P-8 PRESERVATION OF THROMBIN GENERATION IN CIRRHOSIS DESPITE ABNORMAL RESULTS OF INTERNATIONAL NORMALIZED RATIO: IMPLICATIONS FOR INVASIVE PROCEDURES

SummaryAtrial fibrillation (AF) is a prothrombotic condition, involving increased thrombin generation and fibrinogen concentrations. Vitamin K antagonists (VKAs) prevent arterial thromboembolism if optimal anticoagulation is achieved by individualised drug doses, assessed by determining the Prothrombin time-related International Normalized Ratio (Pt-INR). There is evidence that formation of tight-laced fibrin networks is pathogenic in prothrombotic diseases. This study was performed among AF patients, to test whether long-term treatment with VKAs affects the structure of fibrin networks, and whether the effect is altered by employing different coagulation triggers: exogenous thrombin (1 IU/ml), 10 pM tissue factor (TF) or a commercial Pt-INR reagent (containing 400-fold more TF). In the thrombin-based method, fibrin network porosity (scanning electron microscopy) and liquid permeability (flow measurements) correlated inversely to fibrinogen concentrations, while positive correlations to the degree of anticoagulation were shown with the Pt-INR reagent. In the method with 10 pM TF, the two above relationships were detected, though the influence of Pt-INR was more profound than that of fibrinogen concentrations. Moreover, greater shortening of clot lysis time (CLT) arose from more permeable clots. As a coagulation trigger, 10 pM TF vs exogenous thrombin or the Pt-INR reagent is more informative in reflecting the in vivo process from thrombin generation to fibrin formation. Since fibrin network permeability rose in parallel to elevations of INR and shortening of CLT in AF patients, antithrombotic effects on prevention of thrombotic complications may be achieved from impairment of thrombin generation, resulting in formation of permeable clots susceptible to fibrinolysis.

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Thromboelastometry as an Alternative Method for Coagulation Assessment in Pediatric Patients Undergoing Invasive Procedures: A Pilot Study

European Journal of Pediatric Surgery ◽

10.1055/s-0038-1667111 ◽

2018 ◽

Vol 29 (03) ◽

pp. 298-301

Author(s):

Miroslav Durila ◽

Jakub Jonas ◽

Marianna Durilova ◽

Michal Rygl ◽

Jiri Skrivan ◽

...

Keyword(s):

Whole Blood ◽

Pediatric Patients ◽

Point Of Care ◽

Venous Catheter ◽

International Normalized Ratio ◽

Fresh Frozen Plasma ◽

Severe Bleeding ◽

Invasive Procedures ◽

Coagulation Profile ◽

Alternative Method

Introduction Standard coagulation tests (activated partial thromboplastin time [aPTT] and prothrombin time [PT]) are used for the assessment of coagulation profile in critically ill pediatric patients undergoing invasive interventions such as insertion of central venous catheter, tonsillectomy, laparotomy, etc. However, these tests do not reflect the profile of whole blood coagulation. Rotational thromboelastometry (ROTEM) as a point of care (POC) viscoelastic test may serve as an alternative method. Due to its ability to assess coagulation profile of the whole blood, it might yield normal results despite prolonged aPTT/PT results. The aim of this study was to find out if there was any severe bleeding during or after invasive procedures if ROTEM test was normal despite prolonged values of aPTT/PT in pediatric patients. Materials and Methods We retrospectively analyzed data for the years 2015 to 2017 for pediatric patients with prolonged values of aPTT or PT and normal ROTEM tests—internal thromboelastometry (INTEM) (assessing internal pathway of coagulation) and external thromboelastometry (EXTEM) (assessing external pathway of coagulation)—and we looked for severe bleeding during or after invasive procedures. Results In 26 pediatric patients (children from 2 months to 17 years old), we found that INTEM and EXTEM tests showed normal coagulation despite prolonged values of aPTT ratio with a median of 1.47 (minimum 1.04 and maximum 2.05), international normalized ratio with a median of 1.4 (minimum 0.99 and maximum 2.10), and PT ratio with a median of 1.30 (minimum 0.89 and maximum 2.11). In these patients, no severe bleeding was observed during interventions or postoperatively. Conclusion Our data support using thromboelastometry method as an alternative coagulation test for the assessment of coagulation profile in pediatric patients undergoing surgical or other invasive procedures, especially using it as a POC test. All invasive procedures in our study were performed without severe bleeding despite prolonged values of PT/aPTT with normal ROTEM results. It seems that ROTEM assessment of coagulation may lead to decreased administration of fresh frozen plasma and shorten time of patient preparation for intervention.

