What Is the Impact of Baseline Inflammatory and Hemostatic Indicators with the Risk of Mortality in Severe Inpatients with COVID-19: A Retrospective Study.

The purpose of the study was to investigate baseline inflammatory, hemostatic indicators and new-onset deep vein thrombosis (DVT) with the risk of mortality in COVID-19 inpatients. In this single-center study, a total of 401 COVID-19 patients hospitalized in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine were enrolled from December 1, 2022 to January 31, 2023. The basic information, first laboratory examination results, imaging examination, and outcome-related indicators were compared between patients in the moderate and severe subgroups. We found that baseline D-dimer and baseline absolute neutrophil count (ANC) levels were associated with new-onset DVT and death in severe hospitalized patients with COVID-19. The odds ratio (OR) of baseline D-dimer and baseline ANC with mortality was 1.18 (95% confidence interval [CI], 1.08-1.28; P < .001) and 1.13 (95% CI, 1.06-1.21; P < .001). Baseline ANC was associated with the risk of death in severe hospitalized COVID-19 patients, irrespective of the DVT status. In addition, a significantly higher serum neutrophil activity was observed in severe COVID-19 inpatients with DVT or those deceased during hospital stay. New-onset DVT partially mediated the association between baseline D-dimer (indirect effect: 0.011, estimated mediating proportion: 67.0%), baseline ANC (indirect effect: 0.006, estimated mediating proportion: 48.7%), and mortality in severe hospitalized patients with COVID-19. In summary, baseline D-dimer and baseline absolute neutrophil count (ANC) levels were associated with the mortality in severe hospitalized patients with COVID-19, especially DVT inpatients. New-onset DVT partially mediated the association between baseline D-dimer, baseline ANC, and mortality in severe hospitalized patients with COVID-19.

C-reactive protein is a predictor for lower-extremity deep venous thrombosis in patients with primary intracerebral hemorrhage.

OBJECTIVE: Our study aimed to determine whether there exists an association between low-grade systemic inflammation, as measured by serum C-reactive protein (CRP), and the risk of lower-extremity deep venous thrombosis (LEDVT) in patients with primary intracerebral hemorrhage (ICH). METHODS: This observational study was retrospectively conducted on patients with primary ICH who were presented to two tertiary medical centers between January 2021 and August 2022. The primary outcome was detecting LEDVT occurrence within 14 days from the onset of the acute ICH episode. Weighted logistic regression and restricted cubic spline models were employed to estimate the association between CRP and LEDVT following 1:1 propensity score matching (PSM). RESULTS: Of the 538 patients with primary ICH who met the inclusion criteria, 76 (14.13%) experienced LEDVT. Based on the cut-off levels of CRP measured upon admission from the receiver operating characteristic (ROC) curve, patients with primary ICH were categorized into two groups: (i) CRP < 1.59 mg/L and (ii) CRP ≥ 1.59 mg/L. After 1:1 PSM, the LEDVT events occurred in 24.6% of patients with CRP ≥ 1.59 mg/L and 4.1% of patients with CRP < 1.59 mg/L (P < 0.001). ROC curve revealed the area under the ROC curve of 0.717 [95% confidence interval (CI) 0.669-0.761, P < 0.001] for CRP to predict LEDVT with a sensitivity of 85.71% and specificity of 56.29%. After adjusting for all confounding variables, the occurrence of LEDVT in ICH patients with higher CRP levels (≥ 1.59 mg/L) was 10.8 times higher compared to those with lower CRP levels (95% CI 4.5-25.8, P < 0.001). A nonlinear association was observed between CRP and an increased risk of LEDVT in the fully adjusted model (P for overall < 0.001, P for nonlinear = 0.001). The subgroup results indicated a consistent positive link between CRP and LEDVT events following primary ICH. CONCLUSIONS: Higher initial CRP levels (CRP as a dichotomized variable) in patients with primary ICH are significantly associated with an increased risk of LEDVT and may help identify high-risk patients with LEDVT. Clinicians should be vigilant to enable early and effective intervention in patients at high risk of LEDVT.

Preliminary clinical analysis and pathway study of S100A8 as a biomarker for the diagnosis of acute deep vein thrombosis.

