Coagulation Biomarkers Research Articles

Biomarkers can Predict COVID-19 Disease

Abstract:: Health professionals have been confronted with a series of challenges because of the ongoing pandemic of coronavirus disease 2019 (COVID-19). To save the greatest number of lives possible, it is essential to make a prompt diagnosis and admission to the hospital, as well as to stratify risks, make efficient use of intensive care services, choose appropriate treatments, monitor patients, and ensure a prompt discharge. Laboratory markers, also known as biomarkers, can provide additional information that is objective and has the potential to significantly influence various aspects of patient care. Clinical assessment is necessary, but laboratory markers can provide this information. The COVID-19 virus is not an infection that causes the respiratory system; rather, it is a multisystem disease that is caused by a diffuse system-wide process that involves a complex interplay of the immune, nervous, and endocrine systems in inflammatory and coagulative cascades. A wide variety of potential biomarkers have been uncovered because of a better understanding of the virus's effects on the body and how the body responds to them. Here, the pathophysiology and current data are examined in relation to various kinds of biomarkers, such as immunological and inflammation biomarkers, coagulation and hematological biomarkers, as well as cardiac, biochemical, and other biomarkers. This review provides a comprehensive analysis of the research on the association between biomarkers and clinical characteristics, viral load, treatment efficacy, and how this knowledge might most usefully contribute to patient care.

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.

Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2

In the wake of the COVID-19 pandemic caused by SARS-CoV-2, questions emerged about the potential effects of Bacillus Calmette-Guérin (BCG) vaccine on the immune response to SARS-CoV-2 infection, including the neurodegenerative diseases it may contribute to. To explore this, an experimental study was carried out in BCG-stimulated and non-stimulated k18-hACE2 mice challenged with SARS-CoV-2. Viral loads in tissues determined by RT-qPCR, histopathology in brain and lungs, immunohistochemical study in brain (IHC) as well as mortality rates, clinical signs and plasma inflammatory and coagulation biomarkers were assessed. Our results showed BCG-SARS-CoV-2 challenged mice presented higher viral loads in the brain and an increased frequency of neuroinvasion, with the greatest differences observed between groups at 3–4 days post-infection (dpi). Histopathological examination showed a higher severity of brain lesions in BCG-SARS-CoV-2 challenged mice, mainly consisting of neuroinflammation, increased glial cell population and neuronal degeneration, from 5 dpi onwards. This group also presented higher interstitial pneumonia and vascular thrombosis in lungs (3–4 dpi), BCG-SARS-CoV-2 mice showed higher values for TNF-α and D-dimer values, while iNOS values were higher in SARS-CoV-2 mice at 3–4 dpi. Results presented in this study indicate that BCG stimulation could have intensified the inflammatory and neurodegenerative lesions promoting virus neuroinvasion and dissemination in this experimental model. Although k18-hACE2 mice show higher hACE2 expression and neurodissemination, this study suggests that, although the benefits of BCG on enhancing heterologous protection against pathogens and tumour cells have been broadly demonstrated, potential adverse outcomes due to the non-specific effects of BCG should be considered.

Identifying novel biomarkers using proteomics to predict cancer-associated thrombosis.

Comprehensive protein analyses of plasma are made possible by high-throughput proteomic screens, which may help find new therapeutic targets and diagnostic biomarkers. Patients with cancer are frequently affected by venous thromboembolism (VTE). The limited predictive accuracy of current VTE risk assessment tools highlights the need for new, more targeted biomarkers. Although coagulation biomarkers for the diagnosis, prognosis, and treatment of VTE have been investigated, none of them have the necessary clinical validation or diagnostic accuracy. Proteomics holds the potential to uncover new biomarkers and thrombotic pathways that impact the risk of thrombosis. This review explores the fundamental methods used in proteomics and focuses on particular biomarkers found in VTE and cancer-associated thrombosis.

