TAT Levels Research Articles

Decreased Protein C Pathway Activity in COVID-19 Compared to Non-COVID Sepsis: An Observational and Comparative Cohort Study.

Sepsis-associated coagulopathy increases risk of mortality. Impairment of the anticoagulant protein C (PC) pathway may contribute to the thrombotic phenotype in coronavirus disease 2019 (COVID-19) sepsis. This study assessed the functionality of this pathway in COVID-19 and non-COVID sepsis by measuring its key enzymes, thrombin and activated PC (APC). The study population included 30 patients with COVID-19, 47 patients with non-COVID sepsis, and 40 healthy controls. In healthy controls, coagulation activation and subsequent APC formation was induced by 15 µg/kg recombinant activated factor VII one hour before blood sampling. APC and thrombin in plasma were measured using oligonucleotide-based enzyme capture assays. The indirect thrombin markers prothrombin-fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) were also measured. Compared with stimulated healthy controls, median thrombin, F1+2, and TAT levels were higher in patients with COVID-19 (up to 6-fold, p < 2 × 10-6) and non-COVID sepsis (up to 4.7-fold, p < 0.010). APC levels were 2.4-fold higher in patients with COVID-19 (7.44 pmol/L, p = 0.011) and 3.4-fold higher in non-COVID sepsis patients (10.45 pmol/L, p = 2 × 10-4) than in controls (3.08 pmol/L). Thrombin markers and APC showed correlation in both COVID-19 (r = 0.364-0.661) and non-COVID sepsis patients (r = 0.535-0.711). After adjustment for PC levels, median APC/thrombin, APC/F1+2, and APC/TAT ratios were 2-fold (p = 0.036), 6-fold (p = 3 × 10-7) and 3-fold (p = 8 × 10-4) lower in the COVID-19 group than in the non-COVID sepsis group, and the latter two were also lower in the COVID-19 group than in stimulated healthy controls. In conclusion, it was found that a comparatively lower anticoagulant APC response in COVID-19 patients as compared to non-COVID sepsis patients, potentially linked to endothelial dysfunction, contributes to the prothrombotic phenotype of COVID-19 sepsis.

Fibrinogen dysfunction and fibrinolysis state in patients with hepatitis B-related cirrhosis

ABSTRACT Objective To assess the fibrinogen function in patients with hepatitis B-related cirrhosis and explore the relationship between dysfibrinogenemia and bleeding and thrombotic events. Methods Medical records and laboratory data of the patients with hepatitis B-related cirrhosis were collected. Patients were categorized into three groups based on the Child-Pugh score. Fibrinogen activity and antigen, fibrinogen-bound sialic acid (FSA), fibrinogen polymerization and fibrinolysis kinetic analysis, thrombin-antithrombin complex (TAT) and plasmin-α2-antiplasmin complex (PAP) were detected. Results Eighty patients with seventeen, thirty-eight and twenty-five in Child-Pugh A, B and C, respectively, were included. Seventeen patients experienced bleeding events and eight patients had thrombotic events. Fibrinogen activity and antigen levels were reduced with the severity of cirrhosis. Twenty-two patients exhibited dysfibrinogenemia. The FSA levels in patients with non-dysfibrinogenemia and those with dysfibrinogenemia were increased to 1.25 and 1.37 times of healthy controls, negatively correlated with fibrinogen activity (ρ = −0.393, p = 0.006). Compared to healthy controls, the amount of clot formation was reduced (p < 0.001), the polymerization was delayed (p < 0.001) and the rate of fibrinolysis was reduced (p < 0.001). The TAT levels were significantly increased in the Child-Pugh C patients compared to the Child-Pugh B patients (p = 0.032) while the PAP levels were comparable among 3 groups (p = 0.361). Conclusion Sialylation of fibrinogen is one of the main causes of modifications of fibrinogen in patients with hepatitis B-related cirrhosis. The polymerization and fibrinolysis functions of fibrinogen are impaired. The degree of impaired fibrinolysis function is more severe than that of polymerization function, and may be partly related to the occurrence of thrombotic events.

The Effect of Dialysis Membranes on Coagulation Activation during Haemodialysis of Maintenance Haemodialysis Patients

Abstract Background Platelets, leukocytes, and the coagulation cascade are activated during hemodialysis. During hemodialysis, systemic anticoagulation is used to prevent clotting of the extracorporeal circuit which may lead either to complete clotting to the degree that prevent blood return to the patient or to a lesser extent can only affect the dialyzer membrane fibers which will decrease the effective surface area and that will decrease the session efficacy Aim of the Work The aim of the current study was to evaluate contact system activation and overall coagulation activation during in vivo hemodialysis in prevalent hemodialysis patients, using current generation dialyzer membranes. A crossover study design allowed assessment of differences among regular dialyzer membranes. Patients and Methods We performed a single-center sequential interventional clinical trial study. Twenty patients older than 18 years and treated with maintenance hemodialysis (&amp;gt;3 months) underwent 2 hemodialysis study sessions at Ain Shams University hospitals dialysis unit. Exclusion criteria were clopidogrel or anticoagulant therapy, active infection, presence of central venous catheter or arteriovenous graft and known vascular access dysfunction. Results The increase of TAT at 240 minutes after dialysis start in our study, irrespective of the dialyzer membrane used, suggests a late-onset threshold for thrombin generation, which is well before the treatment effect of the UFH is expected to have faded. The changes in TAT dynamics are in line with previously published results. Dialysis treatments were standardized except for dialyzer membrane. Hence, the differences between membranes are most likely due to differences in physicochemical characteristics. Whether these differences are clinically meaningful needs further study. Analysis costs and the exploratory set-up of the trial drove the small sample size and design of the study. A more comprehensive evaluation of the coagulation activation over a longer time period of hemodialysis treatment would be of interest. Conclusion Driven by the recent interest in the therapeutic options of specific contact system inhibitors, we aimed to evaluate contact system activation during in vivo he-modialysis. Chronic hemodialysis patients dialyzed through arteriovenous dialysis access show coagulation activation during hemodialysis, marked by increased TAT levels, despite using systemic anticoagulation to prevent macroscopic clotting of the extracorporeal circuit. The increase in thrombin generation markers was not associated with measurable contact system activation. Our results argue against effective contact system activation during hemodialysis and generate the hypothesis that novel specific contact system inhibitors alone might not suffice as anticoagulant treatment during hemodialysis.