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Prophylactic correction of the international normalized ratio in neurosurgery: a brief review of a brief literature

Journal of Neurosurgery ◽

10.3171/2010.7.jns091857 ◽

2011 ◽

Vol 114 (1) ◽

pp. 9-18 ◽

Cited By ~ 27

Author(s):

Kelly L. West ◽

Cory Adamson ◽

Maureane Hoffman

Keyword(s):

Bleeding Risk ◽

International Normalized Ratio ◽

Fresh Frozen Plasma ◽

Coagulation Cascade ◽

Bleeding Tendency ◽

Invasive Procedures ◽

Clinical Tool ◽

Clotting Factors ◽

Fresh Frozen ◽

Frozen Plasma

Prophylactic fresh-frozen plasma (FFP) transfusion is often undertaken in hemodynamically stable patients with a minimally elevated international normalized ratio (INR) prior to invasive procedures, despite little evidence in support of this practice. The authors review the current literature in an attempt to clarify best clinical practice with regard to this issue. Although the activated partial thromboplastin time and prothrombin time–INR are useful laboratory tests to measure specific clotting factors in the coagulation cascade, in the absence of active bleeding or a preexisting coagulopathy, their utility as predictors of overall bleeding risk is limited. Several studies have shown an imperfect correlation between mild elevations in the INR and subsequent bleeding tendency. Furthermore, FFP transfusion is not always sufficient to achieve normal INR values in patients who have mild elevations (< 2) to begin with. Finally, there are risks associated with FFP transfusion, including potential transfusion-associated [disease] exposures as well as the time delay imposed by laboratory testing and transfusion administration prior to initiation of procedures. The authors propose that the current concept of a “normal” INR value warrants redefinition to make it a more meaningful clinical tool. Based on their review of the literature, the authors suggest that in a hemodynamically stable patient population there is a range of mildly prolonged INR values for which FFP transfusion is not beneficial, and is potentially harmful.

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Evaluation of Thromboelastometry in Sepsis in Correlation With Bleeding During Invasive Procedures

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029617731624 ◽

2017 ◽

Vol 24 (6) ◽

pp. 993-997 ◽

Cited By ~ 1

Author(s):

Pavel Lukas ◽

Miroslav Durila ◽

Jakub Jonas ◽

Tomas Vymazal

Keyword(s):

Venous Catheter ◽

International Normalized Ratio ◽

Fresh Frozen Plasma ◽

University Hospital ◽

Severe Bleeding ◽

Invasive Procedures ◽

Extrinsic Pathway ◽

Fresh Frozen ◽

Assigned Number ◽

Frozen Plasma

Prolongation of prothrombin time (PT) is often encountered in patients with sepsis. On the other hand, thromboelastometry as a global coagulation test might yield normal results. The aim of our study was to evaluate whether prolonged PT in the presence of normal thromboelastometry parameters is associated with severe bleeding in patients with sepsis undergoing invasive procedures. In patients with sepsis undergoing low-risk bleeding invasive procedures (central venous catheter placement, dialysis catheter insertion, drain insertion, and so on) or high-risk bleeding invasive procedures (surgical tracheostomy, surgical laparotomy, thoracotomy, and so on), coagulation was assessed by thromboelastometry using EXTEM test (test for evaluation of the extrinsic pathway of coagulation, contains activator of extrinsic pathway) and with PT. For period of years 2013 to 2016, we assessed occurrence of severe bleeding during those procedures and 24 hours later in patients with prolonged PT and normal thromboelastometry results. This retrospective study was performed at Department of Anaesthesiology and Intensive Care Medicine of Motol University Hospital in Prague. Data from 76 patients with sepsis were analyzed. Median value of international normalized ratio (INR) was 1.59 (min—1.3 and max—2.56), and median value of prothrombin ratio (PR) was 1.5 (min—1.23 and max—2.55) with normal thromboelastometry finding. Despite prolonged INR/PR, no severe bleeding was observed during invasive procedures. Our data show that sepsis may be accompanied by normal thromboelastometry results, despite prolonged values of PT, and invasive procedures were performed without severe bleeding. This approach to coagulation assessment in sepsis may reduce administration of fresh frozen plasma to the patients. The study was registered at Clinical Trials.gov with assigned number NCT02971111.

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Prenatal diagnosis in the Netherlands, 1991–2000: number of invasive procedures, indications, abnormal results and terminations of pregnancy

Prenatal Diagnosis ◽

10.1002/pd.1659 ◽

2007 ◽

Vol 27 (3) ◽

pp. 251-257 ◽

Cited By ~ 6

Author(s):

H. T. C. Nagel ◽

A. C. Knegt ◽

M. D. Kloosterman ◽

H. I. J. Wildschut ◽

N. J. Leschot ◽

...

