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To evaluate BAY 2433334, an oral activated factor XI (FXIa) inhibitor, in volunteers.Phase 1 study of healthy men at a German centre. Part A: randomized, single-blind, multiple dose-escalation study of BAY 2433334 (25/50/100 mg once daily [OD]) vs. placebo. Part B: similar design to Part A; evaluated BAY 2433334 25 mg twice daily. Part C: nonrandomized, open-label study; evaluated potential interactions between BAY 2433334 (25/75 mg OD) and midazolam (7.5 mg), a CYP3A4 index substrate. Primary variables: treatment-emergent adverse events (TEAEs; Parts A and B); area under the plasma concentration-time curve (AUC) and maximum plasma concentration of midazolam and α-hydroxymidazolam (Part C).18 days plus follow-up visit.Parts A and B: 36 participants randomized to BAY 2433334; 12 to placebo. Part C: 48 participants assigned to BAY 2433334 plus midazolam. BAY 2433334 was well tolerated in all study parts. AUC and maximum plasma concentration of BAY 2433334 in plasma appeared dose proportional over 25-100 mg OD, with low-to-moderate variability in pharmacokinetic parameters. Multiple dosing caused minor-to-moderate accumulation and a mean terminal half-life (15.8-17.8 h) supporting once-daily dosing. Dose-dependent FXIa activity inhibition and activated partial thromboplastin time prolongation were observed. BAY 2433334 appeared to have a minor effect on AUC for midazolam (ratio [90% confidence interval]: 1.1736 [1.0963-1.2564]) and α-hydroxymidazolam (0.9864 [0.9169-1.0612]) only for BAY 2433334 75 mg OD on day 10.Multiple dosing of BAY 2433334 in healthy volunteers was well tolerated, with a predictable pharmacokinetic/pharmacodynamic profile and no clinically relevant CYP3A4 induction or inhibition.

The endpoint for all lupus anticoagulant (LA) assays is a clotting time in seconds. This study aimed to clarify the use of normalizing clotting time to ratio and how the use of different denominators is relevant.Whether normalization could reduce reagent variability and possess better diagnostic performances was assessed; denominators included reference interval (RI) mean, local-obtained pooled plasma clotting time, standard plasma clotting time, and control plasma clotting time (CNPPct). Moreover, whether day-to-day variation in CNPPct would impact its application was studied.If not normalized, significant difference existed among different reagent batches; if normalized (against any denominators), no statistically significant difference existed anymore. The validation of in-house RIs achieved a 100% success rate. Normalization against different denominators had different RIs, but the same diagnostic efficacies (when a prolonged LA1 is used to suggest further LA-related testings, normalized LA1 demonstrated a better sensitivity: 1.0 vs. 0.95). Normalization against a "daily" CNPPct (obtained alongside test plasmas day to day) demonstrated low inter-day variations (LA1: ~1%, LA2: ~1%), and it could employ the RI for normalization against a "fixed" CNPPct (obtained alongside normal plasmas when the RI was established).Normalizing clotting time reduces reagent-batch variability and promotes the adoption of common RIs, and therefore reduces the necessity of establishing RI for new reagent batches. Normalized LA1 is more sensitive when used to suggest further LA-related testings, and therefore reduces the rate of missed LA diagnosis. All denominators are of the same application value. Day-to-day variation in CNPPct did not impact its application as a reliable denominator.

Lupus anticoagulant (LA) testing is commonly performed within hemostasis laboratories, and the ACL TOP 50 family of instruments represent a new "single platform" of hemostasis instrumentation. Our aim was to evaluate these instruments and manufacturer reagents or alternatives for utility in LA testing.Comparative evaluations of LA testing using newly installed ACL TOPs 550 and 750 as well as comparative assessments with existing "reference," predominantly Stago, instrumentation, and reagents. Evaluations comprised both dilute Russell viper venom time (dRVVT) and activated partial thromboplastin time (APTT)-based assays. Establishment of normal reference ranges (NRR).The HemosIL dRVVT-based assays showed good comparability with the existing Stago reference method (R 0.9) and could be considered as verified as fit for purpose. A variety of APTT assays was additionally evaluated for LA utility, and we identified from the assessment good utility of a non-Werfen solution in Hyphen BioMed Cephen reagents. NRR were established based on ≥120 normal individual plasma samples.This evaluation of LA reagents on ACL TOP 50 Family instruments identified overall acceptable performance of both dRVVT (Werfen solution) and APTT (non-Werfen solution) to enable harmonization of LA testing in our large network.

Milvexian (BMS‐986177/JNJ‐70033093) is a small molecule, active‐site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two‐part, double‐blind, placebo‐controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200‐ and 500‐mg panels investigated the pharmacokinetic impact of a high‐fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once‐ or twice‐daily) or placebo for 14 days. All milvexian dosing regimens were safe and well‐tolerated, with only mild treatment‐emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half‐life (T1/2) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose‐proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose‐dependent fashion. In MAD panels, steady‐state milvexian plasma concentration was reached within 3 and 6 dosing days with once‐ and twice‐daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development.

Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein-kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first-in-class, fully human, monoclonal antibody targeting activated FXII (FXIIa). We describe how translational pharmacokinetic (PK) and pharmacodynamic (PD) modeling enabled dose selection for the phase I, first-in-human trial of garadacimab. The PK/PD data used for modeling were derived from preclinical PK/PD and safety studies. Garadacimab plasma concentrations rose with increasing dose, and clear dose-related PD effects were observed (e.g., a mechanism-based prolongation of activated partial thromboplastin time). The PK/PD profile from cynomolgus monkeys was used to generate minimal physiologically-based pharmacokinetic (mPBPK) models with target-mediated drug disposition (TMDD) for data prediction in cynomolgus monkeys. These models were later adapted for prediction of human data to establish dose selection. Based on the final mPBPK model with TMDD and assuming a weight of 70 kg for an adult human, a minimal inhibition (10%) of FXIIa with a starting dose of 0.1 mg/kg garadacimab and a near maximal inhibition (95%) at 10 mg/kg garadacimab were predicted. The phase I study is complete, and data on exposure profiles and inhibition of FXIIa-mediated kallikrein activity observed in the trial support and validate these simulations. This emphasizes the utility and relevance of translational modeling and simulation in drug development.

Factor XII (FXII) is the principal initiator of the plasma contact system and has proinflammatory and prothrombotic activities. This single-center, first-in-human phase I study aimed to assess the safety and tolerability of single escalating doses of garadacimab, a monoclonal antibody that specifically inhibits activated FXII (FXIIa), in healthy male volunteers. Volunteers were randomized to eight cohorts, with intravenous (i.v.) doses of 0.1, 0.3, 1, 3, and 10 mg/kg and subcutaneous (s.c.) doses of 1, 3, and 10 mg/kg. Six volunteers in each cohort received garadacimab or placebo in a ratio of 2:1. Follow-up for safety lasted 85 days after dosing. Blood samples were collected throughout for pharmacokinetic/pharmacodynamic analysis. Forty-eight volunteers were enrolled: 32 received garadacimab and 16 received placebo. Most volunteers experienced at least one treatment-emergent adverse event (TEAE), predominantly grade 1. No serious TEAEs, deaths, or TEAEs leading to discontinuation were reported. No volunteers tested positive for garadacimab antidrug antibodies. Garadacimab plasma concentrations increased in a dose-dependent manner. Sustained inhibition of FXIIa-mediated kallikrein activity beyond day 28 resulted from 3 and 10 mg/kg garadacimab (i.v. and s.c.). A dose-dependent increase in activated partial thromboplastin time with no change in prothrombin time was demonstrated. Garadacimab (single-dose i.v. and s.c.) was well-tolerated in healthy volunteers. Dose-dependent increases in plasma concentration and pharmacodynamic effects in relevant kinin and coagulation pathways were observed. These results support the clinical development of garadacimab, including in phase II studies in hereditary angioedema and coronavirus disease 2019 (COVID-19).

