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This study evaluated the effects of sugammadex at conventional doses of 2 and 4 mg/kg on the coagulation profile by analyzing thromboelastographic parameters and performing a traditional laboratory coagulation analysis. A total of 100 patients undergoing arthroscopic shoulder surgery were enrolled. The patients were randomly divided into the 2 mg and 4 mg groups. The laboratory coagulation test and thromboelastographic analysis were performed before and 15 min after administering sugammadex. Prothrombin time (PT) was significantly prolonged after sugammadex administration than before it in intragroup comparisons of the 2 mg group (12.8 ± 0.6 s vs. 13.6 ± 0.7 s, p  < 0.001) and the 4 mg group (13.0 ± 0.5 s vs. 13.7 ± 0.5 s, p  < 0.001). R time, derived from thromboelastography, was also significantly prolonged after sugammadex administration (4.7 ± 1.8 min vs. 5.8 ± 2.1 min, p  = 0.005). In conclusion, the conventional doses of 2 or 4 mg/kg sugammadex prolonged PT. Sugammadex 4 mg/kg also prolonged R time, although the value was within the normal range. Therefore, physicians should be cautious with the higher sugammadex dose, particularly in patients with a high risk of bleeding because the higher dose was associated with less coagulation. Trial registration : KCT0002133 ( https://cris.nih.go.kr ).

Guidelines suggest restarting warfarin at known maintenance doses, although this may result in a delay to achieving therapeutic anticoagulation. As such, we compared the time to achieve an INR ≥ 2.0 between those restarting warfarin maintenance vs loading doses after transient interruption, and the impact on protein C, S and factor II levels. Patients requiring interruption of warfarin for elective procedures without hospitalization were randomized 1:1 to receive warfarin maintenance or loading doses (1.5 times the maintenance dose for 3 days followed by pre-procedural warfarin maintenance dosing). Protein C, S and Factor II were drawn at baseline (prior to warfarin interruption), 7 and 14 days after restarting warfarin. Among 19 patients randomized to maintenance and 20 to loading doses, nearly half in each group had mechanical heart valves with gastrointestinal endoscopic procedures most commonly performed (41%). The median number of days to reach an INR ≥ 2.0 was 7.8 days in the loading and 9.0 in the maintenance group (difference between medians 1.2 days, 95% CI −3.1 to 4.9; P = 0.19). Although levels of protein C, S and factor II were lower in the loading vs maintenance dose group, all remained above that of baseline. Warfarin resumption with loading doses shortened the time to achieve a therapeutic INR by a median of 1.2 days. Prompt warfarin dose escalation should be done in response to the INR. Protein C and S remained above pre-warfarin interruption levels, implying a lack of depletion with restarting warfarin.

Background The aim was to compare the peri-procedural biomarkers of coagulation and platelet activation in patients randomly allocated to intravenous enoxaparin or unfractionated heparin (UFH) in the ATOLL randomized trial (NCT00718471). Methods and Results A total of 129 patients ( n  = 58 enoxaparin and n  = 71 UFH) admitted for ST-segment elevation myocardial infarction (STEMI) treated by percutaneous coronary intervention (PCI) were included in this substudy of the ATOLL trial. Activated partial thromboplastin time ratio, anti-Xa activity, von Willebrand factor antigen, prothrombin fragment 1 + 2 (F1 + 2), thrombin–antithrombin complex (TAT), tissue factor pathway inhibitor and soluble CD40 ligand were measured at sheath insertion (T1) and at the end of the PCI (T2) and correlated with 1-month clinical outcomes. Target anticoagulation levels at T2 were more readily achieved in patients receiving enoxaparin compared to those receiving UFH (80.3 vs 18.2%, p  < 0.0001). Increased levels of F1 + 2 and TAT measured at T2 were associated with the incidence of the composite ischemic endpoint ( p  = 0.04 and p  = 0.03) and all-cause mortality ( p  < 0.0001 and p  = 0.002). Release of F1 + 2 between T1 and T2 also predicted the composite ischemic endpoint (312 ± 513 vs 37 ± 292, p  = 0.04) and net clinical outcome (185 ± 405 vs 3.2 ± 278, p  = 0.03). Conclusions During primary PCI, enoxaparin achieved therapeutic levels more frequently than UFH. Higher level of thrombin generation measured at the end of the PCI procedure was associated with more frequent ischemic events.