Nanoparticle delivery of Tat synergizes with classical latency reversal agents to express HIV antigen targets.

Limited cellular levels of the HIV transcriptional activator Tat are one contributor to proviral latency that might be targeted in HIV cure strategies. We recently demonstrated that lipid nanoparticles containing HIV tat mRNA induce HIV expression in primary CD4 T cells. Here, we sought to further characterize tat mRNA in the context of several benchmark latency reversal agents (LRAs), including inhibitor of apoptosis protein antagonists (IAPi), bromodomain and extra-Terminal motif inhibitors (BETi), and histone deacetylase inhibitors (HDACi). tat mRNA reversed latency across several different cell line models of HIV latency, an effect dependent on the TAR hairpin loop. Synergistic enhancement of tat mRNA activity was observed with IAPi, HDACi, and BETi, albeit to variable degrees. In primary CD4 T cells from durably suppressed people with HIV, tat mRNA profoundly increased the frequencies of elongated, multiply-spliced, and polyadenylated HIV transcripts, while having a lesser impact on TAR transcript frequencies. tat mRNAs alone resulted in variable HIV p24 protein induction across donors. However, tat mRNA in combination with IAPi, BETi, or HDACi markedly enhanced HIV RNA and protein expression without overt cytotoxicity or cellular activation. Notably, combination regimens approached or in some cases exceeded the latency reversal activity of maximal mitogenic T cell stimulation. Higher levels of tat mRNA-driven HIV p24 induction were observed in donors with larger mitogen-inducible HIV reservoirs, and expression increased with prolonged exposure time. Combination LRA strategies employing both small molecule inhibitors and Tat delivered to CD4 T cells are a promising approach to effectively target the HIV reservoir.

Predictive value of thrombin-antithrombin III complex and tissue plasminogen activator-inhibitor complex biomarkers in assessing the severity of early-stage acute pancreatitis.

The development of acute pancreatitis (AP) is strongly linked to blood clotting and fibrinolysis issues. Modern clinical practices now utilize advanced blood markers like thrombin-antithrombin III complex (TAT), plasmin-α2-plasmin inhibitor complex, thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) to assess thrombosis risk. Our study used a highly sensitive chemiluminescence technique to measure these markers in AP patients, aiming to determine their early predictive value for AP severity. There were 173 patients with AP, all of whom developed symptoms within 72h; 102 individuals had onset symptoms within 48h. The biomarkers were measured upon admission before determining the severity of AP. The levels of TAT, plasmin-α2-plasmin inhibitor complex, TM, and t-PAIC were significantly higher in the severe acute pancreatitis (SAP) group compared with the mild acute pancreatitis and moderate severe acute pancreatitis groups. For the patients within 72h of onset, TAT, TM, and t-PAIC predicted the occurrence of SAP. For the patients within 48h of onset, TAT and t-PAIC predicted the occurrence of SAP. The area under the curve (AUC) of prediction models is similar to Bedside Index for Severity in Acute Pancreatitis (BISAP) but significantly higher than C-reactive protein (P<0.05). Notably, t-PAIC had a larger AUC than TAT, BISAP, and C-reactive protein. In the initial 48h, plasma TAT and t-PAIC levels may predict the development of SAP. Within 72h, plasma levels of TAT, TM, and t-PAIC may predict the development of SAP, and the TAT+TM+t-PAIC prediction model achieved a maximum AUC of 0.915, comparable to BISAP.