INTRODUCTION We aimed to evaluate the performance of the fully automated multiparameter CN-6000 hemostasis analyzer. METHODS Performance evaluation of the CN-6000 analyzer was conducted for 10 tests including prothrombin time (PT), activated partial prothrombin time (aPTT), fibrinogen level, anti-Xa activity, and antithrombin activity using a unique portfolio of liquid ready-to-use reagents. Precision, sample and reagent carryovers, throughput, and sample turnaround time (STAT) function were prospectively assessed. Results from 343 samples (normal subjects, critically ill patients, patients receiving anticoagulants, subjects with high or low fibrinogen levels, and patients with decreased levels of factor II, V, VII, and X) were compared to those obtained on the STA-R Max 2® analyzer using dedicated reagents. RESULTS Total precision (coefficient of variation) was below 7% for all parameters in both normal and pathological ranges. For all analyzed parameters, results obtained on the CN-6000 were strongly correlated with those obtained on the STA-R Max 2®analyzer. Agreement between both instruments was excellent for all assays. The CN-6000 demonstrated a 30% higher throughput compared to the STA-R Max 2® (258 vs 185 tests per hour for a panel of tests including PT, aPTT, fibrinogen, factor V, anti-Xa, and D-Dimer). STAT turnaround time for critical care samples testing was

Introduction The Summary of Product Characteristics for the direct thrombin inhibitor argatroban states monitoring should be by activated partial thromboplastin time (APTT), with a target range of 1.5-3.0 times the patients' baseline APTT. APTT may be influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. Previous studies have shown sensitivity differences of APTT reagents to argatroban. Some recent publications have favoured the use of anti-IIa methods to determine the plasma drug concentration of argatroban. This study aims to compare the anti-IIa assays: Hemoclot thrombin inhibitor assay (HTI) and Ecarin chromogenic assay (ECA) alongside the APTT. Methods Residual plasma of 25 samples from 8 patients (3 with COVID-19 and HIT: n = 18, 5 with HIT: n = 7) was tested at two sites: site A: Sysmex CS5100 by HTI and APTT (Actin FS and SynthASil), and also on Stago STA Compact Max: ECA and APTT (CK Prest); and site B: Stago STA R Max 2 by ECA and APTT (Cephascreen). Results Mean APTT ratio was 1.96 (Actin FS), 1.84 (SynthASil), 1.59 (CK Prest) and 2.48 (Cephascreen). Mean argatroban concentration by HTI was 0.60 µg/mL and by ECA was 0.65 µg/mL (site A) and 0.70 µg/mL (site B). There was a poor correlation to HTI in APTT ratios (range r2 = .0235-0.4181) with stronger correlations between ECA methods to HTI (r2 = .8998 site A, r2 = .8734 site B). Conclusion This study confirms previous publications on the unsuitability of APTT and expands this by being multisited and included APTT reagents that use mechanical clot detection. Both anti-IIa methods are more suitable.

Background We aim to determine the clinical utility of reflex coagulation investigations (RCI) for prolonged lupus insensitive activated partial thromboplastin time (aPTT) at our institution. Methods We retrospectively reviewed all potential RCI (lupus insensitive aPTT of ≥32s) from April 2014 to June 2019. Our diagnostic algorithm requires completion of RCI only if samples had no interfering medications to explain a prolonged aPTT and were either from a preoperative sample or from a patient presenting with unexplained bleeding. Appropriate RCI samples undergo further investigations with one-stage factor activity testing for factors 8(FVIII), 9(FIX), and 11(FXI) reflexively. Data were obtained through electronic medical records to capture clinical characteristics, laboratory findings, prophylactic hemostatic replacement, and bleeding outcomes. Results Three thousand and three hundreds seventeen samples from 2940 distinct patients were considered as potential RCI during the study period. 263/3317 (8%) samples had RCI completed. Of those, 55/263 (21%) had abnormal factor testing, with the majority from preoperative setting (43/55; 78%). 5/43 (12%) patients were referred to hematology for preoperative evaluation. 5/43 patients received preoperative hemostatic support. A total of 5 patients (5/43) developed postop bleeding. Six patients (6/55) had RCI for unexplained bleeding, and five patients (83%) had a newly identified clinically significant bleeding disorder. Conclusion Reflex coagulation investigations benefited patients presenting with unexplained bleeding as this expedited the diagnosis and management of clinically significant bleeding disorders. RCI for preoperative evaluation infrequently led to additional hemostatic support/referral to hematology. The lack of additional workup for an abnormal factor activity level suggests laboratory alert fatigue as a potential contributory factor.

OBJECTIVE Although various guidelines have been established for the management of antithrombotic therapy during surgical treatments, surgical tracheostomy (ST) under continued antithrombotic therapy (CAT) remains challenging. Here, we investigated the risk factors for complications after ST by focusing on the application of CAT during ST. DESIGN A retrospective cohort study with medical records from 2009 to 2020. SETTING A single-center study. PARTICIPANTS This study included patients who had undergone ST at the Department of Otolaryngology of our hospital MAIN OUTCOME MEASURES: The primary outcomes were the incidence of complications and blood test results. Secondary outcomes were risk factors for postoperative complications. RESULTS We identified 288 patients (median age: 64 years; 184 men [64%]), among whom 40 (median age: 67 years; 29 men [73%]) underwent CAT. Although the patients undergoing CAT had significantly longer activated partial thromboplastin time (p=0.002) and a higher prothrombin time-international normalized ratio (p=0.006) compared to antithrombotic naive patients, no statistically significant intergroup differences were observed for the risk of bleeding, infection, or subcutaneous emphysema. Instead, ST under local anesthesia (p=0.01) and ST for airway emergency (p=0.02) significantly increased the risk of early postoperative complications. CONCLUSION These results suggest that ST under CAT can be safely performed without any increased risk of postoperative complications. Nevertheless, surgeons should be extra cautious about early complications after ST under local anesthesia without intubation or ST for airway emergencies.

The high concentrated thrombin time (hcTT), a thrombin time modified by increasing the thrombin concentration, is a possible alternative assay to activated partial thromboplastin time (aPTT) in unfractionated heparin (UFH) monitoring. This study aimed to determine the optimal thrombin concentration used in the hcTT assay for UFH monitoring.A total of 30 blood samples obtained from healthy volunteers were included in this study. Thrombin concentrations of 10.0, 15.0, 20.0, and 25.0 IU/ml were used in the hcTT assay. The consistency between the hcTT and anti-FXa assays was evaluated. To validate the hcTT assay, linearity, repeatability, reproducibility, and diagnostic performance of the assay were assessed.The hcTT assay using thrombin concentration of 15.0 IU/ml showed a strong correlation to the anti-FXa assay with RThe hcTT assay can be used as an alternative assay for UFH therapy monitoring. A further study using clinical samples is recommended to confirm the appropriateness of the hcTT assay for clinical application.

Background Double-filtration plasmapheresis (DFPP), a selective therapeutic apheresis, can deplete pathogenic antibodies/substances, but also important coagulation factors. Aim To determine if the use of a separator filter with different characteristics (CascadefloEC-50 W) as compared to the reference filter (PlasmafloOP-08 W) is as efficient in terms of immunoglobulin loss, but can reduce coagulation factor losses and have similar tolerability. Patients/methods This is a single-center prospective study including 14 patients divided into two groups (7 each): that is, group1 = CascadefloEC-50 W and group2 = PlasmafloOP-08 W. We measured immunoglobulins, lipid profiles, blood-cell counts, hemostasis (prothrombin time, activated partial thromboplastin time), coagulation factors, and natural anticoagulants at before and after the first DFPP-session. Results In group 1, the loss of coagulation factors was significantly reduced as compared to group 2 for proteins with a molecular weight of >150 kDa: there was, respectively, an average decrease of 70% vs 31% for fibrinogen (P = 0.004), 66% vs 21% for factor V (P = 2.16e-07), 60% vs 32% for factor XI (P = 6.96e-06), 75% vs 17% for XIII-antigen (P = 0.0002), and 47% vs 0% for VWF-antigen(P = 0.02). The decrease in post-session IgG was, on average, 45% in group 1 and 50% in group 2 (P = 0.13). Those results remained significant even when adjusted to the treated-plasma volume and the pre-DFPP factor values. Conclusion DFPP, using a CascadefloEC-50W as a first-filter, reduces efficiently IgGs similarly to PlasmafloOP-08W but spares clotting factors.

