A comparative in vitro study of the anticoagulant effect of branded versus generic rivaroxaban.

BACKGROUND: Several generic formulations of rivaroxaban were recently marketed to be used interchangeably with their branded equivalent. However, there have been no previously published studies that directly compared the in vitro anticoagulant effect of branded vs. generic rivaroxaban. The aim of this in vitro study was to compare the effects of three raw rivaroxaban materials, obtained from the branded (Xarelto®) and two generic (Rivarolto® and Rivaroxaban Sandoz®) rivaroxaban formulations on an array of coagulation assays. METHODS: A pool of normal plasma was spiked with several concentrations of the three rivaroxaban (range 50-750 ng/ml). The concentrations were assessed with a rivaroxaban calibrated anti-Xa assay and confirmed by ultra-high-performance liquid chromatography-mass spectrometry coupled with tandem mass spectrometry (UHPLC-MS/MS). The following assays were performed: Prothrombin time (PT), activated Partial Thromboplastin time (aPTT), Diluted Russell's Viper Venom Test (dRVVT), Thrombin time (TT), Clauss Fibrinogen, Factor VII, VIII and IX assays, and thromboelastography. RESULTS: The results obtained by the three rivaroxaban at similar concentrations were comparable. Increasing concentrations of the three rivaroxaban showed a strong positive correlation with the PT, aPTT and dRVVT assays (r > 0.95, p < 0.01 for all), and a strong negative correlation with the Factors assays (r < -0.95, p < 0.01 for all). TT and Clauss Fibrinogen were not affected by rivaroxaban. No significant difference was identified in the mean assays' results obtained by the three rivaroxaban. CONCLUSION: This study showed that the branded and generic rivaroxaban exert an identical in vitro anticoagulant effect across a wide range of concentrations.

Navigating through the haemostatic paradox in kidney failure: A practical overview.

Chronic kidney disease (CKD) affects around 9.1% of humankind globally resulting in a significant health burden. Some of these individuals will also require renal replacement therapy with dialysis due to complete kidney failure. Patients with CKD are known to be at increased risk of both bleeding and thrombosis. Often it is very difficult to manage these yin and yang since both risks tend to co-exist. Clinically, very few studies have looked at the effects of antiplatelet agents and anticoagulants in this highly vulnerable subgroup of medical patients and evidence is very limited. This review attempts to explain the current state-of-the-art regarding the basic science of haemostasis in patients with end-stage kidney disease. We also try to transfer this knowledge into the clinics by looking at some common haemostasis challenges that are encountered in this cohort of patients and what evidence and guidance there is for their optimal management.

Long COVID Syndrome: A Case-Control Study.

BACKGROUND: Acute coronavirus disease 2019 (COVID-19) causes various cardiovascular complications. However, it is unknown if there are cardiovascular sequelae in the medium and long-term. The aim of this study was dual. Firstly, we wanted to investigate symptomatology and health-related quality of life (HRQoL) at medium-term follow-up (6 months post-COVID). Secondly, we wanted to assess whether history of COVID-19 and persistent shortness of breath at medium-term follow-up are associated with ongoing inflammation, endothelial dysfunction, and cardiac injury. METHODS: A case-control study was performed. Virologically proven COVID-19 cases and age- and gender-matched controls were interviewed to assess symptoms and HRQoL. Biochemical tests were also performed. RESULTS: The study comprised 174 cases and 75 controls. The mean age of the participants was 46.1±13.8 years. The median follow-up was 173.5 days (interquartile range 129-193.25 days). There was no significant difference in the demographics between cases and controls. At follow-up, cases had a higher frequency of shortness of breath, fatigue, arthralgia, abnormal taste of food (P <.001), and anosmia. Cases also exhibited worse scores in the general health and role physical domains of the Short Form Survey-36. High-sensitivity C-reactive protein (hsCRP) was significantly higher in the cases, and there was a positive correlation of hsCRP with time. Significant determinants of shortness of breath were age, female gender and white cell count, troponin I, and lower hemoglobin levels at follow-up. CONCLUSION: Post-COVID-19 patients have persistent symptomatology at medium-term follow-up. Higher hsCRP in cases and the positive association of hsCRP with time suggest ongoing systemic inflammation in patients persisting for months after COVID-19.

Diagnostic accuracy of D-dimer in patients at high-risk for splanchnic vein thrombosis: A systematic review and meta-analysis.

