Common variants of large effect in F12, KNG1, and HRG are associated with activated partial thromboplastin time.
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SUBMITTER: Houlihan LM
PROVIDER: S-EPMC2850435 | biostudies-literature | 2010 Apr
REPOSITORIES: biostudies-literature
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Common variants of large effect in F12, KNG1, and HRG are associated with activated partial thromboplastin time.
Houlihan Lorna M LM Davies Gail G Tenesa Albert A Harris Sarah E SE Luciano Michelle M Gow Alan J AJ McGhee Kevin A KA Liewald David C DC Porteous David J DJ Starr John M JM Lowe Gordon D GD Visscher Peter M PM Deary Ian J IJ
American journal of human genetics 20100318 4
Activated partial thromboplastin time (aPTT) is associated with risk of thrombosis and coagulation disorders. We conducted a genome-wide association study for aPTT and identified significant associations with SNPs in three coagulation cascade genes, F12 (rs2731672, combined p = 2.16 x 10(-30)), KNG1 (rs710446, combined p = 9.52 x 10(-22)), and HRG (rs9898, combined p = 1.34 x 10(-11)). These three SNPs explain approximately 18% of phenotypic variance in aPTT in the Lothian Birth Cohorts. ...[more]
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Project description:Background To evaluate the prognostic value of preoperative activated partial thromboplastin time (APTT) in patients who underwent coronary artery bypass grafting (CABG). Methods All data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The study population was divided to two groups according to the optimal cut-off value of APTT calculated by X-tile software, and Cox proportional hazard model was used to define independent effect of APTT on 4-year mortality. Survival curves were estimated by the Kaplan-Meier method, and the area under the receiver-operating characteristic curve (AUC) was calculated to compare APTT with other severity scores. Propensity score matching (PSM) analysis were applied to ensure the robustness of this study. Results A total of 2,706 patients were included. The optimal cut-off value of APTT for 4-year mortality was 44 seconds. The Cox proportional hazard model showed that patients with APTT ≥ 44 had a significantly higher risk of all-cause death than those with APTT < 44 both before (HR (95% CI), 1.42 (1.16-1.74), P < 0.001) and after PSM (HR (95% CI), 1.47 (1.14-1.89), P = 0.003). The survival curves showed that patients with longer APTT had a significantly lower 1-year and 4-year cumulative survival probability. The ROC of APTT combined with other severity scores significantly increased predictive ability for 1-year and 4-year mortality. Conclusions A longer APTT (≥44) was associated with a higher risk of mortality and can serve as a prognostic predictor in CABG patients.
| S-EPMC9509521 | biostudies-literature
Project description:(1) Background: The purpose of this study was to evaluate the effect of gene polymorphisms on prothrombin time (PT) and activated partial thromboplastin time (APTT) in a healthy Chinese population. (2) Methods: A total of 403 healthy volunteers from a series of novel oral anticoagulants (NOACs) bioequivalence trials in China were included. Coagulation tests for PT and APTT were performed in the central lab at Peking University First Hospital. Whole-exome sequencing (WES) and genome-wide association analysis were performed. (3) Results: In the correlation analysis of PT, 105 SNPs from 84 genes reached the genome-wide significance threshold (p < 1 × 10−5). Zinc Finger Protein 594 (ZNF594) rs184838268 (p = 4.50 × 10−19) was most significantly related to PT, and Actinin Alpha 1 (ACTN1) was found to interact most with other candidate genes. Significant associations with previously reported candidate genes Aurora Kinase B (AURKB), Complement C5(C5), Clock Circadian Regulator (CLOCK), and Histone Deacetylase 9(HDAC9) were detected in our dataset (p < 1 × 10−5). PiggyBac Transposable Element Derived 2(PGBD2) rs75935520 (p = 4.49 × 10−6), Bromodomain Adjacent To Zinc Finger Domain 2A(BAZ2A) rs199970765 (p = 5.69 × 10−6) and Protogenin (PRTG) rs80064850 (p = 8.69 × 10−6) were significantly correlated with APTT (p < 1 × 10−5). The heritability values of PT and APTT were 0.83 and 0.64, respectively; (4) Conclusion: The PT and APTT of healthy populations are affected by genetic polymorphisms. ZNF594 and ACTN1 variants could be novel genetic markers of PT, while PRTG polymorphisms might be associated with APTT levels. The findings could be attributed to ethnic differences, and need further investigation.
