Impact of dabigatran on a large panel of routine or specific coagulation assays

2012 ◽  
Vol 107 (05) ◽  
pp. 985-997 ◽  
Author(s):  
Séverine Robert ◽  
Christian Chatelain ◽  
Jonathan Douxfils ◽  
François Mullier ◽  
Bernard Chatelain ◽  
...  
Keyword(s):  
Linear Correlation ◽  
Individual Variability ◽  
Thrombin Inhibitor ◽  
Thrombin Time ◽  
Clotting Time ◽  
Thrombin Generation Assay ◽  
Coagulation Assay ◽  
Ecarin Clotting Time ◽  
The Impact ◽  
Higher Sensitivity

SummaryDue to low bioavailability and high inter-individual variability, monitoring of dabigatran may be required in specific situations to prevent the risk of bleedings or thrombosis. The aim of the study was to determine which coagulation assay(s) could be used to assess the impact of dabig-atran on secondary haemostasis. Dabigatran was spiked at concentrations ranging from 4.7 ng/ml to 943.0 ng/ml in pooled citrated human platelet-poor plasma. The following clotting assays were performed: prothrombin time (PT); activated partial thromboplastin time (aPTT); thrombin time (TT); ecarin clotting time (ECT); ecarin chromo-genic assay (ECA); prothrombinase-induced clotting time (PiCT); activated clotting time (ACT); Hemoclot Thrombin Inhibitor (HTI) and thrombin generation assay (TGA). A concentration-dependent prolongation of PT, dPT, and aPTT was observed with aPTT being the more sensitive test. The results varied mostly due to the clotting reagent. HTI, ECT and TGA were the most sensitive tests but are not available 24 hours a day. In addition, HTI showed a linear correlation with a good reproduci-bility. Dabigatran induced a concentration-dependent delay and inhibition of tissue factor-induced TGA. Cut-offs related with higher risk of bleedings or thrombosis were defined for each reagent of aPTT and HTI. In conclusion, aPTT could be used for the monitoring of dabigatran and as screening test for the risk of overdose. However, because of its higher sensitivity, good reproducibility, excellent linear correlation at all doses, its simplicity of use, and possibilities of automation, HTI should be considered as the gold-standard.

Comparison of Laboratory Assays to Measure Rivaroxaban and Dabigatran

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3332-3332
Author(s):  
Severine Robert ◽  
François Mullier ◽  
Hassan Mekouar ◽  
Florence Polet ◽  
Jonathan Douxfils ◽  
...  
Keyword(s):  
Linear Relationship ◽  
Thrombin Generation ◽  
High Sensitivity ◽  
Lag Time ◽  
Thrombin Inhibitor ◽  
Thrombin Time ◽  
Clotting Time ◽  
Coagulation Assay ◽  
High Concentrations ◽  
The Impact