Complete blood count, coagulation biomarkers, and lung function 6 months after critical COVID-19.

Understanding the recovery of post-COVID-19 organ dysfunction is essential. We evaluated coagulation 6 months post-COVID-19, examining its recovery and association with lung function. Patients treated for COVID-19 at intensive care units between 3/2020 and 1/2021 were analyzed for complete blood count (CBC) and coagulation biomarkers (prothrombin time activity (%) (PT%), activated partial thromboplastin time (APTT), fibrinogen, coagulation factor VIII (FVIII), antithrombin (AT), and D-dimer) during the 6 months post-hospitalization. Results were compared with acute phase values and correlated with pulmonary function tests (PFT), including forced vital capacity (FVC) and hemoglobin-corrected diffusing capacity percentage of predicted (DLCOc%), recorded 6 months post-hospitalization. We examined the association between coagulation biomarkers and DLCOc% using linear regression with age, sex, and invasive mechanical ventilation (IMV) duration, and FVIII (correlated with DLCOc%) as covariates. Most CBCs and coagulation biomarkers had median values within the normal range. However, only 21% (15/70) of patients achieved full normalization of all biomarkers. Compared to acute COVID-19, hemoglobin, PT%, and AT increased, while leukocytes, fibrinogen, FVIII, and D-dimer decreased. Despite decreased levels, FVIII remained elevated in 46% (31/68), leukocytes in 26% (18/70), and D-dimer in 27% (18/67) at 6 months. A weak negative correlation (r = -0.37, p = .036) was found between DLCOc% and FVIII. Multivariable analysis revealed a weak, independent association between DLCOc% and FVIII. Excluding patients with anticoagulation therapy, FVIII no longer correlated with DLCOc%, while AT showed a moderate correlation with DLCOc%. Only a few patients had normal CBC and coagulation biomarker values 6 months after critical COVID-19. A weak negative correlation between DLCOc% and FVIII suggests that deranged coagulation activity may be associated with reduced diffusing capacity.

A panel study of exposure to fine particulate matter and modeled respiratory deposition on biomarkers of inflammation, blood coagulation, and oxidative stress in healthy young adults in Hefei, China

Evidence is scarce on the acute cardiovascular health effects of fine particulate matter (PM2.5) and its respiratory tract depositions. We performed a panel study in Hefei, China to explore the relations of PM2.5 and its depositions in 3 respiratory tract regions over different lag times with a range of cardiovascular biomarkers among 40 college students and the potential mediating effects of inflammation. We found significant effects of PM2.5 exposure on the alterations of biomarkers at specific lag days, in a concentration-response manner, even at PM2.5 level below Chinese Ambient Air Quality Standard (CAAQS) Grade I (35 μg/m3). For example, per 10 μg/m3 increase in PM2.5 concentration was associated with −9.33% increase in ADAMTS13 on lag 0-1d. The corresponding increases in D-Dimer, GM-CSF, and MCP-1 for the same change in PM2.5 concentration on lag 5-6d were 30.51%, 11.43%, and 20.05%. Besides, tracheobronchial region (TB) deposition presented more evident effects on these biomarkers than that in PM2.5. Additionally, we observed greater associations of PM2.5-biomarkers among females, those with abnormal body mass index (BMI), and those with physical activity. The results indicated that short-term PM2.5 exposure and its respiratory tract depositions were concentration-responsive associated with damaged cardiovascular health via inducing blood coagulation, oxidative stress and inflammation among healthy young adults even at concentration below CAAQS Grade I. Elevated serum levels of systemic inflammation may be partly responsible for the effects of PM2.5 and its respiratory tract depositions on coagulation function.

Rotational Thromboelastometry as a Diagnostic Tool for Persistent Infection in Two-Stage Exchange Arthroplasty.

