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.

Patients with antiphospholipid syndrome and a first venous or arterial thrombotic event: clinical characteristics, antibody profiles and estimate of the risk of recurrence.

OBJECTIVES: Thrombosis in antiphospholipid syndrome (APS) involves in most cases the venous circulation. Why in some patients thrombotic APS affects the arterial circulation and in particular cerebral circulation is unknown. In previous studies, both patient characteristics and antiphospholipid antibody types and titers have been associated with arterial thrombosis. Aim of this study was to compare the clinical characteristics and laboratory findings of venous and arterial thrombotic APS from a large series of patients. METHODS: Data were retrieved from the Start 2 antiphospholipid, a multicenter prospective register of long-term collected data from Thrombosis Centers in Italy. RESULTS: Of 167 patients with thrombotic APS, 114 (68 %) had a venous and 53 (32 %) had an arterial event as first clinical manifestation. Several clinical characteristics and risk factors were different among groups in univariate analysis. Using logistic regression analysis, reduced creatinine clearance and hyperlipidemia were independent variable for the occurrence of arterial APS. Notably, no difference in antiphospholipid antibody profiles and aß2-Glycoprotein I levels were found between groups. A higher adjusted global antiphospholipid syndrome score (aGAPSS) was found in arterial group indicating a possible high recurrence rate in arterial APS. CONCLUSIONS: These data have pathophysiological and clinical implication since associated conditions might predispose patients to arterial rather than venous events and call to a close monitoring and treatment of arterial APS due to their increased tendency to recurrence.

Discovery of crucial cytokines associated with deep vein thrombus formation by protein array analysis.

BACKGROUND: Expanding the number of biomarkers is imperative for studying the etiology and improving venous thromboembolism prediction. In this study, we aimed to identify promising biomarkers or targeted therapies to improve the detection accuracy of early-stage deep vein thrombosis (DVT) or reduce complications. METHODS: Quantibody Human Cytokine Antibody Array 440 (QAH-CAA-440) was used to screen novel serum-based biomarkers for DVT/non-lower extremity DVT (NDVT). Differentially expressed proteins in DVT were analyzed using bioinformatics methods and validated using a customized array. Diagnostic accuracy was calculated using receiver operating characteristics, and machine learning was applied to establish a biomarker model for evaluating the identified targets. Twelve targets were selected for validation. RESULTS: Cytokine profiling was conducted using a QAH-CAA-440 (RayBiotech, USA) quantimeter array. Cross-tabulation analysis with Venn diagrams identified common differential factors, leading to the selection of 12 cytokines for validation based on their clinical significance. These 12 biomarkers were consistent with the results of previous array analysis: FGF-6 (AUC = 0.956), Galectin-3 (AUC = 0.942), EDA-A2 (AUC = 0.933), CHI3L1 (AUC = 0.911), IL-1 F9 (AUC = 0.898), Dkk-4 (AUC = 0.88), IG-H3 (AUC = 0.876), IGFBP (AUC = 0.858), Gas-1 (AUC = 0.858), Layilin (AUC = 0.849), ULBP-2 (AUC = 0.813)and FGF-9 (AUC = 0.773). These cytokines are expected to serve as biomarkers, targets, or therapeutic targets to differentiate DVT from NDVT. CONCLUSIONS: EDA-A2, FGF-6, Dkk-4, IL-1 F9, Galentin-3, Layilin, Big-h3, CHI3L1, ULBP-2, Gas-1, IGFBP-5, and FGF-9 are promising targets for DVT diagnosis and treatment.

The genetic effects of hormones modulated by the Pituitary-Thyroid/Adrenal/Gonadal axis on the risk of developing venous thromboembolism: a mendelian randomization study.