Abstract Abstract 3332 Introduction: Recently, 2 oral anticoagulants have been marketed: dabigatran, a direct thrombin inhibitor, and rivaroxaban, a direct FXa inhibitor. Thanks to their safety and efficacy profiles, routine coagulation monitoring is generally not required. However, the most commonly reported adverse reactions with these drugs are bleedings. A sensitive laboratory assay might be valuable to measure the pharmacodynamics of these 2 drugs in different situations including risks of drug interaction (i.e. strong P-gp inhibitors), overdose or to measure patient compliance. Due to their different mechanism of action, the measurement of their anticoagulant level in plasma may require different types of clotting assays. Aims: The aim of the present study was to determine which coagulation assay(s) could be used to measure the impact of rivaroxaban and dabigatran among a range of routine or more specific tests. Methods: Both drugs were spiked at increasing concentrations in pooled citrated normal human platelet-poor plasma (PPP). The final concentrations were ranging from 10 nM to 2 μM for dabigatran and from 25 nM to 5 μM for rivaroxaban. Such concentrations covered the plasma range in patients during orthopedic surgery. The following routine clotting assays were performed with the spiked plasma according to the manufacturer's protocols: Prothrombin Time (PT) with Neoplastin CI+ and Neoplastin R on STA-R (Roche Diagnostics), with Innovin on BCS (Siemens) and with Recombiplastin on ACL-TOP (Instrumentation Laboratories); activated Partial Thromboplastin Time (aPTT) with CK-Prest, PTT-A and Cephascreen on STA-R, with Actin FS on BCS and with Synthasil on ACL TOP and Thrombin Time (TT) on STA-R. More specific tests included Prothrombinase-induced Clotting Time (PiCT, Pefakit®, Pentapharm) and Ecarin Clotting Time (ECT) on STA-R; dilute PT (dPT) and activated Clotting time (ACT) on KC10. Thrombin Generation Tests (TGT) were also performed with Calibrated Automated Thrombogram (CAT) using PPP or PPP LOW reagents (Thrombinoscope). Sensitivity of a coagulation assay was defined as the concentration required to double clotting time (2XCT). Results: Dabigatran. A concentration-dependent prolongation of PT, dPT and aPTT was observed. However, at high concentrations, sensitivity of aPTT decreased whereas sensitivity of PT increased. The results varied depending on the clotting reagent used. TT was too sensitive leading to high variability for concentrations higher than 250nM. PiCT showed a linear concentration coagulation time (CT) relationship until a plateau at 750nM. ECT showed a high sensitivity (2X CT &ap; 93 nM), a linear relationship in the whole concentration range and a very low variability (CV≤ 1,8%). ACT gave a similar profile to PT (Innovin) with a slightly higher sensitivity (2X CT &ap; 716 nM vs 842nM). Dabigatran induced a concentration-dependent delay and inhibition of the tissue factor-induced thrombin generation with 5 pM TF or 1 pM TF with 4 μM PL and 16.7 mM CaCl2. The drug strongly increased the lag time and Tmax whereas it slightly decreased the Cmax and ETP. The lag time was the most sensitive CAT parameter with a high sensitivity (2x lag time &ap; 145 nM) and a low variability (CV≤6%). Rivaroxaban. A concentration-dependent prolongation of PT, dPT and aPTT was observed. However, at high concentrations, sensitivity of aPTT increased. Sensitivity of dPT (2X CT &ap; 109 to 550 nM) and PT (2X CT &ap; 138 to 764 nM) were similar and superior to aPTT (2X CT &ap; 897 to 2050 nM). The results varied depending on the clotting reagent used. TT was insensitive to rivaroxaban until 2500nM. Both PiCT and ECT showed a low sensitivity (2X CT &ap; 2536 nM and 5750 nM, respectively). A concentration-dependent prolongation of ACT was observed until 2500nM (2X CT &ap; 2275 nM). Rivaroxaban induced a concentration-dependent reduction and delay of the TF-induced thrombin generation. The Cmax was more strongly decreased than the ETP whereas the Tmax was more prolonged than the lag time, showing a major influence on the amplification phase. The Cmax was the most sensitive CAT parameter with a high sensitivity (Cmax EC50 &ap; 50 nM) and a low variability (CV<1%). Conclusions: ECT and PT are the most appropriate tests to study the pharmacodynamic effects of dabigatran and rivaroxaban respectively, thanks to high sensitivity, linear relationship in the whole concentration range and low variability. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Betrixaban: Impact on Routine and Specific Coagulation Assays—A Practical Laboratory Guide

2018 ◽  
Vol 118 (07) ◽  
pp. 1203-1214 ◽  
Author(s):  
Romain Siriez ◽  
Jonathan Evrard ◽  
Jean-Michel Dogné ◽  
Lionel Pochet ◽  
Damien Gheldof ◽  
...  
Keyword(s):  
Diagnostic Tests ◽  
Factor Xa ◽  
High Sensitivity ◽  
Thrombin Time ◽  
Coagulation Assays ◽  
Thrombin Generation Assay ◽  
Coagulant Activity ◽  
Direct Factor Xa Inhibitors ◽  
Coagulation Assay ◽  
The Impact

Introduction Betrixaban is a novel direct oral factor Xa inhibitor approved by the Food and Drug Administration for prophylaxis of venous thromboembolism in adult patients hospitalized for an acute illness at risk for thromboembolic complications. Assessment of the anti-coagulant effect of betrixaban may be useful in some situations. Also, clinicians need to know how routine coagulation assays are influenced. Objective The aim of this study is to determine which coagulation assay(s) should be used to assess the impact of betrixaban on haemostasis and provide laboratory guidance for their interpretation. Materials and Methods Betrixaban was spiked at final concentrations ranging from 0 to 250 ng/mL in platelet-poor plasma. Different reagents from several manufacturers were tested and the impact of betrixaban on pro-thrombin time (PT), activated partial thromboplastin time (aPTT), dilute Russel viper venom time (dRVV-T), chromogenic anti-Xa assays, thrombin generation assay (TGA), and a large panel of haemostasis diagnostic tests has been assessed. Results A concentration-dependent prolongation of aPTT, PT and dRVV-T is observed. The sensitivity mainly depends on the reagent. Chromogenic anti-Xa assays show high sensitivity depending on the reagent and/or the methodology. These assays applicable for other direct factor Xa inhibitors have to be adapted to obtain a relevant range of measurement. TGA may also be attractive to assess the anti-coagulant activity of betrixaban. Conclusion Adapted chromogenic anti-Xa assays are the most appropriate assays to estimate the concentration of betrixaban. Betrixaban significantly affects several haemostasis diagnostic tests and this needs to be taken into consideration when requesting and interpreting such tests.

