Performance goals for the laboratory testing of antithrombin, protein C and protein S

2006 ◽  
Vol 96 (11) ◽  
pp. 584-589 ◽  
Author(s):  
Frits Haverkate ◽  
Cornelis Kluft ◽  
Piet Meijer
Keyword(s):  
Protein C ◽  
Total Error ◽  
Diagnostic Testing ◽  
Protein S ◽  
Analytical Performance ◽  
Performance Goals ◽  
Analytical Quality ◽  
Performance Goal ◽  
Protein S Activity

SummaryTo achieve a reliable analytical quality for both monitoring and diagnostic testing, laboratories need to fulfil the widely accepted analytical performance goals based on the biological variation of the analytes of testing. Not only is the short-term analytical performance, which regularly is assessed by internal quality control procedures, of importance, but also the long-term analytical performance. To assess the long-term analytical performance, data obtained from an external quality assessment programme can be used. In this study we have used the evaluation model designed by the ECAT Foundation for the assessment of the longterm analytical performance, including imprecision, bias and total analytical error. The model was applied to the data from 136 different laboratories for the assay of antithrombin (activity), protein C (activity and antigen) and protein S (activity, total and free antigen). The imprecision (median; range), reflected by the long-term analytical coefficient of variation (LCVA), was the lowest for antithrombin (7.6%; 2.6 – 43.8%) and the highest for protein S activity (17.2%; 4.3 – 88.6%). For bias and total error the same pattern was observed (antithrombin: 3.8%; 0.3 – 17.1% and 9.1%; 3.4 – 34.3%, respectively; protein S activity: 12.8%; 3.1 – 34.8% and 24.5%; 9.9 – 87.0%, respectively). For the majority of the laboratories (70 – 85%) the imprecision contributes considerably more to the total error than the bias. However the effect of the bias on the analytical quality is not negligible. Assays for antithrombin, protein C and protein S are mainly used for diagnostic testing. About 70 – 100% of the laboratories can fulfil the desirable performance goal for imprecision. The desirable performance goal for bias was reached by 50 – 95% of the laboratories. In all cases the highest numbers of laboratories fulfilling performance goals was obtained for the protein C variables. To improve the analytical quality in assays of antithrombin, protein C and protein S it is highly recommended that primarily imprecision (non-systematic failures) be suppressed. However the effect of the bias (systematic failures) on the analytical quality should not be neglected. A useful tool for determining the imprecision (LCVA) and bias is the long-term analytical performance evaluation model as used by the ECAT Foundation.

scholarly journals Performance Criteria for Testosterone Measurements Based on Biological Variation in Adult Males: Recommendations from the Partnership for the Accurate Testing of Hormones

2012 ◽  
Vol 58 (12) ◽  
pp. 1703-1710 ◽  
Author(s):  
Yeo-Min Yun ◽  
Julianne Cook Botelho ◽  
Donald W Chandler ◽  
Alex Katayev ◽  
William L Roberts ◽  
...  
Keyword(s):  
Total Error ◽  
Full Range ◽  
Biological Variation ◽  
Analytical Performance ◽  
Performance Criteria ◽  
Performance Goals ◽  
Adult Males ◽  
Large Variability ◽  
Wide Range ◽  
Variation Data

