scholarly journals Η εκτίμηση της πηκτικότητας του αίματος σε ασθενείς υψηλού κινδύνου για θρομβοεμβολική νόσο που λαμβάνουν προφύλαξη με ηπαρίνη χαμηλού μοριακού βάρους

2015 ◽  
Author(s):  
Μιχαήλ Γκιώνης
Keyword(s):  
Lag Time ◽  
Endogenous Thrombin Potential ◽  
Time To Peak

ΕΙΣΑΓΩΓΗ Η συνιστωμενη διαρκεια θρομβοπροφυλαξης με Χαμηλου Μοριακου Βαρους Ηπαρινη (ΧΜΒΗ) στους χειρουργικους ασθενεις υψηλου κινδυνου για Φλεβικη Θρομβο Εμβολη (ΦΘΕ), όπως εκεινοι που υποβαλλονται σε Ολικη Αρθροπλαστικη Ισχιου (ΟΑΙ) η’ Γονατος (ΟΑΓ), παραμενει αμφιλεγομενη. Σκοπος μας είναι να μελετησουμε τις μεταβολες της θρομβινογενεσης που επιφερει η εγχειρητικη διαδικασια και να αξιολογησουμε την επιδραση της ΧΜΒΗ (ενοξαπαρινη) στην διαδικασια της θρομβινογενεσης τοσο κατά την συνιστωμενη χρονικη διαρκεια χορηγησης της, οσο και μετα την αποσυρση της, κατά την μετεγχειρητικη περιοδο των ασθενων αυτων. Επισης σκοπος μας είναι να διερευνησουμε την υπαρξη η’ όχι βιολογικης αντιστασης στην αντιθρομβωτικη δραση της ενοξαπαρινης, καθως και το φαινομενο της αναπηδωσας ενεργοποιησης του πηκτικου μηχανισμου μετα την διακοπη χορηγησης της ΧΜΒΗ. Η εργαστηριακη μεθοδος μελετης της θρομβινογενεσης που χρησιμοποιησαμε είναι εκεινη του Θρομβογραμματος. Τελος μελετησαμε και αξιολογησαμε την επικουρικη δραση των αντιαιμοπεταλιακων παραγοντων (κλοπιδογρελη) στις μεταβολες της θρομβινογενεσης τοσο κατά την διαρκεια χορηγησης της ΧΜΒΗ, οσο και μετα την αποσυρση της.ΑΣΘΕΝΕΙΣ & ΜΕΘΟΔΟΣ1η ΚΑΤΗΓΟΡΙΑ (ΟΑΙ vs ΟΑΓ)31 ασθενεις ελαβαν 4000 IU anti-Xa/day ενοξαπαρινης, με την 1η δοση να χορηγειται 8 ωρες μετα το περας της επεμβασης (15 υποβληθηκαν σε ΟΑΙ και ελαβαν θρομβοπροφυλαξη για 30 ημερες και 16 υποβληθηκαν σε ΟΑΓ και ελαβαν θρομβοπροφυλαξη για 15 ημερες). Μελετη θρομβινογενεσης με αναφορα στην αντιθρομβωτικη δραση της ενοξαπαρινης διενεργηθηκε προεγχειρητικα (Ημερα 0), 7 ωρες μετα το περας της επεμβασης και 1 ωρα πριν την χορηγηση της 1ης δοσης ενοξαπαρινης (Ημερα 1), την 8η μετεγχειρητικη ημερα (Ημερα 8) και 2 ημερες μετα την διακοπη χορηγησης της ΧΜΒΗ (Ημερα 32 για ΟΑΙ και Ημερα 17 για ΟΑΓ). Οι δεικτες θρομβινογενεσης στο Θρομβογραμμα που μελετηθηκαν είναι οι εξης: lag time, Endogenous Thrombin Potential (ETP), Peak Generated Thrombin (PGT), time to Peak (ttPeak) & Mean Rate Index (MRI= Peak/ttPeak-lag time).2η ΚΑΤΗΓΟΡΙΑ (ΟΡΘΟΠΕΔΙΚΟΙ vs ΑΓΓΕΙΟΧΕΙΡΟΥΡΓΙΚΟΙ ΑΣΘΕΝΕΙΣ)15 ασθενεις που υποβληθηκαν σε μηρο-ιγνυακη παρακαμψη ελαβαν 4000 IU anti-Xa/day ενοξαπαρινης και 75 mg κλοπιδογρελης για 30 ημερες μετεγχειρητικα και τα αποτελεσματα της μελετης θρομβινογενεσης στις συγκεκριμενες χρονικες στιγμες της μελετης συγκριθηκαν με τα αντιστοιχα 15 ασθενων που υποβληθηκαν σε ΟΑΙ και ελαβαν μονο ενοξαπαρινη 4000 IU anti-Xa/day για επισης 30 ημερες. Οι ιδιες παραμετροι θρομβινογενεσης χρησιμοποιηθηκαν για την διερευνηση πιθανης αντιστασης στην ηπαρινη και εκδηλωσης του φαινομενου της αναπηδωσας ενεργοποιησης της πηξης μετα την αποσυρση της ΧΜΒΗ. Οι μετρησεις ελαβαν χωρα παντα στις ιδιες χρονικες στιγμες της μελετης όπως ηδη προαναφερθηκε.