Biochemical and pharmacological effects of the direct thrombin inhibitor AR-H067637

2009 ◽  
Vol 101 (06) ◽  
pp. 1051-1059 ◽  
Author(s):  
Christer Mattsson ◽  
Tord Inghardt ◽  
Margareta Elg ◽  
Johanna Deinum
Keyword(s):  
Competitive Inhibitor ◽  
Direct Thrombin Inhibitor ◽  
Anticoagulant Effect ◽  
Thrombin Inhibitor ◽  
Thrombin Time ◽  
Clotting Time ◽  
Binding Studies ◽  
Plasma Coagulation ◽  
Coagulation Assays

SummaryAZD0837 is in development as a new oral anticoagulant for use in thromboembolic disorders. In vivo, AZD0837 is converted to AR-H067637, a selective and reversible direct thrombin inhibitor. Established biochemical methods were used to assess and measure the biochemical and pharmacological properties of AR-H067637. Both direct Biacore binding studies of AR-H067637 with immobilised α-thrombin and inhibition studies using pre-steady state kinetics with thrombin in the fluid phase confirmed that AR-H067637 is a rapid-binding, reversible and potent (inhibition constant K i = 2–4 nM), competitive inhibitor of thrombin, as well as of thrombin bound to fibrin (clot-bound thrombin) or to thrombomodulin. The total amount of free thrombin generated in platelet-poor clotting plasma was inhibited concentration-dependently by AR-H067637, with a concentration giving half maximal inhibition (IC50) of 0.6 μM. Moreover, AR-H067637 is, with the exception of trypsin, a se-lective inhibitor for thrombin without inhibiting other serine proteases involved in haemostasis. Furthermore, no anticoagulant effect of the prodrug was found. AR-H067637 prolonged the clotting time concentration-dependently in a range of plasma coagulation assays including activated partial thromboplastin time, prothrombin time, prothrombinase-induced clotting time, thrombin time and ecarin clotting time. The two latter assays were found to be most sensitive for assessing the anticoagulant effect of AR-H067637 (plasma IC50 93 and 220 nM, respectively). AR-H067637 also inhibited thrombin-induced platelet activation (by glycoprotein IIb/IIIa exposure, IC50 8.4 nM) and aggregation (IC50 0.9 nM). In conclusion, AR-H067637 is a selective, reversible, competitive inhibitor of α-thrombin, with a predictable anticoagulant effect demonstrated in plasma coagulation assays.

A novel coagulation assay incorporating adherent endothelial cells in thromboelastometry

2013 ◽  
Vol 109 (05) ◽  
pp. 869-877 ◽  
Author(s):  
Johannes Zipperle ◽  
Wolfgang Holnthoner ◽  
Anna-Maria Husa ◽  
Sylvia Nürnberger ◽  
Heinz Redl ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Whole Blood ◽  
Culture Supernatant ◽  
Umbilical Vein ◽  
Blood Clot ◽  
Clotting Time ◽  
Monitoring Tool ◽  
Coagulation Assay ◽  
Umbilical Vein Endothelial Cells ◽  
The Impact

SummaryFollowing vascular injury or activation, endothelial cells (ECs) participate in the modulation of haemostasis and fibrinolysis. Viscoelastic tests (VETs) are a potent bedside monitoring tool that reports haemostatic parameters in real time. However, VETs neglect the influence of the surrounding endothelium. Our aim was therefore to establish an assay that incorporates ECs in a whole blood VET and to assess the impact of ECs on coagulation parameters. Outgrowth endothelial cells (OECs) and human umbilical vein endothelial cells (HUVECs) were seeded onto microbeads to create transferable EC-microcarriers. Microbeads were then added to citrated whole blood in the measurement cup of a thromboelastometry device (ROTEM). After the addition of CaCl2 (star-TEM®) to the blood sample (NATEM assay), standard ROTEM parameters were analysed. Scanning electron microscopy (SEM) was carried out to visualise the interactions of the beads, whole blood components and the ROTEM pin after clotting. SEM showed that the added microbeads were effectively incorporated into the final blood clot. In the presence of activated ECs, the clotting time (CT) of the blood was shortened fourfold compared to that in uncoated control beads. A significant reduction in CT was also observed in the presence of unstimulated ECs. Interestingly, CT was also reduced by the addition of purified EC culture supernatant. CT shortening was prevented by incubating the supernatant with an inhibiting antibody against tissue factor (TF). Our findings demonstrate that ECs can be incorporated into a ROTEM assay via coated microbeads, and whole blood clotting initiation is accelerated by non-activated and activated ECs.

