TH Open: Companion Journal to Thrombosis and Haemostasis最新文献

Background  A rapid test to detect apixaban treatment would be useful in acute situations such as major bleeding, urgent surgery, or in acute thrombosis. Objective  This article aims to study if the viscoelastic test rotational thromboelastometry (ROTEM) can rapidly detect apixaban in whole blood using modified triggers based on factor Xa (FXa) or Russell viper venom (RVV). Method  ROTEM clotting time (CT) was measured in samples from 40 patients on apixaban treatment, and in vitro in samples spiked with apixaban (20-500 ng/mL). Commercially available trigger Ex-tem was compared with modified triggers based on FXa or RVV. Reversibility of apixaban in the samples was studied; CT was measured with and without addition of DOAC-Stop or andexanet alfa, respectively, and the difference in CT was calculated (CT _diff ). Results  Using FXa as trigger, we detected apixaban concentrations at 20 ng/mL and above with 100% sensitivity and 100% specificity in patient samples and in vitro. Corresponding data for Ex-tem were 92% sensitivity and 100% specificity in patients, and 94% sensitivity and 100% specificity in vitro, and for RVV 97% sensitivity and 94% specificity in patients, and 97% sensitivity and 100% specificity in vitro, respectively. CT _diff data were similar. Patient sample data were obtained within 20 minutes from sampling. Conclusion  Apixaban at low therapeutic concentrations was detected within 20 minutes, and with high sensitivity and specificity. A trigger based on FXa outperformed the commercial trigger Ex-tem and a trigger based on RVV. ROTEM with a FXa-based trigger is a promising method to detect apixaban bedside in acute settings.

Introduction  Light transmission aggregometry (LTA) is regarded as the gold standard in platelet function diagnostics. However, there is a relevant degree of interlaboratory variability in practical applications. Objective  The aim of the present study was to develop a practicable laboratory comparison on LTA and to analyze differences and influencing factors in regard to standardization in five specialized hemostaseological centers. Methods  The study was performed on 30 patients in total. Each center performed LTA on blood samples from six healthy volunteers (three men and three women) using the inductors collagen (Col), adenosine diphosphate (ADP), arachidonic acid (ARA), and ristocetin. The LTA was performed three times using different methods as follows: (1) International Society on Thrombosis and Haemostasis recommendations with identical reagents, (2) in-house protocols and the identical reagents; and (3) in-house protocols and in-house reagents. Results  A total of 396 measurements of 30 probands were performed. Even after standardization of the protocol and using identical reagents, there were significant differences between the centers regarding the final and maximum aggregation ( p  = 0.002 and <0.001) and further significant differences in the maximum and final aggregation according to the wavelength of the device used to measure the LTA (PAP-8: 430 nm, APACT 4004: 740 nm [ p  < 0.001 each]). Using identical reagents but individual inductor concentrations and laboratory protocols also resulted in different maximum and final aggregation. The largest differences were seen with Col and ristocetin; there were significant influences from the reagents' manufacturers in the results of aggregometry for the inductor Col ( p  < 0.01) but not for ADP, ARA, and ristocetin. Conclusion  In this study, we proved that there are significant influences from the used aggregometers, inductors concentrations, and manufacturers. These results illustrate the challenges and importance of standardization of LTA.

Background  Patients with pancreatic cancer are at high risk of developing venous thromboembolism (VTE). It is unknown if aspirin reduces the risk of VTE in this setting. Objectives  We sought to determine whether there is an association between aspirin use and VTE risk in patients with pancreatic cancer receiving chemotherapy with a central venous catheter (CVC). Patients/Methods  We conducted a single-center, retrospective cohort study of adult patients diagnosed with pancreatic cancer and treated with chemotherapy using a CVC. Subjects were excluded if they were on anticoagulation at the time of CVC placement. The probability of VTE was analyzed using a time-to-event analysis framework for the development of VTE using the product-limit method of Kaplan and Meier (univariate) and adjusting for important confounding covariates using Cox proportional hazards regression (cause-specific hazard) and again using Fine and Gray regression (subdistributional hazard) with death prior to VTE considered a competing event. Results  The final analysis included 314 cases (125 with any aspirin use and 189 without). Patients with any aspirin use had fewer VTE events (34.4%) compared with those without aspirin use (42.3%; p  = 0.021) by log-rank test and after adjustment for multiple covariates using a Cox proportional hazards model (hazard ratio [HR] = 0.60; 95% confidence interval [CI]: 0.40-0.92; p  = 0.019). Using Fine and Gray regression to account for death as a competing event, the effect of aspirin remained in the direction of benefit, but was not statistically significant (HR = 0.70; 95% CI: 0.47-1.05, p  = 0.083). Higher body mass index, active smoking, and metastatic stage of cancer were associated with VTE events in the Cox proportional hazards model. Rates of major bleeding or clinically relevant minor bleeding were similar between treatment groups. Conclusions  Aspirin may reduce the risk of VTE in patients with pancreatic cancer with a CVC. We did not observe a significant increase in the rates of major bleeding or clinically relevant nonmajor bleeding.