INTRODUCTION Sigma metric offers a quantitative framework for evaluating process performance in clinical laboratories. This study aimed to evaluate the analytical performance of automated analyzers in hematology unit of Alexandria Main University Hospital using the sigma metric approach. MATERIALS AND METHODS Quality control data were collected for 6 months, and sigma value was calculated from hematology analyzers SYSMEX (XN 1000, XT 1800i), ADVIA (2120i, 2120), and coagulation analyzers SYSMEX CA 1500 (3610, 6336). RESULTS For the normal control level, satisfactory mean sigma value ≥3 was observed for all of the studied parameters by all analyzers. For the high control level, red blood cell count by ADVIA 2120, and hematocrit by ADVIA (2120i and 2120) performed poorly with a mean sigma value

Objective To compare hemostatic variables performed on blood samples obtained from indwelling jugular catheters or direct venipuncture over a 72-hour period. Design Prospective experimental study. Setting University research laboratory. Animals Five healthy neutered male purpose-bred Beagle dogs. Interventions Each dog was sedated to facilitate placement of a long-stay 20-Ga polyurethane IV catheter into the jugular vein. Blood samples were obtained from the preplaced catheters at 4 time points corresponding to 0, 24, 48, and 72 hours relative to placement. Blood samples were also obtained by direct venipuncture of a peripheral vein using a 21-Ga butterfly catheter and evacuated blood tubes at the same time points. Platelet count, platelet closure time, prothrombin time, activated partial thromboplastin time, fibrinogen, and kaolin-activated thromboelastography were performed on these paired samples at each time point. The patency of the indwelling catheters was maintained by flushing every 6 hours with heparinized saline. Measurements and main results No significant differences were identified in any of the hemostatic variables obtained by either blood collection technique at any time point during the study (P > 0.05). There was also no significant day-to-day variation in any catheter-derived hemostatic variable obtained from individual dogs identified over the course of the study. Conclusions These data suggest that accurate hemostatic variables may be obtained using blood collected from indwelling jugular catheters, maintained with heparinized saline for at least 72 hours, in healthy dogs.

The alterations in the hemostatic balance in COVID‐19 patients are strongly disturbed and contribute to a high prothrombotic status. The high rate of venous thromboembolism in COVID‐19 patients goes along with derangements in coagulation laboratory parameters. Hemostasis testing has an important role in diagnosed COVID‐19 patients. Elevated D‐dimer levels were found to be a crucial laboratory marker in the risk assessment of thrombosis in COVID‐19 patients. The diagnostic approach also includes prothrombin time and platelet count. Fibrinogen might give an indication for worsening coagulopathy. Other markers (activated partial thromboplastin time (aPTT), fibrinolysis parameters, coagulation factors, natural anticoagulants, antiphospholipid antibodies and parameters obtained by thromboelastography or thrombin generation assays) have been described as being deranged. These may help to understand the pathophysiology of thrombosis in COVID‐19 patients but have currently no place in diagnosis or management in COVID‐19 patients. For monitoring the heparin anticoagulant therapy, the anti‐Xa assay is suggested, because the severe acute‐phase reaction (high fibrinogen and high factor VIII) shortens the aPTT.

Background Gallbladder mucocele (GBM) is a common biliary disorder in dogs. Limited information is available on the coagulation status of dogs with GBM. Hypothesis/objectives To determine patterns of coagulation alterations in dogs with GBM and correlate them with clinicopathologic abnormalities and ultrasonographic findings of disease severity. Animals Twenty-three dogs with GBM identified on ultrasound examination were prospectively enrolled. Methods At the time of GBM identification, blood and urine were collected for CBC, serum biochemical panel, urinalysis, prothrombin time, activated partial thromboplastin time (aPTT), factor VIII, protein C (PC), von Willebrand's factor (vWF), antithrombin activity, fibrinogen, D-dimers, and thromboelastrography (TEG). Gallbladder mucoceles were classified into ultrasound types 1 to 5. Medical records were reviewed for clinical presentation, underlying conditions and to determine if systemic inflammatory response syndrome (SIRS) was present. Results Based on TEG parameters, maximal amplitude, and G, 19/23 (83%) of dogs with GBM had evaluations consistent with hypercoagulability. On plasma-based coagulation testing, dogs with GBM had increased total PC activity (20/23, 87%), fibrinogen (9/23, 39%), platelet count (9/23, 39%), and D-dimers (6/15, 40%) as well as prolongations in aPTT (9/22, 41%) and low vWF activity (5/21, 24%). No correlation was found between TEG G value and any coagulation or clinical pathology variables, ultrasound stage of GBM or disease severity as assessed by the presence of SIRS. Conclusions and clinical importance Dogs with ultrasonographically identified GBM have changes in whole blood kaolin-activated TEG supporting a hypercoagulable state although traditional plasma-based coagulation testing suggests that a complex state of hemostasis exists.

Background Lupus anticoagulants (LA) are detected by prolongation of clotting times for dilute Russell's viper venom time (dRVVT) and activated partial thromboplastin time (APTT) screening tests. Direct oral anticoagulants (DOACs) can interfere with both screening and confirmatory tests. The present study aimed to investigate the influence of direct factor Xa inhibitors (DiXaIs) on screen, confirm and mixing tests and establish a method for differentiation from other sample types. Materials and methods A total of 257 samples including nonanticoagulated LA positive, LA positive with DiXaIs, factor deficiency, FVIII inhibitors, warfarin and non-APS DiXaIs were tested. APTT reagents Cephen LS/Cephen and dRVVT reagents LA1/LA2 were used, respectively, to screen/confirm the study group. Index of circulating anticoagulant (ICA) was calculated from clotting times based on the following formula as ICA screening and ICA confirmation. ICA= (1:1 Mix sample – Normal pooled plasma) / Screen patient x 100. An ICA matrix was established which suggested the presence of a DiXaI when both ICA screening and confirmation were above the cut-off. When only ICA screening is elevated, LA is suspected. Results Sensitivity and specificity of the ICA matrix were 52.2% and 92.8% for DiXaIs and 38.1% and 96.7% for LA in APTT, and 61.2% and 92.9% for DiXaIs and 22.2% and 88.4% for LA in dRVVT, respectively. Conclusion The ICA matrix achieved high specificity with a lower apparent sensitivity for DiXaI samples comparatively to other devices but due only to less interferences: the matrix could contribute to differentiating DiXaIs from LA in samples where anticoagulation status is unknown.

Objective To compare the blood loss after procedures of primary unilateral or one‐stage bilateral total knee arthroplasty (TKA) caused by open‐box prosthesis and closed‐box prosthesis. Methods This was a retrospective study. Patients undergoing procedures of primary TKA between January 2017 and July 2020 in our institution were assessed for eligibility for this study. Those who were diagnosed with knee osteoarthritis and underwent primary unilateral or one‐stage bilateral TKA by using PFC Sigma PS150 (closed‐box prosthesis) or Vanguard (open‐box prosthesis) knee systems and had complete data of laboratory indexes on postoperative day (POD) 1, POD 3, and POD 5 were the interested population. At last 243 patients were enrolled, among which 88 patients were classified into the unilateral closed‐box group, 66 patients into the unilateral open‐box group, 47 patients into the one‐stage bilateral closed‐box group, and 42 patients into the one‐stage bilateral open‐box group. The perioperative management and operative techniques were almost the same for each patient, except the selection of prosthesis, which was decided according to surgeon's preference. The baseline information, postoperative laboratory indexes tested on POD 1, POD 3, and POD 5 including hemoglobin, hematocrit, platelet, thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR), the primary outcome measurements including the maximum decreased value of hemoglobin and the volume of total blood loss, and the secondary outcome measurements including the transfusion rate and the average transfused red blood cell (RBC) units were well compared between the open‐box group and the closed‐box group. Results The baseline was comparable between groups, except higher preoperative levels of hemoglobin (134.43 g/L vs 126.51 g/L, P = 0.003) and hematocrit (39.92% vs 37.37%, P = 0.000) observed in the one‐stage bilateral open‐box group. The differences of postoperative coagulation function monitored by TT, PT, APTT, and INR were clinically irrelevant between groups. For patients receiving unilateral TKA, significantly higher value of decreased hemoglobin (26.06 g/L vs 21.05 g/L, P = 0.025) and significantly larger amount of total blood loss (920.34 mL vs 723.19 mL, P = 0.013) were observed in the open‐box group. For patients receiving one‐stage bilateral TKA, the open‐box prosthesis was observed to cause more hemoglobin drop (37.81 g/L vs 32.02 g/L, P = 0.071) and total blood loss (1327.26 mL vs 1177.42 mL, P = 0.247) compared to the closed‐box prosthesis, though the differences were not significant. The transfusion rate and the average transfused RBC units were not significantly different between the open‐box group and the closed‐box group no matte whether the patients were from the unilateral TKA group or from one‐stage bilateral TKA group. Conclusion The use of open‐box prosthesis caused more hemoglobin drop and total blood loss than closed‐box prosthesis after primary unilateral or one‐stage bilateral TKA, resulting in comparable transfusion rate and average transfused RBC units between groups., Different characteristics between the closed‐box knee prosthesis and the open‐box knee prosthesis. The closed‐box prosthesis completely covers the whole area of cancellous bone at the distal femur, while the open‐box prosthesis leaves an uncovered area of cancellous bone at the intercondylar fossa, which may be a source of bleeding and results in more total blood loss postoperatively.

