Rapid point-of-care detection and classification of direct-acting oral anticoagulants with the TEG 6s: Implications for trauma and acute care surgery.

BACKGROUND: The trauma patient on direct oral anticoagulant (DOAC) therapy preinjury presents a challenge in trauma and acute care surgery. Our understanding of these patients is extrapolated from vitamin K antagonists. However, DOACs have different mechanisms of action, effects on laboratory coagulation assays, and reversal strategies. Rapid identification of DOACs in the blood will allow timely reversal of factor Xa inhibitors and direct thrombin inhibitors when necessary. The present study evaluated viscoelastic testing to detect and classify DOACs in patient blood samples. METHODS: This observational, prospective, open-label, multicenter study used point-of-care viscoelastic testing to analyze blood samples taken from patients with and without DOAC treatment, and healthy volunteers. Antifactor Xa and direct thrombin inhibition (DTI) assays were used to establish reference ranges for viscoelastic testing parameters on the TEG 6s system. These ranges were applied to produce a DOAC identification algorithm for patient blood samples. Internal consistency of the measurements, as well as algorithm sensitivity and specificity, was evaluated. RESULTS: Using the TEG 6s system, the R parameter reference range was 0.6 minutes to 1.5 minutes for the Antifactor Xa assay and 1.6 minutes to 2.5 minutes for the DTI assay. Our identification algorithm using these ranges for 2.5 minutes or less has sensitives of 98.3% and 100% for factor Xa inhibitor and direct thrombin inhibitor detection, respectively. Specificity was 100%. Both classes of DOAC were detectable, even when samples were collected during the "trough" between doses of medication. CONCLUSION: Point-of-care viscoelastic testing with TEG 6s can detect and classify DOACs with high sensitivity and specificity. This tool can be used to better determine the need for reversal in trauma and acute care surgery patients and guide optimal surgical timing in the acute setting. LEVEL OF EVIDENCE: Prognostic and epidemiological study, level II.

Determination of non-Vitamin K oral anticoagulant (NOAC) effects using a new-generation thrombelastography TEG 6s system.

Non vitamin K oral anticoagulants (NOACs) do not require regular monitoring but information about their pharmacodynamic effect may be importantin situations like trauma, stroke oremergent surgery. Currently, no standardized point-of-care test is available to evaluate the anticoagulant effects of NOACs. We evaluated the anticoagulant effect of NOACs with the next generation point-of-care TEG assay (TEG® 6S) based on a fully-automated thrombelastography system. We used two TEG® 6S assays, the DTI assay and Anti-Factor Xa (AFXa) assay, to detect anticoagulant effects and classify NOACs. Blood from healthy volunteers (n = 26) was used to obtain a baseline reference range. Data derived from patients on factor Xa inhibitors (FXi) (rivaroxaban and apixaban) (n = 39), and direct thrombin inhibitors (DTIs) (dabigatran) (n = 25) were compared against the reference range for detection of drug effect and drug classification. TEG®6s R-time highly correlated to each NOAC. Presence of NOACs caused elongation of R-time on the AFXa assay compared to the reference range (4.3 ± 1.7 vs. 1.3 ± 0.3 min. for FXi, p < 0.001 and 3.5 ± 1.2 vs. 1.3 ± 0.3 min. for DTI, p < 0.001). R-time on the DTI assay was elongated only in presence of a DTI (3.4 ± 1.0 vs. 1.5 ± 0.2 min, p < 0.001). The cutoff for detection of a DTI effect was an R time of 1.9 min and for anti-Xa effect was 1.95 min. For detection of NOAC therapy, there was ≥92% sensitivity and ≥95% specificity. The automated TEG®6s NOAC assay may be an effective tool to identify an anticoagulant effect from NOAC therapy and facilitate care of patients with bleeding or at risk of bleeding in the event of needing emergency surgery.

First report of the point-of-care TEG: A technical validation study of the TEG-6S system.

Thrombelastography (TEG) measured by the TEG5000 Hemostasis Analyzer is an established but the labor-intensive method for assessing global hemostasis. The first true point-of-care TEG, the TEG6s system, uses resonance-frequency viscoelasticity measurements and a disposable multi-channel microfluidic cartridge to assess hemostasis and response to antiplatelet therapy. TEG assays (n = 5,100) were performed on the blood of healthy volunteers (n = 157) and patients undergoing coronary revascularization at three hospitals (n = 300). The results from the TEG6s were compared with the conventional TEG5000 in accordance with Clinical and Laboratory Standards Institute (CLSI) and FDA recommendations. Precision testing was conducted using blood from healthy donors, all assays were run for 5 consecutive days in duplicate using multiple operators, lots, and instruments. Reference ranges were comparable between the TEG systems. Deming regression analysis demonstrated a strong correlation between the two systems for the standard hemostasis tests (R r = 0.932, MA r = 0.972, LY30 r = 0.938). Method comparison analysis showed an acceptable agreement between PlateletMapping (PM) assays for measuring arachidonic acid (indicator of aspirin response)- and adenosine diphosphate (indicator of P2Y12 inhibitor response)-induced platelet aggregation (total agreement = 90%, and 72%, respectively). TEG6s precision testing yielded low variability (CV 0-13%) in all measures. The new point-of-care TEG6s is associated with greater ease of use than the TEG5000 and provides precise results. The results correlated between methods for all variables. TEG6s is a promising device for near-patient hemostasis monitoring and future trials of personalized therapy designed to reduce bleeding and thrombosis.