Background/Objectives: There is a lack of reliable biomarkers for diagnosis of infection eradication prior to second-stage reimplantation in two-stage exchange arthroplasty for periprosthetic joint infections (PJIs). The aim of this study was to assess the diagnostic accuracy of rotational thromboelastometry (ROTEM) for persistent infection in two-stage exchange arthroplasties. Methods: A pilot, retrospective analysis was performed including 70 patients who underwent a two-stage exchange arthroplasty for PJI. They were categorized as patients without (n = 64) or patients with persistent infection (n = 6) prior to reimplantation. Definition of persistent infection prior to reimplantation was based on the 2018 ICM criteria. Conventional coagulation biomarkers and ROTEM parameters were compared between groups. Results: Higher FIBTEM MCF values were associated with persistent infection (odds ratio [OR], 1.30, 95% confidence interval [CI], 1.04-1.63; p = 0.020), and FIBTEM MCF had the highest diagnostic accuracy for persistent infection prior to second-stage reimplantation (AUC, 0.907; 95% CI, 0.812-1.000). A cut-off value ≥ 18 mm for FIBTEM MCF was found to have 100.0% sensitivity and 73.4% specificity for diagnosing persistent infection prior to second-stage reimplantation. Moreover, the diagnostic accuracy of FIBTEM MCF was higher than that of fibrinogen levels (p = 0.036) and D-dimer (p = 0.006). Conclusions: Our findings indicate that ROTEM parameters have the potential to identify persistent infections before reimplantation in two-stage exchange arthroplasties for PJI. Such coagulation biomarkers could provide guidance regarding the optimal timing for reimplantation. Further studies in larger populations are warranted to validate the diagnostic accuracy of ROTEM parameters for persistent PJI.

Abstract 54: Circulating Biomarkers and Anticoagulation Breakthrough Stroke Risk in Atrial Fibrillation: The REGARDS Study

Introduction: Anticoagulation reduces ischemic stroke risk in atrial fibrillation (AF), but “breakthrough” stroke occurs. Blood biomarkers might help identify patients at risk for anticoagulation breakthrough stroke, but existing studies are limited by examining few biomarkers in select populations. Hypotheses: Established biomarkers of ischemic stroke risk will also be associated with ischemic stroke risk in people with AF on anticoagulation sampled from the general population. Methods: REGARDS is a prospective cohort of 30,239 Black or White adults aged ≥45 on enrollment in 2003-7 monitored for stroke. Nine established blood biomarkers of ischemic stroke risk were measured at baseline in participants with AF and with no prior stroke who were taking oral anticoagulation at baseline. Hazard ratios of ischemic stroke were estimated by Cox models adjusted for demographics and stroke risk factors. Results: Among 713 participants with AF on anticoagulation (median age 76, 36% female, 17% Black, all taking vitamin K antagonists), 67 (9%) developed a first-time ischemic stroke over 12 years. In models adjusted for demographics, there were positive associations of all biomarkers with stroke risk except for galectin-3, lipoprotein(a), and cystatin C which had inverse or null associations (Figure). Adjustment for risk factors minimally impacted interpretation of results. The greatest associations were with higher N-terminal pro-B type natriuretic peptide, factor VIII, D-dimer, and growth differentiation factor 15; associations for D-dimer and growth differentiation factor 15 were not statistically significant. Hazards for galectin-3, gamma glutamyl transferase, interleukin 6, and lipoprotein (a) were modest and not statistically significant. Conclusion: Biomarkers of cardiac strain (specifically atriopathy), coagulation, and inflammation were associated with higher ischemic stroke risk in people with AF on anticoagulation at baseline. Findings highlight new avenues for reducing stroke risk in AF.

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.