Herein, we aimed to identify blood biomarkers that compensate for the poor specificity of D-dimer in the diagnosis of deep vein thrombosis (DVT). S100A8 was identified by conducting protein microarray analysis of blood samples from patients with and without DVT. We used ELISA to detect S100A8, VCAM-1, and ICAM-1 expression levels in human blood and evaluated their correlations. Additionally, we employed human recombinant protein S100A8 to induce human umbilical vein endothelial cells and examined the role of the TLR4/MAPK/VCAM-1 and ICAM-1 signaling axes in the pathogenic mechanism of S100A8. Simultaneously, we constructed a rat model of thrombosis induced by inferior vena cava stenosis and detected levels of S100A8, VCAM-1, and ICAM-1 in the blood of DVT rats using ELISA. The associations of thrombus tissue, neutrophils, and CD68-positive cells with S100A8 and p38MAPK, TLR4, and VCAM-1 expression levels in vein walls were explored. The results revealed that blood S100A8 was significantly upregulated during the acute phase of DVT and activated p38MAPK expression by combining with TLR4 to enhance the expression and secretion of VCAM-1 and ICAM-1, thereby affecting the occurrence and development of DVT. Therefore, S100A8 could be a potential biomarker for early diagnosis and screening of DVT.

Neutrophil extracellular traps formation may be involved in the association of propranolol with the development of portal vein thrombosis.

BACKGROUND & AIMS: Nonselective ß blockers (NSBBs) facilitate the development of portal vein thrombosis (PVT) in liver cirrhosis. Considering the potential effect of NSBBs on neutrophils and neutrophil extracellular traps (NETs), we speculated that NSBBs might promote the development of PVT by stimulating neutrophils to release NETs. MATERIALS AND METHODS: Serum NETs biomarkers were measured, use of NSBBs was recorded, and PVT was evaluated in cirrhotic patients. Carbon tetrachloride and ferric chloride (FeCl3) were used to induce liver fibrosis and PVT in mice, respectively. After treatment with propranolol and DNase I, neutrophils in peripheral blood, colocalization and expression of NETs in PVT specimens, and NETs biomarkers in serum were measured. Ex vivo clots lysis analysis was performed and portal vein velocity and coagulation parameters were tested. RESULTS: Serum MPO-DNA level was significantly higher in cirrhotic patients treated with NSBBs, and serum H3Cit and MPO-DNA levels were significantly higher in those with PVT. In fibrotic mice, following treatment with propranolol, DNase I significantly shortened the time of FeCl3-induced PVT formation, lowered the peripheral blood neutrophils labelled by CD11b/Ly6G, inhibited the positive staining of H3Cit and the expression of H3Cit and MPO proteins in PVT tissues, and reduced serum nucleosome level. Furthermore, the addition of DNase I to tissue plasminogen activator (tPA) significantly accelerated clots lysis as compared with tPA alone. Propranolol reduced portal vein velocity in fibrotic mice, but did not influence coagulation parameters. CONCLUSION: Our study provides a clue to the potential impact of NETs formation on the association of NSBBs with the development of PVT.

Predictive value of prenatal ultrasound combined with long non-coding RNA CRNDE of women for their postpartum lower extremity deep venous thrombosis.

OBJECTIVE: Deep vein thrombosis (DVT) is a common complication in obstetrics that needs early interaction. The study examined the expression change and clinical value of long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) in DVT early diagnosis. METHODS: One hundred patients with DVT after delivery and 100 healthy parturients without DVT were enrolled. Serum samples were collected one day before delivery and received qRT-PCR for mRNA detection. Prenatal coagulation markers including prothrombin time (PT), activated partial prothrombin time (APTT), fibrinogen (FIB) and thrombin time (TT), D-dimer (D-D), thrombomodulin (TM), and peroxidase anti-peroxidase soluble complex (PAP) were tested. The receiver operating characteristic (ROC) curve was drawn for the diagnostic value assessment. RESULTS: LncRNA CRNDE levels increased remarkably in the serum of DVT patients compared with the healthy controls, which were negatively correlated with serum concentration of PT, APTT, and TT while positively correlated with FIB, D-D, TM, and PAP. Serum CRNDE (HR = 5.973, 95% CI = 2.990-11.933, p < .001) was independently related to the occurrence of DVT after delivery. Then, ROC curve using serum CRNDE showed a good diagnostic value for DVT with the AUC of 0.899. ROC curve of ultrasonography combined with CRNDE produced an AUC of 0.968, and both sensitivity and specificity were enhanced compared to a single indicator. CONCLUSIONS: The increase of CRNDE level was an independent risk factor for postpartum DVT. Prenatal ultrasonography combined with CRNDE can improve the predictive efficacy for DVT.