ΑΠΟΤΕΛΕΣΜΑΤΑ 1η ΚΑΤΗΓΟΡΙΑΗ ΟΑΓ ως επεμβαση μειωνει τις παραμετρους lag time & ttPeak και αυξανει τον MRI την Ημερα 1 vs Ημερα 0 (p<0.05). Αντιθετως, η ΟΑΙ δεν επιφερει ως επεμβαση ουσιαστικες αλλαγες στη διαδικασια της θρομβινογενεσης. Η ενοξαπαρινη αναστελλει επαρκως την θρομβινογενεση τοσο στην ΟΑΙ, οσο και στην ΟΑΓ. Η διακοπη της θρομβοπροφυλαξης οδηγησε σε αναπηδωσα ενεργοποιηση της πηξης στους ασθενεις με ΟΑΓ (ETP, Peak & MRI αυξηθηκαν την Ημερα 17 vs Ημερα 0 και Ημερα 1 – p<0.05). Το αντιστοιχο όμως δεν αναδειχθηκε στους ασθενεις με ΟΑΙ. Επισης, τοσο στους ασθνεις με ΟΑΙ, οσο και σε εκεινους με ΟΑΓ, παρατηρηθηκε εξατομικευμενη διαφοροποιηση στην ανταποκριση τους ως προς την αντιθρομβωτικη δραση της ΧΜΒΗ, γεγονος που μεταφραζεται ως αντισταση στην ηπαρινη, καθως και παρουσια φαινομενου αναπηδωσας ενεργοποιησης της πηξης μετα την διακοπη χορηγησης της ΧΜΒΗ, σε ικανο αριθμο ασθενων.ΑΠΟΤΕΛΕΣΜΑΤΑ 2η ΚΑΤΗΓΟΡΙΑΗ εγχειρητικη διαδικασια αυξησε την θρομβινογενεση στους Αγγειοχειρουργικους ασθενεις, παρα την διεγχειρητικη χορηγηση ηπαρινης, όταν αυτοι συγκριθηκαν με τους Ορθοπεδικους ασθενεις (MRI p=0.039, ETP p=0.001, PGT p=0.003). Αυτή η περιεγχειρητικη προθρομβωτικη ταση αναστραφηκε από την μετεγχειρητικη χορηγηση θρομβοπροφυλαξης. Δεν παρατηρηθηκαν κατά την διαρκεια της μελετης φλεβικα η’ αρτηριακα οξεα θρομβωτικα επεισοδια. Οι Αγγειοχειρουργικοι ασθενεις είναι επαρκως προστατευμενοι μετα την διακοπη χορηγησης ΧΜΒΗ προφανως λογω της επικουρικης δρασης του αντιαιμοπεταλιακου παραγοντα που ελαμβαναν κα συνεχιζουν να λαμβανουν (χωρις μεταβολες στις τιμες των παραμετρων του θρομβογραμματος μεταξυ της 8ης και της 32ης μετεγχ/κης ημερας σ’αυτή την ομαδα ασθενων). Αντιθετως, οι Ορθοπεδικοι ασθενεις αυξησαν την θρομβινογενεση την Ημερα 32 σε συγκριση με την Ημερα 8 στις τιμες θρομβογραμματος για την δικη τους ομαδα (p=0.03 για lag time & ttPeak). Επιπλεον, η ιδια προθρομβωτικη ταση κατά την Ημερα 32 επανεμφανιζεται στους Ορθοπεδικους ασθενεις όταν οι δεικτες του θρομβογραμματος για τη συγκεκριμενη ημερα συγκρινονται με τους αντιστοιχους για την συγκεκτιμενη ημερα δεικτες των Αγγειοχειρουργικων ασθενων. Επισης αντισταση στην ενοξαπαρινη και αναπηδωσα ενεργοποιηση της πηξης μετα την διακοπη χορηγησης της παρατηρηθηκε σε ικανο αριθμο τοσο Αγγειοχειρουργικων, οσο και Ορθοπεδικων ασθενων και παρα την χορηγηση θρομβοπροφυλαξης με ενοξαπαρινη.ΣΥΜΠΕΡΑΣΜΑΤΑ Η ΟΑΓ είναι περισσοτερο θρομβογεννητικη ως επεμβαση από την ΟΑΙ.Στους ασθενεις με ΟΑΙ η θρομβινογενεση ανεσταλλη επαρκως από την χορηγηση ΧΜΒΗ για 30 ημερες, ενώ σε εκεινους που υποβληθηκαν σε ΟΑΓ και ελαβαν θρομβοπροφυλαξη για 15 ημερες, η θρομβινιγενεση δεν ανεσταλλη επαρκως.Αντισταση στη ΧΜΒΗ και αναπηδωσα ενεργοποιηση της πηξης μετα την διακοπη χορηγησης ΧΜΒΗ εμφανισθηκε σε ολες τις ομαδες & κατηγοριες ασθενων σε ικανο αριθμο περιπτωσεων. Κατά συνεπεια, συμπεραινουμε ότι ένας ικανος αριθμος ασθενων παραμενει εκτεθιμενος στον κινδυνο οξεους θρομβωτικου (φλεβικου η’ αρτηριακου) συμβαματος, παρα το γεγονος ότι λαμβανει θρομβοπροφυλαξη συμφωνα με τις τρεχουσες παγκοσμιες κατευθυντηριες οδηγιες.Το υπερπηκτικο status μετα την διακοπη χορηγησης ΧΜΒΗ μπορει να υφεθει σε ικανο βαθμο από την επικουρικη δραση των αντιαιμοπεταλιακων παραγοντων.Τελος, η μεθοδος του Θρομβογραμματος παρεχει εξατομικευμενες ανα πασα χρονικη στιγμη για την πηκτικη κατασταση του εκαστοτε ασθενη και μελλοντικα θα μπορουσε να αποτελεσει το οχημα διαμεσου του οποιου θα επιτευχθει η πλεον δοκιμη αντιθρομβωτικη στρατηγικη για την πλεον ασφαλη θρομβοπροφυλαξη στις κλινικες ομαδες υψηλου κινδυνου για ΦΘΕ.