Coagulation and fibrinolytic markers offer utility when distinguishing between benign and malignant gallbladder tumors: A cross-sectional study

BackgroundThe metabolic or proliferative abnormalities that are characteristic of tumor cells can lead to abnormal fibrinolysis or coagulation system activity, with certain tumors exhibiting hypercoagulability or existing in a fibrinolytic state. However, the utility of biomarkers of coagulation and fibrinolysis when seeking to differentiate between benign gallbladder disease and malignant gallbladder tumors remains uncertain. MethodsThis study included a total of 81 patients with benign gallbladder polyps and 94 patients with malignant gallbladder tumors. Pre-biopsy or pretreatment levels of PT, APTT, FIB, D-dimer, FDP, PLT, PIC, TAT, TM, and t-PAIC from these patients were compared using Mann-Whitney tests. The baseline data of the patients were analyzed using chi-square tests, and the diagnostic utility of these biomarkers in distinguishing between benign and malignant gallbladder lesions was evaluated using ROC curves, and Spearman correlation analysis was employed to assess the correlation between these indicators and tumor parameters. ResultsThe average age of malignant gallbladder tumor group was higher than benign gallbladder polyp group. And the base line analysis showed that there was a statistic difference in age, history of smoking, drinking, biliary tract disease, BMI of over weight between these two groups. In patients with malignant gallbladder tumors, FIB, D-dimer, FDP, PIC, TAT, TM, and t-PAIC levels were significantly elevated relative to those in patients affected by benign gallbladder polyp. The AUC for FIB, D-dimer, and FDP was 0.8469, 0.6514, 0.5950, while for PIC, TAT, TM, t-PAIC and four biomarker combined diagnosed was 0.8455, 0.6554, 0.7130, 0.6806, and 0.8859. Among these, TM was associated with the vascular invasion of tumor patients; TAT and t-PAIC were associated with neural invasion; D-dimer and FDP were related to the maximum tumor diameter; and FDP had a certain correlation with the tumor stage. ConclusionsIn gallbladder tumor patients, conventional coagulation metrics like FIB, D-dimer, and FDP, as well as newer thrombotic indicators such as PIC, TAT, TM, and t-PAIC, were obviously increased. Correlations with tumor parameters suggested their potential as biomarkers to distinguish benign from malignant gallbladder growths.

The clinical significance of TAT, PIC, TM, and t-PAIC in vascular events of BCR/ABL-negative myeloproliferative neoplasms

Predicting the likelihood vascular events in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN) is essential for the treatment of the disease. However, effective assessment methods are lacking. Thrombin-antithrombin complex (TAT), plasmin-α2- plasmininhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) are the new direct indicators for coagulation and fibrinolysis. The aim of this study was to investigate the changes of these four new indicators in thrombotic and hemorrhagic events in BCR/ABL1-negative MPN. The study cohort of 74 patients with BCR/ABL negative myeloproliferative disorders included essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF). A panel of 4 biomarkers, including TAT, PIC, TM, and t-PAIC were determined using Sysmex HISCL5000 automated analyzers, whereas fibrin/fibrinogen degradation products (FDP), D-dimer and Antithrombin III (ATIII) were analyzed using Sysmex CS5100 coagulation analyzer. A total of 24 (32.4%) patients experienced thrombotic events and hemorrhagic events occurred in 8 patients (10.8%). Compared to patients without hemorrhagic-thrombotic events, patients with thrombotic events had higher fibrinogen (FIB) level, FDP level and lower ATIII activity, while patients with hemorrhagic events had lower white blood cell count and hemoglobin level, higher FDP level (P < 0.05). Patients with a JAK2V617F mutation were more likely to experience thrombotic events (P < 0.05). In addtion, patients with thrombotic events had higher TAT, PIC, TM, and t-PAIC levels than patients without hemorrhagic-thrombotic events (P < 0.05), whereas patients with hemorrhagic events had a lower median value in TAT and TM (no statistical difference, P > 0.05). Patients with higher TAT, TM and t-PAIC were more likely to experience thrombotic events (P < 0.05), and only TAT was positively correlated with thrombotic events (Spearman r =0.287, P = 0.019). TAT, PIC, TM, and t-PAIC combined with ATIII and FDP have a certain value for predicting thrombosis in patients with BCR/ABL1-negative MPN. These 6 parameters are worth further exploration as predictive factors and prognostic markers for early thrombotic events.

Development of a chemiluminescence assay for tissue plasminogen activator inhibitor complex and its applicability to gastric cancer

BackgroundVenous thromboembolism (VTE), is a noteworthy complication in individuals with gastric cancer, but the current diagnosis and treatment methods lack accuracy. In this study, we developed a t-PAIC chemiluminescence kit and employed chemiluminescence to detect the tissue plasminogen activator inhibitor complex (t-PAIC), thrombin-antithrombin III complex (TAT), plasmin-α2-plasmin inhibitor complex (PIC) and thrombomodulin (TM), combined with D-dimer and fibrin degradation products (FDP), to investigate their diagnostic potential for venous thrombosis in gastric cancer patients. The study assessed variations in six indicators among gastric cancer patients at different stages.ResultsThe t-PAIC reagent showed LOD is 1.2 ng/mL and a linear factor R greater than 0.99. The reagents demonstrated accurate results, with all accuracy deviations being within 5%. The intra-batch and inter-batch CVs for the t-PAIC reagent were both within 8%. The correlation coefficient R between this method and Sysmex was 0.979. Gastric cancer patients exhibited elevated levels of TAT, PIC, TM, D-D, FDP compared to the healthy population, while no significant difference was observed in t-PAIC. In the staging of gastric cancer, patients in III-IV stages exhibit higher levels of the six markers compared to those in I-II stages. The ROC curve indicates an enhancement in sensitivity and specificity of the combined diagnosis of four or six indicators.ConclusionOur chemiluminescence assay performs comparably to Sysmex’s method and at a reduced cost. The use of multiple markers, including t-PAIC, TM, TAT, PIC, D-D, and FDP, is superior to the use of single markers for diagnosing VTE in patients with malignant tumors. Gastric cancer patients should be screened for the six markers to facilitate proactive prophylaxis, determine the most appropriate treatment timing, ameliorate their prognosis, decrease the occurrence of venous thrombosis and mortality, and extend their survival.