BACKGROUND Testosterone measurements that are accurate, reliable, and comparable across methodologies are crucial to improving public health. Current US Food and Drug Administration–cleared testosterone assays have important limitations. We sought to develop assay performance requirements on the basis of biological variation that allow physiologic changes to be distinguished from assay analytical errors. METHODS From literature review, the technical advisory subcommittee of the Partnership for the Accurate Testing of Hormones compiled a database of articles regarding analytical and biological variability of testosterone. These data, mostly from direct immunoassay-based methodologies, were used to specify analytical performance goals derived from within- and between-person variability of testosterone. RESULTS The allowable limits of desirable imprecision and bias on the basis of currently available biological variation data were 5.3% and 6.4%, respectively. The total error goal was 16.7%. From recent College of American Pathologists proficiency survey data, most currently available testosterone assays missed these analytical performance goals by wide margins. Data from the recently established CDC Hormone Standardization program showed that although the overall mean bias of selected certified assays was within 6.4%, individual sample measurements could show large variability in terms of precision, bias, and total error. CONCLUSIONS Because accurate measurement of testosterone across a wide range of concentrations [approximately 2–2000 ng/dL (0.069–69.4 nmol/L)] is important, we recommend using available data on biological variation to calculate performance criteria across the full range of expected values. Additional studies should be conducted to obtain biological variation data on testosterone from women and children, and revisions should be made to the analytical goals for these patient populations.

Impact of Erythrocytapheresis on Endogenous Anticoagulants in Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4590-4590
Author(s):  
Ruchika Sharma ◽  
Gary Woods ◽  
Susan E Creary ◽  
Kan Hor ◽  
Cody Young ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Total Protein ◽  
Research Funding ◽  
Protein C ◽  
Protein S ◽  
Cell Disease ◽  
Educational Grant ◽  
Protein C Activity ◽  
D Dimer ◽  
Protein S Activity

Abstract Introduction The rate of venous thrombo-embolism (VTE) in patients with sickle cell disease (SCD) is estimated to be 4 - 8%; the incidence of catheter-associated VTE in this cohort is 0.16-0.99 per 1000 catheter days. Possible mechanisms for VTE in patients with SCD include hyperviscosity, ischemia reperfusion injury and chronic vascular inflammation. Additionally, patients with SCD exhibit decreased plasma levels of natural anticoagulants such as proteins C and S compared to healthy adults. A retrospective review at our institution found that the incidence of central venous line (CVL)-associated VTE in children with SCD was 0.12/1000 catheter days. On multivariate analysis, CVLs were identified as the only independent risk factor for VTE. Among patients with CVL, we found an association between bilateral CVLs and VTE (Odds Ratio [95% CI] = 10.3 [1.1-92.2]). Children with SCD frequently require CVLs for intravenous access or chronic erythrocytapharesis to reduce SCD-related complications. It is unknown, however, if erythrocytapharesis may also disrupt their natural anticoagulants levels and further increase their risk for subsequent VTE. We hypothesized that erythrocytapheresis may contribute to the pro-coagulant phenotype by altering patients' natural anticoagulants levels. Methods As part of a quality improvement initiative we measured antithrombin (AT), protein C antigen and activity, protein S antigen (total and free) and activity prior to being placed on the apheresis circuit and after completion of exchange in patients with SCD (0-21 years of age) undergoing chronic erythrocytapheresis who had a CVL (between January 1, 2009 and January 31, 2015). D-Dimer levels were obtained pre exchange only. Protein C and S levels were measured using ELISA based assays; protein C and S activities were measured using a clotting based assay and AT was measured using a chromogenic assay. The resulting levels, pre and post-erythrocytapheresis were analyzed using a paired nonparametric Wilcoxon rank test. Results Eleven patients were eligible for this study (8 females, 3 males). Median age at the time of erythrocytapheresis was 14 years (±3.65 SD) years. Indications for erythrocytapheresis included primary/ secondary stroke prevention or recurrent acute chest syndrome. All patients had bilateral CVLs in place. Four of the included patients had a history of VTE; 2 patients were on anticoagulation with low molecular weight heparin at the time of the study. The mean value for total protein S antigen (65u/dL; normal >72u/dL), free protein S antigen (53u/dL; normal >70u/dL), and protein S activity (51IU/mL; normal 65-138IU/ml) were all abnormal pre- erythrocytapheresis and decreased significantly following erythrocytapheresis (52u/dL, 44u/dL, and 44IU/mL respectively). Mean protein C antigen (71u/dL; normal >55u/dL), protein C activity (71%; normal 55-111%), and AT activity (104%; normal 77-132%) were within the normal range pre-erythrocytapheresis and decreased significantly post-erythrocytapheresis. We demonstrated significantly lower levels of protein C antigen (p=0.01), protein C activity (p=0.01), total protein S antigen (p=0.005), free protein S antigen (p=0.036), protein S activity (p=.04), and AT activity (p=.004) following erythrocytapheresis (Figure). D-Dimer levels were elevated in 6/11 patients (54.5%). Conclusions Pre- and post-erythrocytapheresis levels of natural endogenous anticoagulants investigated in a cohort of patients with SCD undergoing chronic erythrocytapheresis demonstrated that levels of all investigated proteins were significantly lower in patients following erythrocytapheresis. D-dimer levels were elevated in the majority of patients pre exchange but the importance of this finding is unclear. Given the relatively short half-life of the natural anticoagulants (2-3 hours for protein C and 36-60 hours for AT and protein S), it is unclear if this acute decrease of natural anticoagulants is clinically relevant. Further investigation is needed to determine if this acute decrease may contribute to an increased VTE risk in children with SCD undergoing apheresis. Figure 1. Figure 1. Disclosures Woods: Biogen: Other: Educational Grant. Dunn:Novo Nordisk: Consultancy, Other: Educational Grant; CSL Behring: Consultancy, Other: Data Safety Monitoring Board; Bayer: Consultancy, Other: educational grant; Biogen: Consultancy, Other: Educational grant, Research Funding; Baxalta: Consultancy, Other: educational grant, Research Funding; Ohio State University: Employment; Pfizer: Other: Grant Review Board.