The anticoagulant effect of dabigatran is reflected in the lag time and time-to-peak, but not in the endogenous thrombin potential or peak, of thrombin generation

2018 ◽  
Vol 171 ◽  
pp. 160-166 ◽  
Author(s):  
Saartje Bloemen ◽  
Suzanne Zwaveling ◽  
Jonathan Douxfils ◽  
Mark Roest ◽  
Romy Kremers ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Lag Time ◽  
Anticoagulant Effect ◽  
Endogenous Thrombin Potential ◽  
Time To Peak

Abstract P683: Thrombin Generation in Plasma of Stroke Patients With Atrial Fibrillation

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Sarina Falcione ◽  
Gina Sykes ◽  
Joseph Kamtchum Tatuene ◽  
Danielle Munsterman ◽  
Twinkle Joy ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Thrombin Generation ◽  
Thrombus Formation ◽  
Lag Time ◽  
Thrombin Time ◽  
Stroke Patients ◽  
Time To Peak ◽  
Generation Capacity

Background and Purpose: Thrombus formation is central to pathophysiology of stroke in patients with atrial fibrillation. Whether factors in plasma contribute to thrombus generation in patients with atrial fibrillation remains unclear. In this study we sought to determine whether plasma contributes to thrombin generation in patients with atrial fibrillation. Methods: There were 78 acute ischemic strokes with atrial fibrillation and 37 non-stroke controls. Plasma thrombin generation was measured by thrombin generation assay, resulting lag time, peak thrombin, time to peak and area under the curve was assessed. Thrombin generation capacity was compared in stroke patients with atrial fibrillation to non-stroke controls. The relationship to anticoagulation was assessed. In vitro, the effect of anticoagulation on plasma thrombin generation was determined. Results: Thrombin generation capacity was increased (shorter lag time and time to peak) in ischemic stroke patients with atrial fibrillation compared to non-stroke atrial-fibrillation controls (p<0.05 and p<0.01, respectively). Anticoagulation decreased plasma induced thrombin generation. Ischemic stroke patients with atrial fibrillation treated with anticoagulation (DOAC or warfarin) had lower plasma induced thrombin generation compared to atrial-fibrillation patients not on anticoagulation (p<0.05). Thrombin generation by plasma could be further reduced by DOAC in an in-vitro assay. Conclusions: Stroke patients with atrial fibrillation have a higher plasma induced thrombin generation compared to atrial fibrillation controls. Factors in plasma such as leukocyte derived tissue factor likely contribute to thrombus formation in patients with atrial fibrillation. As such, components in plasma may represent new targets to reduce thrombus formation and stroke risk in patients with atrial fibrillation.