BACKGROUND: The aim of this study was to explore the genetic effects of hormones modulated through the pituitary-thyroid/adrenal/gonadal axis on the risk of developing venous thromboembolism (VTE) and to investigate the potentially causal relationships between them. METHODS: A two-sample Mendelian randomization (MR) design was used. The single-nucleotide polymorphisms (SNPs) used as instrumental variables for various hormones and hormone-mediated diseases were derived from published genome-wide association studies (GWASs). Summary statistics for the risk of developing VTE (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) were obtained from the UK Biobank and the FinnGen consortium. Inverse-variance weighting (IVW) was applied as the primary method to analyse causal associations. Other MR methods were used for supplementary estimates and sensitivity analysis. RESULTS: A genetic predisposition to greater free thyroxine (FT4) concentrations was associated with a greater risk of developing DVT (OR = 1.0007, 95%CI [1.0001-1.0013], p = 0.0174) and VTE (OR = 1.0008, 95%CI [1.0002-1.0013], p = 0.0123). Genetically predicted hyperthyroidism was significantly associated with an increased risk of developing DVT (OR = 1.0685, 95%CI [1.0139-1.1261], p = 0.0134) and VTE (OR = 1.0740, 95%CI [1.0165-1.1348], p = 0.0110). According to the initial MR analysis, testosterone concentrations were positively associated with the risk of developing VTE (OR = 1.0038, 95%CI [1.004-1.0072], p = 0.0285). After sex stratification, estradiol concentrations were positively associated with the risk of developing DVT (OR = 1.0143, 95%CI [1.0020-1.0267], p = 0.0226) and VTE (OR = 1.0156, 95%CI [1.0029-1.0285], p = 0.0158) in females, while the significant relationship between testosterone and VTE did not persist. SHBG rs858518 was identified as the only SNP that was associated with an increased risk of developing VTE, mediated by estradiol, in females. CONCLUSIONS: Genetically predicted hyperthyroidism and increased FT4 concentrations were positively associated with the risk of developing VTE. The effects of genetically predicted sex hormones on the risk of developing VTE differed between males and females. Greater genetically predicted estradiol concentrations were associated with an increased risk of developing VTE in females, while the SHBG rs858518 variant may become a potential prevention and treatment target for female VTE.

ET1 acts as a potential plasma biomarker and therapeutic target in deep venous thrombosis rat model.

Deep venous thrombosis (DVT) is the third leading cause of death in cardiovascular disease, following heart attacks and strokes. Early diagnosis and intervention are crucial for effective DVT therapy. We aim to investigate whether endothelin-1 (ET-1) could serve as an early diagnostic marker or a potential therapeutic target in a DVT rat model. CCK8 assay, invasion assay, and flow cytometry were used to detect the proliferation, migration and apoptosis of HUVECs, respectively. Elisa assay was used to detect ET-1 and coagulation factor VII in cell supernatant and rat?s plasma. Western blot was used to detect antioxidant signaling protein. Inferior vena cava stenosis was used to construct the DVT rat model. Lentivirus mediated overexpression of ET-1 in HUVECs impaired the cell proliferation and migration, increased cell apoptosis, inhibited the antioxidant signaling pathway proteins expression (e.g., NQO1, GCLC, Nrf-2), and upregulated coagulation factor VII. Furthermore, overexpression of ET-1 further impaired antioxidant signaling pathway protein in response to H2O2 treatment. However, lentivirus mediated ET-1 knockdown and BQ123 (an ET-1 inhibitor), showed the opposite results with ET-1 overexpression. We then established a DVT rat model by inferior vena cava stenosis. The stenosis induced early expression of ET-1 and coagulation factor VII in plasma at day 1 and restore their level at day 10. BQ123 could downregulate the coagulation factor VII to ameliorate the stenosis effects. Our findings suggest that ET-1 might serve as an early diagnostic marker for DVT rat model and a potential therapeutic target for treating DVT.

Overall haemostatic potential assay for prediction of outcomes in venous and arterial thrombosis and thrombo-inflammatory diseases.