Early detection of hepatocellular carcinoma (HCC) among hepatitis B virus (HBV)-infected patients remains a challenge, especially in China. We sought to create an online calculator of serum biomarkers to detect HCC among patients with chronic hepatitis B (CHB). Participants with HBV-HCC, CHB, HBV-related liver cirrhosis (HBV-LC), benign hepatic tumors, and healthy controls (HCs) were recruited at 11 Chinese hospitals. Potential serum HCC biomarkers, protein induced by vitamin K absence or antagonist-II (PIVKA-II), α-fetoprotein (AFP), lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3) and α-l-fucosidase (AFU) were evaluated in the pilot cohort. The calculator was built in the training cohort via logistic regression model and validated in the validation cohort. In the pilot study, PIVKA-II and AFP showed better diagnostic sensitivity and specificity compared with AFP-L3 and AFU and were chosen for further study. A combination of PIVKA-II and AFP demonstrated better diagnostic accuracy in differentiating patients with HBV-HCC from patients with CHB or HBV-LC than AFP or PIVKA-II alone [area under the curve (AUC), 0.922 (95% CI, 0.908-0.935), sensitivity 88.3% and specificity 85.1% for the training cohort; 0.902 (95% CI, 0.875-0.929), 87.8%, and 81.0%, respectively, for the validation cohort]. The nomogram including AFP, PIVKA-II, age, and sex performed well in predicting HBV-HCC with good calibration and discrimination [AUC, 0.941 (95% CI, 0.929-0.952)] and was validated in the validation cohort [AUC, 0.931 (95% CI, 0.909-0.953)]. Our results demonstrated that a web-based calculator including age, sex, AFP, and PIVKA-II accurately predicted the presence of HCC in patients with CHB. NCT03047603.

The aim of our study was to analyse inherited thrombotic disorders that influence the long-term outcome of PTA. Methods. Diabetic patients with peripheral arterial disease (PAD) treated by PTA in our centre between 2008 and 2011 were included in the study. Patients were divided into unsuccessful PTA group (75 patients), successful PTA group (58 patients), and control group (65 patients, with diabetes but no PAD). Diagnosis of inherited thrombotic disorders included mutation in factor V (Leiden), factor II (prothrombin), and mutation in genes for methylenetetrahydrofolate reductase—MTHFR (C677T and A1298C). Results. The genotypic frequency of Leiden allele G1691A was significantly associated with a risk of unsuccessful PTA in comparison with successful PTA group and control group (OR 8.8 (1.1–70.6), p=0.041, and OR 9.8 (1.2–79.2), p=0.032, resp.). However, we only observed a trend for the association of the prothrombin allele G20210A and risk of PTA failure. The frequencies of alleles of MTHFR 677 or 1298 did not differ significantly among the groups. Conclusion. Our study showed higher frequency of heterozygous form of Leiden mutation in diabetic patients with unsuccessful outcome of PTA in comparison with patients with successful PTA and diabetic patients without PAD.