AIM To develop a model of clinical factors that may predict: (1) technically and clinically successful embolization of a bleeding vessel at digital subtraction angiography (DSA) for lower gastrointestinal bleed (LGIB); (2) a negative DSA in the presence of positive CT-mesenteric angiography (CTMA) for LGIB. METHODS A retrospective cohort study of all DSAs conducted with intent for embolization for acute LGIB over a 10-year period was undertaken. Pre-procedural and intra-procedural clinical variables were evaluated using uni- and multi-variate analysis. RESULTS One hundred and twenty-three DSAs were evaluated. Technical success was 81% and clinical success 78% where DSA was positive. Technical success was associated with super-selective approach, contrast extravasation on CT, haemoglobin drop, anatomical source and time from CT to DSA on univariate analysis. On multivariate analysis, time from CT to DSA was significant with a higher success probability within 120 min with different factors being salient depending on degree of delay. Clinical success was only associated with activated partial thromboplastin time (

Patients with liver diseases acquire complex alterations in their hemostatic system that may lead to abnormalities in routine diagnostic test of hemostasis. Thrombocytopenia, prolongations in the prothrombin time and activated partial thromboplastin time, and decreased plasma fibrinogen are common in patients with advanced liver disease. Historically, liver diseases therefore have been classified as an acquired bleeding disorder. Laboratory and clinical observations have demonstrated that although routine diagnostic tests of hemostasis suggest a hypocoagulable state, patients with liver disease also tend to develop thrombotic events. Overall, patients have commensurate changes in both pro‐ and antihemostatic pathways. This new hemostatic balance, however, appears much more fragile than the hemostatic balance in individuals with normal liver function, and patients with liver disease can readily experience both hemostasis‐related bleeding and thrombotic events. These insights into the hemostatic balance in patients with liver disease have led to revised recommendations for clinical management of hemostasis. In 2020, an SSC working group within the ISTH has been founded with the aim to disseminate new concepts on prevention and treatment of bleeding and thrombosis in patients with liver disease. The current document will outline the hemostatic changes in patients with liver disease, the limitations of routine diagnostic tests of hemostasis, and the concept of rebalanced hemostasis.

OBJECTIVE To compare the efficacy of fresh frozen plasma (FFP) with cryopoor plasma (CPP) to treat vitamin K-dependent factor deficiency in a canine in vitro setting. DESIGN In vitro laboratory study. SETTING University veterinary medical teaching hospital. ANIMALS Seven units of FFP and 6 units of CPP from unique canine donors from the university veterinary blood bank. INTERVENTIONS Canine FFP was adsorbed by oral barium sulfate suspension to mimic vitamin K-dependent coagulopathy. A sequential mixing study was completed by adding FPP or CPP to the adsorbed plasma. Measurements of prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and factor activities of factors II, VII, and IX (FII, FVII, and FIX) were compared between the 2 treatment groups. MEASUREMENTS AND MAIN RESULTS When comparing the sequential addition of CPP or FPP to adsorbed plasma, the following had no statistical significance: PT (P = 0.94), aPTT (P = 0.66), FII (P = 0.05), and FIX (P = 0.90). There was a dose-dependent decrease with PT and aPTT and a dose-dependent increase with FII and FIX. In contrast, after the addition of either CPP or FFP, there was a significant difference between the treatment groups for the concentration of fibrinogen (P = 0.005) and activity of FVII (P = 0.044), with FFP resulting in a greater concentration of fibrinogen and CPP resulting in a greater concentration of FVII. Measurements of factor X (FX) were initially included in the study but were later excluded because FX appeared to be continually adsorbed even after the addition of CPP or FFP. CONCLUSIONS CPP partially corrected the coagulation times and concentration of vitamin K-dependent coagulation factors to the same degree as FFP. CPP, generally less expensive than FFP, may provide an alternative treatment option for vitamin K-dependent coagulopathies, although in vivo testing is needed.

BACKGROUND Intraoperative bleeding during functional endoscopic sinus surgery (FESS) poses a challenge to both surgeon and anesthetist. The primary aim of this study was to evaluate the effectiveness of local, intravenous and combined use of tranexamic acid (TA) in improving the surgical field quality during FESS. METHODS We conducted a randomized controlled double-blinded prospective trial on 120 patients scheduled for elective FESS. After induction of general anesthesia, patients were randomly and evenly assigned to one of four groups; IV TA, local TA, both IV and local TA, and placebo. Surgical field was assessed using five-point Boezaart scale. Total fentanyl and esmolol consumption, operative time, recovery time, and postoperative complications were recorded. RESULTS Surgical field quality score was the best in IV and local TA group compared to others (p

BACKGROUND Plasmapheresis can deplete pathogenic antibodies and allow ABO- and/or HLA-incompatible transplantation. AIM To determine the impacts of three modalities of plasmapheresis (centrifugal plasmapheresis [cTPE], single-filtration plasmapheresis [mTPE], double-filtration plasmapheresis [DFPP]) on hemostasis parameters and thrombin generation. MATERIALS/METHODS Prospective, comparative study on 21 patients that received three modalities of plasmapheresis (7 patients/group). Hemostasis (prothrombin time [PT], activated partial thromboplastin time [aPTT], procoagulant factors and natural anticoagulants) were measured before and after the first plasmapheresis session. Thrombin generation was also assessed in platelet-poor plasma using an STA-Genesia (Stago) analyzer and Thromboscreen reagents (Stago) in 4-5 patients from each group. RESULTS Both cTPE and mTPE resulted in high decreases in proteins, whatever their molecular weights. Median post/pre ratios were 0.27 to 0.55 for cTPE for most proteins (except FVIII [0.64] and VWF [0.57]). Median post/pre-ratios of mTPE were 0.28 to 0.56 for all proteins. DFPP decreased high-molecular-weight proteins (fibrinogen, FV, FVIII, FXI, VWF) and proteins strongly bound to large molecules (protein SandTFPI). Median post/pre ratios with cTPE and mTPE were similar to DFPP for fibrinogen and FXIII. Regarding thrombin generation, cTPE and mTPE did not significantly modify endogenous thrombin potential (ETP) and DFPP induced a slight decrease in ETP (median post/pre ratio at 0.73) in the absence of thrombomodulin. ETP inhibition by thrombomodulin was decreased for all procedures. CONCLUSIONS DFPP depleted high molecular-weight proteins in contrast to cTPE and mTPE, which significantly decreased all proteins. Regarding thrombin generation, depletion of procoagulant factors was counterbalanced by a decrease in some natural anticoagulants whatever plasmapheresis method used; with all methods, fibrinogen and FXIII were highly depleted.

Aims The objectives of this study were to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of ONO-7684, a novel activated factor XI (FXIa) inhibitor, in healthy subjects. Methods This was a first-in-human (FIH), randomised, placebo-controlled, double-blind, single and multiple dose study in healthy subjects under fed and fasted conditions. This study consisted of two parts: single ascending dose (Part A; 1, 5, 20, 80, 150 or 300 mg ONO-7684 or placebo) and multiple ascending doses (Part B; 80, 150 or 250 mg ONO-7684 or placebo daily for 14 days). In both parts, subjects were randomised in a 3:1 ratio to receive ONO-7684 or placebo. Results ONO-7684 was well tolerated at all dose levels tested following both single and repeated doses, with a low overall incidence of treatment-emergent adverse events. There was no evidence to suggest a bleeding risk. Dose proportionality in exposure was observed for the range of 1-300 mg ONO-7684 in Part A. In Part A, the half-life of ONO-7684 administered in the fasted state ranged from 16.0 to 19.8 hours. In Part B, the half-life of ONO-7684 administered in the fed state ranged from 22.1 to 27.9 hours, supporting once daily oral dosing. ONO-7684 strongly inhibited factor XI coagulation activity (FXI:C) and increased activated partial thromboplastin time (aPTT), with a mean maximum on treatment percentage inhibition versus baseline of 92% and a mean maximum on treatment ratio-to-baseline of 2.78, respectively, at 250 mg ONO-7684 daily. Conclusions The data generated in this FIH study demonstrate the promising potential of oral FXIa inhibition and ONO-7684 for indications requiring anticoagulation.