scholarly journals Influence of hyperinsulinemic – hypoglycemic clamp on induced platelet aggregation, activity of physiological anticoagulants and von Willebrand factor in patients with type I diabetes

2018 ◽  
Vol 21 (2) ◽  
pp. 84-91
Author(s):  
Iwona R. Jarek-Martynowa ◽  
Mikhail Y. Martynov ◽  
Karina G. Sarkisova ◽  
Ekaterina O. Koksharova ◽  
Ekaterina E. Mishina ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Platelet Aggregation ◽  
Platelet Activation ◽  
Protein C ◽  
Protein S ◽  
Normal Limits ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Protein S Activity

Background. Intensive glycaemic control in patients with type 1 diabetes may lead to hypoglycaemia and thus increase the risk of cardiovascular and cerebrovascular events. Platelet activation and/or decreased activity of physiological anticoagulants during hypoglycaemia may play a role in the development of cardiovascular or cerebrovascular complications. Aims. To investigate induced platelet activity, the activity of physiological anticoagulants, and the von Wil-lebrand factor in patients with type 1 diabetes with the hyperinsulinaemichypoglycaemic clamp. Materials and methods. We examined 11 patients with type 1 diabetes without macro- and micro-vascular complications (6 males, 5 females, mean age 23.7 5.6 years, A1C 9.7 2.3%). Induced platelet aggregation, physiological anticoagulants (Protein S, Protein C, AT III) and the von Willebrand factor were studied at hyperglycaemic, euglycaemic, and hypoglycaemic stages during use of a hyperinsulinaemic (1 mU/kg/min) hypoglycaemic clamp. Results. Platelet aggregation to all agonists increased significantly during the hypoglycaemic stage, compared with the euglycaemic or hyperglycaemic stages. There was no difference in platelet aggregation between the euglycaemic and hyperglycaemic stages. Platelet aggregation to all agonists increased during the hypoglycaemic stage compared with the hyperglycaemic period: thrombin23.9%, ADP30.6%, arachidonic acid30.9%, collagen69.4% and ristocetin70.8%. During hypoglycaemia aggregation to ADP, arachidonic acid and collagen remained within normal limits (upper quartile); aggregation to thrombin was significantly above normal limits and aggregation to ristocetin remained significantly below lower limits. Protein S activity was significantly increased during hypoglycaemia compared with euglycaemia (p = 0.046) and hyperglycaemia (p = 0.046). Antithrombin-III activity decreased significantly at the euglycaemic and hypoglycaemic stages, compared with the hyperglycaemic period, but still remained significantly elevated above the upper threshold. Protein C and vWf activity did not change significantly. Conclusions. In patients with type 1 diabetes platelet aggregation and protein S activity increases significantly at the hypoglycaemic stage of the hyperinsulinaemichypoglycaemic clamp. Platelet activation is directly caused by hypoglycaemia and not by decreasing glucose levels. Increased protein S activity is a compensatory response to platelet activation.