scholarly journals Thrombin generation in cardiovascular disease and mortality - results from the Gutenberg Health Study

Haematologica ◽  
2019 ◽  
Vol 105 (9) ◽  
pp. 2327-2334 ◽  
Author(s):  
Pauline C.S. van Paridon ◽  
Marina Panova-Noeva ◽  
Rene van Oerle ◽  
Andreas Schultz ◽  
Iris M. Hermanns ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Diseases ◽  
Cardiovascular Risk Factors ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Cox Regression ◽  
Total Mortality ◽  
Lag Time ◽  
Endogenous Thrombin Potential

Thrombin generation may be a potential tool to improve risk stratification for cardiovascular diseases. This study aims to explore the relation between thrombin generation and cardiovascular risk factors, cardiovascular diseases, and total mortality. For this study, N=5000 subjects from the population-based Gutenberg Health Study were analysed in a highly standardized setting. Thrombin generation was assessed by the Calibrated Automated Thrombogram method at 1 and 5 pM tissue factors trigger in platelet poor plasma. Lag time, endogenous thrombin potential, and peak height were derived from the thrombin generation curve. Sex-specific multivariable linear regression analysis adjusted for age, cardiovascular risk factors, cardiovascular diseases and therapy, was used to assess clinical determinants of thrombin generation. Cox regression models adjusted for age, sex, cardiovascular risk factors and vitamin K antagonists investigated the association between thrombin generation parameters and total mortality. Lag time was positively associated with obesity and dyslipidaemia for both sexes (p<0.0001). Obesity was also positively associated with endogenous thrombin potential in both sexes (p<0.0001) and peak height in males (1 pM tissue factor, p=0.0048) and females (p<0.0001). Cox regression models showed an increased mortality in individuals with lag time (1 pM tissue factor, hazard ratio=1.46, [95% CI: 1.07; 2.00], p=0.018) and endogenous thrombin potential (5 pM tissue factor, hazard ratio = 1.50, [1.06; 2.13], p=0.023) above the 95th percentile of the reference group, independent of the cardiovascular risk profile. This large-scale study demonstrates traditional cardiovascular risk factors, particularly obesity, as relevant determinants of thrombin generation. Lag time and endogenous thrombin potential were found as potentially relevant predictors of increased total mortality, which deserves further investigation.

scholarly journals Liraglutide in polycystic ovary syndrome: a randomized trial, investigating effects on thrombogenic potential

2017 ◽  
Vol 6 (2) ◽  
pp. 89-99 ◽  
Author(s):  
Malin Nylander ◽  
Signe Frøssing ◽  
Caroline Kistorp ◽  
Jens Faber ◽  
Sven O Skouby
Keyword(s):  
Thrombin Generation ◽  
Polycystic Ovary ◽  
Plasminogen Activator Inhibitor ◽  
Lag Time ◽  
Plasminogen Activator Inhibitor 1 ◽  
Cvd Risk ◽  
Ovary Syndrome ◽  
Time To Peak ◽  
Thrombogenic Potential ◽  
Activator Inhibitor

Polycystic ovary syndrome (PCOS) is associated with increased risk of venous thromboembolism (VTE) and cardiovascular disease (CVD) in later life. We aimed to study the effect of liraglutide intervention on markers of VTE and CVD risk, in PCOS. In a double-blind, placebo-controlled, randomized trial, 72 overweight and/or insulin-resistant women with PCOS were randomized, in a 2:1 ratio, to liraglutide or placebo 1.8 mg/day. Endpoints included between-group difference in change (baseline to follow-up) in plasminogen activator inhibitor-1 levels and in thrombin generation test parameters: endogenous thrombin potential, peak thrombin concentration, lag time and time to peak. Mean weight loss was 5.2 kg (95% CI 3.0–7.5 kg, P < 0.001) in the liraglutide group compared with placebo. We detected no effect on endogenous thrombin potential in either group. In the liraglutide group, peak thrombin concentration decreased by 16.71 nmol/L (95% CI 2.32–31.11, P < 0.05) and lag time and time to peak increased by 0.13 min (95% CI 0.01–0.25, P < 0.05) and 0.38 min (95% CI 0.09–0.68, P < 0.05), respectively, but there were no between-group differences. There was a trend toward 12% (95% CI 0–23, P = 0.05) decreased plasminogen activator inhibitor-1 in the liraglutide group, and there was a trend toward 16% (95% CI −4 to 32, P = 0.10) reduction, compared with placebo. In overweight women with PCOS, liraglutide intervention caused an approximate 5% weight loss. In addition, liraglutide affected thrombin generation, although not significantly differently from placebo. A concomitant trend toward improved fibrinolysis indicates a possible reduction of the baseline thrombogenic potential. The findings point toward beneficial effects of liraglutide on markers of VTE and CVD risk, which should be further pursued in larger studies.