[Value of serum levels in predicting lower extremity deep vein thrombosis after hip joint surgery in the elderly].

OBJECTIVE: To explore the value of serum D-dimer (D-D), fibrinogen (FIB), platelet (PLT), C-reactive protein (CRP) and tissue plasminogen activator inhibitor (PAI)-1 levels in predicting lower extremity deep vein thrombosis (DVT) after hip joint surgery in the elderly. METHODS: A retrospective analysis was performed on 165 elderly patients with hip joint surgery admitted from February 2020 to May 2022, including 89 males and 76 females, aged from 60 to 75 years old with an average of (66.43±5.48) years, and there were 102 cases of femoral neck fracture and 63 cases of femoral head necrosis. Serum levels of D-D, FIB, PLT, CRP and PAI-1 tests were performed in all patients within 24 hours after admission, and the patients were divided into DVT group and non-DVT group according to whether they developed DVT. RESULTS: The levels of D-D, FIB, PLT, CRP, and PAI-1 in the DVT group were higher than those in the non-DVT group (P<0.001). Spearman analysis showed that DVT was positively correlated with PLT, CRP, D-D, FIB, and PAI-1 levels (r=0.382, 0.213, 0.410, 0.310, 0.353, all P<0.001). The results of binary Logistic regression analysis showed that D-D and PLT were independent factors affecting the occurrence of DVT (OR=0.038, 0.960, P=0.032, 0.011). The area under curve (AUC) of D-D, FIB, PLT, CRP, PAI-1, and the five combined predictions for DVT were 0.843, 0.692, 0.871, 0.780, 0.819, and 0.960, respectively. The AUC of the five combined predictions was higher than that of the single prediction (P<0.05). CONCLUSION: D-D, FIB, PLT, CRP and PAI-1 are effective in predicting DVT after hip surgery in the elderly, and the combined prediction of the five factors has higher efficacy.

Exploring Risk Factors for Lower Extremity Deep Vein Thrombosis Patients with Co-existing Pulmonary Embolism Based on Multiple Logistic Regression Model.

Valuable data on deep vein thrombosis (DVT) patients with coexisting pulmonary embolism (PE) is scarce. This study aimed to identify risk factors associated with these patients and develop logistic regression models to select high-risk DVT patients with coexisting PE. We retrospectively collected data on 150 DVT patients between July 15, 2022, and June 15, 2023, dividing them into groups based on the presence of coexisting PE. Univariate and multivariate logistic regression analyses were performed to identify significant risk factors and construct predictive models. Discrimination and calibration statistics evaluated the validation and accuracy of the developed models. Of the 130 patients analyzed, 40 (30.77%) had coexisting PE. Univariate analysis revealed four significant predictors of DVT patients with coexisting PE: sex (OR 3.83, 95% CI: [1.76; 8.59], P = 0.001), body mass index (BMI) (OR 1.50, 95% CI: [1.28; 1.75], P < 0.001), chronic disease (OR 5.15, 95% CI: [2.32; 11.8], P < 0.001), and high-density lipoprotein (HDL) (OR 0.03, 95% CI: [0.01; 0.20], P < 0.001). Additionally, BMI > 24 kg/m2 (OR 9.70, 95% CI: [2.70; 67.5], P < 0.001) and BMI > 28 kg/m2 (OR 4.80, 95% CI: [2.15; 11.0], P < 0.001) were associated with concurrent PE. Three multiple regression models were constructed, with areas under the receiver-operating characteristic curves of 0.925 (95% CI: [0.882; 0.968]), 0.908 (95% CI: [0.859; 0.957]), and 0.890 (95% CI: [0.836; 0.944]), respectively. Sex, BMI, chronic disease, and HDL levels are significant predictors of DVT patients with coexisting PE.

Acute phase determinant of post-thrombotic syndrome: A review of the literature.

