Significantly different coagulation factor activities underlying the variability of 'normal' activated partial thromboplastin time
The activated partial thromboplastin time (aPTT) is a widely used coagulation screening test in routine laboratories. The aPTT level in the control population varies and is reflected by the reference interval. However, there have been no studies to investigate the coagulation status determining the variability of the aPTT. The aim of this study was to investigate the coagulation factor activities underlying the variability of aPTT in the population. The study participants were reference individuals with prothrombin time and aPTT within reference intervals. The aPTT was determined using STA-PTT Automate (Diagnostica Stago, Asnieres, France; local reference interval, 29.1-41.9 s). Those with aPTT within the marginal ranges of reference interval were selected for factor assays. We defined the lower marginal group as the lowest 10 percentile of reference interval (29.1-30.9 s) and the upper marginal group as the highest 10 percentile (38.0-41.9 s). Activities of factor II, V, VIII, IX, X, XI, and XII were determined in both groups. The lower marginal and upper marginal groups consisted of 220 and 209 individuals, respectively. All coagulation factors were significantly higher in the lower marginal than in the upper marginal group (P = 0.0127 for factor II and P < 0.0001 for the others). Multiple logistic regression analyses revealed factor XII and VIII were two strongest contributors determining the aPTT level, whereas factor XI was not significantly different between the groups (P = 0.095). This study firstly demonstrated significantly different coagulation factor activities underlying the variability of aPTT in reference individuals. The results suggested the possibility of disease association or phenotypic contribution of variable coagulation activities in the population.
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ABSTRACT: It remains unclear how coagulation and anticoagulant factors influence global coagulation assays such as prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin generation assay (TGA). We measured PT, aPTT, coagulation factor and protein levels, and TGA parameters (lag time, endogenous thrombin potential [ETP], and peak thrombin) in 252 apparently healthy adults. Vitamin K-dependent coagulation and anticoagulant factors were significantly correlated with blood lipids. PT was determined by factor (F) V and FVII; aPTT was dependent on antithrombin, protein C, FVIII, and FXII. Lag time was mainly determined by FVII, FXII, and protein S and peak thrombin by FVIII and FIX. Antithrombin (for ETP and lag time) and protein S (for lag time) contributed significantly to TGA inhibition. This knowledge about determinants of global coagulation assays may help interpret the results of coagulation assays and contribute to the future development of diagnostic tools. The synchronized plasma levels of vitamin K-dependent proteins with opposite functionalities may compensate a propensity to hyper- or hypocoagulability in a normal population.
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ABSTRACT: The activated partial thromboplastin time (aPTT) is a routine coagulation test that reflects the activities of multiple coagulation proteins. Given the known genetic elements underlying the different coagulation factor activities, a low intraindividual variability is expected in aPTT values, but has not been demonstrated in a large population. In this regard, we evaluated the intraindividual variability of aPTT by analyzing serial aPTTs from a large population. The study population consisted of control individuals who had three or more consecutive aPTT values at at least 6-month intervals at a single institution. The coefficient of variation of serial aPTT values was determined in each control individual, and the mean value of the coefficient of variations in the control population was calculated. The aPTT values from a total of 10 487 individuals [mean age 57 years (range 21-93 years); male-to-female ratio 1 : 0.9] were included. The mean value of the coefficient of variation of aPTTs in those individuals was 3.75%, which indicates a very low intraindividual variability. This is the first study to demonstrate a low intraindividual variability of aPTT in a large population. The result supports the previous notion that aPTT is a genetically determined parameter and has potential clinical implications.
Available from: Johanna Deinum
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ABSTRACT: In the activated partial thromboplastin time (APTT) assay, a variety of nonphysiological reagents is used to induce contact activation. The sensitivity of the APTT response for different thrombin inhibitors has previously been found to be dependent on the used reagent. Recently, infusion of prothrombin (FII) has been used in in-vivo coagulopathy models and its effect has been analyzed in different assays. Therefore, we investigated whether the FII plasma concentration might affect APTT using different commercial reagents, applying both turbidimetry and viscometry. We compared both plasma-derived human FII (pd-hFII) and recombinant human FII (r-hFII). Similar results were found for pd-hFII and r-hFII with different APTT reagents. As expected, no effect on APTT was found by increasing the plasma concentration of FII using APTT reagents consisting of ellagic acid (Actin FS or Actin). Although with Pathromtin SL, consisting of SiO2, only a slight increase was found, with most other commercial APTT reagents, consisting of SiO2 or kaolin, APTT dose-dependently increased by increasing concentration of FII. Therefore, both Pathromtin SL and Actin FS were used to compare r-hFII and pd-hFII by determining the KM at 37C using FII-depleted plasma, providing values of 6 ± 0.3 nmol/l FII for both. Thus, at normal plasma concentrations of FII, the maximal initial thrombin generation rate should be reached and no effect on the coagulation time is expected at higher FII concentrations. To completely avoid the paradoxical effect in the APTT assay at FII concentrations higher than normal, Actin or Actin FS is the preferable reagent.
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