Factor VIII Efficacy and Tissue Factor Levels in Hemophilia A Patients Undergoing Total Knee Replacement.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4029-4029
Author(s):  
Wolfgang Wegert ◽  
Manuela Krause ◽  
Inge Scharrer ◽  
Ulla Stumpf ◽  
Andreas Kurth ◽  
...  
Keyword(s):  
Total Knee Replacement ◽  
Plasma Levels ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Lag Time ◽  
Major Surgery ◽  
Plasma Samples ◽  
Time To Peak ◽  
Thrombin Generation Assay ◽  
Total Knee

Abstract The changes of tissue factor (TF) blood levels in patients undergoing major surgery has been reported presenting controversial data. Whether this TF is hemostatically active or if it interacts with other coagulation factors, e.g. FVIII, is still unclear, making thrombotic risk and complications assessment for even more difficult. We analyzed plasma samples from four male patients aged 27–55 with severe hemophilia A without inhibitory antibodies, undergoing total knee replacement, which all gave informed consent. Initial FVIII doses before intervention was 75–80 U/kg. Treatment following intervention was targeted at 100 % FVIII serum levels. None received heparin. No bleeding events occurred during the observation period. The samples were taken at these timepoints (TP): 1. before preoperative FVIII substitution, 2. at the time of first incision (intervention start), 3. at circulation arrest release + 90 s after prosthesis implantation, 4. final suture (intervention end), 5. 24 h and 6. 48 h after intervention to assay procedurally induced TF production. Coagulation analyses were carried out using a fluorometric thrombin generation assay (TGA) in platelet rich plasma (PRP), RoTEG (rotation thrombelastography) in whole blood and a TF ELISA for the plasma samples’ TF levels. Both clotting function tests were started using TF diluted 1:100.000 and calcium chloride 16,7 mM (final conc.). TGA parameters were ETP, PEAK (maximum thrombin generation velocity), TIME TO PEAK, LAG TIME. TGA parameters directly related to thrombin activity (ETP; PEAK) showed no change during the intervention, but a sharp decrease 24 h later with a partial recovery 48 h later. TGA time marks (TIME TO PEAK, LAG TIME) changed in an inverse way, except for the difference from LAG TIME and TIME TO PEAK, which shortened continously after circulation arrest removal. RoTEG was characterized using 4 parameters: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF) and clot formation rate (CFR). After preoperative FVIII substitution, CT decreased by 10 % and CFT by 50 % in 48 h. MCF stayed unchanged during the intervention and the following 24 h, but increased by 20 % at 48 h. CFR increased by 10 % during intervention, and by 20 % from 24 to 48 h. TF ELISA showed preoperative TF plasma levels from 11 to 271 pg/ml. After release of circulation arrest (TP 3) TF concentration increased sharply (4 times the initial value), which was not detectable in the samples taken at TPs 2 and 4. TF levels further increased at TPs 5 and 6 to 170 % and 317 % resp. Altogether, TF plasma levels elevated after major surgery seem to correspond to a potential risk factor for postoperative thrombosis, especially when elevation is induced after intervention. However, functional coagulation assays do not change uniformly, as the thrombin generation assay reflects no marked changes under intervention, but in the period after(24–48 h). Changes in the RoTEG whole blood clotting assay are not dramatic but indicate a thrombophilic shift in coagulation balance also pronouned at 24–48h, too. These results demonstrate that increased coagulability after orthopedic surgery detected using functional clotting assays correlates with increased TF levels, but further studies must be performed to prove this relation in healthy individuals.

