Dataset Information

Common variants of large effect in F12, KNG1, and HRG are associated with activated partial thromboplastin time.

ABSTRACT: 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.

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]

PMID: 20303064

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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.

Project description:BACKGROUND:Conventional coagulation assays (CCAs), prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time (aPTT), detect clotting factor (CF) deficiencies in hematologic disorders. However, there is controversy about how these CCAs should be used to diagnose, treat, and monitor trauma-induced coagulopathy. Study objectives were to determine whether CCA abnormalities are reflective of deficiencies of coagulation factor activity in the setting of severe injury. METHODS:Patients without previous CF deficiency within a prospective database at an ACS-verified Level I trauma center had CF activity levels, PT/INR, aPTT, and fibrinogen levels measured upon emergency department arrival from 2014 to 2017. Linear regression assessed how CF activity explained the aPTT and PT/INR variation. Prolonged CCA values were set as INR greater than 1.3 and aPTT greater than 34 seconds. CF deficiency was defined as less than 30% activity, except for fibrinogen, defined as less than 150 mg/dL. RESULTS:Sixty patients with a mean age of 35.8 (SD, 13.6) years and median New Injury Severity Score of 32 (interquartile range, 12-43) were included; 53.3% sustained blunt injuries, 23.3% required massive transfusion, and mortality was 11.67%. Overall, 44.6% of the PT/INR variance and 49.5% of the aPTT variance remained unexplained by CF activity. Deficiencies of CFs were: common pathway, 25%; extrinsic pathway, 1.7%; and intrinsic pathway, 6.7%. The positive predictive value for CF deficiencies were: (1) PT/INR greater than 1.3:4.4% for extrinsic pathway, 56.5% for the common pathway; (2) aPTT greater than 34 seconds:16.7% for the intrinsic pathway, 73.7% for the common pathway. CONCLUSION:Almost half of the variances of PT/INR and aPTT were unexplained by CF activity. Prolonged PT/INR and aPTT were poor predictors of deficiencies in the intrinsic or extrinsic pathways; however, they were indicators of common pathway deficiencies. LEVEL OF EVIDENCE:Prognostic, level III.

Dataset Information

Common variants of large effect in F12, KNG1, and HRG are associated with activated partial thromboplastin time.

Publications

Common variants of large effect in F12, KNG1, and HRG are associated with activated partial thromboplastin time.

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