| S-EPMC9602091 | biostudies-literature
Project description:BackgroundA substantial fraction of all American healthcare expenditures are potentially wasted, and practices that are not evidence-based could contribute to such waste. We sought to characterize whether Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) tests of preoperative patients are used in a way unsupported by evidence and potentially wasteful.Methods and findingsWe evaluated prospectively-collected patient data from 19 major teaching hospitals and 8 hospital-affiliated surgical centers in 7 states (Delaware, Florida, Maryland, Massachusetts, New Jersey, New York, Pennsylvania) and the District of Columbia. A total of 1,053,472 consecutive patients represented every patient admitted for elective surgery from 2009 to 2012 at all 27 settings. A subset of 682,049 patients (64.7%) had one or both tests done and history and physical (H&P) records available for analysis. Unnecessary tests for bleeding risk were defined as: PT tests done on patients with no history of abnormal bleeding, warfarin therapy, vitamin K-dependent clotting factor deficiency, or liver disease; or aPTT tests done on patients with no history of heparin treatment, hemophilia, lupus anticoagulant antibodies, or von Willebrand disease. We assessed the proportion of patients who received PT or aPTT tests who lacked evidence-based reasons for testing.ConclusionsThis study sought to bring the availability of big data together with applied comparative effectiveness research. Among preoperative patients, 26.2% received PT tests, and 94.3% of tests were unnecessary, given the absence of findings on H&P. Similarly, 23.3% of preoperative patients received aPTT tests, of which 99.9% were unnecessary. Among patients with no H&P findings suggestive of bleeding risk, 6.6% of PT tests and 7.1% of aPTT tests were either a false positive or a true positive (i.e. indicative of a previously-undiagnosed potential bleeding risk). Both PT and aPTT, designed as diagnostic tests, are apparently used as screening tests. Use of unnecessary screening tests raises concerns for the costs of such testing and the consequences of false positive results.
| S-EPMC4532488 | biostudies-literature
Project description:Although the activated partial thromboplastin time (aPTT) has historically been the method of choice for anticoagulation monitoring in patients undergoing mechanical circulatory support with intravenous unfractionated heparin, it is being progressively superseded by the anti-factor Xa (anti-Xa) method. A retrospective single-arm, single-centre analysis of 20 patients who underwent total artificial heart implantation entailed simultaneous determinations of aPTT and anti-Xa. Agreement between these parameters was assessed using the Bland-Altman method. Despite a positive correlation between aPTT and anti-Xa, normal target ranges were poorly aligned: from 5th to 30th postoperative day, for anti-Xa values of 0.2 and 0.4 U/ml corresponding aPTT values were 52.1 and 65.2 s, 7.9 and 14.8 lower than predicted values, respectively. This was not associated with thromboembolic sequalae. It was not possible to demonstrate a significant relationship between the predictor variables (postoperative day; white blood cell count; C-reactive protein concentration; alanine transaminase and alkaline phosphatase level; bilirubin; haemoglobin; albumin and total protein concentration) and the agreement between aPTT and anti-Xa levels. In summary, when anti-Xa levels were used to guide anticoagulation therapy, corresponding aPTT levels were low with respect to target range. Methodology applied in this study is generalizable to other forms of mechanical circulatory support.