Usefulness of Combined Measurement of Surfactant Protein D, Thrombin-Antithrombin III Complex, D-Dimer, and Plasmin-α2 Plasmin Inhibitor Complex in Acute Exacerbation of Interstitial Lung Disease: A Retrospective Cohort Study.

Background/Objectives: The coagulation cascade due to tissue damage is considered to be one of the causes of poor prognostic outcomes in patients with acute exacerbations of interstitial lung disease (AE-ILD). This study aimed to confirm coagulopathy in AE-ILD by evaluating the differences in the clinical characteristics of coagulation/fibrinolysis markers between stable ILD and AE-ILD. Methods: Overall, 81 patients were enrolled in this retrospective study and categorized into the following two groups: a chronic ILD group comprising 63 outpatients and an acute ILD group comprising 18 inpatients diagnosed with AE-ILD. Serum markers, including thrombin-antithrombin III complex (TAT), D-dimer, plasmin-α2 plasmin inhibitor complex (PIC), and surfactant protein D (SP-D), were compared between the groups. Results: Among the 18 patients with acute ILD, 17 did not meet the International Society of Thrombosis and Hemostasis scoring system for disseminated intravascular coagulation. In acute ILD, the SP-D levels were statistically significantly positively correlated with TAT, D-dimer, and PIC levels, while the Krebs von den Lungen 6 (KL-6) levels showed no correlation with any of these coagulation/fibrinolytic markers. A positive correlation was observed between SP-D levels and TAT, D-dimer, and PIC levels in acute ILD. Serum TAT, D-dimer, and PIC all showed good area under the receiver operating characteristic (ROC) curve (AUC) values in ROC analysis for the diagnosis of acute ILD. Conclusions: In the clinical setting of AE-ILD, it may be important to focus not only on alveolar damage markers such as SP-D but also on coagulation/fibrinolytic markers including TAT, D-dimer, and PIC.

Clinical value of TAT, PIC and t-PAIC as predictive markers for severe sepsis in pediatric patients.

Sepsis in pediatric patients can progress to severe sepsis, and identifying biomarkers of this progression may permit timely intervention to prevent it. This study aimed to investigate the ability of thrombin-antithrombin complex (TAT), α2-plasmininhibitor-plasmin complex (PIC) and tissue-type plasminogen activator-inhibitor complex (t-PAIC) to predict severe sepsis in pediatrics early. 148 eligible pediatric sepsis patients were enrolled in this study, and were then divided into those who progressed to severe sepsis (n = 50) or not (n = 98). Serum levels of TAT, PIC, and t-PAIC were analysed, and simplified pediatric critical illness score (PCIS) and DIC score were calculated on the day of pediatric sepsis diagnosis. Compared with sepsis patients, severe sepsis patients had higher levels of TAT, PIC and t-PAIC. Correlation analysis revealed that TAT, PIC and t-PAIC were significantly correlated with simplified PCIS and DIC score. ROC curve analysis suggested that TAT, PIC and t-PAIC could serve as biomarkers for predicting severe sepsis with the AUC up to 0.862, 0.759 and 0.851, respectively. Stratified analysis demonstrated that the patients with increased levels of TAT, PIC and t-PAIC had worse illness severity and clinical outcome. Univariate logistic regression analysis revealed that TAT, PIC and t-PAIC were all risk factors for severe sepsis, yet only TAT and t-PAIC were independent risk factors in multivariate model. TAT, PIC and t-PAIC could serve as biomarkers for predicting severe sepsis, and correlated with illness severity in pediatrics, what's more, serum levels of TAT and t-PAIC may be independent risk factors for pediatric severe sepsis.

Perioperative Treatment with Rivaroxaban and Dabigatran on Changes of Coagulation and Platelet Activation Biomarkers following Left Atrial Appendage Closure.

Insufficient data exist regarding the investigation of the impact of novel oral anticoagulants (NOACs) on coagulation activation biomarkers in the context of left atrial appendage closure (LAAC) and device-related thrombosis (DRT). The study was designed to investigate the changes and presence of coagulation activation biomarkers between different antithrombotic strategies following LAAC. A total of 120 nonvalvular atrial fibrillation patients intolerant of long-term anticoagulants, who underwent successful WATCHMAN closure implantation, were enrolled (rivaroxaban, n = 82; dabigatran, n = 38). Blood samples were obtained from left atrium (LA) and left atrial appendage (LAA) during the operation and fasting blood samples on the same day of LAAC and 45 days after discharge. The biochemical indicators, thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), von Willebrand factor (vWF), and CD40 ligand (CD40L), were measured by enzyme-linked immunosorbent assay. The primary endpoints of this study were the efficacy and safety characteristics of different antithrombotic strategies, including DRT incidence, stroke or transient ischemic attack, systemic embolism, and clinical major and nonmajor bleeding complications during the follow-up of 180 days. The results revealed that TAT, vWF, sP-selectin, and CD40L levels in vein were significantly reduced by 2.4% (p = 0.043), 5.0% (p < 0.001), 8.7% (p < 0.001), and 2.5% (p = 0.043) from their baseline levels after rivaroxaban treatment. Conversely, no significant changes were detected in the dabigatran group. Furthermore, the plasma levels of platelet activation biomarkers (CD40L and sP-selectin) in both LA and LAA groups were significantly lower after anticoagulation with rivaroxaban, as compared to dabigatran treatment (CD40L: 554.62 ± 155.54 vs. 445.02 ± 130.04 for LA p = 0.0013, 578.51 ± 156.28 vs. 480.13 ± 164.37 for LAA p = 0.0052; sP-selectin: 2849.07 ± 846.69 vs. 2225.54 ± 799.96 for LA p = 0.0105, 2915.52 ± 1402.40 vs. 2203.41 ± 1061.67 for LAA p = 0.0022). Notably, the present study suggests that rivaroxaban may be more effective in the prevention of DRT for patients undergoing LAAC.

