Intraindividual variability over time of thrombin generation in patients with cirrhosis.

BACKGROUND: Patients with cirrhosis are at high risk of thrombotic events, including portal vein thrombosis and venous thromboembolism. In such patients, hypercoagulability is not detected by conventional coagulation tests, but only by the thrombin generation assay (TGA) that integrates the role of pro- and anticoagulant factors. However, TGA use to predict clinical events depends on thrombin generation variability over time. OBJECTIVES: The aim of this study was to compare TGA intraindividual variability over time in patients with cirrhosis and in healthy controls. METHODS: Blood samples were prospectively collected from 34 healthy controls and 52 patients with cirrhosis at week 0 (inclusion), 6, and 12. TGA was performed with the calibrated automated thrombogram method, tissue factor (5 pM), phospholipids, and with and without thrombomodulin (4 nM) or activated protein C (1 nM). RESULTS: When TGA was performed with thrombomodulin, endogenous thrombin potential in patients with cirrhosis was higher compared with controls and increased with cirrhosis severity. Stability over time of all thrombin generation parameters was excellent in healthy controls, good in Child-Turcotte-Pugh (CTP)-A patients, and poor in CTP-B/C patients (severe cirrhosis). In CTP-B/C patients, the phenotype was more variable because one-third of patients switched to normal or hypercoagulability during the 3-month follow-up. CONCLUSION: A study with longer monitoring is needed to correlate the hypercoagulable phenotype of patients with cirrhosis with the occurrence of thrombotic events.

Plasma hypercoagulability in the presence of thrombomodulin but not of activated protein C in patients with cirrhosis.

BACKGROUND AND AIMS: Cirrhosis significantly changes all hemostasis steps. Recent studies suggest that cirrhosis is associated with a coagulopathy leading to a hypercoagulable state. The underlying mechanisms are not fully understood, but protein C deficiency is probably a major determinant of this phenotype. The aim of this study was to compare the results of thrombin generation assays performed with addition of thrombomodulin or activated protein C to assess the effect of by-passing the protein C activation step in cirrhotic patients and healthy controls. METHODS: Fifty-eight patients with cirrhosis and 26 healthy controls were prospectively included in this study. Thrombin generation was determined in platelet-poor plasma using 5 pM of tissue factor and 4 nM of phospholipids, without and with external addition of 1 nM thrombomodulin or 4 nM activated protein C. All results were normalized with the values of a pool of normal plasma samples to limit inter-plate variability. RESULTS: When thrombin generation assays were performed in the presence of thrombomodulin, endogenous thrombin potential (ETP) and ETP with/ETP without TM ratio were significantly higher in cirrhotic patients than in healthy controls (P < 0.0001). Moreover, these values progressively increased with cirrhosis severity. When thrombin generation assays were performed with activated protein C, all thrombin generation parameters were comparable between healthy controls and cirrhotic patients, despite an acquired protein S deficiency. CONCLUSION: In the presence of activated protein C, no hypercoagulability was observed, adding to the current evidence that acquired protein C deficiency plays a key role in the coagulation imbalance.

[Low sensibility to the action of thrombomodulin in cirrhotic patients. Interest of thrombinography]. / Faible sensibilité à l'action de la thrombomoduline chez le patient cirrhotique. Intérêt de la thrombinographie.

Cirrhosis is associated with complex hemostatic modifications. Most coagulation factors, either procoagulants or anticoagulants, are reduced. Conventional coagulation tests (prothrombin time, activated partial thromboplastin time) don't allow to precisely identify the thrombotic risk as they are not sensible to coagulation inhibitors deficiencies. The aim of this study was to evaluate the coagulation in a population of cirrhotic patients using thrombinography. We analyzed the plasma samples from 30 cirrhotic patients (10 Child A, 10 Child B, Child C 10) compared to 10 healthy controls using thrombinography with and without thrombomodulin to sensiblise this test at the activated protein C pathway. The results of endogenous thrombin potential, the main parameter, expressed as a ratio (thrombinography with/without thrombomodulin) were significantly higher in cirrhotic patients (0.69 ± 0.16) than in controls (0.49 ± 0.10) which reflects a low sensibility to the action of thrombomodulin. This resistance increases with the severity of the disease assessed by the Child-Pugh score, demonstrating a potential hypercoagulable state. The results of the thrombinography challenge the dogma that cirrhotic patients are naturally "anticoagulated." These results highlight the potential interest of the thrombinography in the detection and monitoring of hypercoagulability in cirrhotic patient. Increasing hypercoagulability with the severity of the disease seems to be correlated with clinical observations since the occurrence of thrombosis is more common when cirrhosis is at an advanced stage.

Factors influencing acute infusion reactions in inflammatory bowel disease patients treated with infliximab in the era of scheduled maintenance therapy.

BACKGROUND: An acute infusion reaction during infliximab infusions could lead to drug withdrawal and limit the therapeutic armamentarium in inflammatory bowel diseases. AIM: To determine the risk and protective factors of an acute infusion reaction. MATERIALS AND METHODS: Data were retrieved retrospectively from electronic charts of patients from the 'Clermont-Ferrand IBD cohort'. RESULTS: Among 80 patients, including 51 (63.8%) patients with Crohn's disease, 23 (28.8%) experienced an acute infusion reaction. In multivariate analysis, the Crohn's disease nonstricturing nonfistulizing phenotype predicted an acute infusion reaction (odds ratio=11.40, 95% confidence interval 1.5-87.6; P=0.019).Among 1107 infusions, we observed 38 acute infusion reactions (3.4%). In multivariate analysis, only resumption of infliximab after drug holiday was a major risk factor (odds ratio=24.87, 95% confidence interval 4.4-140.0; P<0.001). Concomitant premedication or immunosuppressant therapies did not prevent an acute infusion reaction.The patients who experienced an acute infusion reaction had a trend toward a higher rate of infliximab discontinuation (69.6 vs. 50.9%, P=0.14). CONCLUSION: An acute infusion reaction is a major event in the history of inflammatory bowel diseases patients treated with infliximab as it could lead to drug discontinuation and thus limits the therapeutic armamentarium considerably. The resumption of infliximab after drug holiday is a major risk factor for an acute infusion reaction. Premedication efficacy remains questionable and should be limited to these high-risk patients.