Development of Prothrombinase Induced Clotting Time (Pefakit ®, PiCT) Assay and its Validation in the Monitoring of Anti-Xa and Anti-FIIa Drugs.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1858-1858
Author(s):  
Debra A. Hoppensteadt ◽  
Josephine Cunanan ◽  
Jeanine M. Walenga ◽  
Jawed Fareed
Keyword(s):  
Dose Range ◽  
Fibrin Clot ◽  
Thrombin Time ◽  
Plasma Samples ◽  
Clotting Time ◽  
Prothrombinase Complex ◽  
Anticoagulant Drugs ◽  
Normal Human ◽  
Ecarin Clotting Time ◽  
Direct Acting

Abstract Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux, danaparoid, direct and indirect (via a cofactor) acting anti-FIIa and anti-Xa anticoagulant drugs are being used in patients for the prophylaxis and treatment of thrombosis. The aPTT does not reliably measure the effects of these drugs. Therefore, there is no simple/reliable method for monitoring patients administered these drugs, particularly those with renal insufficiency and obesity. The newly developed Prothrombinase Induced Clotting Time (PiCT) assay (Pefakit®; Pentapharm, Ltd.; Basel, Switzerland) was developed for monitoring heparins. The PiCT is based on the activation of plasma coagulation by a defined amount of activated FXa, phospholipid and Russell’s viper venom (RVV). The prothrombinase complex formed following recalcification is independent of endogenous thrombin mediated FV activation because the RVV directly activates FV. In this study, the PiCT was used to determine the relative anticoagulant actions of UFH, LMWH, anti-FIIa and anti-FXa drugs. Drugs were supplemented to normal human pooled plasma in a concentration range of 10- 0.08 μg/ml. Plasma samples were analyzed using the PiCT, aPTT, Heptest, thrombin time (TT), ecarin clotting time (ECT), chromogenic anti-FIIa, chromogenic anti-FXa and fibrinopeptide A (FPA) generation assays. In addition, plasma samples from patients treated with these drugs were also tested. The UFH, LMWH, anti-FIIa drugs and the indirect acting anti-FXa drugs produced a concentration-dependent prolongation of the PiCT. Different responses were obtained for each drug. The anti-FIIa drugs gave the strongest dose-response response followed by UFH, LMWH and fondaparinux, in that order. The direct acting anti-FXa agents showed a weak response in the PiCT. Compared to the other assays, the PiCT response showed better sensitivity, reproducibility and linearity over a broader dose range than the aPTT, Heptest, TT, ECT, anti-FIIa and anti-FXa assays. Samples from patients treated with enoxaparin (0.5 mg/kg IV) gave peak concentrations of 0.92± 0.11 U/ml by the PiCT, compared to 0.95± 0.24 U/ml by the anti-FXa assay. Samples from patients treated with bivalirudin, lepirudin or argatroban gave comparable values by the PiCT, aPTT and ECT. The relative prolongation of the PiCT was proportional to the inhibition of thrombin generation as measured by FPA. The PiCT is as simple to perform as the aPTT and can be adapted to any instrument capable of detecting a fibrin clot. Unlike other clot-based tests, the PiCT is sensitive to most old and new anticoagulant drugs and the results are linear through both the therapeutic and interventional dosing ranges. The PiCT may offer the first available single assay that can be universally used for monitoring most of the new anticoagulant drugs regardless of their mechanism of action.

Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and Ecarin Clotting Time

2004 ◽  
Vol 91 (06) ◽  
pp. 1137-1145 ◽  
Author(s):  
Jochen Graff ◽  
Ute Klinkhardt ◽  
Nils von Hentig ◽  
Jeanine Walenga ◽  
Hikari Watanabe ◽  
...  
Keyword(s):  
Prothrombin Time ◽  
Partial Thromboplastin Time ◽  
Combined Treatment ◽  
Activated Partial Thromboplastin Time ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Sensitivity Index ◽  
Clotting Time ◽  
Ecarin Clotting Time

SummaryTreatment with the direct thrombin inhibitor argatroban (ARG) is often followed by vitamin K-antagonist treatment (VKA). Phenprocoumon (PC) and acenocoumarol (AC) are frequently used in Europe. The standard monitoring test for VKA, prothrombin time (PT), is prolonged by direct thrombin inhibitors. Therefore the International Normalized Ratio (INR) obtained during combined treatment does not reflect the true effect of the VKA. A similar interference of the VKA on the activated partial thromboplastin time (aPTT), a monitoring assay for direct thrombin inhibitors, can occur. In 39 healthy volunteers the effect of ARG alone or combined with PC or AC on PT, INR, aPTT, and Ecarin Clotting Time (ECT) was investigated. 6 groups each of 6-8 volunteers received a 5-hour infusion of either 1.0, 2.0 or 3.0 µg/kg/min ARG (days 1, 3, 4 and 5) before initiation of either PC or AC (day 1) and during continued VKA dosing (target INR 2-3). A linear relationship (INR ARG+VKA = intercept + slope * INR VKA alone) was observed between the INR measured “on” and “off” ARG.The slope depended on the argatroban dose and on the International Sensitivity Index (ISI) of the PT reagent, the steepest slope (i.e., the largest difference between INR ARG+VKA and INR VKA alone) was seen with the highest ARG dose and the PT reagent with an ISI of 2.13.There was a close correlation between plasma levels of ARG and aPTT or ECT. Under VKA the ARG-aPTT relationship indicated an increased sensitivity of the aPTT to ARG, VKA treatment had no effect on the prolongation of the ECT induced by argatroban. In conclusion, ARG at doses up to 2 µg/kg/min can be discontinued at an INR of 4.0 on combined therapy with VKA, as this would correspond to an INR between 2.2 and 3.7 for the VKA. If it is necessary to monitor ARG in the critical transition period, the ECT which is not influenced by VKA can be used as an alternative to the aPTT.

Comparison of calibrated dilute thrombin time and aPTT tests with LC-MS/MS for the therapeutic monitoring of patients treated with dabigatran etexilate

2013 ◽  
Vol 110 (09) ◽  
pp. 543-549 ◽  
Author(s):  
Jean-Michel Dogné ◽  
François Mullier ◽  
Bernard Chatelain ◽  
Yuko Rönquist-Nii ◽  
Rickard E. Malmström ◽  
...  
Keyword(s):  
Dabigatran Etexilate ◽  
Plasma Concentrations ◽  
Internal Standard ◽  
Individual Variability ◽  
Therapeutic Monitoring ◽  
Thrombin Inhibitor ◽  
Clinical Samples ◽  
Thrombin Time ◽  
Plasma Samples ◽  
The Poor

SummaryWays to monitor dabigatran etexilate (DE) therapy would be useful in certain situations. Functional assays such as aPTT or Hemoclot® Thrombin Inhibitor (HTI) have been proposed to evaluate dabigatran concentrations, but previous findings are based on in vitro studies and results must be confirmed in clinical samples. The aim of this study was to compare aPTT and HTI measurements with liquid chromatography- tandem mass spectrometry (LC-MS/MS) measurements of dabigatran in plasma samples from DE treated patients. Seventy-one plasma samples were included. aPTT was performed using STA-CKPrest® and SynthASil®. HTI was performed according to instructions from the manufacturer. The LC-MS/MS method utilised dabigatran- d3 as internal standard. The plasma concentration range was 0 to 645 ng/ml as measured by LC-MS/MS. Overall, the HTI and LC-MS/ MS analyses correlated well (r2=0.97). The Bland-Altman analysis showed a mean difference of 9 ng/ml (SD: 20 ng/ml). However, the HTI performed poorly at concentrations <50 ng/ml. LC-MS/MS was sensitive (limit of quantification 1.1 ng/ml) and specific for dabigatran. The aPTT methods did not correlate well with plasma concentrations measured by LC-MS/MS (r2 = 0.59 with SynthASil® and 0.50 with STACKPrest ®). In conclusion, the poor sensitivity, the important inter-individual variability, and the poor correlation with LC-MS/MS preclude the use of aPTT to estimate dabigatran concentrations. Due to its small inter-individual variability and good agreement with LC-MS/MS measurements, we recommend the use of HTI assays to rather accurately estimate concentrations of dabigatran <50 ng/ml. Quantification of lower dabigatran levels in DE-treated patients requires the “reference” LC-MS/MS method.