The present study was performed to investigate the protective effect of Protaetia brevitarsis seulensis (Kolbe) against carbon tetrachloride (CCl₄)‐induced liver damage and coagulation disturbances in rats, in comparison to silymarin. Rats were orally pre‐treated with P. brevitarsis larvae and silymarin at a dose of 300 mg/kg once daily for 5 days, and then a single dose of CCl₄ (4 mL/kg i.p.). P. brevitarsis larvae showed significant hepatoprotection by reducing the liver enzymes (AST, ALT and ALP) activity levels that had been raised by CCl₄ administration. In addition, P. brevitarsis larvae significantly restored prothrombin time (PT) and activated partial thromboplastin time (aPTT) values to nearly silymarin level, which were abnormalized after CCl₄ administration. The histopathological results of liver tissues treated with P. brevitarsis larvae supported the serum biochemical results, indicating improved liver functions. The current study showed that P. brevitarsis larvae have potential against CCl₄‐induced liver damage and coagulation disorders.

AIMS Our study aimed to determine the impact of genetic polymorphisms of ABCB1 and CES1 on the pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran in patients with nonvalvular atrial fibrillation (NVAF). METHODS We conducted a prospective study and enrolled NVAF patients treated with dabigatran. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration (PDC) and coagulation parameters including activated partial thromboplastin time (APTT) and thrombin time. Patients' demographics and clinical outcomes from scheduled follow-up visits were all recorded. Statistical analysis was performed to identify the impact of genetic polymorphisms on the PK/PD and bleeding risk of dabigatran. RESULTS A total of 198 patients were included in analysis. For the ABCB1 polymorphisms rs4148738 and rs1045642, no significant association was found with dabigatran PK/PD. For the CES1 polymorphism rs8192935, the minor allele(C) was associated with increased trough PDCs (ANOVA: P < .001; CC vs. TT genotype, P < .001; CT vs. TT genotype, P = .014) and with APTT values at trough level (P = .015). For the CES1 polymorphism rs2244613, the minor allele(A) carriers had higher levels of trough PDC than noncarriers (ANOVA: P < .001; AA vs. CC genotype, P < .001; CA vs. CC genotype, P = .004) and increased risk for minor bleeding (P = .034; odds ratio = 2.71, 95% confidence interval 1.05-7.00). CONCLUSION Our study indicated that the minor allele(C) on the CES1 SNP rs8192935 was associated with PDCs and APTT values at trough level. The minor allele(A) on the CES1 SNP rs2244613 was associated with increased trough PDCs and higher risk for minor bleeding in NVAF patients treated with dabigatran.

Herba Erigerontis injection (HEI) is an aqueous solution derived from whole plants of Erigeron breviscapus, which may be co-administered with warfarin to treat cardiovascular and cerebrovascular disorders. This research was conducted to make sure whether HEI would affect anticoagulation of warfarin to guarantee reasonable medication. The pharmacodynamic study was designed to measure prothrombin time (PT) and activated partial thromboplastin time (APTT) values, and international normalized ratio (INR) values were calculated. For pharmacokinetic study, ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) technology was applied to measure plasma concentrations of warfarin enantiomers. The influence of HEI on plasma protein binding rate of warfarin was assessed by ultrafiltration. Pharmacodynamic study demonstrated that both HEI alone and co-administered with warfarin could increase PT and INR values significantly (P .05). Pharmacokinetic study manifested that Cmax , AUC and t1/2 prolonged significantly (P < .01) for R/S-warfarin in presence of HEI. Low (3.6 mL/kg), medium (7.2 mL/kg) and high (10.8 mL/kg) doses of HEI could decrease plasma protein binding rate of warfarin significantly (P < .01). The results mean that HEI can potentiate the anticoagulant response of warfarin through both pharmacodynamics and pharmacokinetics.

Acute lung injury (ALI) caused by gas explosion is common, and warrants research on the underlying mechanisms. Specifically, the role of abnormalities of coagulation and fibrinolysis in this process has not been defined. It was hypothesized that the abnormal coagulation and fibrinolysis promoted ALI caused by gas explosion. Based on the presence of ALI, 74 cases of gas explosion injury were divided into the ALI and non‐ALI groups. The results of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and platelet count (PLT) were collected within 24 hours and compared between the groups. ALI models caused by gas explosion were established in Sprague Dawley rats, and injuries were evaluated using hematoxylin and eosin (HE) staining and histopathological scoring. Moreover, the bronchoalveolar lavage fluid (BALF) was collected to examine thrombin‐antithrombin complex (TAT), tissue factor (TF), tissue factor pathway inhibitor (TFPI), and plasminogen activator inhibitor‐1 (PAI‐1) levels by enzyme‐linked immunosorbent assay (ELISA). The patients in ALI group had shorter PT and longer APTT, raised concentration of FIB and decreased number of PLT, as compared to the non‐ALI group. In ALI rats, the HE staining revealed red blood cells in alveoli and interstitial thickening within 2 hours which peaked at 72 hours. The levels of TAT/TF in the BALF increased continually until the seventh day, while the PAI‐1 was raised after 24 hours and 7 days. The TFPI was elevated after 2 hours and 24 hours, and then decreased after 72 hours. Abnormalities in coagulation and fibrinolysis in lung tissues play a role in ALI caused by gas explosion.

The capability of viscoelastic measurement parameters to screen anticoagulation activity of edoxaban in relation to its plasma concentrations was evaluated in 15 healthy male volunteers. Blood samples were drawn before the oral administration of edoxaban 60 mg and 2, 4, 6, 8, and 24 hours after administration. At each time, standard coagulation tests were performed, blood viscoelastic properties were measured with a thromboelastometry device ROTEM delta analyzer (Instrumentation Laboratory, Werfen, Barcelona, Spain), and edoxaban plasma concentrations were measured. Our primary interest was the possible correlation between edoxaban plasma concentrations and values for ROTEM ExTEM, and FibTEM. We also studied the correlation of edoxaban plasma concentrations with the results of standard coagulation tests. We saw the effect of a single dose of edoxaban most clearly in clotting time (CT) of ROTEM ExTEM and FibTEM. Changes in these parameters correlated significantly with edoxaban plasma concentrations up to 6 hours from the ingestion of the drug. Activated partial thromboplastin time, prothrombin time, and anti-factor Xa were also affected. Peak changes were observed 2 and 4 hours after administration of edoxaban. The changes were mostly reversed after 8 hours. In conclusion, ROTEM CT correlates significantly with edoxaban plasma concentrations and can be used to estimate the effect of edoxaban. ROTEM should be considered as part of the assessment of coagulation, with the big advantage of being readily available on site.

Background The efficacy and safety of thrombomodulin alfa (TM-α), a cofactor protein promoting thrombin-mediated protein C activation, have been examined in a phase 3 randomized, double-blinded, parallel-group trial in Japan. We have previously reported that TM-α is noninferior to heparin for the resolution of disseminated intravascular coagulation (DIC). Objective To investigate the basis for the efficacy of TM-α in the phase 3 clinical trial in Japan through post hoc analysis of coagulation and fibrinolysis parameters. Patients/methods The 227 patients of the full analysis set population described in the original phase 3 trial in Japan were included in this analysis. Changes in parameters between before and after TM-α or heparin administration in each of the two patient groups, with underlying diseases of either hematologic malignancy or infection, were studied separately and results were compared between TM-α and heparin treatment groups in a post hoc manner. Results TM-α administration did not prolong activated partial thromboplastin time but significantly decreased thrombin-antithrombin complex levels compared with heparin treatment. TM-α administration reduced consumption of endogenous anticoagulants such as antithrombin and protein C by DIC, compared with the heparin group. DIC scores were decreased in both TM-α and heparin groups during the 6-day treatment. Conclusion TM-α can alleviate intravascular coagulation and consumption of anticoagulants without extending coagulation times. This may be associated with the relatively low risk of bleeding during TM-α treatment.