Background  The Caprini Risk Score (CRS) is one of the most widely used risk assessment models for venous thromboembolism (VTE). A well-validated patient-completed CRS form may allow patients to self-report and simplify the evaluation by health care workers. Methods  The Chinese version of the CRS was optimized for easy understanding in a pilot study. The amended CRS form was completed by prospectively recruited patients and blinded nurses. The agreement levels of the individual questions and the total scores of patient and nurse-completed forms were compared using the Kappa value. The total scores were used for risk stratification of patients. Correlation and differences between patient and nurse-completed forms were analyzed using the Spearman correlation and Bland-Altman method, respectively. Results  We recruited 504 medical patients and 513 surgical patients, aged 52.7 ± 16.3 years, of which 443 (43.6%) were men, and 91.6% of the patients were educated beyond junior high school. The patients spent less time to complete the form compared with trained nurses. There was good question-to-question agreement between patient and nurse-completed CRS ( k >0.6 for most questions, p  < 0.0001). The total scores also showed good agreement ( k  = 0.6097, p  < 0.0001), and enabled the classification of patients into different risk groups. The patient and nurse-derived scores were highly correlated (Spearman's r  = 0.84), and without extreme values ( p  < 0.0001). Conclusion  We have created and verified a Chinese version of the patient-completed CRS, which showed good agreement and correlation with nurse-completed CRS. CRS represents a suitable tool for VTE risk assessment of hospitalized patients in China.

Emicizumab constitutes a novel and effective prophylaxis for hemophilia A patients with and without inhibitors. In this case report, we describe an emicizumab-induced photosensitivity that forced permanent sun-exposure suppression. To the best of our knowledge, this side effect had not been communicated until present.

Background  The MARINER trial evaluated whether postdischarge thromboprophylaxis with rivaroxaban could reduce the primary outcome of symptomatic venous thromboembolism (VTE) or VTE-related death in acutely ill medical patients at risk for VTE. Although aspirin use was not randomized, approximately half of the enrolled patients were receiving aspirin at baseline. We hypothesized that thromboprophylaxis with once-daily rivaroxaban (10 mg or, if creatinine clearance was 30-49 mL/min, 7.5 mg) plus aspirin (R/A) would be superior to placebo without aspirin (no thromboprophylaxis [no TP]). Methods  We compared the primary and major secondary outcomes in the intention-to-treat population in four subgroups defined at baseline: (1) R/A ( N  = 3,159); (2) rivaroxaban alone ( N  = 2,848); (3) aspirin alone ( N  = 3,046); and (4) no TP ( N  = 2,966). Major bleeding (MB) and nonmajor clinically relevant (NMCR) bleeding were assessed in the safety population on treatment plus 2 days. Results  Patients on R/A had reduced symptomatic VTE and VTE-related death compared with no TP (0.76 vs 1.28%, p  = 0.042), and experienced less symptomatic VTE and all-cause mortality ( p  = 0.005) and all-cause mortality alone ( p  = 0.01) compared with no TP. Event incidences for rivaroxaban alone (0.91%) or aspirin alone (0.92%) were similar. MB was low in all groups but lowest in the no TP group. NMCR bleeding was increased with R/A compared with no TP ( p  = 0.009). Limitations  Aspirin use was not randomized. Conclusion  Extended postdischarge thromboprophylaxis with R/A was associated with less symptomatic VTE and VTE-related death compared with no TP in previously hospitalized medical patients at risk for VTE. NMCR bleeding was increased with R/A compared with no TP. These post hoc findings need confirmation in a prospective trial.

Thrombomodulin (TM) is a type-I transmembrane protein that is mainly expressed on endothelial cells and plays important roles in many biological processes. Circulating TM of different forms are also present in biofluids, such as blood and urine. Soluble TM (sTM), comprised of several domains of TM, is the major circulating TM which is generated by either enzymatic or chemical cleavage of the intact protein under different conditions. Under normal conditions, sTM is present in low concentrations (<10 ng/mL) in the blood but is elevated in several pathological conditions associated with endothelial dysfunction such as cardiovascular, inflammatory, infection, and metabolic diseases. Therefore, sTM level has been examined for monitoring disease development, such as disseminated intravascular coagulation (DIC), sepsis and multiple organ dysfunction syndrome in patients with novel coronavirus disease 2019 (COVID-19) recently. In addition, microvesicles (MVs) that contain membrane TM (MV-TM) have been found to be released from activated cells which also contribute to levels of circulating TM in certain diseases. Several release mechanisms of sTM and MV-TM have been reported, including enzymatic, chemical, and TM mutation mechanisms. Measurements of sTM and MV-TM have been developed and explored as biomarkers in many diseases. In this review, we summarize all these advances in three categories as follows: (1) release mechanisms of circulating TM, (2) methods for measuring circulating TM in biological samples, and (3) correlation of circulating TM with diseases. Altogether, it provides a whole picture of recent advances on circulating TM in health and disease.