scholarly journals Functional and immunologic protein S levels are decreased during pregnancy

Blood ◽  
1986 ◽  
Vol 68 (4) ◽  
pp. 881-885 ◽  
Author(s):  
PC Comp ◽  
GR Thurnau ◽  
J Welsh ◽  
CT Esmon
Keyword(s):  
Pregnant Women ◽  
Total Protein ◽  
Postpartum Period ◽  
Protein C ◽  
Binding Protein ◽  
Activated Protein C ◽  
Protein S ◽  
Functional Protein ◽  
Protein Levels ◽  
Protein S Activity

Abstract Protein S, is a natural anticoagulant protein which serves as a cofactor for activated protein C. During pregnancy and in the postpartum period, functional protein S levels are significantly reduced (38% +/- 17.3%, mean +/- 1 SD) when compared to nonpregnant females (97% +/- 31.6%) (P less than 0.001). In plasma an equilibrium exists between functionally active free protein S and protein S complexed with C4b-binding protein, which is functionally inactive. As a result of this equilibrium either a decreased level of total protein S antigen or an elevation of C4b-binding protein could lead to reduced protein S activity. C4b-binding protein levels measured by enzyme- linked immunoassay are not significantly different in pregnant women versus nonpregnant controls (103.5% +/- 21.2% v 100% +/- 16.9%). However, during pregnancy and in the postpartum period, total protein S levels are reduced (68% +/- 10.7%) compared to nonpregnant controls (100% +/- 17.0%). This difference is significant at P less than 0.001. These data demonstrated that the reduction in protein S activity observed during pregnancy is a result of reduced total protein S antigen.

The 1999 Stockholm Consensus Conference on quality specifications in laboratory medicine

2015 ◽  
Vol 53 (6) ◽  
Author(s):  
Callum G. Fraser
Keyword(s):  
Laboratory Medicine ◽  
Consensus Conference ◽  
Analytical Performance ◽  
Performance Goals ◽  
Analytical Quality ◽  
Global Consensus ◽  
Current State ◽  
Regulatory Bodies ◽  
Quality Specifications ◽  
Stockholm Conference

AbstractThe setting of analytical quality specifications in laboratory medicine has been a topic of discussion and debate for over 50 years: 15 years ago, as the subject matured and a profusion of recommendations appeared, many of them from expert groups, it was realised by a number of leading professionals that there was a need for a global consensus on the setting of such specifications. The Stockholm Conference held in 1999 on “Strategies to set global analytical quality specifications in laboratory medicine” achieved this and advocated the ubiquitous application of a hierarchical structure of approaches. The hierarchy has five levels, namely: 1) evaluation of the effect of analytical performance on clinical outcomes in specific clinical settings; 2) evaluation of the effect of analytical performance on clinical decisions in general using a) data based on components of biological variation, or b) analysis of clinicians’ opinions; 3) published professional recommendations from a) national and international expert bodies, or b) expert local groups or individuals; 4) performance goals set by a) regulatory bodies, or b) organisers of external quality assessment (EQA) schemes; and 5) goals based on the current state of the art as a) demonstrated by data from EQA or proficiency testing scheme, or b) found in current publications on methodology. This approach has been much used since its wide promulgation, but there have been ongoing criticisms and new developments. The time seems right for an objective reappraisal of recommended strategies to set analytical performance goals.