The correlation between coagulation biomarkers, bone turnover markers, and bone mineral density in Chinese adults aged ≥ 50 years

IntroductionOsteoporosis patients undergoing surgery often have significant bleeding, which is closely related to coagulation function. This study aimed to assess the correlation between bone turnover markers (BTMs), bone mineral density (BMD), and coagulation biomarkers.Material and methodsCases meeting the inclusion criteria were included from our center from January 2020 to December 2021. The relationships between coagulation biomarkers, BTMs, and BMD were investigated by Spearman correlation analysis and canonical correlation analysis (CCA). Consequently, age, bone mass stage, 25-hydroxyvitamin D (25-(OH)D), and BMD were included as independent variables in the logistic regression model. Furthermore, the international normalized ratio (INR), fibrinogen, platelets, and D-dimer levels were set as dependent variables in the regression analysis. Finally, multivariable regressions were conducted to adjust for differences in demographics and comorbidities among groups.ResultsA total of 306 patients were included in the study. Significant differences were observed in prothrombin time, fibrinogen, INR, D-dimer, and platelets (p &lt; 0.05). D-dimer exhibited the most significant positive association with age and the most pronounced negative correlation with the BMD of Ward’s triangle (r = 0.322, p &lt; 0.001; r = –0.298, p &lt; 0.001; respectively). 25-(OH)D and calcium were related to coagulation biomarkers. Multivariate analysis demonstrated that age was positively associated with D-dimer levels (odd ratio [OR] = 1.046, p = 0.007), while the BMD of Ward’s triangle was negatively related to D-dimer levels (OR = 0.004, p = 0.0017).ConclusionsFor the Chinese population aged 50 and above, attention should be paid to alterations in coagulation biomarkers.

Impact of therapeutic plasma exchange on intact protein S, apolipoproteins, and thrombin generation

IntroductionTherapeutic plasma exchange (TPE), with solvent/detergent (S/D)-treated plasma as replacement fluid, is an extracorporeal blood purification technique with major impact on both coagulation and lipids. Our previous in vitro study showed that S/D-plasma enhances thrombin generation by lowering intact protein S (PS) levels. Aims: To evaluate the impact of altered lipid balance on coagulation phenotype during heparin-anticoagulated TPE with S/D-plasma, and to investigate whether the lowered intact PS levels with concomitant procoagulant phenotype, are recapitulated in vivo. Methods: Coagulation biomarkers, thrombin generation with Calibrated Automated Thrombogram (CAT), and lipid levels were measured before and after the consecutive 1st, 3rd and 5th episodes of TPE performed to six patients with Guillain-Barré syndrome or myasthenia gravis. The effects of in vitro dilution of S/D-plasma on thrombin generation were explored with CAT to mimic TPE. Results: Patients did not have coagulation disorders, except elevated FVIII. Intact PS, lipoproteins, especially LDL, Apolipoprotein CIII (ApoC3) and ApoB/ApoA1 ratio declined (p < 0.05). In contrast, VLDL and triglyceride levels stayed intact. CAT lag time shortened (p < 0.05). In vitro dilution of S/D plasma with co-transfused Ringer's lactate and 4% albumin partially reduced its procoagulant phenotype in CAT, which is mainly seen as peak thrombin, and modestly shortened lag time. Conclusions: After the five settings of TPE using S/D-plasma in vivo, which associated with heparinization and reduced coagulation factor activities, our observations of declining natural anticoagulant intact PS and apolipoproteins refer to rebalance of the hemostatic and lipid profiles.

Neutrophil extracellular traps - a potential trigger for the development of thrombocytopenia during extracorporeal membrane oxygenation.