Objective  Venous thromboembolism (VTE) is a major cause of morbidity and mortality in surgical patients. Surgery for esophageal cancer carries a high risk of VTE. This study identifies the risk factors and associated mortality of thrombotic complications among patients undergoing esophageal cancer surgery. Methods  All patients in the province of Ontario undergoing esophageal cancer surgery from 2007 to 2017 were identified. Logistic regression identified VTE risk factors at 90 days and 1 year postoperatively. A flexible parametric survival analysis compared mortality and survival up to 5 years after surgery for patients with and without a postoperative VTE. Results  Overall 9,876 patients with esophageal cancer were identified; 2,536 (25.7%) underwent surgery. VTE incidence at 90 days and 1 year postoperatively were 4.1 and 6.3%, respectively. Patient factors including age, sex, performance status, and comorbidities were not associated with VTE risk. VTE risk peaked at 1 month after surgery, with a subsequent decline, plateauing after 6 months. Adenocarcinoma was strongly associated with VTE risk compared with squamous cell carcinoma (SCC) (odds ratio [OR] 2.53, 95% confidence interval [CI] 1.38-4.63, p  = 0.003). VTE risk decreased with adjuvant chemotherapy (OR = 0.58, 95% CI 0.36-0.94, p  = 0.028). Postoperative VTE was associated with decreased survival at 1 and 5 years (hazard ratio = 1.57, 95% CI 1.23-2.00, p  < 0.001). Conclusion  Esophageal cancer patients with postoperative VTE have worse long-term survival compared with those without thrombotic complications. Adenocarcinoma carries a higher VTE risk compared with SCC. Strategies to reduce VTE risk should be considered to reduce the negative impacts on survival conferred by thrombotic events.

Background  Like immune cells, platelets express toll-like receptors (TLRs) on their surface membrane. TLR2 and TLR4 are able to recognize bacterial antigens and have the potential to influence hemostatic functions and classical intracellular signaling pathways. This study investigated the role of TLR2 and TLR4 for immune-related functions in human platelets. Materials and Methods  Washed platelets and neutrophils were prepared from fresh human peripheral blood. Basal-, Pam3CSK4- (as TLR2 agonist) and Lipopolysaccharides (LPS; as TLR4 agonist) -induced CD62P expression, fibrinogen binding and TLR2 or TLR4 expression, intracellular reactive oxygen species (ROS) production in H ₂ DCFDA-loaded platelets and uptake of fluorescence-labeled TLR ligands, and fluorophore-conjugated fibrinogen were evaluated by flow cytometry. Analysis of platelet-neutrophil complexes was performed after coincubation of washed platelets and neutrophils in the presence and absence of TLR2 or TLR4 agonists on poly-L-lysine coated surfaces, followed by immunostaining and immunofluorescence imaging. Results  Pam3CSK4 rapidly and transiently increased TLR2 and TLR4 expression. Over the course of 30 minutes after activation with Pam3CSK4 and LPS, the expression of both receptors decreased. Pam3CSK4-stimulated intracellular ROS production and the uptake of TLR ligands or fibrinogen much stronger than LPS. Besides, TLR4 activation led to a significant increase of platelet-neutrophil contacts. Conclusion  Stimulation leads to rapid mobilization of TLR2 or TLR4 to the platelet surface, presumably followed by receptor internalization along with bound TLR ligands. After activation, platelet TLR2 and TLR4 mediate different immune-related reactions. In particular, TLR2 induces intracellular responses in platelets, whereas TLR4 initiates interactions with other immune cells such as neutrophils.

Background  There is scarce information regarding the prevalence and clinical impact of saddle pulmonary embolism (PE) in patients with cancer. Objectives  This study aimed to assess the prevalence, clinical findings, and short-term outcomes of patients with cancer-related saddle PE including acute symptomatic and unsuspected events. Patients/Methods  Consecutive patients with cancer-related PE (March 1, 2006-October 31, 2014) were retrospectively reviewed by a chest radiologist to assess PE burden and signs of right ventricular (RV) overload. The clinical outcomes within 30 days were evaluated according to saddle versus nonsaddle PE. Results  Thirty-six (12%) out of 289 patients with newly diagnosed cancer-related PE presented with saddle PE. Saddle PE was found in 21 cases (58%) with acute symptomatic PE and the remaining 15 cases (42%) were found as unsuspected findings. Patients with saddle PE had more frequently experienced a previous thrombotic event (31 vs. 13%; p  = 0.008), and it occurred more frequently as an acute symptomatic event (58 vs. 39%; p  = 0.025) compared with those with nonsaddle PE. Signs of RV overload including RV/left ventricle ratio ≥1 (22 vs. 4%; p  < 0.001) and interventricular septum displacement (53 vs. 20%; p  < 0.001) were also more common in patients with saddle PE compared with nonsaddle PE. Overall, PE-related mortality, venous thromboembolism recurrence, and major bleeding within 30 days were found to be similar according to saddle versus nonsaddle PE. Conclusion  Saddle PE is not uncommon in patients with cancer-related PE including in those with unsuspected PE. Similar 30-day outcomes were found according to saddle versus nonsaddle PE in our cohort.