Introduction Activated partial thromboplastin time (aPTT) and antifactor Xa (anti-Xa) activity are used to monitor unfractionated heparin therapy in children on extracorporeal membrane oxygenation (ECMO). Elevated C-reactive protein (CRP) can prolong aPTT and cause discrepancy between these two assays. We aimed to evaluate CRP effect on aPTT and anti-Xa assays in the presence of heparin and to determine whether elevated CRP affects laboratory monitoring in pediatric ECMO patients. Materials and methods Citrated normal specimens were spiked with CRP, heparin, and recombinant factor VIII (FVIII) and followed by measurement of aPTT and anti-Xa activity. Additionally, aPTT, anti-Xa activity, FVIII, fibrinogen, and CRP were measured in 18 ECMO specimens. Results Elevated CRP prolonged aPTT in normal specimens with or without heparin, but did not affect anti-Xa assay. In contrast, ECMO specimens showed similar aPTT and anti-Xa values regardless of CRP level. Elevated CRP in specimens was accompanied by increased fibrinogen and FVIII activity. Additional in vitro experiments confirmed that FVIII spiked simultaneously with CRP attenuated CRP-induced aPTT prolongation in heparinized specimens. Conclusion In vitro CRP-induced aPTT prolongation is not observed in pediatric ECMO samples due to concomitant FVIII increase. Discordant changes of CRP and FVIII in plasma could contribute to aPTT/anti-Xa discrepancies observed during heparin therapy in the pediatric population. The anti-Xa assay is preferable for heparin monitoring in pediatric ECMO settings.

The outbreak of 2019 novel coronavirus disease (COVID‐19) has posed a grave threat to the global public health. The COVID‐19‐induced infection is closely related to coagulation dysfunction in the affected patients. This paper attempts to conduct a meta‐analysis and systematically review the blood coagulation indicators in patients with severe COVID‐19. A meta‐analysis of eligible studies was performed to compare the blood coagulation indicators in patients with severe and nonsevere COVID‐19. PubMed, Embase, Web of Science, and the Cochrane Library were searched for studies published between 1 December 2019 and 7 May 2020. A total of 13 studies with 1341 adult patients were enrolled in this analysis. Platelet (weighted mean difference [WMD] = −24.83, 95% confidence interval [CI]: −34.12 to −15.54; P, Highlights Coagulation dysfunction affects the prognosis of COVID‐19 patients.Lower platelet, higher d‐dimer and fibrinogen indicate increased severity risk in COVID‐19 patients.No difference in PT and APTT is evident between severe and non‐severe COVID‐19 patients upon admission.

In this study, ginger polysaccharide (GP), ginger polysaccharide 1 (GP1), and ginger polysaccharide 2 (GP2) from ginger were firstly modified by sulfation. Fourier transform infrared, and nuclear magnetic resonance spectra investigation of sulfated ginger polysaccharide (SGP), sulfated ginger polysaccharide 1 (SGP1), and sulfated ginger polysaccharide 2 (SGP2) revealed that the sulfation successfully occurred with the characteristic absorption peak of polysaccharide. Congo red experiment showed that triple helical structure existed in SGP and SGP1, but random coils existed in SGP2. SGP, SGP1, and SGP2 all showed a rough and rugged surface with plenty of small pores. The blood clotting time of SGP2 or SGP at 2 mg/mL in activated partial thromboplastin time (APTT) assay was 41.42 or 38.01 s, respectively, which were approximately 1.33- and 1.22-fold longer than that of the physiological saline. Compared to the saline control group, prothrombin time (PT) was increased by 1.22-fold with the addition of GP at 2 mg/mL. However, no clotting inhibition phenomenon was observed in thrombin time test even at the concentrations that APTT and PT were obviously prolonged. It indicated that GP2, SGP2, and SGP inhibited the intrinsic pathway of coagulation, but GP inhibited both the intrinsic and extrinsic pathways of coagulation. Hence, ginger polysaccharides might be used as anticoagulants and therapeutic reagents for thrombosis.

OBJECTIVES To evaluate the in vitro efficacy of specific Daboia (Vipera) palaestinae (Dp) antivenom or fresh frozen plasma (FFP) against Dp venom-induced hemostatic changes DESIGN: In vitro study. SETTING Laboratory of a university referral hospital. ANIMALS Five healthy dogs. INTERVENTIONS Rotational thromboelastometry (including recombinant tissue factor or kaolin activators [EXTEM and INTEM, respectively]) and conventional hemostatic tests were evaluated in citrated whole blood samples that underwent 4 treatments: (1) no additives (control); (2) 15 μg of Dp venom; (3) 15 μg of Dp venom and 10 μL of specific Dp antivenom; (4) 15 μg of Dp venom and 0.3 mL of FFP. A linear mixed-effects regression model was used to compare results between each treatment and the control. MEASUREMENTS AND MAIN RESULTS Dp-venom engendered statistically significant (P < 0.05) EXTEM changes in 8/17 variables, all indicative of hypercoagulability, which were negated by antivenom but not with FFP. Similarly, Dp-venom induced hypercoagulable, hyperfibrinolytic changes in 12 of 17 INTEM variables, of which only 5 of 12 were negated by antivenom but not with FFP. Fibrinogen concentration was decreased, and the activated partial thromboplastin time (aPTT) was shortened (P < 0.05 for both) in all treatments compared to the control. CONCLUSIONS This study demonstrated the ephemeral procoagulant phase of Dp envenomation for the first time. Many venom-induced thromboelastometric changes were reversed by specific antivenom but not with FFP. Prospective clinical studies are warranted to investigate whether the present findings translate to clinical efficacy.

BACKGROUND: It is well known that low platelet count on admission to intensive care units (ICU) is associated with increased mortality. However, it is unknown whether prothrombin time (PT-INR) and activated partial thromboplastin time (APTT) on admission correlate with mortality and organ failure. Therefore, the aim of this study was to investigate if PT-INR and APTT at admission can predict outcome in the critically ill patient after adjusting for severity of illness measured with Simplified Acute Physiology Score 3 (SAPS 3).MATERIALS AND METHODS: Data were retrospectively collected. APTT and PT-INR taken on admission and SAPS 3 score, were independent variables in all regression analyses. Survival analysis was done with Cox regression. Organ failure was reported as days alive and free (DAF) of vasopressors and invasive ventilation, need of continuous renal replacement therapy (CRRT) and Acute Kidney Injury Network creatinine score (AKIN-crea).RESULTS: 3585 ICU-patients were included. Prolonged APTT correlated with mortality with 95% confidence interval (CI) of hazard ratio 1.001-1.010. Prolonged APTT also correlated with DAF vasopressor, CRRT, and AKIN-crea with 95% CI of odds ratio (OR) 1.009-1.034, 1.016-1.037 and 1.009-1.028, respectively. Increased PT-INR correlated with DAF vasopressor and DAF ventilator with 95% CI of OR 1.112-2.014 and 1.135-1.847, respectively.CONCLUSIONS: APTT prolongation was associated with mortality and all morbidity outcomes except the DAF ventilator. PT-INR increase at admission was associated with DAF vasopressor and DAF ventilator. APTT and PT-INR at admission correlate with morbidity, which is not accounted for in the SAPS 3 model.