HIV-1 Tat is present in the serum of people living with HIV-1 despite viral suppression

ObjectivesDespite successful human immunodeficiency virus (HIV) control with combination antiretroviral therapy (cART), individuals with HIV still face health risks, including cancers, cardiovascular and neurocognitive diseases. An HIV protein, Tat, is potentially involved in these HIV-related diseases. Previous studies demonstrated circulating Tat in the blood of untreated people with HIV. Here, we measured Tat levels in the serum of cART-treated people with HIV to examine the effect of cART on Tat production. MethodsSerum samples from 63 HIV-positive and 20 HIV-seronegative individuals were analyzed using an ELISA assay that detected Tat concentrations above 2.5 ng/mL. ResultsAmong HIV-positive individuals, the Tat level ranged from 0 to 14 ng/mL. 25.4% (16 out of 63) exceeded the 2.5 ng/mL cut-off, with a median HIV Tat level of 4.518 [3.329-8.120] ng/mL. No correlation was revealed between Tat levels and CD4+ T cell counts, serum HIV RNA, p24 antigen, or anti-Tat levels. ConclusionsDespite cART, circulating HIV Tat persists and may contribute to HIV-related diseases. This emphasizes the need for further research on the mechanisms of Tat action in non-infected cells where it can penetrate upon circulation in the blood.

Alterations of Hemostatic Molecular Markers During Acute Large Vessel Occlusion Stroke.

This study aimed to investigate regional levels of TAT (thrombin-antithrombin complex), PIC (plasmin-α2 plasmin inhibitor complex), t-PAIC (tissue plasminogen activator-plasminogen activator inhibitor complex), sTM (soluble thrombomodulin), and D-dimer, along with their associations with clinical and procedural characteristics in patients with acute ischemic stroke undergoing endovascular thrombectomy. We retrospectively analyzed 166 consecutive patients with acute ischemic stroke (62±11.54 years of age, 34.3% women) using prospectively maintained clinical databases and blood samples from local ischemic (proximal to thrombus) and systemic (femoral artery, self-control) arterial compartments. Levels of TAT, PIC, t-PAIC, and D-dimer were significantly elevated, whereas sTM was significantly reduced, in local ischemic regions compared with their systemic levels. Each 1-unit increase in ischemic TAT (adjusted odds ratio [aOR], 1.086 [95% CI, 1.03-1.145]; P=0.002; area under the curve [AUC], 0.833) and PIC (aOR, 1.337 [95% CI, 1.087-1.644]; P=0.006; AUC, 0.771) correlated significantly with higher symptomatic intracranial hemorrhage risk. Additionally, each 1-unit increase in ischemic TAT (aOR, 1.076 [95% CI, 1.016-1.139]; P=0.013; AUC, 0.797), PIC (aOR, 1.554 [95% CI, 1.194-2.022]; P=0.001; AUC, 0.798), and sTM (aOR, 0.769 [95% CI, 0.615-0.961]; P=0.021; AUC, 0.756) was significantly associated with an increased risk of an unfavorable 90-day outcome (modified Rankin scale of 3-6). These hemostatic molecules, individually or combined, significantly improved the predictive power of conventional risk factors, as evidenced by significant increases in net reclassification improvement and integrated discrimination improvement (all P<0.01). We observed a hyperactive state of the coagulation-fibrinolysis system within the local ischemic region during hyperacute stroke. Rapid automated measurement of hemostatic molecular markers, particularly TAT, PIC, and sTM, during intra-arterial procedures may provide additional information for stroke risk stratification and therapeutic decision-making, and warrants further investigation.

Prognostic value of coagulation markers in patients with colorectal caner: A prospective study.