Risk Factors and Long-term Follow-up of Patients with the Immune Type of Heparin-Induced Thrombocytopenia

2002 ◽  
Vol 8 (4) ◽  
pp. 347-352 ◽  
Author(s):  
Edelgard Lindhoff-Last ◽  
Britta Wenning ◽  
Martina Stein ◽  
Frank Gerdsen ◽  
Rupert Bauersachs ◽  
...  
Keyword(s):  
Risk Factors ◽  
Factor Viii ◽  
Protein C ◽  
Protein S ◽  
Factor Xii ◽  
Factor V ◽  
Heparin Induced Thrombocytopenia ◽  
Long Term Follow Up

Dispositional risk factors for developing the immune-type of heparin-induced thrombocytopenia (HIT) are yet unclear. This article presents a long-term follow-up of patients with HIT to define possible risk factors that may increase the risk of HIT. The clinical course of acute HIT was analyzed retrospectively in 52 patients with HIT. Thirteen patients died;8 due to HIT. A follow-up investigation was performed in 28 of the remaining 39 patients 29 ± 12 months after the onset of HIT, including genotyping for the factor V G1691A- and the prothrombin G20210A-mutation, measurement of antithrombin, protein C, protein S, factor VIII, and factor XII activity as well as the concentration of antiphospholipid antibodies. The results were compared to an age- and sex-matched control group. New thromboembolic events and re-exposure to heparin were also documented. No difference between patients and controls was observed concerning the factor V Leiden mutation, the prothrombin mutation, factor XII, antithrombin, protein S, or protein C deficiency and antiphospholipid antibodies. Increased factor VIII activity was found in 16 of 21 HIT patients compared to 4 of 21 controls (p=0.0005). New thromboembolic events developed in 5 patients within 9 months after HIT. One patient had been re-exposed to heparin 9 months after acute HIT without any complications. Increased factor VIII activity was frequently observed in patients in whom HIT developed. Thromboembolic complications within the first months after onset of HIT occurred often.

Variability of INR in patients on stable long-term treatment with phenprocoumon and acenocoumarol and implications for analytical quality requirements

2009 ◽  
Vol 102 (09) ◽  
pp. 588-592 ◽  
Author(s):  
Johanna H. H. van Geest-Daalderop ◽  
Nathalie C. V. Péquériaux ◽  
Anton M. H. P. van den Besselaar
Keyword(s):  
Term Treatment ◽  
Biological Variation ◽  
Vitamin K Antagonist ◽  
Analytical Quality ◽  
Performance Goal ◽  
Quality Requirements ◽  
Long Term Treatment ◽  
Target Intensity ◽  
The Mean

SummaryWithin each patient treated with vitamin K antagonist (VKA), variation of the international normalised ratio (INR) occurs over the treatment period. The purpose of the present study was to assess INR variation in selected patients on long-term treatment in whom the dose of VKA was not changed.This type of variation is considered as “biological variation” which is caused by many factors but not VKA dose changes or other medication. Four groups of long-term patients were examined: each group with a different VKA (acenocoumarol or phenprocoumon) or a different target intensity (INR 2.0–3.5 or 2.5–4.0). All patients were monitored with the same PT system (Hepato Quick, STA-R Evolution coagulation instrument) by one laboratory.The variation of the INR within each patient was expressed as coefficient of variation (CV, in %).The CV was corrected for the average imprecision of the INR measurement (CV, 2.4%). The mean corrected CV values for the four groups were: 10.9% (acenocoumarol, target INR 2.0–3.5); 10.5% (acenocoumarol, target INR 2.5–4.0); 10.4% (phenprocoumon, target INR 2.0–3.5); 9.1% (phenprocoumon, target INR 2.5–4.0). The analytical performance goal for the INR measurement (imprecision) can be derived from the within-subject biological variation. Desirable INR imprecision goals are <4.9% and <5.3% CV for monitoring of phenprocoumon and acenocoumarol, respectively. These goals were achieved using the aforesaid PT system.