Objective To investigate whether intravenous combined with topical administration of tranexamic acid (TXA) is superior to intravenous administration alone in terms of blood loss, incision complications, functional recovery, and pain relief in high tibial osteotomy (HTO). Methods Clinical data of patients with knee osteoarthritis (OA) treated with unilateral HTO were retrospectively reviewed. The patients were grouped according to the TXA administration method, with 24 patients in the combined group and 21 in the solo group. In the combined group, 100 mL saline containing 1 g TXA was intravenously administered before application of a tourniquet, and 20 mL saline containing 2 g TXA was injected through a drainage tube after closure of the incision. Alternatively, 100 mL of saline containing 1 g TXA was intravenously administered before application of a tourniquet in the solo group. The blood loss and adverse events were compared between the two groups. Results All patients were followed for more than half a year. The drainage volume on the first day and total blood loss on the second day after surgery in the combined and single treatment groups were 130.06 ± 29.22 and 165.35 ± 43.08 mL (P

Background/aim There are few studies in the literature evaluating possible alterations in laboratory tests in patients with maxillofacial fractures. The aim of this study was to analyze the changes in admission laboratory tests of patients with maxillofacial fractures with indications for surgical treatment, including the influence of dento-alveolar trauma. Material and methods Data from complete blood counts, blood coagulation tests, blood chemistries, and urinalysis results were obtained. The occurrence of concomitant dento-alveolar trauma was noted. The medical records were also re-evaluated later to verify the treatment outcome and the occurrence of complications. Statistical analyses were performed using the likelihood-ratio test to verify significant changes in the evaluated parameters (P ≤ .050). Results There was a prevalence of males (78%) with a mean age of 35.9 years. Lower erythrocyte counts, hemoglobin levels, and/or hematocrit were observed in males with associated fractures and with simultaneous dento-alveolar fractures. Higher mean neutrophil, segmented neutrophil, and lymphocyte counts were observed in patients with simultaneous dento-alveolar trauma. A higher mean activated partial thromboplastin time (aPTT) ratio was also observed. Lower potassium levels were observed for patients in the fourth decade of life. Higher leukocyte counts not associated with trauma were observed in the urinalysis results of females and in the group of patients aged 20 or younger. Verification of treatment outcome showed two cases of infections and two cases that needed re-operation after mandible fractures. These four cases showed no significant changes in laboratory tests regarding the predisposition for complications. Conclusion Patients with maxillofacial fractures had neutrophilia, increased aPTT, and non-traumatic leukocyturia. There was an influence of associated fractures and dento-alveolar trauma on the decrease in red blood cell parameters, neutrophilia, and lymphocytosis and of age on hypokalemia.

Peripheral artery disease (PAD) is defined as peripheral blood flow impairment, especially in the legs, caused by atherosclerotic stenosis. The disease decreases quality of life because of intermittent claudication or necrosis of the leg. The hindlimb ischaemia model, in which ischaemia is induced by femoral artery ligation, is often utilized as a PAD model. In the hindlimb ischaemia model, nonmetabolic syndrome animals are mainly used. In this study, we investigated the usefulness of Spontaneously Diabetic Torii Leprfa (SDT fatty) rats, a new model for obese type 2 diabetes, as a new PAD animal model. We found that hindlimb blood flow in SDT fatty rats was significantly lower than that in Sprague-Dawley (SD) rats under nonischaemic conditions. Furthermore, SDT fatty rats showed a significantly higher plasma nitrogen oxide level, shorter prothrombin time, and shorter activated partial thromboplastin time than SD rats. In addition, we found that the change in blood flow 7 days after induction of hindlimb ischaemia and the number of Von Willebrand factor-positive vessels in gastrocnemius muscles were significantly lower in SDT fatty rats than in SD rats. These results suggest that excess production of reactive oxygen species and coagulation activation could be involved in lower blood flow in non-ischaemic rats and that decreased angiogenesis could be involved in the poor recovery of blood flow in SDT fatty rats with hindlimb ischaemia. Taken together, our results suggest that SDT fatty rats might be useful as a new model for PAD with metabolic syndrome.

Coronavirus disease 2019, COVID-19, has reached all the corners of the world and was declared by the WHO as a global pandemic and public health emergency of international concern on the January 31, 2020. Allocating quick and specific biomarkers to predict the disease severity upon admission to hospital became a crucial need. This study, therefore, aimed at exploring the relationship between laboratory results in COVID-19 patients admitted to hospital and the final outcome in these patients.Retrospective analysis was performed on the medical records of 310 COVID-19-positive patients admitted to Uhod Hospital, the referral hospital in the area of Madinah, Kingdom of Saudi Arabia, between the April 13 and the July 29, 2020. The association of laboratory results with the survival/mortality outcomes was studied.It was demonstrated that lymphopenia, prolonged aPTT, high INR, high D. dimer and high CK are valuable prognostic predictors of the severity of the disease at early stages that can determine the outcome. Based on the results of the multiple logistic regression, the variables that are associated with death outcome are aPTT, HR, RR, ALT and CK level CONCLUSION: It is proposed to perform these tests on admission to hospital for moderate to severe COVID-19 patients to improve the management of those cases and reduce mortality.

Objective The aim of the present study was to investigate whether an innovative way of administering tranexamic acid (TXA), that is, injecting it retrogradely through the drain and clamping it for 1 h, can reduce postoperative bleeding after degenerative lumbar scoliosis surgery. Methods Sixty degenerative lumbar scoliosis patients who underwent posterior lumbar decompression with fusion of three or more levels were retrospectively enrolled and categorized into three groups (TXA, Gelfoam, and control groups). The demographic distribution, operative parameters, length and amount of Hemovac drainage, blood transfusion rate, length of stay, laboratory results (complete blood count and coagulogram), and the postoperative complications were collected and analyzed. Results The age of patients in the Gelfoam group was significantly younger than in the TXA and control groups (59.75 ± 6.95 vs 66.10 ± 8.80, P = 0.016 and 59.75 ± 6.95 vs 67.90 ± 5.33, P = 0.000, respectively). There were no significant differences in sex, body mass index, comorbid medical status, and operation level between each of the two groups. The three groups did not differ significantly in estimated blood loss during surgery, the mean red blood cell transfusion requirement during hospitalization, and the entire perioperative allogenic blood transfusion rate. The postoperative total blood loss and total drainage were lower in the TXA group than in the control group (1027.14 ± 466.56 vs 1390.07 ± 314.85 mL, P = 0.006; 322.20 ± 187.32 vs 605.50 ± 184.70 mL, P = 0.000, respectively). The length of drainage retention in the TXA group was significantly shorter than in the Gelfoam and control groups (46.10 ± 9.00 vs 68.00 ± 12.31 h, P = 0.000 and 46.10 ± 9.00 vs 76.40 ± 10.97 h, P = 0.000, respectively). The TXA and Gelfoam groups also had significantly shorter hospital stays than the control group (7.50 ± 0.95 vs 9.80 ± 2.44 days, P = 0.000, and 7.90 ± 1.16 vs 9.80 ± 2.44 days, P = 0.003, respectively). At discharge, the mean hemoglobin and hematocrit level were significantly higher in the TXA group compared with the control group (11.77 ± 1.78 g/dL vs 10.67 ± 0.94 g/dL, P = 0.002; 34.82 ± 3.57% vs 31.79 ± 3.85%, P = 0.014). No significant difference was identified with respect to prothrombin time, activated partial thromboplastin time, and D-dimmer among groups (P > 0.05). The three groups were comparable in wound problem incidences. Symptomatic deep vein thrombosis and pulmonary embolism were not observed in this study. Conclusion Topical injection of TXA retrogradely via a drain at the end of a degenerative lumbar scoliosis operation and clamping the drain for an hour can effectively decrease the postoperative blood loss and the length of hospitalization without increasing the complication rate.

Coagulopathic bleeding during and after cardiac surgery is associated with increased morbidity and mortality. Viscoelastic testing is increasingly used instead of laboratory testing. Our aim was to compare a new viscoelastic point-of-care device, the Quantra® System, with thromboelastography and standard laboratory testing. After ethical approval and with written informed consent, we prospectively recruited adult patients undergoing urgent cardiac surgery at increased risk of bleeding. Clot time and clot stiffness values were compared before, during and after cardiopulmonary bypass. We prospectively recruited 52 patients, of whom 34 (65%) were transfused with red blood cells. Our usual transfusion thresholds for fibrinogen (1.5 g.l-1 ), platelets (100,000.μl-1 ), prothrombin time (20 s), activated partial thromboplastin time (48 s) and maximum amplitude on thromboelastography (50 mm) corresponded to Quantra values of fibrinogen clot stiffness 2.0 hPa, platelet clot stiffness 13.5 hPa, clot time 159 s, clot time 183 s and clot stiffness 17.0 hPa, respectively. These Quantra thresholds showed high negative predictive value for low platelets (platelet clot stiffness, 97.4%), prolonged activated partial thromboplastin time (clot time, 92.6%) and reduced maximum amplitude on thromboelastography (clot stiffness, 93.6%). The Quantra predicted clinical need for transfusion of platelets (area under the curve 0.71, p = 0.001) but all tests performed poorly at predicting the need for fresh frozen plasma transfusion. We have shown that point-of-care testing using the novel Quantra system provides useful data for guiding transfusion management.