The occurrence, growth, and metastasis of colorectal cancer (CRC) are connected to the hypercoagulable state of blood (CRC). This study aimed to identify significant coagulation factors to predict metastasis and prognosis of CRC. Thrombomodulin (TM), thrombin-antithrombin complex (TAT), α2-plasmininhibitor-plasmin complex (PIC), and tissue plasminogen activator-inhibitor complex (t-PAIC) were detected by chemiluminescence immunoassay using Sysmex HISCL5000 automated analyzers. The Sysmex CS 5100 automatic blood coagulation analyzer was used to detect d-dimer (DD), fibrin degradation product (FDP), prothrombin time (PT), thrombin time (TT), international normalized ratio (INR), fibrinogen (Fbg), and activated partial thromboplastin time (APTT). Area under the curve (AUC) and the receiver operating characteristic curve (ROC) were used to assess the diagnostic efficacy of markers. Kaplan-Meier analysis was used to calculate survival probabilities. Independent prognostic factors and the nomogram were developed using single-factor and multifactor cox regression analysis model. The following indicators (TM, TAT, PIC, t-PAIC, DD, FDP, PT, INR, APTT, and Fbg) were markedly higher in CRC patients than in healthy controls, and they were higher in the metastasis (M) group than in the nonmetastasis (NM) group. The combination "TAT + PIC + DD + FDP + Fbg" can distinguish M from NM with exceptional sensitivity and specificity. Patients with CRC who had high levels of TAT, PIC, DD, FDP, Fbg, TM, tPAIC, PT, and INR had significantly shorter survival. The prognosis of CRC patients can be predicted by coagulation indicators. The independent predictive variables for overall survival were found to be TM and DD. To forecast CRC patient survival, a nomogram was created.

Analysis of the diagnostic value of coagulation markers and coagulation function indices on the occurrence of DIC in sepsis and its prognosis.

Sepsis is a life-threatening condition that has the potential to multiple organ dysfunction and mortality. One of its frequent complications is disseminated intravascular coagulation (DIC), characterized by hyperactive clotting mechanisms that cause widespread clot formation and tissue damage. This study aimed to investigate early diagnostic markers of sepsis-associated DIC by comparing inflammatory factor levels, 28-day survival rates, coagulation function, and markers between patients with sepsis (non-DIC group) and those with sepsis-induced DIC (DIC group). The study analyzed the diagnostic efficacy of coagulation function and markers in predicting the occurrence and prognosis of sepsis-associated DIC, presenting survival curves. Results indicated significantly increased levels of APTT, TAT, tPAIC, PIC, and sTM in the DIC group compared to the non-DIC group. Sequential Organ Failure Assessment (SOFA) scores on days 1, 3, and 7 were notably lower in the non-DIC group. Correlation analysis revealed positive associations between PT, APTT, TAT, tPAIC, PIC, sTM levels, and SOFA scores, as well as negative associations with Fib and SOFA scores. Survival curves showed substantially lower mortality rates in the non-DIC group, highlighting significant survival disparities between groups. Combining all four coagulation indicators (TAT+ tPAIC + PIC + sTM) showed promising diagnostic value in evaluating disease severity, early DIC diagnosis, and sepsis prognosis.

The Proactive Diagnostic Value of Thrombin-Antithrombin Complex and Antithrombin III in Disseminated Intravascular Coagulation

Introduction Disseminated intravascular coagulation (DIC) is a life-threatening condition with high mortality, necessitating timely and accurate diagnosis for effective management. However, current diagnostic systems can not recognize DIC at its reversible phase, causing suboptimal treatment outcomes. One reason is that most venous thrombosis cases are asymptomatic. Moreover, the focus on abnormalities in coagulation consumption often fails to identify DIC until in a later and irreversible phase. Consequently, the current diagnostic criteria for DIC lacks earlier laboratory indicators. Therefore, our objective was to evaluate the diagnostic potential of selected hemostatic biomarkers (thrombin-antithrombin complex (TAT), soluble thrombomodulin (sTM), tissue plasminogen activator inhibitor complex (tPAI-C), α 2-plasmin inhibitor plasmin complex (PIC) and anti-thrombin III (ATIII)) in assessing DIC before reaching its irreversible phase. Methods We included 451 patients from intensive care unit who met the following criteria:≥18 years old, non-perinatal period, and a hospitalization length of≥3 days, excluding those with primary hematologic diseases, decompensated liver cirrhosis or chemotherapy history. In total, 101, 57, and 293 patients were diagnosed with overt-DIC (decompensated DIC), pre-DIC (compensated DIC), and non-DIC, respectively. The DIC scores were calculated in accordance with the diagnostic criteria outlined by the International Society on Thrombosis and Haemostasis (ISTH). Day 0 was defined as the day on which hemostatic biomarkers were detected. Global parameters including prothrombin time (PT), fibrinogen (FIB), fibrinogen degradation product (FDP), d-dimer, and platelet count were collected on day 0, 1, 3, 5, and 7. The spearman correlation analysis was used to analyze the linear relation. Binary logistic regression analysis and receiver operating characteristic curves were used to calculate the area under the receiver operating characteristic curve (AUC). The cutoff value maximizes the sum of the sensitivity and specificity. P&amp;lt;0.05 was considered statistically significant. Results Correlation analysis revealed significant linear correlations between TAT, ATIII, and the global parameters relevant to DIC (pre-DIC and overt-DIC). Specifically, TAT exhibited positive correlation with d-dimer and FDP, while ATIII was correlated with PT, FIB, and platelet count. Of note, TAT/ATIII ratio on day 0 exhibited strong associations not only with fibrinolytic markers but also with coagulation parameters within a week, indicating its potential to be a valuable diagnostic and predictive tool for DIC assessment. Comparative analysis demonstrated elevated TAT and decreased ATIII levels in DIC group. Remarkably, the TAT/ATIII ratio demonstrated superior diagnostic performance compared to individual biomarkers. Among individual biomarkers, TAT/ATIII ratio had the highest AUC of 0.818 with a cutoff value of 22.1, followed by ATIII (AUC=0.752) and TAT (AUC=0.749). Moreover, when a combination of TAT and ATIII was applied, the AUC increased to 0.847 higher than TAT/ATIII ratio's, improving the diagnostic accuracy for DIC. TAT and ATIII in pre-DIC group were consistent with those observed in DIC group above: elevated TAT levels, decreased ATIII activity, TAT/ATIII ratio with superior diagnostic performance. Among individual biomarkers, TAT/ATIII ratio had the highest AUC 0.771 with a cutoff value of 22.1 that maximized the sum of sensitivity (55%) and specificity (89%), followed by TAT (AUC=0.73) and ATIII (AUC=0.707). The AUC of TAT combination with ATIII was 0.796, higher than AUC 0.771 of TAT/ATIII ratio, suggesting that TAT and ATIII may also identify the pre-DIC status and predict overt-DIC. Conclusion This study underscores the remarkable potential of TAT, ATIII, and the TAT/ATIII ratio in predicting DIC with accuracies of 73%, 71%, and 77%, respectively. Moreover, for patients with an ISTH-DIC score of &amp;lt; 5, the presence of following conditions-TAT level ≥10.8 ng/mL, ATIII activity ≤0.58, or TAT/ATIII ratio ≥22.1-indicates a likelihood of developing into irreversible DIC within 7 days. Integrating TAT, ATIII, and the TAT/ATIII ratio into the diagnostic process holds the potential to expedite clinical interventions during the pre-DIC state and enhance outcomes for DIC patients, further covering the shortage of current ISTH criteria.