| S-EPMC8766202 | biostudies-literature
Project description:(1) Background: The activated partial thromboplastin time (APTT)- based clot waveform analysis (CWA) quantitatively extends information obtained from the APTT waveform through its derivatives. However, pre-analytical variables including reagent effects on the CWA parameters are poorly understood and must be standardized as a potential diagnostic assay. (2) Methods: CWA was first analysed with patient samples to understand reagent lot variation in three common APTT reagents: Pathromtin SL, Actin FS, and Actin FSL. A total of 1055 healthy volunteers were also recruited from seven institutions across the Asia-Pacific region and CWA data were collected with the Sysmex CS analysers. (3) Results: CWA parameters varied less than 10% between lots and the linear mixed model analysis showed few site-specific effects within the same reagent group. However, the CWA parameters were significantly different amongst all reagent groups and thus reagent-specific 95% reference intervals could be calculated using the nonparametric method. Post-hoc analysis showed some degree of influence by age and gender with weak correlation to the CWA (r < 0.3). (4) Conclusions: Reagent type significantly affects APTT-based CWA with minimal inter-laboratory variations with the same coagulometer series that allow for data pooling across laboratories with more evidence required for age- and gender-partitioning.
| S-EPMC10377778 | biostudies-literature
Project description:PurposeTo evaluate the prognostic role of prothrombin time (PT) and activated partial thromboplastin time (APTT) for newly diagnosed multiple myeloma (MM).MethodsWe retrospectively analyzed 354 patients with newly diagnosed MM who received primary treatment in our center. The propensity score matching technique was used to reduce the bias between groups.ResultsAmong 354 patients, lengthened PT or APTT was observed in 154 (43.5%) patients and 200 (56.5%) patients had normal PT and APTT. Patients with lengthened PT or APTT had significantly shorter median overall survival (OS) (37.5 vs. 73.8 months, p < 0.001) and progression-free survival (PFS) (23.1 vs. 31.6 months, p = 0.001) than those with normal PT and APTT. Univariate Cox proportional hazards regression analyses showed that lengthened PT or APTT was associated with shorter OS (HR = 2.100, 95% CI: 1.525-2.893, p < 0.001). Lengthened PT or APTT was also a poor prognostic factor for OS (HR = 3.183, 95% CI: 1.803-5.617, p < 0.001) in multivariable analyses. The poor effect of lengthened PT or APTT on PFS was confirmed in univariate analysis (HR = 1.715, 95% CI: 1.244-2.365, p = 0.001), but it had no impact on PFS in multivariate analysis (p = 0.197). In the propensity score matching analysis, 154 patients, 77 in each group, were identified. Among 154 matched patients, the OS of patients with lengthened PT or APTT was shorter (38.4 vs. 51.0 months, p = 0.030), but PFS was similar (29.0 vs. 35.0 months, p = 0.248).ConclusionThese results demonstrated that lengthened PT or APTT was an independent poor prognostic factor for patients with newly diagnosed MM.
| S-EPMC8159641 | biostudies-literature
Project description:Activated partial thromboplastin time (aPTT) is an important routine measure of intrinsic blood coagulation. Addition of activated protein C (APC) to the aPTT test to produce a ratio, provides one measure of APC resistance. The associations of some genetic mutations (eg, factor V Leiden) with these measures are established, but associations of other genetic variations remain to be established. The objective of this work was to test for association between genetic variants and blood coagulation using a high-density genotyping array. Genetic association with aPTT and APC resistance was analysed using a focused genotyping array that tests approximately 50 000 single-nucleotide polymorphisms (SNPs) in nearly 2000 cardiovascular candidate genes, including coagulation pathway genes. Analyses were conducted on 2544 European origin women from the British Women's Heart and Health Study. We confirm associations with aPTT at the coagulation factor XII (F12)/G protein-coupled receptor kinase 6 (GRK6) and kininogen 1 (KNG1)/histidine-rich glycoprotein (HRG) loci, and identify novel SNPs at the ABO locus and novel locus kallikrein B (KLKB1)/F11. In addition, we confirm association between APC resistance and factor V Leiden mutation, and identify novel SNP associations with APC resistance in the HRG and F5/solute carrier family 19 member 2 (SLC19A2) regions. In conclusion, variation at several genetic loci influences intrinsic blood coagulation as measured by both aPTT and APC resistance.