BACKGROUND: Post-thrombotic syndrome (PTS) is the main long-term complication of deep vein thrombosis (DVT). Several therapies are being evaluated to prevent or to treat PTS. Identifying the patients most likely to benefit from these therapies presents a significant challenge. OBJECTIVES: The objective of this review was to identify risk factors for PTS during the acute phase of DVT. ELIGIBILITY CRITERIA: We searched the PubMed and Cochrane databases for studies published between January 2000 and January 2021, including randomized clinical trials, meta-analyses, systematic reviews and observational studies. RESULTS: Risk factors for PTS such as proximal location of DVT, obesity, chronic venous disease, history of DVT are associated with higher risk of PTS. On the initial ultrasound-Doppler, a high thrombotic burden appears to be a predictor of PTS. Among the evaluated biomarkers, some inflammatory markers such as ICAM-1, MMP-1 and MMP-8 appear to be associated with a higher risk of developing PTS. Coagulation disorders are not associated with risk of developing PTS. Role of endothelial biomarkers in predicting PTS has been poorly explored. Lastly, vitamin K antagonist was associated with a higher risk of developing PTS when compared to direct oral anticoagulants and low molecular weight heparin. CONCLUSIONS: Several risk factors during the acute phase of VTE are associated with an increased risk of developing PTS. There is a high-unmet medical need to identify potential biomarkers for early detection of patients at risk of developing PTS after VTE. Inflammatory and endothelial biomarkers should be explored in larger prospective studies to identify populations that could benefit from new therapies.

Analysis of four hereditary protein C deficiencies associated with vascular thromboembolism.

OBJECTIVE: To analyze the clinical features and gene mutations in four families with hereditary protein C (PC) deficiency and explore their association with vascular thromboembolism. METHODS: The clinical data of four patients with PC deficiency were retrospectively analyzed. Venous blood samples were collected from the four affected patients and their family members, and relevant coagulation indexes and thrombin production and inhibition tests were performed. PCR was used to amplify and directly sequence the PROC gene of the probands. Software analysis was conducted to assess the conservativeness and pathogenicity of the mutated loci. Protein models were constructed to analyze the spatial structure before and after the mutation. RESULTS: Thrombin generation and inhibition assays demonstrated impaired anticoagulation in all four probands. Proband 1 and 4 presented clinically with pulmonary embolism and lower extremity deep vein thrombosis (DVT), Proband 2 with cerebral infarction, and Proband 3 with DVT. Genetic analysis revealed the presence of the following mutations: c.541T > G heterozygous missense mutation, c.577-579delAAG heterozygous deletion mutation, c.247-248insCT heterozygous insertion mutation, c.659G > A heterozygous missense mutation, and a new variant locus c.1146_1146delT heterozygous deletion mutation in the four probands, respectively. In particular, c.1146_1146delT heterozygous deletion mutations not reported previously. Conservativeness and pathogenicity analyses confirmed that most of these amino acid residues were conserved, and all the mutations were found to be pathogenic. Analysis of protein modeling revealed that these mutations induced structural alterations in the protein or led to the formation of truncated proteins. According to the American College of Medical Genetics and Genomics (ACMG) classification criteria and guidelines for genetic variants, c.1146_1146delT was rated as pathogenic (PVS1 + M2 + PM4 + PP1 + PP3 + PP4). CONCLUSION: The identified mutations are likely associated with decreased PC levels in each of the four families. The clinical manifestations of hereditary PC deficiency exhibit considerable diversity.

Homozygous MTHFR C677T carriers develop idiopathic portal vein thrombosis 20 years earlier than wild type.

The aim of this study was to evaluate the impact of methylene tetrahydrofolate reductase (MTHFR) rs1801133 (C→T667 transition) on age at first idiopathic portal vein thrombosis (PVT) and to identify clinical and/or laboratory variables influencing age at first PVT, including plasma homocysteine and the prothrombin rs1799963 PT (G→A transition at position 20210) (PT) mutation. A retrospective cross-sectional cohort, including 15 MTHFR TT, 32 MTHFR TC and 22 MTHFR CC idiopathic PVT participants contributing demographics, age at PVT, plasma concentrations of homocysteine and of natural anticoagulants. MTHFR TT carriers presented with a lower age at PVT than heterozygous or wild-type genotypes (31 ±â€Š8 vs. 48 ±â€Š15 vs. 52 ±â€Š13 years, P  = 0.001) and were more likely to have a plasma HC concentration above the cut-off (73.3 vs. 32 vs. 50%, P  = 0.04). MTHFR TT and protein C predicted age at PVT ( P  < 0.0001 and P  = 0.06); MTHFR TT predicted plasma homocysteine ( P  = 0.05). In the MTHFR TT group, plasma homocysteine inversely related to protein C ( P  = 0.03). Plasma homocysteine predicted the extent of PVT ( P  = 0.03). Compound MTHFR TT + PT GA did not lower age at first PVT compared to MTHFR TT alone (35 ±â€Š9 vs. 30 ±â€Š8 years). MTHFR TT is associated with a 20-year earlier PVT presentation than heterozygous and wild-type MTHFR genotypes. The inverse relation between plasma homocysteine and protein C contributes to the prematurity of PVT in the MTHFR TT group, whereas plasma homocysteine contributes to the extent of PVT. The recent exclusion of MTHFR genotyping from the thrombophilia screen needs revisiting in this setting.