Comprehensive Characterization of Coagulation Parameters in Venous Malformations

Introduction: Localized intravascular coagulopathy (LIC) is a well-recognized, though poorly characterized complication of venous malformations (VM) that can lead to bleeding, thrombosis, and phlebolith formation. While LIC has classically been characterized by elevations in D-dimer and reductions in fibrinogen, no comprehensive studies of coagulation parameters in VM have been performed to date. Since 2021, all patients with VM undergoing evaluation for LIC in the Yale Vascular Malformations Program (VaMP) and the Yale Classical Hematology clinic have been subjected to an extensive set of coagulation tests to fully analyze LIC. Our aim was to use these laboratory test results to comprehensively characterize LIC in this population. Methods: We conducted a retrospective chart review of all VM patients presenting to the Yale VaMP and the Yale Classical Hematology clinic for assessment of LIC from 2021 to 2023. All included patients were evaluated for LIC using the following coagulation parameters: von Willebrand Factor (VWF) antigen, VWF activity, factor VIII (FVIII), alpha-2 antiplasmin (A2AP), plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex (TAT), D-dimer (DD), fibrinogen, prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (PTT). Measurements of VWF antigen, VWF activity, FVIII and A2AP were performed using an ACL TOP system (Instrumentation Laboratory; Bedford, MA, USA), while D-dimer and fibrinogen were measured using a BCS XP System (Siemens; Malvern, PA, USA) at our institution's clinical laboratory. PAI-1 and TAT were processed at national Clinical Laboratory Improvement Amendment-certified reference laboratories using ELISA-based assays. Baseline patient characteristics and coagulation test results were extracted via manual chart review. Data analysis was done using IBM SPSS statistics software and GraphPad Prism 9 software. Categorical variables were described using frequency and percentages, while quantitative variables were described using central tendency and dispersion measures. We performed univariate analysis using the Chi-square test. We also analyzed the coagulation tests using a correlation matrix. Statistical significance was set at p&amp;lt;0.05. This project was approved by our Institutional Review Board. Results: A total of 23 patients with VM were included in the analysis (Table 1). The mean age was 38 ± 16 years; the majority (82.6%) were female. The most common anatomic location was the head and neck (52.2%), while the most frequent extent of tissue involvement was muscle (54.5%), with most patients having a single lesion (59.1%) rather than multiple ones. No patients had venous thromboembolism. Normal DD and high TAT levels were observed in most patients (68.2% and 69.6%, respectively). VWF activity, VWF antigen, FVIII, PAI-1, and fibrinogen all were positively correlated (Figure 1). TAT was positively correlated with PAI-1 and inverselycorrelated withPT and INR. DD was positively correlated only with vWF activity. TAT and DD had a poor correlation; among patients with a normal TAT (n=7), 85.7% had a normal DD, while among patients with a normal DD (n=15), only 40% had a normal TAT. Three out of 4 (75%) patients with skin involvement had a high TAT with normal DD, while 2 out of 3 (66.7%) patients with visceral involvement had both high TAT and DD, although these patternswere not statistically significant (P=0.42 and 0.31, respectively). Among patients with muscle involvement (n=11), 45.5% had a high TAT and normal DD while 36.3% had both high TAT and DD. Conclusions: In this first comprehensive hematologic study of VM, we demonstrate that VM-related LIC is characterized by derangements of multiple coagulation parameters. Due to this, measurements of DD and fibrinogen alone may be inadequate for assessing LIC, and the addition of TAT and multiple other coagulation tests may yield a more complete picture of hemostatic derangements in LIC. A lack of correlation between DD and TAT is unexpected and merits further study. Differences in the depth of the VM tissue involvement and TAT/DD correlation may indicate a progression of coagulopathy related to the extent of VM but require further investigation in a larger study.

Increased thromboinflammatory load in hereditary angioedema.

