Defining trauma-induced coagulopathy with respect to future implications for patient management : Communication from the SSC of the ISTH

Peer reviewedPostprin

Biomarkers of coagulation, endothelial function, and fibrinolysis in critically ill patients with COVID-19: A single-center prospective longitudinal study

Background: Immunothrombosis and coagulopathy in the lung microvasculature may lead to lung injury and disease progression in coronavirus disease 2019 (COVID-19). We aim to identify biomarkers of coagulation, endothelial function, and fibrinolysis that are associated with disease severity and may have prognostic potential. Methods: We performed a single-center prospective study of 14 adult COVID-19(+) intensive care unit patients who were age- and sex-matched to 14 COVID-19(−) intensive care unit patients, and healthy controls. Daily blood draws, clinical data, and patient characteristics were collected. Baseline values for 10 biomarkers of interest were compared between the three groups, and visualized using Fisher\u27s linear discriminant function. Linear repeated-measures mixed models were used to screen biomarkers for associations with mortality. Selected biomarkers were further explored and entered into an unsupervised longitudinal clustering machine learning algorithm to identify trends and targets that may be used for future predictive modelling efforts. Results: Elevated D-dimer was the strongest contributor in distinguishing COVID-19 status; however, D-dimer was not associated with survival. Variable selection identified clot lysis time, and antigen levels of soluble thrombomodulin (sTM), plasminogen activator inhibitor-1 (PAI-1), and plasminogen as biomarkers associated with death. Longitudinal multivariate k-means clustering on these biomarkers alone identified two clusters of COVID-19(+) patients: low (30%) and high (100%) mortality groups. Biomarker trajectories that characterized the high mortality cluster were higher clot lysis times (inhibited fibrinolysis), higher sTM and PAI-1 levels, and lower plasminogen levels. Conclusions: Longitudinal trajectories of clot lysis time, sTM, PAI-1, and plasminogen may have predictive ability for mortality in COVID-19

Impact of Tai Chi exercise on multiple fracture-related risk factors in post-menopausal osteopenic women: a pilot pragmatic, randomized trial

Background: Tai Chi (TC) is a mind-body exercise that shows potential as an effective and safe intervention for preventing fall-related fractures in the elderly. Few randomized trials have simultaneously evaluated TC's potential to reduce bone loss and improve fall-predictive balance parameters in osteopenic women. Methods: In a pragmatic randomized trial, 86 post-menopausal osteopenic women, aged 45-70, were recruited from community clinics. Women were assigned to either nine months of TC training plus usual care (UC) vs. UC alone. Primary outcomes were changes between baseline and nine months of bone mineral density (BMD) of the proximal femur and lumbar spine (dual-energy X-ray absorptiometry) and serum markers of bone resorption and formation. Secondary outcomes included quality of life. In a subsample (n = 16), quiet standing fall-predictive sway parameters and clinical balance tests were also assessed. Both intent-to-treat and per-protocol analyses were employed. Results: For BMD, no intent-to-treat analyses were statistically significant; however, per protocol analyses (i.e., only including TC participants who completed $\geq$ 75% training requirements) of femoral neck BMD changes were significantly different between TC and UC (+0.04 vs. -0.98%; P = 0.05). Changes in bone formation markers and physical domains of quality of life were also more favorable in per protocol TC vs. UC (P = 0.05). Changes in sway parameters were significantly improved by TC vs. UC (average sway velocity, P = 0.027; anterior-posterior sway range, P = 0.014). Clinical measures of balance and function showed non-significant trends in favor of TC. Conclusions: TC training offered through existing community-based programs is a safe, feasible, and promising intervention for reducing multiple fracture risks. Our results affirm the value of a more definitive, longer-term trial of TC for osteopenic women, adequately powered to detect clinically relevant effects of TC on attenuation of BMD loss and reduction of fall risk in this population

Tai Chi for osteopenic women: design and rationale of a pragmatic randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Post-menopausal osteopenic women are at increased risk for skeletal fractures. Current osteopenia treatment guidelines include exercise, however, optimal exercise regimens for attenuating bone mineral density (BMD) loss, or for addressing other fracture-related risk factors (e.g. poor balance, decreased muscle strength) are not well-defined. Tai Chi is an increasingly popular weight bearing mind-body exercise that has been reported to positively impact BMD dynamics and improve postural control, however, current evidence is inconclusive. This study will determine the effectiveness of Tai Chi in reducing rates of bone turnover in post-menopausal osteopenic women, compared with standard care, and will preliminarily explore biomechanical processes that might inform how Tai Chi impacts BMD and associated fracture risks.</p> <p>Methods/Design</p> <p>A total of 86 post-menopausal women, aged 45-70y, T-score of the hip and/or spine -1.0 and -2.5, have been recruited from primary care clinics of a large healthcare system based in Boston. They have been randomized to a group-based 9-month Tai Chi program plus standard care or to standard care only. A unique aspect of this trial is its pragmatic design, which allows participants randomized to Tai Chi to choose from a pre-screened list of community-based Tai Chi programs. Interviewers masked to participants' treatment group assess outcomes at baseline and 3 and 9 months after randomization. Primary outcomes are serum markers of bone resorption (C-terminal cross linking telopeptide of type I collagen), bone formation (osteocalcin), and BMD of the lumbar spine and proximal femur (dual-energy X-ray absorptiometry). Secondary outcomes include health-related quality-of-life, exercise behavior, and psychological well-being. In addition, kinetic and kinematic characterization of gait, standing, and rising from a chair are assessed in subset of participants (n = 16) to explore the feasibility of modeling skeletal mechanical loads and postural control as mediators of fracture risk.</p> <p>Discussion</p> <p>Results of this study will provide preliminary evidence regarding the value of Tai Chi as an intervention for decreasing fracture risk in osteopenic women. They will also inform the feasibility, value and potential limitations related to the use of pragmatic designs for the study of Tai Chi and related mind-body exercise. If the results are positive, this will help focus future, more in-depth, research on the most promising potential mechanisms of action identified by this study.</p> <p>Trial registration</p> <p>This trial is registered in Clinical Trials.gov, with the ID number of NCT01039012.</p