Association rate constants rationalise the pharmacodynamics of apixaban and rivaroxaban

2015 ◽  
Vol 114 (07) ◽  
pp. 78-86 ◽  
Author(s):  
Georges Jourdi ◽  
Virginie Siguret ◽  
Anne Céline Martin ◽  
Jean-Louis Golmard ◽  
Anne Godier ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Factor Xa ◽  
Lag Time ◽  
Lower Sensitivity ◽  
Association Rate ◽  
Time To Peak ◽  
Thrombin Generation Assay ◽  
Direct Inhibitors ◽  
Association Rate Constants ◽  
Kinetics Of

SummaryRivaroxaban and apixaban are selective direct inhibitors of free and prothrombinase-bound factor Xa (FXa). Surprisingly prothrombin time (PT) is little sensitive to clinically relevant changes in drug concentration, especially with apixaban. To investigate this pharmacodynamic discrepancy we have compared the kinetics of FXa inhibition in strictly identical conditions (pH 7.48, 37 °C, 0.15 M). KI values of 0.74 ± 0.03 and 0.47 ± 0.02 nM and kon values of 7.3 ± 1.6 106 and 2.9 ± 0.6 107 M-1 s-1 were obtained for apixaban and rivaroxaban, respectively. To investigate if these constants rationalise the inhibitor pharmacodynamics, we used numerical integration to evaluate impact of FXa inhibition on thrombin generation assay (TGA) and PT. Simulation predicted that in TGA triggered with 20 pM tissue factor, 100 ng/ml apixaban or rivaroxaban increased 1.8– or 3.0-fold the lag time and 1.4– or 2.0-fold the time to peak, whilst decreasing 1.2– or 3.1-fold the maximum thrombin and 1.7– or 3.5-fold the endogenous thrombin potential. These numbers were consistent with those obtained through the corresponding TGA triggered in plasma spiked with apixaban or rivaroxaban. Simulated PT ratios were also consistent with the corresponding plasma PT: markedly less sensitive to apixaban than to rivaroxaban. Analogous differences in TGA and PT were obtained irrespective of the drug amount added. We concluded that kon values for FXa of apixaban and rivaroxaban rationalise the unexpected lower sensitivity of PT and TGA to the former.

scholarly journals The Rate of Prothrombin Conversion Is Increased in Antiphospholipid Syndrome and Is Insensitive to Thrombomodulin

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 718-718
Author(s):  
Romy Kremers ◽  
Stéphane Zuily ◽  
Hilde Kelchtermans ◽  
Tessa Peters ◽  
Saartje Bloemen ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Antiphospholipid Syndrome ◽  
Conversion Rate ◽  
Healthy Subjects ◽  
Thrombin Generation ◽  
Lag Time ◽  
Peak Height ◽  
Thrombin Inhibitors ◽  
Time To Peak ◽  
Glycoprotein I

Abstract Background: The antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid antibodies directed mainly against prothrombin and β2-glycoprotein I. The syndrome is associated with an increased risk of thrombosis. The global hemostatic state in a patient can be tested by measuring thrombin generation (TG). Recently, we developed a method to study the main pro- and anticoagulant processes at the basis of TG, called the thrombin dynamics method. Aim: In this study we investigated the dynamics of thrombin generation in healthy subjects and APS patients. Materials and methods: Healthy subjects (n=129) and antiphospholipid syndrome (APS) patients (n=31) were included in the study. Sixty-eight percent of the APS patients were lupus anticoagulant positive, anti-cardiolipin antibodies were detected in 84% of the patients, and 52% presented with anti-β2-glycoprotein I antibodies. Patients on anticoagulant therapy were excluded from the study. Thrombin generation was measured at 1 pM tissue factor (TF) and activated protein C (APC) system sensitivity was tested by measuring TG in the presence and absence of 20 nM thrombomodulin (TM). Results: Thrombin generation was measured in platelet poor plasma at 1 pM tissue factor. The lag time and time-to-peak were significantly prolonged in APS patients compared to healthy subjects (lag time: 3.30 ± 0.59 vs. 6.69 ± 4.26 min, p<0.001; time-to-peak: 8.33 ± 1.29 vs. 10.76 ± 4.51 min, p<0.001). The peak height was significantly higher in APS patients (240 ± 84 vs. 214 ± 58 nM, p<0.05) and the velocity index was elevated in APS patients (134 ± 66 vs. 70 ± 32 nM/min, p<0.001) compared to healthy subjects. The ETP values were comparable between healthy subjects and APS patients (1260 ± 235 vs. 1176 ± 362 nM*min). The pro- and anticoagulant processes underlying thrombin generation were studied separately. The total amount of prothrombin converted during thrombin generation (PCtot) did not differ between healthy subjects and patients (1234 vs. 1165 nM). However, the maximum rate of prothrombin conversion (PCmax) was significantly elevated in APS patients (291 vs 425 nM/min; p<0.001). The amount of thrombin-antithrombin (T-AT) complexes formed was comparable between patients and controls (1169 vs. 1098 nM), and the thrombin decay capacity (TDC) was comparable as well (0.675 vs. 0.674 min-1). These results are in line with the finding that the plasma levels of the main thrombin inhibitors are unchanged in APS patients. Antithrombin levels are on average 2.31 ± 0.44 μM in healthy subjects and 2.36 ± 0.56 μM in APS patients, and the mean α2-macroglobulin levels were 3.22 ± 0.77 μM in healthy subjects and 3.23 ± 1.11 μM in patients. Thrombomodulin reduced the ETP by 45% in healthy subjects, but had significantly less effect in APS patients (10%). The addition of TM decreased total prothrombin conversion by 40% and the maximum prothrombin conversion rate by 50% in healthy subjects. In patients, TM only slightly reduced total prothrombin conversion (8%) and the maximum prothrombin conversion rate (7%). Discussion: The thrombin generation results indicate a predisposition to thrombosis in APS patients, as the TG parameters peak height and the velocity index are increased. Examination of the underlying pro- and anticoagulant processes of prothrombin conversion and thrombin inactivation revealed that although the same amount of prothrombin is converted in patients, the maximum activity of the prothrombinase complex is higher, indicating that patients can generate thrombin faster. In addition, APS patients have a dysfunctional APC system, as prothrombin conversion and thrombin generation could be only slightly inhibited by the addition of thrombomodulin. Disclosures No relevant conflicts of interest to declare.