Background and Objective Genetic polymorphisms of cytochrome P450 (CYP) 2C9 ( CYP2C9 ) and vitamin K epoxide reductase complex subunit 1 ( VKORC1 ) and patient demographic characteristics are responsible for inter-individual differences in warfarin maintenance dosage requirements. At present, however, the factors associated with over-anticoagulation responses, especially before achieving the maintenance phase, have not been completely clarified. In this study, we investigated the effects of baseline coagulation activity assessed in terms of the level of fully carboxylated plasma normal prothrombin (NPT) on international normalized ratio (INR) control during the induction phase of warfarin therapy. Our objectives were to (1) identify factors associated with inter-patient variability in baseline NPT (NPT 0 ); (2) estimate the therapeutic NPT (NPT tx ) levels that can achieve an INR of 2–3; and (3) investigate the influence of NPT 0 on the INR response to warfarin by employing modelling and simulation techniques. Methods We measured NPT before (NPT 0 ) and during the introduction of warfarin therapy for up to 3 months and analysed functional single nucleotide polymorphisms (SNPs) of VKORC1 and CYP4F2 in 179 Chinese patients. The patients were classified into tertile groups according to NPT 0 values (i.e. high, intermediate and low groups), and in each group the NPT tx achieving therapeutic INR, the absolute reduction of NPT from NPT 0 to NPT tx , and the percentage inhibition of NPT 0 [{(NPT 0  − NPT tx )/NPT 0 } × 100] were obtained. The nonlinear relationship between NPT and INR was modelled on the basis of the INR value before warfarin treatment (INR 0 ) added by the nonlinear increase in INR after warfarin initiation, which was predicted using the percentage inhibition of NPT 0 and a nonlinear coefficient (λ). The population parameter λ and its inter-individual variability and intra-individual variability in INR in the NPT–INR model were estimated by nonlinear mixed-effect modelling software NONMEM ® . Results Multivariate analysis identified age and liver disease as covariates of NPT 0 , but none of the SNPs had a significant influence. Although the mean absolute NPT reduction necessary to achieve NPT tx was dependent on NPT 0 (i.e. the higher the NPT 0 , the larger the reduction in NPT), the percentage inhibition was within the narrow range of 67–72 % of NPT 0 , irrespective of NPT 0 . However, a significantly higher percentage inhibition (80 % on average) was observed in patients with INR values exceeding 4.0. As the nonlinear coefficient λ in the developed model was dependent on NPT 0 (i.e. the higher the NPT 0 , the larger the nonlinear λ value), the simulated nonlinear NPT–INR curves were superimposable in the three respective NPT 0 groups, and the only difference was the starting median NPT 0 level. As a result, a steeper increase in the slope of the nonlinear NPT–INR curve might be expected in patients with a lower NPT 0 after initiation of warfarin. Conclusions The present study suggests that INR may be prolonged by warfarin nonlinearly as a function of the percentage inhibition of NPT 0 . Furthermore, these results indicate that NPT 0 may contribute to inter-individual variability in the INR response, and that patients with low NPT 0 may have the potential to show a sharp increase in INR during initiation therapy with warfarin.

Venous thromboembolism is a relevant social and health care problem because of its high incidence among patients who undergo surgery (20-30% after general surgical operations and 50-75% after orthopedic procedures), its pulmonary embolism-related mortality rate, and its long-term sequelae (postthrombotic syndrome and ulceration), which may be disabling. This study aimed to determine the coagulation status and the presence of postoperative deep vein thrombosis (DVT) in patients undergoing laparoscopic (LC) and open cholecystectomy (OC). Prospectively, 114 patients were randomized into two groups. group 1 (58 patients undergoing LC) and group 2 (56 patients who are undergoing OC). The coagulation parameters (prothrombin time [PT], partial thromboplastin time [PTT], D-dimer, prothrombin F1 + 2, antithrombin III, and factor VII) were monitored preoperatively and during the operation, then 24 and 72 h after the operation. The patients in both groups underwent color duplex scan examination preoperatively, then 3 and 7 days after surgery to establish the presence of DVT. None of the patients in either group received thrombosis prophylaxis. In the LC group, postoperative DVT developed in four patients (6.9%; in the calf veins of 3 patients and in the popliteal vein of 1 patient). In the OC group, nine patients (16.07%) had postoperative DVT (in the calf veins of 7 patients and in the popliteal and femoral veins of 2 patients). The plasma levels of monitored parameters in the patients of both groups were altered, but the difference between the groups was not statistically significant. For the patients in both groups who experienced DVT, only the decrease of factor VII had statistical significance (p < 0.05). The incidence of postoperative DVT among the patients who underwent OC was higher than among the patients who underwent LC (p < 0.05). The decrease in factor VII among the patients who underwent surgery could be a potentially useful parameter indicating the patients at high risk for developing DVT.

Coagulation system is heavily involved into the process of infective endocarditis (IE) vegetation formation and can facilitate further embolization. In this study we aimed to assess the coagulation and platelet state in IE implementing a wide range of standard and global laboratory assays. We also aim to determine whether prothrombotic genetic polymorphisms play any role in embolization and mortality in IE patients. 37 patients with IE were enrolled into the study. Coagulation was assessed using standard coagulation assays (activated partial thromboplastin time (APTT), prothrombin, fibrinogen, D-dimer concentrations) and integral assays (thromboelastography (TEG) and thrombodynamics (TD)). Platelet functional activity was estimated by flow cytometry. Single nuclear polymorphisms of coagulation system genes were studied. Fibrinogen concentration and fibrinogen-dependent parameters of TEG and TD were increased in patients indicating systemic inflammation. In majority of patients clot growth rate in thrombodynamics was significantly shifted towards hypercoagulation in consistency with D-dimers elevation. However, in some patients prothrombin, thromboelastography and thrombodynamics were shifted towards hypocoagulation. Resting platelets were characterized by glycoprotein IIb-IIIa activation and degranulation. In patients with fatal IE, we observed a significant decrease in fibrinogen and thrombodynamics. In patients with embolism, we observed a significant decrease in the TEG R parameter. No association of embolism or mortality with genetic polymorphisms was found in our cohort. Our findings suggest that coagulation in patients with infective endocarditis is characterized by general hypercoagulability and platelet pre-activation. Some patients, however, have hypocoagulant coagulation profile, which presumably can indicate progressing of hypercoagulation into consumption coagulopathy.

