, antithrombin III, alpha-1-antitrypsin, thrombomodulin, plasminogen, tissue plasminogen activator, urokinase plasminogen activator, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, protein C inhibitor, alpha-2-plasmin inhibitor, kallistatin, lipoprotein a, interleukin 6, interleukin 1, cystathionine-beta-synthase, and methylenetetrahydrofolate reductase. Mutations in many of these genes have been previously established as independent risk factors for thrombosis. However, linkage analysis provided no evidence to implicate any of the candidate genes as the second inherited factor that promotes thrombophilia in this kindred.
Asunto(s)
Pruebas Genéticas , Deficiencia de Proteína C/genética , Trombofilia/genética , Factores de Coagulación Sanguínea/genética , Proteínas Sanguíneas/genética , Salud de la Familia , Femenino , Frecuencia de los Genes , Ligamiento Genético , Marcadores Genéticos , Predisposición Genética a la Enfermedad/genética , Genoma , Humanos , Masculino , Mutación , Linaje , Polimorfismo Genético , Deficiencia de Proteína C/complicaciones , Secuencias Repetidas en Tándem , Trombosis/etiología , Trombosis/genéticaRESUMEN
We sought to assess the longitudinal stability of risk factors for atherosclerosis and thrombosis. including several coagulation. fibrinolysis, and inflammation factors, in frozen plasma samples stored at -70 degrees C for months or years. We reviewed data collected on 29 different control pools over periods ranging from 7 to 59 months for two functional assays (factor VII and fibrinogen) and seven antigen measurements (C-reactive protein. D-dimer, plasmin-alpha2-antiplasmin complex, plasminogen activator inhibitor-1, protein C, protein S, and tissue plasminogen activator), totaling more than 15,000 data points. Screening of the data using least squares regression revealed only sporadic associations between monthly means and time, with no consistent trends. Analysis by repeated measures and summary measure methods revealed no evidence of sample degradation over time for the factors studied. Our finding of longitudinal stability in the biochemical properties of frozen plasma strengthens the presumption of sample stability on which molecular epidemiologic studies are based.
Asunto(s)
Coagulación Sanguínea , Conservación de la Sangre , Proteínas Sanguíneas/análisis , Criopreservación , Mediadores de Inflamación/sangre , Proteínas de Fase Aguda/análisis , Antifibrinolíticos/sangre , Arteriosclerosis/sangre , Arteriosclerosis/epidemiología , Proteína C-Reactiva/análisis , Factor VII/análisis , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Fibrinógeno/análisis , Fibrinolisina , Fibrinólisis , Humanos , Análisis de los Mínimos Cuadrados , Inhibidor 1 de Activador Plasminogénico/análisis , Proteína C/análisis , Desnaturalización Proteica , Proteína S/análisis , Reproducibilidad de los Resultados , Factores de Riesgo , Trombosis/sangre , Trombosis/epidemiología , Factores de Tiempo , Activador de Tejido Plasminógeno/análisis , alfa 2-AntiplasminaRESUMEN
BACKGROUND: Whether smokers with a past history (PH) but not current history of alcohol dependence are more nicotine dependent than smokers with no such history (NH) is unclear. The present study was an experimental test of this hypothesis. METHOD: Twenty PH and 10 NH smokers abstained from smoking for 16 hr on each of 4 days. On each of 3 days, participants received three doses per day of 0, 2, or 4 mg nicotine gum in a within-subjects, randomized, double-blind, crossover design. To examine subjective effects, participants completed the Profile of Mood States, Addiction Research Inventory, and other ratings before and after each dose. To examine nicotine reinforcement, participants reported preference among the gums, reported on money versus gum choices, and, on the 4th day, underwent a double-blind self-administration test. RESULTS: Across the 21 subjective measures, with one exception, PH and NH smokers did not differ in subjective response to nicotine. However, across all three reinforcement measures, nicotine was a more potent reinforcer in PH than NH smokers. CONCLUSIONS: These results provide a behavioral mechanism to explain prior findings that PH smokers are more nicotine dependent than NH smokers.