Comparison of Two Thrombin Generation Methods, CAT and ST-Genesia, in Liver Transplant Patients

2019 ◽  
Vol 119 (06) ◽  
pp. 899-905
Author(s):  
Stéphanie Roullet ◽  
Sylvie Labrouche ◽  
Geneviève Freyburger
Keyword(s):  
Clustering Analysis ◽  
Thrombin Generation ◽  
Lag Time ◽  
Peak Time ◽  
Homogeneous Groups ◽  
New Device ◽  
Time To Peak ◽  
Quantitative Parameters ◽  
Transplant Patients ◽  
Complete Automation

Background During liver transplantation (LT), thrombin generation (TG) is altered. The most frequently used assay for TG is the Calibrated Automated Thrombogram (CAT). It is designed for series of plasmas and is semi-automated. Complete automation has led to a new device, the ST-Genesia, enabling quantitative standardized TG evaluation. Objective The aim of this observational study was to compare the TG results of the CAT and the ST-Genesia on frozen-thawed plasma samples prepared from the blood of LT patients. Patients and Methods Poor platelet plasma aliquots were prepared from blood samples from six LT patients selected to get the whole range of TG and were assessed with CAT (recombinant human tissue factor [TF] concentration 5 pm) and with ST-Genesia Bleedscreen assay (BS, using ‘low’ recombinant human TF concentration) and Thromboscreen assay (TS, using ‘medium’ recombinant human TF concentration). The TG parameters studied were: lag time, peak, time to peak, endogenous thrombin potential, velocity index and start tail. Results BS and TS did not differ significantly from each other whatever the parameter studied, whereas most of the CAT parameters were significantly different from those obtained with BS and TS. Hierarchical clustering analysis of the different parameters of TG showed three homogeneous groups. One cluster gathered TG quantitative parameters from ST-Genesia. A second cluster gathered all the kinetic parameters. The last cluster isolated the quantitative parameters of CAT. Conclusion In patients undergoing LT, TG performed with CAT and with ST-Genesia provided different results, for unknown reasons.

Factor VIII Supplementation Improves Recombinant VIIa Initiated Thrombin Generation in Hemophilia A Inhibitor Patient Plasmas

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 28-28
Author(s):  
Bhavya Doshi ◽  
Courtney Cox ◽  
Bagirath Gangadharan ◽  
Christopher B Doering ◽  
Shannon L. Meeks
Keyword(s):  
Factor Viii ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Factor Viia ◽  
Treatment Options ◽  
Lag Time ◽  
Time To Peak ◽  
Fviii Inhibitor