Dabigatran and Argatroban Diametrically Modulate Thrombin Exosite Function.

Thrombin is a highly plastic molecule whose activity and specificity are regulated by exosites 1 and 2, positively-charged domains that flank the active site. Exosite binding by substrates and cofactors regulates thrombin activity by localizing thrombin, guiding substrates, and by inducing allosteric changes at the active site. Although inter-exosite and exosite-to-active-site allostery have been demonstrated, the impact of active site ligation on exosite function has not been examined. To address this gap, we used surface plasmon resonance to determine the effects of dabigatran and argatroban, active site-directed inhibitors, on thrombin binding to immobilized γA/γA-fibrin or glycoprotein Ibα peptide via exosite 1 and 2, respectively, and thrombin binding to γA/γ'-fibrin or factor Va, which is mediated by both exosites. Whereas dabigatran attenuated binding, argatroban increased thrombin binding to γA/γA- and γA/γ'-fibrin and to factor Va. The results with immobilized fibrin were confirmed by examining the binding of radiolabeled thrombin to fibrin clots. Thus, dabigatran modestly accelerated the dissociation of thrombin from γA/γA-fibrin clots, whereas argatroban attenuated dissociation. Dabigatran had no effect on thrombin binding to glycoprotein Ibα peptide, whereas argatroban promoted binding. These findings not only highlight functional effects of thrombin allostery, but also suggest that individual active site-directed thrombin inhibitors uniquely modulate exosite function, thereby identifying potential novel mechanisms of action

Enhancing achievement and interest in mathematics learning through Math-Island

Abstract Conventional teacher-led instruction remains dominant in most elementary mathematics classrooms in Taiwan. Under such instruction, the teacher can rarely take care of all students. Many students may then continue to fall behind the standard of mathematics achievement and lose their interest in mathematics; they eventually give up on learning mathematics. In fact, students in Taiwan generally have lower interest in learning mathematics compared to many other regions/countries. Thus, how to enhance students’ mathematics achievement and interest are two major problems, especially for those low-achieving students. This paper describes how we designed a game-based learning environment, called Math-Island, by incorporating the mechanisms of a construction management game into the knowledge map of the elementary mathematics curriculum. We also report an experiment conducted with 215 elementary students for 2 years, from grade 2 to grade 3. In this experiment, in addition to teacher-led instruction in the classroom, students were directed to learn with Math-Island by using their own tablets at school and at home. As a result of this experiment, we found that there is an increase in students’ mathematics achievement, especially in the calculation and word problems. Moreover, the achievements of low-achieving students in the experimental school outperformed the low-achieving students in the control school (a control group in another school) in word problems. Moreover, both the low-achieving students and the high-achieving students in the experimental school maintained a rather high level of interest in mathematics and in the system

Effect of dabigatran, argatroban, DAPA or hirudin on ¹²⁵I-thrombin binding to fibrin clots.

<p>Binding of ¹²⁵I-thrombin to γ_A/γ_A- or γ_A/γ′-fibrin clots in the absence or presence of dabigatran, argatroban, DAPA, or hirudin was determined by measuring the amount of ¹²⁵I-thrombin in the supernatants of compacted clots prepared by incubating γ_A/γ_A- or γ_A/γ′-fibrinogen with a catalytic amount of batroxobin. EC₅₀ values were determined by nonlinear regression analysis and converted to K_i values by correction for K_d of ¹²⁵I-thrombin for fibrin. Change denotes the maximal change in the percentage of bound ¹²⁵I-thrombin compared with that in the absence of inhibitor.</p

Effect of dabigatran, argatroban, DAPA, or hirudin on the binding of ¹²⁵I-thrombin to fibrin clots.

<p>Increasing concentrations of dabigatran (circles), argatroban (triangles), DAPA (squares), or hirudin (diamonds) were added to samples containing 10 nM ¹²⁵I-thrombin, 2 mM CaCl₂, 1 U/mL batroxobin and (A) 3 μM γ_A/γ_A-fibrinogen, or (B) 1 μM γ_A/γ′-fibrinogen. After incubation for 1 h, clots were pelleted and aliquots of supernatant were counted for radioactivity. The ratios of ¹²⁵I-thrombin bound in the absence or presence of inhibitor are plotted against the inhibitor concentrations. Data points represent the mean ± S.D. of 2–3 experiments, each performed in duplicate, and the <i>lines</i> represent nonlinear regression analysis.</p