Neutrophil extracellular traps (NETs) have recently emerged as a potential link between inflammation, immunity, and thrombosis, as well as other coagulation disorders which present a major challenge in the context of extracorporeal membrane oxygenation (ECMO). By examining blood from ECMO patients for NETs and their precursors and correlating them with clinical and laboratory biomarkers of coagulation and inflammation, this study aims to evaluate the association between the presence of NETs in the bloodstream of ECMO patients and the development of potentially severe coagulation disorders during ECMO therapy. Therefore, blood samples were collected from healthy volunteers (n=13) and patients receiving veno-venous (VV) ECMO therapy (n=10). To identify NETs and their precursors, DNA and myeloperoxidase as well as granulocyte marker CD66b were visualized simultaneously by immunofluorescence staining in serial blood smears. Differentiation of DNA-containing objects and identification of NETs and their precursors was performed semiautomatically by a specific algorithm using the shape and size of DNA staining and the intensity of MPO and CD66b signal. Neutrophil extracellular traps and their precursors could be detected in blood smears from patients requiring VV ECMO. Compared to volunteers, ECMO patients presented significantly higher rates of NETs and NET precursors as well as an increased proportion of neutrophil granulocytes in all detected nucleated cells. A high NET rate prior to the initiation of ECMO therapy was associated with both increased IL-6 and TNF-α levels as an expression of a high cytokine burden. These patients with increased NET release also presented an earlier and significantly more pronounced decrease in platelet counts and ATIII activity following initiation of therapy compared with patients with less elevated NETs. These findings provide further indications for the development of immune-mediated acquired thrombocytopenia in ECMO patients.

Coarse Particulate Matter and Markers of Inflammation and Coagulation in the Multi-Ethnic Study of Atherosclerosis (MESA) Population: A Repeat Measures Analysis.

In contrast to fine particles, less is known of the inflammatory and coagulation impacts of coarse particulate matter (, particulate matter with aerodynamic diameter ). Toxicological research suggests that these pathways might be important processes by which impacts health, but there are relatively few epidemiological studies due to a lack of a national monitoring network. We used new spatiotemporal exposure models to examine associations of both 1-y and 1-month average concentrations with markers of inflammation and coagulation. We leveraged data from 7,071 Multi-Ethnic Study of Atherosclerosis and ancillary study participants 45-84 y of age who had repeated plasma measures of inflammatory and coagulation biomarkers. We estimated at participant addresses 1 y and 1 month before each of up to four exams (2000-2012) using spatiotemporal models that incorporated satellite, regulatory monitoring, and local geographic data and accounted for spatial correlation. We used random effects models to estimate associations with interleukin-6 (IL-6), C-reactive protein (CRP), fibrinogen, and D-dimer, controlling for potential confounders. Increases in were not associated with greater levels of inflammation or coagulation. A increase in annual average was associated with a 2.5% decrease in CRP [95% confidence interval (CI): , 0.6]. We saw no association between annual average and the other markers (IL-6: , 95% CI: , 1.2; fibrinogen: , 95% CI: , 0.3; D-dimer: , 95% CI: , 2.4). Associations consistently showed that a increase in 1-month average was associated with reduced inflammation and coagulation, though none were distinguishable from no association (IL-6: , 95% CI: , 0.5; CRP: , 95% CI: , 0.4; fibrinogen: , 95% CI: , 0.1; D-dimer: , 95% CI: , 0.3). We found no evidence that is associated with higher inflammation or coagulation levels. More research is needed to determine whether the inflammation and coagulation pathways are as important in explaining observed health impacts in humans as they have been shown to be in toxicology studies or whether might impact human health through alternative biological mechanisms. https://doi.org/10.1289/EHP12972.

Ultrasound-powered hydrogen peroxide-responsive Janus micromotors for targeted thrombolysis and recurrence inhibition