Human endothelial cells (ECs) synthesize, store, and secrete von Willebrand factor multimeric strings and coagulation factor (F) VIII. It is not currently known if ECs produce other coagulation factors for active participation in coagulation. We found that 3 different types of human ECs in primary culture produce clotting factors necessary for FX activation via the intrinsic (FVIII-FIX) and extrinsic (tissue factor [TF]-FVII) coagulation pathways, as well as prothrombin. Human dermal fibroblasts were used as comparator cells. TF, FVII, FIX, FX, and prothrombin were detected in ECs, and TF, FVII, FIX, and FX were detected in fibroblasts. In addition, FVII, FIX, FX, and prothrombin were detected by fluorescent microscopy in EC cytoplasm (associated with endoplasmic reticulum and Golgi proteins). FX activation occurred on human umbilical vein EC surfaces without the addition of external coagulation proteins, proteolytic enzymes, or phospholipids. Tumour necrosis factor, which suppresses the generation of activated protein C and increases TF, augmented FX activation. Fibroblasts also produced TF, but (in contrast to ECs) were incapable of activating FX without the exogenous addition of FX and had a marked increase in FX activation following the addition of both FX and FVII. We conclude that human ECs produce their own coagulation factors that can activate cell surface FX without the addition of exogenous proteins or phospholipids.

Background and Objectives: Thrombophilia is a prothrombotic disorder that increases the risk of blood clotting and can pose serious health problems. It is considered a condition of gene–gene or gene–environment interactions. Variation in the prevalence of thrombophilia mutations and their interaction among populations necessitates localized genetic assessments. However, population-based genetic data remains limited for developing effective preventive strategies. Materials and Methods: This cross-sectional observational study was conducted over five years (2020–2024) at a tertiary university hospital in Northern Greece. A total of 2961 individuals aged 18–85 years (mean: 50.5) were registered based on family or medical history of venous thromboembolism (VTE) or clinical symptoms of VTE. The final analysis included 2078 participants comprising 1143 males (55%) and 935 females (45%), who met all the inclusion criteria. Inclusion criteria were absence of acute illness or malignancy, informed consent, and an adequate DNA quantity for genotyping, whereas excluded criteria included incomplete laboratory data, active inflammatory or malignant disease, and cognitive or psychiatric conditions. Peripheral blood samples were collected in 2 mL K3-EDTA tubes, and genomic DNA was analyzed using real-time polymerase chain reaction (PCR) with melting curve analysis and hybridization probes (LightMix® in vitro diagnostics, TIB MolBiol, Berlin, Germany). Five thrombophilia-related polymorphisms, Factor V Leiden (F5 G1691A), prothrombin (F2 G20210A), methylenetetrahydrofolate reductase (MTHFR C677T and MTHFR A1298C), and Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G, were examined for allele and genotype frequencies, Hardy–Weinberg equilibrium testing, pairwise linkage disequilibrium (D′ and r2), and power analysis. For subjects tested for Factor V Leiden (n = 1476), the activated protein C resistance (APC) ratio was additionally evaluated using the ACL TOP 750 analyzer. Results: Allele frequencies were 7.3% for FV Leiden and 3.7% for FII. The PAI-1 allele was distributed at 44%, while the MTHFR (C677T and A1298C) alleles were each present at 33%. Significant linkage disequilibrium was identified between MTHFR (C677T and A1298C) and between MTHFR A1298C and PAI-1. No evolutionary pressure or demographic bias was found in the Hardy–Weinberg equilibrium. The APC ratio demonstrated a high sensitivity (99.2%) and specificity (96.6%), indicating that it may serve as a reliable screening method. Conclusions: Our findings highlight informative patterns in the genetic predisposition to thrombophilia, which may help develop rule-based strategies for implementing thromboprophylaxis guidelines and personalized medical interventions.