C1 inhibitor (C1Inh) is a serine protease inhibitor involved in the kallikrein-kinin system, the complement system, the coagulation system, and the fibrinolytic system. In addition to the plasma leakage observed in hereditary angioedema (HAE), C1Inh deficiency may also affect these systems, which are important for thrombosis and inflammation. The aim of this study was to investigate the thromboinflammatory load in C1Inh deficiency. We measured 27 cytokines including interleukins, chemokines, interferons, growth factors, and regulators using multiplex technology. Complement activation (C4d, C3bc, and sC5b-C9/TCC), haemostatic markers (β-thromboglobulin (β-TG), thrombin-antithrombin complexes (TAT), prothrombin fragment 1 + 2 (F1 + 2), active plasminogen activator inhibitor-1 (PAI-1), and the neutrophil activation marker myeloperoxidase (MPO) were measured by enzyme immunoassays. Plasma and serum samples were collected from 20 patients with HAE type 1 or 2 in clinical remission and compared with 20 healthy age- and sex-matched controls. Compared to healthy controls, HAE patients had significantly higher levels of tumour necrosis factor (TNF), interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-7, IL-9, IL-12, and IL-17A, chemokine ligand (CXCL) 8, chemokine ligand (CCL) 3, CCL4, IL-1 receptor antagonist (IL-1RA), granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor (FGF) 2 and platelet-derived growth factor (PDGF)-BB. HAE patients also had higher levels of TAT and F1 + 2. Although granulocyte colony-stimulating factor (G-CSF), β-TG and PAI-1 were higher in HAE patients, the differences did not reach statistical significance after correction for multiple testing. In conclusion, C1Inh deficiency is associated with an increased baseline thromboinflammatory load. These findings may reflect that HAE patients are in a subclinical attack state outside of clinically apparent oedema attacks.

Coagulation Biomarkers and Clinical Outcomes in Elderly Patients With Nonvalvular Atrial Fibrillation: ANAFIE Subcohort Study

BackgroundLittle is known about the relationship between coagulation biomarkers and clinical outcomes in patients with atrial fibrillation (AF) treated with anticoagulants, especially direct oral anticoagulants (DOACs) and warfarin. ObjectivesThis subcohort study evaluated the association between coagulation biomarkers and clinical outcomes in elderly Japanese patients with nonvalvular AF using the ANAFIE (All Nippon AF In the Elderly) Registry. MethodsPatients with a definitive diagnosis of nonvalvular AF and aged ≥75 years at enrollment were included. At enrollment, biomarker levels for D-dimer, thrombin–antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), and soluble fibrin monomer complex (SFMC), along with data on anticoagulant use, were recorded. ResultsOf the 3,194 patients, 95.1% were using oral anticoagulants (OACs) (71.7% DOACs, 23.4% warfarin). D-dimer, TAT, and F1+2 levels, as well as the proportion of patients with a positive SFMC, were lower among those receiving OACs compared with those not receiving OACs. In the DOAC group, higher levels of D-dimer (≥1.0 μg/mL) and TAT (>3 ng/mL) were significantly associated with increased incidences of cardiovascular (CV) events (stroke, myocardial infarction, cardiac intervention, heart failure, and CV death), all-cause death, and CV death. In the warfarin group, higher levels of D-dimer were significantly associated with increased rates of all-cause death, higher levels of TAT with increased major bleeding, and positive SFMC with increased major bleeding and CV events. ConclusionsHigher levels of coagulation biomarkers were associated with a higher risk of worse clinical outcomes, and the relationships between the coagulation biomarkers and outcomes differed between the DOAC and warfarin groups. (Prospective Observational Study in Late-Stage Elderly Patients with Non-Valvular Atrial Fibrillation All Nippon AF In Elderly Registry-ANAFIE Registry; UMIN000024006)

Tissue factor activates the coagulation cascade in mouse models of acute promyelocytic leukemia

AbstractAcute promyelocytic leukemia (APL) is associated with a high risk of bleeding and thrombosis. APL patients have an activated coagulation system, hyperfibrinolysis, and thrombocytopenia. APL cells express tissue factor (TF), a receptor and cofactor for factor VII/VIIa. This study had 2 goals. Firstly, we measured biomarkers of coagulation and fibrinolysis activation as well as platelet counts and bleeding in both mouse xenograft and allograft models of APL. Secondly, we determined the effect of inhibiting TF on the activation of coagulation in these models. We observed increased levels of plasma thrombin-antithrombin complexes (TAT), D-dimer, and plasmin-antiplasmin complexes, reduced platelet counts, and increased tail bleeding in both mouse models of APL. Fibrinogen levels decreased in the xenograft model but not in the allograft model. In contrast, the red blood cell count decreased in the allograft model but not in the xenograft model. Inhibition of APL-derived human TF with an anti-human TF monoclonal antibody reduced the level of TAT, increased platelet count, and normalized tail bleeding in a xenograft model. Inhibition of all sources of TF (APL cells and host cells) in the allograft model with a rat anti-mouse TF monoclonal antibody decreased the levels of TAT but did not affect the platelet count. Our study demonstrates that TF plays a central role in the activation of coagulation in both the xenograft and allograft mouse models of APL. These APL mouse models can be used to investigate the mechanisms of coagulopathy and thrombocytopenia in APL.