Keyword(s):

Prenatal Diagnosis ◽

The Netherlands ◽

Invasive Procedures ◽

Abnormal Results

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INR vs. thrombin generation assays for guiding VKA reversal: a retrospective comparison

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-0877 ◽

2015 ◽

Vol 53 (8) ◽

Cited By ~ 5

Author(s):

Robert Herpers ◽

André P. van Rossum ◽

Rachel T. van Beem ◽

W. Margot Michel ◽

Viola J.F. Strijbis ◽

...

Keyword(s):

Thrombin Generation ◽

Prothrombin Complex Concentrate ◽

International Normalized Ratio ◽

Added Value ◽

Current Debate ◽

Dosing Regimen ◽

Exponential Relationship ◽

Thrombin Generation Assay ◽

Retrospective Comparison

AbstractProthrombin complex concentrate (PCC) is used to reverse vitamin K antagonist (VKA)-induced anticoagulation. Prothrombin time-derived international normalized ratio (INR) measurements are widely used in determining the required PCC dose, but this approach requires reappraisal. The aim of the present study was to determine the added value of the thrombin generation assay (TGA) compared with the INR in guidance of VKA reversal by PCC.In an open, observational study, INR and TGA measurements were carried out on plasma samples from phenprocoumon-treated patients receiving VKA reversal. Following both analytical methods, PCC dosing correlates were calculated and compared retrospectively. Alternatively, in vitro PCC spiking experiments were performed.As expected, an exponential relationship between PCC dose and INR was found. For the TGA parameters peak thrombin and endogenous thrombin potential (ETP), however, this relationship was found to be linear throughout the full therapeutic range. Additional computational analysis showed a positive correlation (rOur results support the current debate questioning the rationale for the use of the INR in the management of anticoagulation by VKA. Compared with INR, TGA-based calculations may enable a more accurate PCC dosing regimen for patients requiring VKA reversal.

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Wide variation in thrombin generation in patients with atrial fibrillation and therapeutic International Normalized Ratio is not due to inflammation

British Journal of Haematology ◽

10.1111/j.1365-2141.2008.07279.x ◽

2008 ◽

Vol 142 (6) ◽

pp. 946-952 ◽

Cited By ~ 30

Author(s):

A. Gatt ◽

J. J. van Veen ◽

A. Bowyer ◽

A. M. Woolley ◽

P. Cooper ◽

...

Keyword(s):

Atrial Fibrillation ◽

Thrombin Generation ◽

International Normalized Ratio

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P1251THROMBIN GENERATION ASSAY: A POTENTIAL TOOL TO STRATIFY THROMBOTIC RISK IN HEMODIALYSIS PATIENTS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1251 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Ileana Kalikatzaros ◽

Massimo Radin ◽

Irene Cecchi ◽

Savino Sciascia ◽

Giacomo Forneris ◽

...

Keyword(s):