| S-EPMC3682876 | biostudies-literature
Project description:BackgroundAnticoagulation therapy with heparin is a frequent treatment in intensive care units and is monitored by activated partial thromboplastin clotting time (aPTT). It has been demonstrated that reaching an established anticoagulation target within 24 hours is associated with favorable outcomes. However, patients respond to heparin differently and reaching the anticoagulation target can be challenging. Machine learning algorithms may potentially support clinicians with improved dosing recommendations.ObjectiveThis study evaluates a range of machine learning algorithms on their capability of predicting the patients' response to heparin treatment. In this analysis, we apply, for the first time, a model that considers time series.MethodsWe extracted patient demographics, laboratory values, dialysis and extracorporeal membrane oxygenation treatments, and scores from the hospital information system. We predicted the numerical values of aPTT laboratory values 24 hours after continuous heparin infusion and evaluated 7 different machine learning models. The best-performing model was compared to recently published models on a classification task. We considered all data before and within the first 12 hours of continuous heparin infusion as features and predicted the aPTT value after 24 hours.ResultsThe distribution of aPTT in our cohort of 5926 hospital admissions was highly skewed. Most patients showed aPTT values below 75 s, while some outliers showed much higher aPTT values. A recurrent neural network that consumes a time series of features showed the highest performance on the test set.ConclusionsA recurrent neural network that uses time series of features instead of only static and aggregated features showed the highest performance in predicting aPTT after heparin treatment.
| S-EPMC9614623 | biostudies-literature
Project description:Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p = 4.26 × 10(-24)). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p = 3.22 × 10(-9)) and AGBL1 (rs2469184, p = 3.61 × 10(-8)). For PT, significant associations were identified and confirmed in F7 (rs561241, p = 3.71 × 10(-56)) and PROCR/EDEM2 (rs2295888, p = 5.25 × 10(-13)). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for ?29% of the variance in aPTT and two loci that account for ?14% of the variance in PT were detected and supported by functional data.
| S-EPMC3397273 | biostudies-literature
Project description:Reduced activated partial thromboplastin time (aPTT) is a risk marker for incident and recurrent venous thromboembolism (VTE). Genetic factors influencing aPTT are not well understood, especially in populations of non-European ancestry. The present study aimed to identify aPTT-related gene variants in both European Americans (EAs) and African Americans (AAs). We conducted a genetic association study for aPTT in 9719 EAs and 2799 AAs from the Atherosclerosis Risk in Communities (ARIC) study. Using the Candidate Gene Association Resource (CARe) consortium candidate gene array, the analyses were based on ∼50 000 SNPs in ∼2000 candidate genes. In EAs, the analyses identified a new independent association for aPTT in F5 (rs2239852, P-value = 1.9 × 10(-8)), which clusters with a coding variant rs6030 (P-value = 7.8 × 10(-7)). The remaining significant signals were located on F5, HRG, KNG1, F11, F12 and ABO and have been previously reported in EA populations. In AAs, significant signals were identified in KNG1, HRG, F12, ABO and VWF, with the leading variants in KNG1, HRG and F12 being the same as in the EAs; the significant variant in VWF (rs2229446, P-value = 1.2 × 10(-6)) was specific to the AA sample (minor allele frequency = 19% in AAs and 0.2% in EAs) and has not been previously reported. This is the first study to report aPTT-related genetic variants in AAs. Our findings in AAs demonstrate transferability of previously reported associations with KNG1, HRG and F12 in EAs. We also identified new associations at F5 in EAs and VWF in AAs that have not been previously reported for aPTT.
| S-EPMC4375421 | biostudies-literature