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• W1572242958 abstract "Thrombin generation (TG) assays are increasingly used to investigate the coagulopathy associated with hemophilia and allied disorders and the hypercoagulability associated with clinical conditions at increased thrombosis risk. Although standardization is not yet achieved [1Dargaud Y. Luddington R. Gray E. Negrier C. Lecompte T. Petros S. Hogwood J. Bordet J.C. Regnault V. Siegemund A. Baglin T. Effect of standardization and normalization on imprecision of calibrated automated thrombography: an international multicentre study.Br J Haematol. 2007; 139: 303-9Crossref PubMed Scopus (110) Google Scholar, 2Dargaud Y. Luddington R. Gray E. Lecompte T. Siegemund T. Baglin T. Hogwood J. Regnault V. Siegemund A. Negrier C. Standardisation of thrombin generation test‐‐which reference plasma for TGT? An international multicentre study.Thromb Res. 2010; 125: 353-6Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar], these tests are usually carried out by triggering coagulation with small amounts of tissue factor (TF) with or without exogenous negatively charged phospholipids according to whether the test is performed in platelet‐free or platelet‐rich plasma. Concentrations of phospholipids/TF, blood drawing and plasma preparation are crucially related to the test results and may affect conclusions stemming from studies employing the test [3Chantarangkul V. Clerici M. Bressi A. Giesen P.L. Tripodi A. Thrombin generation assessed as endogenous thrombin potential (ETP) in patients with hypo‐ or hyper‐coagulability. Effects of phospholipids, tissue factor and residual platelets on the measurement performed in platelet‐poor and platelet‐rich plasma.Haematologica. 2003; 88: 547-54PubMed Google Scholar]. Accordingly, TG should be performed under strict controlled experimental conditions and preferably in case–control studies, where samples from patients and controls are collected, stored and assayed in the same way. Among the variables that may affect the results of TG assays, the addition of corn trypsin inhibitor (CTI) has been the focus of debate over the last years [4Luddington R. Baglin T. Clinical measurement of thrombin generation by calibrated automated thrombography requires contact factor inhibition.J Thromb Haemost. 2004; 2: 1954-9Crossref PubMed Scopus (162) Google Scholar, 5Dargaud Y. Luddington R. Baglin T.P. Elimination of contact factor activation improves measurement of platelet‐dependent thrombin generation by calibrated automated thrombography at low‐concentration tissue factor.J Thromb Haemost. 2006; 4: 1160-1Crossref PubMed Scopus (46) Google Scholar, 6Spronk H.M. Dielis A.W. Panova‐Noeva M. van Oerle R. Govers‐Riemslag J.W. Hamulyák K. Falanga A. Cate H.T. Monitoring thrombin generation: is addition of corn trypsin inhibitor needed?.Thromb Haemost. 2009; 101: 1156-62Crossref PubMed Scopus (81) Google Scholar, 7van Veen. J.J. Gatt A. Cooper P.C. Kitchen S. Bowyer A.E. Makris M. Corn trypsin inhibitor in fluorogenic thrombin‐generation measurements is only necessary at low tissue factor concentrations and influences the relationship between factor VIII coagulant activity and thrombogram parameters.Blood Coagul Fibrinolysis. 2008; 19: 183-9Crossref PubMed Scopus (83) Google Scholar], but conclusions are not yet reached. In order to contribute to this debate we sought to compare TG results performed on paired‐blood samples collected with/without CTI from hemophilia patients treated with factor VIII (FVIII) inhibitor bypassing agents. Ten hemophilia patients with inhibitors to FVIII were enrolled in this study, which was approved by the review board of the Department of Medicine. On the occasion of treatment with FVIII‐inhibitor bypassing agents (either NovoSeven, Novo Nordisk, Bagsvaerd, Denmark, or FEIBA, Baxter, Glendale, CA, USA) patients were informed about the aim of the study and after consent paired‐blood samples were collected by syringe technique into tubes (broken‐vacuum, Vacutainer, Becton Dickinson, Plymouth, UK) containing plain‐citrate (109 mm) (blood:anticoagulant proportion 9:1) and citrate‐CTI (Calbiochem, Darmstadt, Germany) (final concentration 18.3 μg mL−1) [4Luddington R. Baglin T. Clinical measurement of thrombin generation by calibrated automated thrombography requires contact factor inhibition.J Thromb Haemost. 2004; 2: 1954-9Crossref PubMed Scopus (162) Google Scholar] immediately before and after 30 min from the end of the infusion. The difference in dilution effect (citrate‐CTI vs. plain‐citrate) was < 1%; however, the final TG results were corrected accordingly. Some of the patients underwent more than one infusion at different times. For the purpose of this study results from these patients were considered as independent observations and analyzed accordingly. Because of this design, 49 paired observations were available for analysis. The present study is part of a more comprehensive project meant to evaluate the clinical efficacy of two FVIII‐inhibitor bypassing agents, whose results will be reported separately. As there is no reason to believe that the CTI addition per se can influence plasma samples from patients treated with different bypassing agents, the results of this study were analyzed cumulatively in order to increase the number of observations and hence the power of statistical analyses. Thrombin generation was assessed on platelet‐rich plasma as previously described [3Chantarangkul V. Clerici M. Bressi A. Giesen P.L. Tripodi A. Thrombin generation assessed as endogenous thrombin potential (ETP) in patients with hypo‐ or hyper‐coagulability. Effects of phospholipids, tissue factor and residual platelets on the measurement performed in platelet‐poor and platelet‐rich plasma.Haematologica. 