Platelet factor 4 promotes deep venous thrombosis by regulating the formation of neutrophil extracellular traps.

The presence of neutrophil extracellular traps (NETs) in thrombotic diseases has been extensively studied. The exact mechanism of NET formation in deep venous thrombosis (DVT) has not been largely studied. This study is aimed to explore the role of NETs and their interaction with platelet factor 4 (PF4) in DVT. In plasma samples from 51 healthy volunteers and 52 DVT patients, NET markers and PF4 were measured using enzyme-linked immunosorbent assays (ELISA). NET generation in blood samples from healthy subjects and DVT patients was analyzed by confocal microscopy and flow cytometry. The plasma levels of NETs were significantly elevated in DVT patients, and neutrophils from patients showed a stronger ability to generate NETs after treatment. PF4 was upregulated in plasma samples from DVT patients and mediated NET formation. NETs enhanced procoagulant (PCA) via tissue factor and activating platelets to induce procoagulant activity. In addition, we established an inferior vena cava ligation (IVC) model to examine the role of NETs in thrombogenicity in DVT. In conclusion, NET formation was mediated by PF4 and enhance the procoagulant activity in DVT.

Fibrinogen levels and clot properties identify patients who benefit from catheter-directed thrombolysis after DVT.

ABSTRACT: Ultrasound-accelerated catheter-directed thrombolysis (UA-CDT) to improve patency after deep vein thrombosis (DVT) has not conclusively been shown to prevent postthrombotic syndrome (PTS) but might benefit patients who are unlikely to obtain patency with standard treatment. We hypothesized that these patients could be selected based on their fibrin clot properties. To study this, patients with acute iliofemoral DVT from the CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis Versus Anticoagulation for the Prevention of Post-thrombotic Syndrome) trial had blood samples taken at inclusion. Fibrin clot properties in plasma were determined by turbidimetric clotting (lag time and maximal turbidity) and lysis assays (time to 50% lysis and lysis rate), permeation assay, and confocal microscopy (fiber density), as well as levels of fibrin clot modifiers fibrinogen and C-reactive protein (CRP). Patency was defined as >90% iliofemoral vein compressibility at 12-month ultrasound. PTS was defined as ≥5 Villalta score at 6 or 12 months. In total, 91 of 152 patients were included, including 43 with additional UA-CDT and 48 with standard treatment. Patients with additional UA-CDT more often obtained patency (55.8 vs 27.1%) Patients who obtained patency had longer lag times and lower maximal turbidity, fibrinogen, and CRP; only maximal turbidity and fibrinogen remained associated when adjusting for treatment, thrombus load, and body mass index. Fibrinogen levels had an optimal cutoff at 4.85 g/L. Low fibrinogen levels best predicted patency. Additional UA-CDT decreased the risk of PTS only in patients with high fibrinogen. Therefore, additional UA-CDT might prevent PTS in selected patients based on routinely measured fibrinogen levels. This study was registered at www.ClinicalTrials.gov as #NCT00970619.

Mucin 1 and venous thrombosis in tumor-bearing mice and patients with cancer.