The influence of vitamin E supplementation on erythropoietin responsiveness in chronic hemodialysis patients with low levels of erythrocyte superoxide dismutase.

About 12-15 % of hemodialysis patients have a poor response to recombinant human erythropoietin (rHuEPO). The aim of this prospective study was to examine the influence of oxidative stress and vitamin E supplementation on rHuEPO responsiveness in chronic hemodialysis patients. Sixty-five hemodialysis patients treated with rHuEPO were studied. Those with iron deficiency, blood loss, malignancy, vitamin B12 and folate deficiency, severe hyperparathyroidism, liver cirrhosis, and congestive heart failure were excluded. Twenty-one healthy volunteers served as a control group. Malondialdehyde, carbonyl proteins, erythrocyte superoxide dismutase (SOD), ceruloplasmin, and serum antioxidant capacity were measured. Values of SOD > 150 U/ml were considered as normal. Patients with SOD < 150 U/ml were divided in two groups: group A (n = 11): treated with vitamin E 400 mg/day (600 IU/day) for 8 weeks; group B (n = 13): not treated. A third, group C consisted of patients with normal SOD. rHuEPO doses (U/kg/week) were recorded. rHuEPO responsiveness index was calculated as rHuEPO U/week/hematocrit. A poor response was defined as a rHuEPO responsiveness index >200. SOD positively correlated with hemoglobin (p = 0.0018, R = 0.337) and negatively with rHuEPO responsiveness index (p = 0.0122, R = 0.319). Vitamin E-treated patients from group A exhibited significantly increased hemoglobin levels as compared to initial values (10.5 ± 0.3 vs. 8.6±0.4, p = 0.002). In comparison with group B, the vitamin E-treated patients displayed a higher hemoglobin (10.5 ± 0.3 vs. 9.4 ± 0.3, p = 0.04), had a lower rHuEPO dose (85.7 ± 7.4 vs. 136.8 ± 13.8, p = 0.025), and a significantly improved rHuEPO responsiveness (rHuEPO responsiveness index 177.9 ± 28.6 vs. 314.1 ± 34.0, p = 0.006). Patients from group A significantly improved their rHuEPO responsiveness after vitamin E therapy as compared to baseline (rHuEPO responsiveness index 177.9 ± 28.6 vs. 271.7 ± 30.3, p = 0.034). We conclude that lower values of SOD correlate with lower hemoglobin, higher rHuEPO dose and poor response to rHuEPO in chronic hemodialysis patients. Vitamin E supplementation significantly improves rHuEPO responsiveness, increases hemoglobin level, and decreases rHuEPO dose.

Cancer mortality in Romania, 1955-2004. Digestive sites: esophagus, stomach, colon and rectum, pancreas, liver, gallbladder and biliary tree.

AIM: Until recently, gastric cancer was the most frequent digestive neoplasia in our country. Our study presents the first synthesis of data regarding mortality rates from digestive cancers, for a period covering 50 years, in Romania. METHODS: Age-standardized mortality rates /100,000 population, general and/or per gender, concerning six digestive cancers, were identified from the statistics of IARC/OMS (Lyon, France) (years 1955-2002) and of the Ministry of Public Health (Bucharest, Romania) (year 2004). For 2002, incidence and mortality rates per sex from digestive cancers were available and case fatality ratios could be calculated as an approximation of survival rates, as well as sex ratio. RESULTS: Age standardized mortality rates per sex and cancer site registered the following changes: esophageal cancer increased from 2.03/0.62 (M/F) to 2.8/0.5; gastric cancer registered a decrease, from 33.14/18.77 to 17.0/6.6; colorectal cancer increased from 4.65/4.57 to 13.6/9.0; pancreatic cancer increased from 5.50/2.92 to 8.1/4.2 and liver cancer (including peripheric cholangiocarcinoma) increased from 1.77/0.83 to 8.8/3.9. In our population, the case fatality ratio appeared to be better only in colorectal cancer, 0.61 in males and 0.62 in females, respectively. Sex ratio was highest for esophageal cancer (males/females 5.8/1) and lowest for colorectal cancer (1.5/1). CONCLUSIONS: Our study found opposite trends in the mortality rates from digestive cancers, with gastric cancer rates decreasing and the other five digestive cancers increasing. A new hierarchy of digestive cancers has been drawn up, with colorectal cancer as the main cause of death, and gastric cancer in second position, followed by pancreatic, liver, esophageal, and gallbladder and biliary tree cancers.