2003; 88: 547-54PubMed Google Scholar]. Platelet counts were adjusted by dilution of platelet‐rich plasma into autologous platelet‐free plasma to obtain a platelet count of 150 × 109 L−1. The test was triggered by human‐recombinant TF (Recombiplastin, Instrumentation Laboratory, Orangeburg, NY, USA) 1 or 2 pm; the required concentration was obtained by appropriate dilution based on the manufacturer’s provided concentration (6000 pm). Continuous registration of the generated thrombin was obtained by a fluorogenic substrate (Z‐Gly‐Gly‐Arg‐AMC HCl; Bachem, Bubendorf, Switzerland) added to the test system (617 μm final concentration). The procedure was carried out by an automated fluorometer (Fluoroskan‐Ascent®; ThermoLabsystem, Helsinki, Finland). Readings from the fluorometer were recorded and calculated by a dedicated software (Thrombinoscope™; Thrombinoscope BV, Maastricht, the Netherlands), which displays TG curves (time‐vs.‐generated thrombin) and calculates the peak thrombin (nm) and the area under the TG curve (nm min), defined as the endogenous thrombin potential (ETP). TG was measured as function of an internal thrombin calibrator (Thrombin Calibrator; Thrombinoscope BV). Median ETP and peak thrombin at pre‐ and post‐infusion both with and without CTI are shown in Fig. 1. Non‐parametric statistical analysis is reported for the measurement obtained by triggering coagulation with 1 or 2 pm TF. Median ETP was significantly increased at post‐infusion both without (206 [16–3281] vs. 902 [12–3828], P < 0.001) and with (165 [0–2767] vs. 732 [0–2301], P < 0.001) CTI addition when coagulation was triggered with 1 pm TF (Fig. 1, upper‐panels A). Similar results were obtained for peak thrombin both without (6.5 [1.3–148] vs. 30.7 [2.2–192], P < 0.001) and with (5.2 [0–161] vs. 23.4 [0–181], P < 0.001) CTI addition (Fig. 1, lower‐panels A). In particular, median ETP was increased at post‐infusion by 77% regardless of whether CTI was added (Fig. 1). Similar results were obtained for peak thrombin (i.e. 79% without and 77% with CTI) (Fig. 1). Median ETP was decreased by CTI addition both at pre‐ (206 [16.3–3281] vs. 165 [0–2767], P = 0.49) and post‐infusion (902 [12–3828] vs. 732 [0–2301], P = 0.18) without reaching statistical significance, with a percentage decrease of 20% and 19% at pre‐ and post‐infusion, respectively. Median peak thrombin was decreased by the addition of CTI both at pre‐ (6.5 [1.3–148] vs. 5.2 [0–161], P = 0.37] and post‐infusion (30.7 [2.2–192] vs. 23.4 [0–181], P = 0.21) without reaching statistical significance, with a percentage decrease of 20% and 24% at pre‐ and post‐infusion, respectively. Similar differences, although to a smaller extent, were obtained when coagulation was triggered with 2 pm TF (see Fig. 1 panels B). The addition of CTI before collection of blood samples needed for TG assays was advocated years ago [4Luddington R. Baglin T. Clinical measurement of thrombin generation by calibrated automated thrombography requires contact factor inhibition.J Thromb Haemost. 2004; 2: 1954-9Crossref PubMed Scopus (162) Google Scholar], but there has since been debate on whether it is strictly needed [6Spronk H.M. Dielis A.W. Panova‐Noeva M. van Oerle R. Govers‐Riemslag J.W. Hamulyák K. Falanga A. Cate H.T. Monitoring thrombin generation: is addition of corn trypsin inhibitor needed?.Thromb Haemost. 2009; 101: 1156-62Crossref PubMed Scopus (81) Google Scholar, 7van Veen. J.J. Gatt A. Cooper P.C. Kitchen S. Bowyer A.E. Makris M. Corn trypsin inhibitor in fluorogenic thrombin‐generation measurements is only necessary at low tissue factor concentrations and influences the relationship between factor VIII coagulant activity and thrombogram parameters.Blood Coagul Fibrinolysis. 2008; 19: 183-9Crossref PubMed Scopus (83) Google Scholar]. The main advantage of CTI addition is the prevention of unpredictable in vitro contact‐factor activation that might occur in those assays triggered with very low TF concentrations, in which the contribution of the contact pathway to TG may be relevant. Another advocated advantage of CTI addition is the improvement in the assay reproducibility. This was not directly investigated; however, the median CV of the within‐assay replicates was 4.6% with CTI and 7.6% without CTI. Among the arguments against CTI, one may consider the costs of this inhibitor and the fact that it should be added during blood collection (i.e. added to the anticoagulant), as the efficacy of the CTI addition to plasma before analysis was not thoroughly investigated and it would also be less effective in preventing contact‐factor activation during plasma storage. If CTI was strictly needed post‐hoc studies on plasmas prepared from blood collected without the addition of CTI could not have been carried [8Besser M. Baglin C. Luddington R. van Hylckama Vlieg A. Baglin T. High rate of unprovoked recurrent venous thrombosis is associated with high thrombin‐generating potential in a prospective cohort study.J Thromb Haemost. 