INTRODUCTION: Mucins released from epithelial tumors have been proposed to play a role in cancer-associated thrombosis. Mucin1 (MUC1) is a transmembrane mucin that is overexpressed in a variety of human malignancies, including breast and pancreatic cancer. We analyzed the association of MUC1 and venous thrombosis in a mouse tumor model and in patients with cancer. MATERIALS AND METHODS: We used a human pancreatic cancer cell line HPAF-II that expresses a high level of MUC1. We grew HPAF-II tumors in the pancreas of Crl:NU-Foxn1nu male mice. MUC1 in plasma and extracellular vesicles (EVs) isolated from plasma was measured using an enzyme-linked immunosorbent assay. MUC1 in EVs and venous thrombi from tumor-bearing mice was assessed by western blotting. We measured MUC1 in plasma from healthy controls and patients with stomach, colorectal or pancreatic cancer with or without venous thromboembolism. RESULTS AND DISCUSSION: MUC1 was detected in the plasma of mice bearing HPAF-II tumors and was associated with EVs. MUC1 was present in venous thrombi from mice bearing HFAP-II tumors. Recombinant MUC1 did not induce platelet aggregation. Levels of MUC1 were higher in patients with pancreatic cancer compared with healthy controls. In contrast to the mouse model, MUC1 was present in EV-free plasma in samples from healthy controls and patients with cancer. There was no significant difference in the levels of MUC1 in cancer patients with or without VTE. Our data did not find any evidence that MUC1 contributed to VTE in patients with cancer.

Time-dependent ultrastructural changes during venous thrombogenesis and thrombus resolution.

BACKGROUND: Deep vein thrombosis is a common vascular event that can result in debilitating morbidity and even death due to pulmonary embolism. Clinically, patients with faster resolution of a venous thrombus have improved prognosis, but the detailed structural information regarding changes that occur in a resolving thrombus over time is lacking. OBJECTIVES: To define the spatial-morphologic characteristics of venous thrombus formation, propagation, and resolution at the submicron level over time. METHODS: Using a murine model of stasis-induced deep vein thrombosis along with scanning electron microscopy and immunohistology, we determine the specific structural, compositional, and morphologic characteristics of venous thrombi formed after 4 days and identify the changes that take place during resolution by day 7. Comparison is made with the structure and composition of venous thrombi formed in mice genetically deficient in plasminogen activator inhibitor type 1. RESULTS: As venous thrombus resolution progresses, fibrin exists in different structural forms, and there are dynamic cellular changes in the compositions of leukocytes, platelet aggregates, and red blood cells. Intrathrombus microvesicles are present that are not evident by histology, and red blood cells in the form of polyhedrocytes are an indicator of clot contraction. Structural evidence of fibrinolysis is observed early during thrombogenesis and is accelerated by plasminogen activator inhibitor type 1 deficiency. CONCLUSION: The results reveal unique, detailed ultrastructural and compositional insights along with documentation of the dynamic changes that occur during accelerated resolution that are not evident by standard pathologic procedures and can be applied to inform diagnosis and effectiveness of thrombolytic treatments to improve patient outcomes.

Circulating Cytokines and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

BACKGROUND: Epidemiological evidence has linked circulating cytokines to venous thromboembolism (VTE). However, it remains uncertain whether these associations are causal due to confounding factors or reverse causality. We aim to explore the causality between circulating cytokines and VTE, encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: In the current bidirectional Mendelian randomization (MR) study, instrumental variables of 41 circulating cytokines were obtained from the genome-wide association study meta-analyses (8,293 individuals). Summary statistics for the association of VTE (17,048 cases and 325,451 controls), DVT (8,077 cases and 295,014 controls), and PE (8,170 cases and 333,487 controls) were extracted from the FinnGen Study. A multivariable MR study was conducted to adjust for potential confounders. The inverse-variance weighted method was employed as the main analysis, and comprehensive sensitivity analyses were conducted in the supplementary analyses. RESULTS: The MR analysis indicated stromal cell-derived factor-1α was suggestively associated with a reduced risk of VTE (odds ratio [OR]: 0.90; 95% confidence interval [CI]: 0.81-0.99; p = 0.033) and DVT (OR: 0.85; 95% CI: 0.75-0.97; p = 0.015). In addition, suggestive association of granulocyte colony-stimulating factor with PE (OR: 1.20; 95% CI: 1.06-1.37; p = 0.005) was observed. Multivariable MR analysis showed that the effect of cytokines on VTE was partly mediated through hemoglobin A1c and systolic blood pressure. Reverse MR analysis revealed that VTE was linked to decreased levels of several cytokines. CONCLUSION: We provide suggestive genetic evidence supporting the bidirectional causal effect between circulating cytokines and VTE, highlighting the importance of targeting circulating cytokines to reduce the incidence of VTE.

Combination of Circulating miR-125a-5p, miR-223-3p and D-dimer as a Novel Biomarker for Deep Vein Thrombosis.