scholarly journals Apixaban Does Not Interfere With Protein S or Activated Protein C Resistance (Factor V Leiden) Testing Using aPTT-Based Methods

2020 ◽  
Vol 144 (11) ◽  
pp. 1401-1407 ◽  
Author(s):  
Elena Maryamchik ◽  
Elizabeth M. Van Cott
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Dna Testing ◽  
Activated Protein C Resistance ◽  
S Deficiency ◽  
Free Antigen ◽  
Protein S Activity

Context.— Apixaban causes a false increase in activated protein C resistance (APCR) ratios and possibly protein S activity. Objective.— To investigate whether this increase can mask a diagnosis of factor V Leiden (FVL) or protein S deficiency in an actual population of patients undergoing apixaban treatment and hypercoagulation testing. Design.— During a 4.5-year period involving 58 patients, we compared the following 4 groups: heterozygous for FVL (FVL-HET)/taking apixaban, wild-type/taking apixaban, heterozygous for FVL/no apixaban, and normal APCR/no apixaban. Patients taking apixaban were also tested for protein S functional activity and free antigen (n = 40). Results.— FVL-HET patients taking apixaban had lower APCR ratios than wild-type patients (P &lt; .001). Activated protein C resistance in FVL-HET patients taking apixaban fell more than 3 SD below the cutoff of 2.2 at which the laboratory reflexes FVL DNA testing. No cases of FVL were missed despite apixaban. In contrast to rivaroxaban, apixaban did not interfere with the assessment of protein S activity (mean activity 93.9 IU/dL, free antigen 93.1 IU/dL, P = .39). A total of 3 of 40 patients (8%) had low free protein S antigen (30, 55, and 57 IU/dL), with correspondingly similar activity results (27, 59, and 52 IU/dL, respectively). Apixaban did not cause a missed diagnosis of protein S deficiency. Conclusions.— Despite apixaban treatment, APCR testing can distinguish FVL-HET from healthy patients, rendering indiscriminate FVL DNA testing of all patients on apixaban unnecessary. Apixaban did not affect protein S activity.

Total error vs. measurement uncertainty: revolution or evolution?

2016 ◽  
Vol 54 (2) ◽  
Author(s):  
Wytze P. Oosterhuis ◽  
Elvar Theodorsson
Keyword(s):  
Clinical Chemistry ◽  
Total Error ◽  
Error Theory ◽  
Theory And Practice ◽  
Analytical Performance ◽  
Performance Goals ◽  
Comprehensive Overview ◽  
Medical Diagnoses ◽  
Stockholm Conference ◽  
Monitoring Treatment

AbstractThe first strategic EFLM conference “Defining analytical performance goals, 15 years after the Stockholm Conference” was held in the autumn of 2014 in Milan. It maintained the Stockholm 1999 hierarchy of performance goals but rearranged them and established five task and finish groups to work on topics related to analytical performance goals including one on the “total error” theory. Jim Westgard recently wrote a comprehensive overview of performance goals and of the total error theory critical of the results and intentions of the Milan 2014 conference. The “total error” theory originated by Jim Westgard and co-workers has a dominating influence on the theory and practice of clinical chemistry but is not accepted in other fields of metrology. The generally accepted uncertainty theory, however, suffers from complex mathematics and conceived impracticability in clinical chemistry. The pros and cons of the total error theory need to be debated, making way for methods that can incorporate all relevant causes of uncertainty when making medical diagnoses and monitoring treatment effects. This development should preferably proceed not as a revolution but as an evolution.

Sign in / Sign up

Export Citation Format

Share Document