Ischemic Stroke ◽

Venous Thrombosis ◽

Thrombin Generation ◽

Previous History ◽

International Normalized Ratio ◽

Vascular Events ◽

Thrombotic Risk ◽

Thrombin Generation Assay ◽

Autoimmune Conditions ◽

History Of

Abstract Background and Aims Patients with Chronic Kidney Disease (CKD) in hemodialysis (HD) show both high thrombotic and hemorrhagic risks. However, routine laboratory techniques aimed to evaluate haemostasis, i.e. activated prothrombin time (PT) and activated partial thromboplastin time (aPTT), are not sensitive enough to detect mild hypocoagulable or hypercoagulable states in this population. Indeed, these methods evaluate the start-up phase of the coagulation, but omit the amplification stage in which an exponential increase of thrombin generation occurs. Thrombin generation assay (TGA) is a second-level global coagulative test able to evaluate thrombin generation and decay. So far the TGA has never been used for assessing thrombotic risk in HD patients. Method This is a monocentric observational retrospective study conducted at San Giovanni Bosco Hospital and University of Turin, Italy. After chart-reviewing of all patients with CKD in HD, we enrolled: Group A) 100 Patients with CKD in HD, treated or not treated with warfarin Group B) 60 Patients treated with Warfarin with normal kidney function Group C) 60 Healthy Controls Results Compared to healthy donor patients on hemodialysis that were not treated with warfarin had significantly lower tLag (mean tLag 8.2±3.4 vs. 9.7±2.9, p < 0.05), lower tPeak (mean tPeak 14.3±6 vs. 16.2±4.7, p < 0.05), lower Peak (mean Peak 151.8±77.4 vs. 209.2±103.8, p < 0.001) and lower AUC (mean AUC 1624.5±564.4 vs. 2023±489.2, p < 0.001) (Figure 1). Compared to controls with normal renal function treated with warfarin, HD patients treated with warfarin had higher tLag (mean tLag 10.5±3.3 vs. 8.3±2.1, p < 0.05), higher tPeak (mean tPeak 16.5±4.9 vs. 13±2.9, p < 0.05). Among HD patients who were not treated with warfarin, those with autoimmune conditions showed a pro-thrombotic TGA profile when compared to HD patients without autoimmune diseases, with significantly higher Peak (mean Peak 188.4±30 vs. 149.9±78.7, p < 0.05) and higher AUC (mean AUC 2066.9±138.2 vs. 1601.5±569, p < 0.001). Similarly, compared to patients without previous history of vascular events (59), patients with previous ischemic stroke or venous thrombosis (41), had significantly lower tLag (mean tLag 8±2.9 vs. 14.2±8.5, p < 0.001), lower tPeak (mean tPeak 14±5.6 vs. 21.7±12.3, p <0.05), higher Peak (mean Peak 154.9±76.8 vs. 71.83±49.2, p<0.05) and higher AUC (mean AUC 1653.7±548.7 vs. 863.4±501.4, p < 0.05). Of note, a significant positive relationship was detected between the International Normalized Ratio (INR) and both tLag (Pearson 0.46, p <0.001) and tPeak (Pearson 0.35, p <0.001). INR was inversely correlated to Peak (Pearson -0.47, p <0.001) and AUC (Pearson -0.61, p <0.001) (Figure 2). Conclusion Identifying patients at high risk for cardiovascular diseases and thrombosis has an important impact on the management of patients with CKD in HD. In this study, we observed a prothrombotic TGA profile in patients with CKD in HD, especially those with autoimmune conditions or previous history of arterial events (especially ischemic stroke) or venous thrombosis. Prospective studies are needed to evaluate the possible clinical use of TGA as thrombotic risk stratification tool in HD patients.

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Efficacy of Prothrombin Complex Concentrate Treatment in Patients with Liver Coagulopathy Who Underwent Various Invasive Hepatobiliary and Gastrointestinal Procedures

Case Reports in Gastroenterology ◽

10.1159/000447290 ◽

2016 ◽

Vol 10 (2) ◽

pp. 315-322 ◽

Cited By ~ 8

Author(s):

Cosmas Rinaldi A. Lesmana ◽

Lidwina Cahyadinata ◽

Levina S. Pakasi ◽

Laurentius A. Lesmana

Keyword(s):

Anticoagulation Therapy ◽

Bleeding Event ◽

International Normalized Ratio ◽

Bleeding Complications ◽

Rank Test ◽

Upper Gastrointestinal Endoscopy ◽

Invasive Procedures ◽

Open Label ◽

Before And After ◽

Signed Rank Test

Background: Prothrombin complex concentrates (PCCs) containing prothrombin, factors VII, IX, and X, as well as the inhibitors protein C and S have been used as an emergent reversal for oral anticoagulation therapy. The use of PCCs in hepatobiliary disorder patients or patients with liver coagulopathy who need to undergo invasive procedures has not been well studied. Objective: To evaluate the efficacy of PCC treatment in order to control or prevent bleeding complications in patients with liver coagulopathy who undergo various invasive procedures. Methods: This was a prospective, open-label, non-randomized, before-and-after study in patients with hepatobiliary disorders who underwent invasive procedures accompanied by liver impairment and received PCC injection (Cofact®, Sanquin, The Netherlands). Patients with coagulopathy from various causes were recruited consecutively. Data collected were the episodes of bleeding, liver function test and the international normalized ratio (INR) before and after PCC therapy. The primary endpoint was INR change after treatment, while secondary endpoints included bleeding control and bleeding event after treatment. Results: Thirty patients (17 men, 13 women) were enrolled. Patients’ mean age was 57.0 + 15.5 years. Liver cirrhosis was found in 14 patients (46.7%). The procedures consisted of liver biopsy, liver abscess aspiration, abdominal paracentesis, therapeutic upper gastrointestinal endoscopy, abdominal surgery, endoscopic retrograde cholangiopancreatography and percutaneous transhepatic biliary drainage. After treatment, 25 patients (83.3%) showed a decreased median INR (from 1.6 to 1.3) (p < 0.001, Wilcoxon’s signed-rank test). Five patients failed to show INR reduction. No new bleeding event related to the invasive procedures was observed. Conclusion: PCC treatment is effective to control and prevent bleeding complications in patients with liver coagulopathy who undergo invasive procedures.

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