BACKGROUND: D-dimer is included in the diagnostic algorithm for deep vein thrombosis and pulmonary embolism. However, its role in the diagnosis of splanchnic vein thrombosis (SVT) is still controversial. The aim of this study was to evaluate the diagnostic accuracy of D-dimer for SVT. METHODS: We performed a systematic review of the literature with meta-analysis (PROSPERO protocol registration number: CRD42020184300). The electronic databases MEDLINE, EMBASE, and CENTRAL were searched from inception to March 2021 week 4. Studies which evaluated D-dimer accuracy for SVT in any category of patients were selected. The index test was any D-dimer assay; the reference standard was any radiological imaging. The QUADAS-2 checklist was used for the risk of bias assessment. A bivariate random-effects regression model was used to calculate summary estimates of sensitivity and specificity. RESULTS: 12 studies (with a total of 1298 patients) evaluating the accuracy of D-dimer in patients at high risk of SVT (surgical patients, patients with liver cirrhosis or hepatocellular carcinoma) were included. None of the included studies was at low risk of bias. The weighted mean prevalence of SVT was 33.4% (95% CI, 22.5-45.2%, I2 = 94.8%). D-dimer accuracy was expressed by sensitivity 96% (95% CI, 72-100%); specificity 25% (95% CI, 5-67%); positive likelihood ratio 1.3 (95% CI, 0.9-1.9); negative likelihood ratio 0.16 (95% CI, 0.03-0.84); area under the ROC curve 0.80 (95% CI, 0.76-0.83). CONCLUSIONS: D-dimer seems to have high sensitivity in the diagnosis of patients at high-risk for SVT. However, there is a strong need for more robust evidence on this topic.

Fibrinogen measurement in liver disease: validation of the functional fibrinogen thromboelastography assay and a novel mathematical predictive model.

BACKGROUND: Fibrinogen is produced in the liver and tends to be reduced in liver cirrhosis. Quantitative and qualitative tests exist to measure fibrinogen. We aimed to validate the functional fibrinogen thromboelastography assay (FF-TEG) and propose a new model to estimate fibrinogen levels via the Clauss method (Clauss) using data from a prothrombin time-derived fibrinogen assay (PT-Fg) in patients with liver cirrhosis. MATERIALS AND METHODS: Clauss, PT-Fg, fibrinogen antigen (Fib-Ag) and FF-TEG were studied in 55 patients with liver cirrhosis (26 with Child-Turcotte-Pugh [CTP]-A disease, 14 with CTP-B and 15 CTP-C) and 20 healthy individuals. RESULTS: The results of all four assays correlated strongly with each other, but gave significantly different mean levels in all cohorts. PT-Fg gave the highest levels whereas the Clauss gave the lowest levels. The FF-TEG performed well with results which were in between the Clauss and the PT-Fg. Significant differences were only observed between CTP-A and CTP-C for the Clauss, PT-Fg and Fib-Ag but not functional fibrinogen level. We devised a simple linear regression model in order to estimate Clauss from the PT-Fg. DISCUSSION: The results of the FF-TEG correlate well with those of routine fibrinogen assays in patients with liver cirrhosis. However, the FF-TEG assay does not discriminate between early and late stages of disease, pointing to a preserved fibrin clot strength in cirrhosis. Through linear regression models, fibrinogen levels can be accurately estimated using the Clauss method based on fibrinogen levels obtained in the cheaper PT-Fg.

Biomarkers for the diagnosis of venous thromboembolism: D-dimer, thrombin generation, procoagulant phospholipid and soluble P-selectin.

BACKGROUND: The diagnostic algorithm for venous thromboembolism (VTE) currently involves a composite of pre-test probability, D-dimer and imaging. Other laboratory tests, however, may assist in the identification of patients with VTE. AIM: To assess the accuracy of different coagulation tests (D-dimer, thrombin generation, phospholipid-dependent (PPL) clotting time, soluble P-selectin (sP-selectin)) as biomarkers of acute VTE. METHODS: Random samples arriving at the Coagulation Laboratory at Mater Dei Hospital (Msida, Malta) from the Accident and Emergency Department with a request for D-dimer measurement were collected between August 2015 and February 2016. The following tests were performed: Innovance D-dimer (Siemens Healthcare Diagnostics), HemosIL D-dimer HS (Instrumentation Laboratory), thrombin generation (using the calibrated automated thrombogram), STA Procoag PPL (Diagnostica Stago) and sP-selectin (Affymetrix; eBioscience). VTE was objectively confirmed by compression ultrasonography, CT pulmonary angiography or ventilation/perfusion lung scan. RESULTS: 100 samples were collected (33 with VTE). A strong positive linear correlation was found between the two D-dimer tests (r=0.97, p<0.001). Patients with VTE showed significantly higher sP-selectin concentrations compared with patients without VTE (75.7 ng/mL vs 53.0 ng/mL, p<0.001). In the random forest plot, the two D-dimer assays showed the highest variable importance, followed by sP-selectin. A sP-selectin cut-off of 74.8 ng/mL was associated with 72.7% sensitivity and 78.2% specificity for acute VTE in our cohort. CONCLUSION: Our results confirmed D-dimer as the main biomarker of VTE and speculated a role for sP-selectin. The impact of thrombin generation was limited and no role emerged for the PPL clotting time. These observations need to be confirmed in large management studies.