Thrombosis seriously endangers human health with high incidence and mortality worldwide, and the clinical treatment is challenged by low bioavailability of thrombolytic agents, high bleeding risk and thrombosis relapse. Herein, ultrasound-powered Janus micromotors with stimuli-responsive multiple release capabilities are developed for efficient thrombolysis and inhibition of thrombosis recurrence. Resveratrol-loaded hyaluronic acid (HARes) nanoparticles (NPs) and urokinase plasminogen activator (uPA) were entrapped into H2O2-sensitive poly(1,4-cyclohexanedimethanol-co-oxalate) (POX) microparticles (MPs), followed by polydopamine capping and RGD grafting to obtain Janus rJPox@u-HARes MPs. After RGD-mediated delivery to the thrombus site, the peroxalate ester bonds of POX are oxidized by the elevated H2O2 to produce CO2, and the MP collapse accelerates the local release of uPA and HARes NPs. The resulting CO2 bubbles amplify the cavitation effect of ultrasound to promote thrombus penetration and site-specific uPA thrombolysis. The endothelial cell targeting and sustained resveratrol release from HARes NPs dramatically improve endothelial cell viability, nitric oxide production and migration. Compared with free drug administration, the uPA loading into MPs significantly extends the half-life (15 folds) and bioavailability (7 folds), while the resveratrol inoculation into NPs increases the bioavailability 29 times. On an acute lower limb thrombosis model, the thrombus accumulation of MPs is promoted by RGD-mediated interactions with the activated platelets and ultrasound-driven penetration into thrombi, leading to almost full removal of blood clots. The H2O2-scavenging capability of POX, sustained resveratrol release and efficient thrombolysis alleviate oxidative stresses, eliminate coagulation biomarkers and repair the damaged endothelial layer to effectively inhibit thrombosis relapse. It is demonstrated that rJPox@u-HARes/US treatment could not only achieve safe and site-specific thrombolytic therapy at the early stage but also restore vascular homeostasis to effectively prevent thrombosis recurrence.

Biomarkers of coagulation, endothelial, platelet function, and fibrinolysis in patients with COVID-19: a prospective study

Prospective and sequential evaluation of homeostatic changes leading to thrombosis across COVID 19 disease severity spectrum are limited. In this prospective observational study, haemostasis was evaluated in patients with mild, moderate-severe, and critical COVID-19 infection. Markers of endothelial activation [Soluble thrombomodulin (sTM), von Willebrand Factor (VWF)], platelet activation [Soluble P-selectin, beta-thromboglobulin (BTG)] and global haemostasis [Rotational thromboelastometry (ROTEM)] were evaluated on days 1 and 5 after admission. The study cohort comprised of 100 adult patients (mild = 20, moderate-severe = 22, critical = 58). Sixty-five patients received anticoagulation for 10 (7–14) days. Thrombotic events were seen in 9 patients. In-hospital mortality was 21%. Endothelial activation markers were elevated at baseline in all subgroups, with levels in moderate-severe (sTM = 4.92 ng/ml, VWF = 295 U/dl) [reference-ranges: sTM = 2.26–4.55 ng/ml; Soluble P-selectin = 13.5–31.5 ng/ml; BTG = 0.034–1.99 ng/ml] and critical patients (sTM = 6.07 ng/ml, VWF = 294 U/dl) being significantly higher than in the mild group (sTM = 4.18 ng/ml, VWF = 206 U/dl). In contrast, platelet activation markers were elevated only in critically ill patients at baseline (Soluble P-selectin = 37.3 ng/ml, BTG = 2.51 ng/ml). The critical group had significantly lower fibrinolysis on days 1 and 5 when compared with the moderate-severe arm. COVID-19 infection was associated with graded endothelial activation and lower fibrinolysis that correlated with illness severity.

Prognostic implications of thyroid hormones in acute aortic dissection: mediating roles of renal function and coagulation.