2008; 6: 1720-5Crossref PubMed Scopus (163) Google Scholar] out and this limitation should be taken into serious consideration as there are many observations stemming from measuring TG in large series of plasmas collected without CTI that could be of value. As an additional argument against CTI addition one may consider that the in vitro inhibition of contact factors (e.g. FXII) might make the test unlikely to mimic the conditions operating in vivo. Little is known so far and this issue remains controversial. In general, one may wonder whether it is appropriate from the pathophysiological standpoint to quench the contribution of the contact factors to TG. For instance, it was reported that plasma FXII or the presence of FXII gene polymorphisms might be risk factors for thrombosis [9Gailani D. Renne T. Intrinsic pathway of coagulation and arterial thrombosis.Arterioscler Thromb Vasc Biol. 2007; 27: 2507-13Crossref PubMed Scopus (221) Google Scholar]. Furthermore, Kilinic et al. [10Kilinç E. van Oerle R. Borissoff J.I. Oschatz C. Gerlofs‐Nijland M.E. Janssen N.A. Cassee F.R. Sandström T. Renné T. ten Cate H. Spronk H.M. Factor XII activation is essential to sustain the procoagulant effects of particulate matter.J Thromb Haemost. 2011; 9: 1359-67Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] reported that FXII activation is essential to sustain the procoagulant effects of particulate matter. Therefore, one may assume that the contact system in vivo has something to do with the mechanisms of thrombogenesis and therefore ignoring purposely its contribution to TG in vitro is not reasonable. On the other hand, one may argue that beside the ‘physiological’ contact activation there might be an ‘artificial’ contact activation affecting TG, owing to poor blood collection, plasma preparation and storage. However, this unwanted/variable activation may be limited by adopting stringent/standardized protocols for blood collection (non‐contact systems), quick‐freezing and storage as well as plasma thawing (2–3 min in a water bath at 37 °C) before analysis. Furthermore, if TG assays are carried out within the frame of case–control studies, it is reasonable to assume that any ‘artificial’ contact activation will likely have the same effect on plasmas from patients and controls if they were collected, prepared and stored in the same way, thus minimizing the effect on the conclusions that are derived thereafter. The above considerations notwithstanding we appreciate the importance of this debate and sought to compare TG results performed on paired blood samples collected with and without CTI from hemophiliacs treated with FVIII inhibitor bypassing agents. We chose this setting because studies on TG are important from the clinical standpoint for decision making on the assay levels attained after infusion of these agents. Our results show that omitting CTI does not influence the result interpretation. ETP and peak‐thrombin were higher in post‐infusion than in pre‐infusion samples collected without CTI as significantly (i.e. P < 0.001) as in samples collected with CTI (Fig. 1). Furthermore, the percentage change of ETP and peak‐thrombin at pre‐ vs. post‐infusion were almost identical regardless of whether CTI was added (Fig. 1). These results indicate that although CTI slightly impairs the absolute value of TG parameters, the relative percentage increase after infusion is independent from CTI. Therefore, CTI addition is not strictly needed, at least when the TF concentration is not smaller than 1 pm. It should be emphasized that although similar conclusions were reached by Spronk et al. [6Spronk H.M. Dielis A.W. Panova‐Noeva M. van Oerle R. Govers‐Riemslag J.W. Hamulyák K. Falanga A. Cate H.T. Monitoring thrombin generation: is addition of corn trypsin inhibitor needed?.Thromb Haemost. 2009; 101: 1156-62Crossref PubMed Scopus (81) Google Scholar] in another clinical setting, our conclusions are valid only for the investigated clinical setting and TF concentrations used to trigger coagulation and cannot be generalized to other conditions where TG is used to investigate hypo‐ or hypercoagulability. In general, we suggest adopting strict protocols for blood collection, plasma preparation and storage in order to limit as much as possible ‘artificial’ contact‐factor activation. Furthermore, it is important to evaluate results of TG assays within the frame of case–control studies where pre‐analytical conditions are comparable for patients and controls. The authors state that they have no conflict of interest." @default.
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• W1572242958 title "Comparison of thrombin generation for paired‐platelet‐rich plasma collected with and without corn trypsin inhibitor from hemophiliacs treated with factor‐VIII inhibitor bypassing agents" @default.
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