Abstract Abstract 28 Hemophilia A is an X-linked recessive disorder that is caused by a deficiency or defect of factor VIII (fVIII) coagulant protein. Approximately 20–30% of patients with severe hemophilia A develop antibodies (Abs) against fVIII (inhibitors) following fVIII replacement therapy, which makes bleeding episodes more difficult to control. Patients with inhibitors are treated with fVIII-bypassing agents such as recombinant factor VIIa (rfVIIa) or activated prothrombin-complex concentrate. However for unknown reasons, some patients display poor hemostatic response to bypass therapy and improved treatment options are needed. Thrombin generation assays provide an in vitro methodology for monitoring bypass therapy in hemophilia (Turecek PL et al. Pathophysiol Haemost Thromb 2003; Varadi K et al. Haemophilia 2004). Recently, it was demonstrated by us and others that combination of fVIII and by-passing agents potentiates in vitro thrombin production in hemophilia A inhibitor plasma (Klintman J et al. Br J Haematol 2010). In our study we investigated the potentiation fVIII confers to fVIIa initiated in vitro thrombin generation using a panel of anti-fVIII Abs with known epitopes. We showed that kinetics of inhibition and Ab epitope were the dominant factors influencing ability of fVIII to potentiate in vitro thrombin production. Specifically, monoclonal Abs targeting only 2 of 11 epitopes, 1 of 3 non-overlapping A2 epitopes and 1 of 2 non-overlapping C2 epitopes, inhibited thrombin generation in a manner that could not be recovered by fVIII supplementation. Here, we analyzed in vitro thrombin generation in epitope-mapped plasmas from 10 patients with hemophilia A and long-standing inhibitors after addition of fVIIa alone or in conjunction with fVIII. Methods: FVIII inhibitor plasmas from 10 patients with hemophilia A were obtained as part of an IRB approved study at the Emory Comprehensive Hemophilia Center. FVIII inhibitor titers and inhibitor kinetics were determined using a modified Bethesda assay. Samples were classified as having type II inhibitors if undiluted plasma resulted in incomplete inhibition of residual fVIII activity (Meeks SL et al. Blood 2007). Thrombin generation assays were carried out in the presence of 2.25 μg/ml recombinant fVIIa in the presence or absence of 1 U/ml recombinant full-length fVIII using reagents purchased from DiaPharma (West Chester, OH). The parameters analyzed include endogenous thrombin potential (area under thrombin generation curve), peak thrombin concentration, time to peak thrombin, lag time (time to 1/6th of peak thrombin) and index velocity (Vi-peak thrombin divided by time to peak minus lag time). Domain specific epitope mapping was carried out using direct ELISA and human/porcine domain hybrid fVIII proteins. Results: Domain mapping of the Abs in the plasmas identified 2 plasmas with predominantly anti-A2 Abs, 4 with predominantly anti-C2 Abs, 2 with both anti-A2 and anti-C2 Abs, and 2 with antibodies that were porcine fVIII cross-reactive (see Table). Plasmas with inhibitor titers less than 25 BU/ml were more responsive to fVIII supplementation with 6 of 7 having increased thrombin generation. Plasmas harboring even trace anti-A2 Abs were more resistant to increased thrombin generation with fVIII supplementation than plasmas with anti-C2 Abs alone. Conclusion: This study suggests a more favorable response to fVIII supplementation of rfVIIa may be predicted by the presence of anti-C2 Abs or inhibitory titers less than 25 BU/ml. In conjunction with our previous monoclonal Ab data, further mapping of epitopes within the fVIII A2 and C2 domains may help improve the ability to predict positive responses to fVIII supplementation of by-passing agents.PatientInhibitor Titer (BU/ml)DomainFVIII InhibitorThrombin Generation (fVIII + fVIIa vs. fVIIa)122A2Type IIIncreased242A2Type IIEqual384C2, small A2Type IEqual47C2Type IIncreased58C2Type IIIncreased620C2Type IEqual78C2Type IIncreased842C2, small A2Type IEqual922Porcine cross-reactiveType IIIncreased105.2Porcine cross-reactiveType IIncreased Disclosures: No relevant conflicts of interest to declare.

scholarly journals Ratio of basin lag times for runoff and sediment yield processes recorded in various environments

2015 ◽  
Vol 367 ◽  
pp. 163-169 ◽  
Author(s):  
K. Banasik ◽  
A. Hejduk
Keyword(s):  
River Basin ◽  
Sediment Yield ◽  
Time Lag ◽  
Lag Time ◽  
Storm Event ◽  
Time To Peak ◽  
Elapsed Time ◽  
Equivalent Parameter ◽  
Lag Times ◽  
Peak Value

Abstract. River basin lag time (LAG), defined as the elapsed time between the occurrence of the centroids of the effective rainfall intensity hyetograph and the storm runoff hydrograph, is an important factor in determining the time to peak and the peak value of the instantaneous unit hydrograph (IUH). In the procedure of predicting a sedimentgraph (suspended sediment load as a function of time), the equivalent parameter is the lag time for the sediment yield (LAGs), which is defined as the elapsed time between the occurrence of the centroids of sediment production during a storm event and the observed sedimentgraph at the gauging station. Data of over 150 events recorded in 11 small river catchments (located in Poland, Germany, UK and USA) with a drainage area of 0.02 km2 to 82 km2 have been analysed to estimate the ratio of LAGs/LAG. The ratio, in majority of cases was smaller than 1, and decreased with increase of river basin slope. Special attention is given to the data collected in a small agricultural catchment and also during snowmelt periods, which is located in central Poland.

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