Thyroid hormones significantly influence cardiovascular pathophysiology, yet their prognostic role in acute aortic dissection (AAD) remains inadequately explored. This study assesses the prognostic value of thyroid hormone levels in AAD, focusing on the mediating roles of renal function and coagulation. We included 964 AAD patients in this retrospective cohort study. Utilizing logistic regression, restricted cubic splines, and causal mediation analysis, we investigated the association between thyroid hormones and in-hospital mortality and major adverse cardiovascular events (MACEs). In AAD patients overall, an increase of one standard deviation in FT4 levels was associated with a 31.9% increased risk of MACEs (OR 1.319; 95% CI 1.098-1.584) and a 36.1% increase in in-hospital mortality (OR 1.361; 95% CI 1.095-1.690). Conversely, a higher FT3/FT4 ratio was correlated with a 20.2% reduction in risk of MACEs (OR 0.798; 95% CI 0.637-0.999). This correlation was statistically significant predominantly in Type A AAD, while it did not hold statistical significance in Type B AAD. Key renal and coagulation biomarkers, including blood urea nitrogen, creatinine, cystatin C, prothrombin time ratio, prothrombin time, and prothrombin time international normalized ratio, were identified as significant mediators in the interplay between thyroid hormones and MACEs. The FT3/FT4 ratio exerted its prognostic influence primarily through the mediation of renal functions and coagulation, while FT4 levels predominantly impacted outcomes via a partial mediation effect on coagulation. FT4 levels and the FT3/FT4 ratio are crucial prognostic biomarkers in AAD patients. Renal function and coagulation mediate the association between the thyroid hormones and MACEs.

D-dimer and HbA1c levels findings in COVID-19 Iraqi patients.

On March 11, 2020, the World Health Organization (WHO) declared a new coronavirus infection caused by the SARS-CoV-2 virus as a pandemic, making it the 11th pandemic of the 20th and 21st centuries. This study investigated the clinical and laboratory results (D-dimer, conventional coagulation, and HbA1c biomarker concentrations) of 150 patients (75 male and 75 female) with confirmed COVID-19 pneumonia and 50 controls (25 male and 25 female). For disease diagnosis, all COVID-19 patients were given a Real-Time Reverse Transcription Polymerase Chain Reaction Assay (RT-PCR). The findings revealed that D-dimer and HbA1c levels in COVID-19 patients were significantly higher (P 0.001) at the time of admission; In COVID-19 patients, there was also a strong correlation between D-dimer levels and HbA1c levels (P 0.001). In conclusion, COVID-19 patients are more likely to have a poor prognosis if their D-dimer and HbA1c levels remain uncontrolled over a lengthy period. To lower the likelihood of a bad prognosis in COVID-19, patients with higher levels of D-dimer and HbA1c should be continuously monitored.

Tissue factor pathway-related biomarkers in liver cancer: activated factor VII–antithrombin complex and tissue factor mRNA levels are associated with mortality

BackgroundTissue factor (TF), the main initiator of the coagulation cascade, plays a role in cancer progression and prognosis. Activated factor VII–antithrombin complex (FVIIa-AT) is considered an indirect marker of TF exposure by reflecting TF-FVIIa interaction. ObjectivesTo assess the link between FVIIa-AT plasma levels, TF messenger RNA (mRNA) expression, and survival in cancer. MethodsTF pathway–related coagulation biomarkers were assessed in 136 patients with cancer (52 with hepatocellular carcinoma, 41 with cholangiocarcinoma, and 43 with colon cancer) undergoing surgical intervention with curative intent. TF mRNA expression analysis in neoplastic vs nonneoplastic liver tissues was evaluated in a subgroup of 91 patients with primary liver cancer. ResultsFVIIa-AT levels were higher in patients with cancer than in 136 sex- and age-matched cancer-free controls. In patients with cancer, high levels of FVIIa-AT and total TF pathway inhibitor were associated with an increased mortality risk after adjustment for confounders, but only FVIIa-AT remained a predictor of mortality by including both FVIIa-AT and total TF pathway inhibitor in Cox regression (hazard ratio, 2.80; 95% CI, 1.23-6.39; the highest vs the lowest quartile). This association remained significant even after adjustment for extracellular vesicle–associated TF-dependent procoagulant activity. In the subgroup of patients with primary liver cancer, patients with high TF mRNA levels had an increased mortality risk compared with that for those with low TF mRNA levels (hazard ratio, 1.92; 95% CI, 1.03-3.57), and there was a consistent correlation among high FVIIa-AT levels, high TF mRNA levels, and increased risk of mortality. ConclusionHigh FVIIa-AT levels may allow the identification of patients with cancer involving high TF expression and predict a higher mortality risk in liver cancer.

Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks

BackgroundEmicizumab is a bispecific antibody that bridges activated factor (F)IX and FX, mimicking the function of missing activated FVIII and thus improving hemostasis in people with hemophilia A. The efficacy and safety of emicizumab were demonstrated in 4 phase III clinical trials (HAVEN 1-4). ObjectivesHere, we describe pharmacokinetics (PKs), pharmacodynamics (PDs), and exploratory safety biomarkers in HAVEN 1 to 4. MethodsParticipants received emicizumab at a loading dose of 3 mg/kg weekly for 4 weeks, followed by maintenance doses of 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. PKs, PDs, and safety biomarkers were assessed in samples collected at regular intervals during the trials. ResultsEmicizumab plasma trough concentrations increased during the loading dose period, reaching a mean of 52.9 μg/mL (SD, 13.6 μg/mL) at week 5, and were sustained at 42.1 to 52.3 μg/mL thereafter with maintenance dosing. Activated partial thromboplastin time shortened following the first emicizumab dose. Mean FVIII-like activity and thrombin generation peak height increased to 25.2 IU/dL (SD, 6.9 IU/dL) and 115.2 nM (SD, 42.5 nM) at week 5, with levels sustained at 17 to 23 IU/dL and >116 nM thereafter, respectively. Emicizumab did not notably affect FIX or FX plasma antigen levels, prothrombin time, or concentrations of exploratory safety markers of coagulation activation (D-dimer, prothrombin fragment 1 + 2, and fibrinogen). ConclusionIn HAVEN 1 to 4, emicizumab demonstrated sustained PKs and PDs and improved coagulation parameters without affecting safety biomarkers.

No Detectable Coagulation Activation After Vitamin K (MK-7) Supplementation in Patients on Dialysis With Functional Vitamin K Deficiency: A One-Year Randomized, Placebo-Controlled Study

Patients on dialysis treatment have poor functional vitamin K status, and this may increase the risk of vascular calcification. Vitamin K supplementation may therefore be relevant in patients on dialysis, but the procoagulant effects have not been studied. We evaluated effects of menaquinone-7 (MK-7) supplementation on biomarkers of coagulation in patients on dialysis. Double-blinded, placebo-controlled study in 123 patients on dialysis randomized to 52weeks of vitamin K (MK-7, 360μg/daily, n=61) or placebo (n=62). Measurements at baseline and after 52weeks of intervention included thrombin generation (endogenous thrombin potential, peak thrombin concentration, time to peak, and lag time); clot activities of vitamin K-dependent coagulation factors (F) II, VII, IX, and X; prothrombin fragment 1+2 (F1+2); and proteins induced by vitamin K absence II (PIVKA-II). Between-group differences (vitamin K vs. placebo) at 52weeks were determined with an analysis of covariance. Within-group changes in vitamin K and placebo groups were analyzed with a paired t-test. Vascular adverse events and serious adverse events were registered based on hospital records, laboratory data, and participant interviews and compared between groups using Fisher's exact test or Pearson's Chi-Squared test. A between-group difference at 52weeks was observed for PIVKA-II (P<.001). PIVKA-II decreased significantly from baseline to 52weeks in the vitamin K group, but not in the placebo group. We observed no between-group differences or within-group changes for biomarkers of coagulation, except for FVII clot activity which was reduced in the placebo group (P=.04), and no between-group differences in adverse events and serious adverse events. One year of vitamin K supplementation in patients on dialysis has no detectable effects on biomarkers of coagulation activation, clot activities of vitamin K-dependent coagulation factors, and vascular events or death, indicating no procoagulant effects of this treatment.