scholarly journals Anticoagulant Effects of Dabigatran in Paediatric Patients Compared with Adults: Combined Data from Three Paediatric Clinical Trials

2018 ◽  
Vol 118 (09) ◽  
pp. 1625-1636 ◽  
Author(s):  
Hugo Maas ◽  
Savion Gropper ◽  
Fenglei Huang ◽  
Joachim Stangier ◽  
Igor Tartakovsky ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Dabigatran Etexilate ◽  
Age Groups ◽  
Graphical Analysis ◽  
Physiological Age ◽  
Thrombin Time ◽  
Clotting Time ◽  
Age Related ◽  
Coagulation Assay ◽  
The Relationship

Background Physiological age-related changes in the haemostatic and coagulation systems result in differing anticoagulant assay responses to standard anticoagulants. Therefore, we investigated the response of anticoagulant assays to dabigatran etexilate (DE) in children compared with adults. Objective This article assesses the relationship between plasma dabigatran concentration and coagulation assay results across age groups in children and adults. Patients and Methods Data from three clinical trials in which children received DE following standard of care for venous thromboembolism were compared with data from adult clinical trials. The effects of dabigatran concentration on diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) were analysed graphically and with modelling. Results The concentration–dTT relationships were consistent in children across all ages and adults in the graphical analysis. For ECT and aPTT, relationships based on ratios over baseline were similar across all ages; absolute clotting times showed that the same exposure resulted in longer clotting times in some of the children aged < 1 year versus adults. Modelling showed concentration–clotting time relationships for all three assays were largely comparable between adults and children, except in those aged < 2 months, in whom there was a slight upward shift in ECT and aPTT relative to adults. Conclusion Results suggest that developmental haemostatic changes will have little impact on response to DE. However, further paediatric clinical trials assessing the relationship between coagulation assay responses and clinical outcomes will be needed to confirm this finding.

Chronic Antithrombinaemia (Antithrombin V) with Haemorrhagic Diathesis in a Case of Rheumatoid Arthritis with Hypergammaglobulinaemia

1957 ◽  
Vol 01 (03/04) ◽  
pp. 499-528 ◽  
Author(s):  
A Loeliger ◽  
J. F. Ph Hers
Keyword(s):  
Rheumatoid Arthritis ◽  
Gradual Increase ◽  
Thrombin Inhibitor ◽  
Thrombin Time ◽  
Clotting Time ◽  
Laboratory Findings ◽  
Protamine Sulphate ◽  
The Past ◽  
Heat Stable ◽  
Γ Globulins

SummaryA report is represented on a 44-year-old patient suffering, since 1938, from very slowly progressive rheumatoid arthritis. Haemorrhagic manifestations have been seen since 1951 (large cutaneous and muscular haemorrhages, microhaematuria and macrohaematuria, possibly also articular haemorrhages). In addition to an extremely marked increase in γ-globulins to values above 8 g/100 ml (γ-globulins with a normal sedimentation constant S 7) a circulating anticoagulant was demonstrable, which is held responsible for the marked increase in clotting time, “prothrombin” time and thrombin time. The hypothesis is forwarded that this is a physiological anticoagulant showing a marked increase. Since it is different from the four antithrombins described by Seegers it is referred to as antithrombin-V. Antithrombin-V occurs both in the plasma and in the serum and appears to be bound to the (ß)γ-fraction. It is a thrombin inhibitor which, unlike antithrombin-II, has no direct effect on thromboplastin and thrombin formation. Antithrombin-V cannot be neutralized by protamine sulphate; it is heat-stable, not dialysable and not adsorbed onto BaSO4. Thrombelastography made it possible clearly to demonstrate that an increase in antithrombin-V is associated with a marked increase in clotting time but causes no pathological course of clot formation.Therapeutic results obtained with ACTH and cortisone are favourable: the activity of antithrombin-V decreases parallel with a decrease in γ-globulin values, and the clotting time is normalized. The patient has received, during the past 16 months, oral cortisone treatment (25 mg thrice daily), and is at present free of complaints, although clinical and laboratory findings show a gradual increase in symptoms respectively γ-globulin values with a slight increase in clotting time.The possible significance of the antithrombin-V activity in the protection against thrombo-embolism is briefly mentioned.

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