BACKGROUND: Deep venous thrombosis (DVT) is a thrombus formed in the deep venous cavity and can cause a fatal pulmonary embolism. Since circulating miRNAs are used as molecular markers for the early warning and diagnosis of various diseases, such as tumors and cardiovascular diseases, the purpose of the present study was initially to identify differential expression circulating miRNAs in plasma, and then explore potential biomarkers for DVT. METHODS: The plasma of 30 patients with DVT before and after DVT-related endovascular interventions constituted 6 sample pools for miRNA sequencing, and the levels of 22 plasma miRNAs were significantly changed. Then, various bioinformatics tools were utilized to screen out 8 miRNAs with potential DVT diagnostic value. Furthermore, their diagnostic values were evaluated in 120 patients with DVT and 120 healthy individuals. RESULTS: The levels of 22 circulating plasma miRNAs (12 up-regulated, 10 down-regulated) were significantly changed in patients with DVT before and after endovascular interventions, especially miR-125a-5p (up-regulation) and miR-223-3p (down-regulation). The values of area under the ROC curve (AUC) of miR-125a-5p and miR-223-3p were both >0.8, indicating that they were valuable in diagnosing DVT. The combination of miR-125a-5p and miR-223-3p with D-dimer significantly improved the efficiency of diagnosing DVT, (AUC >0.97, the sensitivity and specificity >95%), and was better than those of D-dimer alone. CONCLUSIONS: The levels of miR-125a-5p and miR-223-3p were the most significantly changed in patients with DVT before and after endovascular interventions; together with the classic biomarker D-dimer, they can be used as a potential biomarker for diagnostic and therapeutic process of DVT.

[Predictive value of D-dimer for deep venous thrombosis of lower extremity in adult burn patients].

Objective: To investigate the predictive value of D-dimer for deep venous thrombosis (DVT) of lower extremity in adult burn patients. Methods: A retrospective case series study was conducted. The clinical data of 3 861 adult burn patients who met the inclusion criteria and were admitted to the Department of Burns of Zhengzhou First People's Hospital from January 1, 2015 to December 31, 2019 were collected. The patients were divided into DVT group (n=77) and non-DVT group (n=3 784) according to whether DVT of lower extremity occurred during hospitalization or not. Data of patients in the two groups were collected and compared, including the gender, age, total burn area, D-dimer level, with lower limb burn and inhalation injury or not on admission, with sepsis/septic shock, femoral vein indwelling central venous catheter (CVC), history of surgery, and infusion of concentrated red blood cells or not during hospitalization. Data were statistically analyzed with independent sample t test, Mann-Whitney U test, and chi-square test. The indicators with statistically significant differences between the two groups were analyzed with multivariate logistic regression analysis to screen the independent risk factors for DVT of lower extremity in 3 861 adult burn patients. The receiver operating characteristic (ROC) curve of the independent risk factors predicting DVT of lower extremity in 3 861 adult burn patients were drawn, and the area under the curve (AUC), the optimal threshold value, and the sensitivity and specificity under the optimal threshold value were calculated. The quality of the AUC was compared by Delong test, and the sensitivity and specificity under the optimal threshold value were compared using chi-square test. Results: There were no statistically significant differences in gender, occurrence of sepsis/septic shock or history of surgery during hospitalization between patients in the two groups (P>0.05), while there were statistically significant differences in age, total burn area, D-dimer level, lower limb burn and inhalation injury on admission, and femoral vein indwelling CVC and infusion of concentrated red blood cells during hospitalization between patients in the two groups (t=-8.17, with Z values of -5.04 and -10.83, respectively, χ2 values of 21.83, 5.37, 7.75, and 4.52, respectively, P<0.05 or P<0.01). Multivariate logistic regression analysis showed that age, total burn area, and D-dimer level were the independent risk factors for DVT of lower extremity in 3 861 adult burn patients (with odds ratios of 1.05, 1.02, and 1.14, respectively, 95% confidence intervals of 1.04-1.06, 1.00-1.03, and 1.10-1.20, respectively, P<0.05 or P<0.01). The AUCs of ROC of age, total burn area, and D-dimer level for predicting DVT of lower extremity in 3 861 adult burn patients were 0.74, 0.67, and 0.86, respectively (with 95% confidence intervals of 0.68-0.80, 0.60-0.74, and 0.83-0.89, respectively, P values<0.01), the optimal threshold values were 50.5 years old, 10.5% total body surface area, and 1.845 mg/L, respectively, the sensitivity under the optimal threshold values were 71.4%, 70.1%, and 87.0%, respectively, and the specificity under the optimal threshold values were 66.8%, 67.2%, and 72.9%, respectively. The AUC quality and sensitivity and specificity under the optimal threshold value of D-dimer level were significantly better than those of age (z=3.29, with χ2 values of 284.91 and 34.25, respectively, P<0.01) and total burn area (z=4.98, with χ2 values of 326.79 and 29.88, respectively, P<0.01), while the AUC quality and sensitivity and specificity under the optimal threshold values were similar between age and total burn area (P>0.05). Conclusions: D-dimer level is an independent risk factor for DVT of lower extremity in adult burn patients, its AUC quality and sensitivity and specificity under the optimal threshold value are better than those of age and total burn area, and it has good predictive value for DVT of lower extremity in adult burn patients.