Introduction Interference on biological assays due to hemolysis, icterus, or lipemia (HIL) could represent a significant source of analytical errors leading to inaccurate interpretation of results. The aim of this study was to assess the HIL interference on prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen, using mechanical and optical detection methods. Methods Control plasmas and plasmas from patients treated with vitamin K antagonists or unfractionated heparin, with or without HIL, were performed on two analytical detection systems in order to identify potential analytical biases. Whether HIL lead to significant biological interferences was also evaluated, and a cutoff point for HIL-induced analytical bias was determined. Results Hemolysis influenced PT and aPTT when hemoglobin was at 5 and 1.5 g/L in plasma, respectively. At 1.8 g/L, a positive relationship was found between the bias and the hemoglobin supernatant level only for fibrinogen measurement, using optical detection. For icteric interference, no significant bias was observed until a bilirubin concentration of 30 mg/dL. Lipamia (>500 mg/dL) led to analytical interference when using the optical analyzer. Conclusion The present study detected analytical interferences such as lipemia (>500 mg/dL) on coagulation tests on the optical analyzer. We also found a biological impact on the results in case of hemolyzed sample: Fibrinogen was decreased when the hemoglobin level was superior to 1.8 g/L, PT was prolonged beyond 5 g/L, and aPTT was shortened beyond 1.5 g/L hemoglobin concentration, especially in patients treated with heparin. Above these thresholds, it is important not to give results that could influence the clinical decision.

Introduction The one‐stage clotting assay is used to measure factor IX (FIX) activity in patients’ plasma samples and in FIX products for hemophilia treatment. However, the diversity of reagents and instruments has resulted in significant FIX assay variability. Methods The accuracy of the one‐stage clotting assay to measure recombinant FIX Fc fusion protein (rFIXFc) activity was evaluated by major Japanese hemophilia treatment centers and commercial laboratories that measure factor IX activity for a majority of hemophilia B patients in Japan. Plasma‐derived FIX (pdFIX) and recombinant FIX (rFIX) products were used as comparators. FIX‐deficient plasma was spiked with four levels of FIX products based on label potency and measured under blinded conditions by routine one‐stage clotting assay procedures in 19 participating laboratories. Interlaboratory coefficient of variation and spike recovery were calculated. Results Interlaboratory coefficient of variation of rFIXFc was not significantly different from that of rFIX, but appeared larger than that of pdFIX. Mean spike recovery for rFIXFc was generally comparable to rFIX and pdFIX. However, larger discrepancies between pdFIX and rFIX were observed in three of nine laboratories using ellagic acid‐based activated partial thromboplastin time reagents. Conclusion Recombinant FIX Fc fusion protein activity was found to be similar to that of rFIX or pdFIX by the one‐stage clotting assay. However, minimizing interlaboratory variability is vital for optimizing future patient care.

Factor replacement therapy with factor VIII (FVIII) concentrates is the current standard of care for patients with haemophilia A. Postadministration monitoring of FVIII activity during on‐demand or prophylactic treatment is important, for example to guide a suitable dosing regimen. While the use of two‐stage chromogenic substrate (CS) assays is increasing, activated partial thromboplastin time (APTT)‐based one‐stage clotting (OSC) assays are most commonly used to measure FVIII activity in clinical laboratories. Substantial variations in activity measurements have been observed in association with some OSC assay reagents when assessing extended half‐life FVIII molecules. Certain silica‐based APTT reagents have previously been shown to underestimate FVIII activity with the polyethylene glycol (PEG)‐conjugated product turoctocog alfa pegol (N8‐GP [ESPEROCT®]; Novo Nordisk A/S). As a wide range of assay reagents are used in clinical laboratories worldwide, it is essential to establish which can be used to accurately measure activity with modified FVIII concentrates. Here, we describe the approach taken by Novo Nordisk to determine the suitability and accuracy of assays and reagents to measure FVIII activity in samples that contain N8‐GP. While accurate activity measurements were possible with all tested CS assays and most of the OSC APTT reagents tested, three APTT reagents that contain silica as a contact activator were found to underestimate N8‐GP recovery (APTT‐SP, TriniCLOT™, STA® PTT‐Automate). The data demonstrate the importance of characterizing the accuracy of each FVIII activity assay. Any limitations should be communicated to treating physicians and the clinical laboratories that test samples containing N8‐GP.

Introduction Patients with COVID‐19 frequently exhibit a hypercoagulable state with high thrombotic risk, particularly those admitted to intensive care units (ICU). Thromboprophylaxis is mandatory in these patients; nevertheless, thrombosis still occurs in many cases. Thus, the problem of assessing an adequate level of anticoagulation in ICU patients becomes evident during the COVID‐19 pandemic. The aim of this study was to evaluate the heparin resistance and the efficacy of heparin monitoring using an anti‐Xa activity assay. Methods Thirty‐seven heparin‐treated patients admitted to ICU for SARS‐CoV‐2 pneumonia were retrospectively studied for antifactor Xa activity (anti‐Xa), activated partial thromboplastin time (APTT), Antithrombin, Fibrinogen, D‐Dimer, Factor VIII, von Willebrand Factor, and the total daily amount of heparin administered. The correlation between APTT and anti‐Xa was evaluated for unfractionated heparins (UFH). The correlations between the daily dose of UFH or the dosage expressed as IU/kg b.w. for low molecular weight heparin (LMWH) and anti‐Xa were also evaluated. Results Twenty‐one patients received calcium heparin, 8 sodium heparin, and 8 LMWH. A moderate correlation was found between APTT and anti‐Xa for UFH. APTT did not correlate with coagulation parameters. 62% of UFH and 75% of LMWH treated patients were under the therapeutic range. About 75% of patients could be considered resistant to heparin. Conclusions SARS‐COV2 pneumonia patients in ICU have frequently heparin resistance. Anti‐Xa seems a more reliable method to monitor heparin treatment than APTT in acute patients, also because the assay is insensitive to the increased levels of fibrinogen, FVIII, and LAC that are common during the COVID‐19 inflammatory state.

Background At present, SARS‐CoV‐2 epidemic in the world rapidly spread. It is a serious global public health emergency. Methods In this study, we described the clinical characteristics of 11 COVID‐19 patients hospitalized in the Meizhou People's Hospital, and viral genome sequences of SARS‐CoV‐2 from these patients were analyzed. Results Of the 11 patients, six cases developed fever, 9 cases developed a cough, and two cases developed headache and chills. Four patients (36.4%) had underlying diseases. Pneumonia is the most common complication. The laboratory test results showed that there were no adult patients with increased lymphocyte/lymphocyte percentage (LYM/LYM%). Most patients had normal total protein (TP) and albumin (ALB), but only two patients had decreased. Most patients had increased or normal levels of erythrocyte sedimentation rate (ESR), C reactive protein (CRP), activated partial thromboplastin time (APTT), fibrinogen (FIB), creatine kinase isoenzymes (CK‐MB), and lactate dehydrogenase (LDH). Neutrophil (NEU) (r = 0.664, p = 0.026), CK‐MB (r = 0.655, p = 0.029) and blood urea nitrogen (BUN) (r = 0.682, p = 0.021) were significantly associated with SARS‐CoV‐2 virus cycle threshold (Ct) value. Multiple sequence alignment (MSA) shows that two different SNPs were identified at positions 8781 and 28144, and have a complete linkage genetic form of 8781C‐28144T and 8781T‐28144C. Conclusions The reports of the 11 COVID‐19 patients in our hospital will provide useful information for the diagnosis, treatment, and drug development of SARS‐CoV‐2., SARS‐CoV‐2 epidemic in the world rapidly spread. It is a serious global public health emergency. We described the clinical characteristics of 11 SARS‐CoV‐2 infected patients hospitalized in the Meizhou People's Hospital. And viral genome sequences of SARS‐CoV‐2 from these patients were analyzed. Neutrophil (NEU) (r = 0.664, p =0.026), creatine kinase isoenzymes (CK‐MB) (r = 0.655, p = 0.029), blood urea nitrogen (BUN) (r = 0.682, p = 0.021) and SARS‐CoV‐2 virus cycle threshold (Ct) value were significantly correlated. Multiple sequence alignment (MSA) shows that we identified two different SNPs at positions 8781 and 28144, and have a completely linked genetic form of 8781C‐28144T and 8781T‐28144C. The reports of these cases in our hospital will provide useful information for the diagnosis, treatment and drug development of SARS‐CoV‐2.