The influence of corn trypsin inhibitor on the contribution of coagulation determinants to the Technoclone Thrombin Generation Assay (TGA) and the Calibrated Automated Thrombogram (CAT).

In thrombin generation (TG) assays, regarded as global coagulation tests, contact activation is considered a major problem which can be eliminated by adding Corn Trypsin Inhibitor (CTI). In previous studies, however, venous thrombosis risk prediction using TG assays did not improve after CTI addition. However, it is unknown whether CTI addition could help to detect subtle but relevant nuances in determinants of TG, making the assay more suitable to detect disturbances in the coagulation system. This study's objective was to assess whether the addition of CTI is associated with a broader contribution of individual coagulation factors to the total amount of thrombin formed in Calibrated Automated Thrombogram (CAT) and Technoclone Thrombin Generation Assay (TGA). Thrombin generation was measured in 326 healthy individuals from THE VTE study at very low tissue factor concentrations, with and without addition of CTI prior to blood sampling. The influence of several coagulation factors on total amount of thrombin formed, i.e. area under the curve (AUC) or endogenous thrombin potential (ETP), was analysed using multiple linear regression with standardisation of all values resulting in Z-scores with 95% confidence intervals (95%CI). Association between coagulation factors and TG changed minimally after addition of CTI. Largest changes after CTI addition were found for following factors: for CAT: free protein S (from 0.00 (95%CI -0.12 to 0.12) to -0.29 (95%CI -0.43 to -0.15)) and protein S (from -0.05 (95%CI -0.18 to 0.08) to -0.21 (95%CI -0.37 to -0.05)); for TGA: antithrombin (from -0.11 (-0.23 to 0.02) to -0.19 (-0.30 to -0.07)), factor VIII (from 0.15 (0.03 to 0.27) to 0.24 (0.13 to 0.36)) and fibrinogen (from 0.12 (-0.01 to 0.26) to 0.19 (0.06 to 0.32)). In conclusion, there is no clear trend towards a broader contribution of coagulation factors in samples handled with CTI compared with those handled without CTI.

Low Mean Platelet Volume is Associated with Deep Vein Thrombosis in Older Patients with Hip Fracture.

This study aimed to explore the association between mean platelet volume (MPV) and preoperative deep vein thrombosis (DVT) in older patients with hip fracture. A total of 352 consecutive older patients with hip fracture were included from January 2014 to December 2020. MPV values were measured on admission, and color Doppler ultrasonography was performed for DVT screening before the planned surgery. The receiver operating characteristic (ROC) curve was used to establish the optimal cut-off value for the prediction of DVT. Univariate and multivariate logistic regression analysis were used to examine the association between factors and DVT. The overall prevalence of preoperative DVT was 15.1%, and patients with DVT had a lower value of MPV than non-DVT patients (11.6 ± 1.2 fL vs 12.3 ± 1.4 fL, P < .01). The cut-off point according to the ROC curve for MPV was 13.3 fL, and multivariate logistic regression analysis showed that MPV level < 13.3 fL was significantly associated with an increased risk of DVT (OR = 4.857, 95% CI: 1.091-21.617, P = .038), and with every 1.0 fL decrease in MPV, the risk increased by 27.7% (OR = 1.277, 95% CI: 1.001-1.629, P = .047). Our findings indicate that a low MPV level is associated with DVT in older patients with hip fracture. As MPV is a simple indicator that can be calculated from the blood routine test, it may be a potential biomarker of DVT with the combination of other tests, further studies are needed to confirm these results.