Thromboembolic diseases including arterial and venous thrombosis are common causes of morbidity and mortality globally. Thrombosis frequently recurs and can also complicate many inflammatory conditions through the process of 'thrombo-inflammation,' as evidenced during the COVID-19 pandemic. Current candidate biomarkers for thrombosis prediction, such as D-dimer, have poor predictive efficacy. This limits our capacity to tailor anticoagulation duration individually and may expose lower risk individuals to undue bleeding risk. Global coagulation assays, such as the Overall Haemostatic Potential (OHP) assay, that investigate fibrin generation and fibrinolysis, may provide a more accurate and functional assessment of hypercoagulability. We present a review of fibrin's critical role as a central modulator of thrombotic risk. The results of our studies demonstrating the OHP assay as a predictive biomarker in venous thromboembolism, chronic renal disease, diabetes mellitus, post-thrombotic syndrome, and COVID-19 are discussed. As a comprehensive and global measurement of fibrin generation and fibrinolytic capacity, the OHP assay may be a valuable addition to future multi-modal predictive tools in thrombosis.

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.

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.

[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.

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.

Protein profile of circulating extracellular vesicles reveals biomarker candidates for diagnosis of post-traumatic deep vein thrombosis.

BACKGROUND AND OBJECTIVE: Deep vein thrombosis (DVT) is a common complication after trauma and mostly without specific symptoms. Timely diagnosis and early appropriate treatment measures can prevent further development of thrombosis for patients with traumatic lower extremity fractures. Although extracellular vesicles (EVs) are confirmed as promising disease biomarkers, little is known about the role of altered levels and composition in the diagnosis of post-traumatic DVT. METHOD: The levels of circulating EVs subgroups were measured using flow cytometry. Isolated EVs were characterized and subjected to proteomics analysis to screen for differentially expressed proteins (DEPs) between DVT and non-DVT patients. Regularized logistic regression analysis based on L2 penalty terms using R's caret package was applied to build a model for DVT diagnosis. RESULTS: Compared to non-DVT patients, DVT patients had higher circulating hepatocyte-derived EVs (hEVs) with good predictive value for post-traumatic DVT diagnosis. The results of the proteomic analysis showed that differentially expressed proteins (DEPs) of circulating EVs between the DVT group and non-DVT group were enriched in the complement and coagulation cascade. Finally, an integrated model of five biomarkers including SERPING1, C8G, CFH, FIX, and hEVs level was established for post-traumatic DVT diagnosis with robust identification of the traumatic patients with and without DVT (AUC 0.972). CONCLUSION: Post-traumatic DVT patients had changed levels and composition of circulating EVs compared to non-DVT patients and healthy controls. Circulating EVs may acquire pathological protein signatures and become potential biomarkers for identifying subjects' post-traumatic DVT.

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.

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.

Analysis of Risk Factors for Postoperative Deep Vein Thrombosis in Traumatic Spinal Fracture Complicated with Spinal Cord Injury.

The purpose of this study is to investigate the risk factors for postoperative deep vein thrombosis (DVT) in patients with traumatic spinal fractures complicated with Spinal Cord Injury(SCI). We conducted a retrospective analysis of 110 patients with traumatic spinal fractures and SCI admitted to our hospital from March 2021 to April 2024. DVT was diagnosed using ultrasound. Patient history, general data, surgical data, laboratory tests, and thromboelastogram (TEG) results were collected. The patients were divided into a DVT group and a non-DVT group according to the results of ultrasound one week after surgery. The risk factors and diagnostic value were analyzed using binary logistic regression and receiver operating characteristic (ROC) curves in both univariate and multivariate analyses. Multivariate and ROC analysis results showed that D-dimer, lower extremity, duration of bedrest, and MA values of TEG were independent risk factors for DVT in SCI, with D-dimer having the highest diagnostic value (AUC = 0.883). The AUC values for lower extremity, duration of bedrest, and MA were 0.731, 0.750, and 0.625. In conclusion, Postoperative D-dimer > 5.065 mg/l, lower extremity < 3, duration of bedrest, and MA value of TEG are independent risk factors for postoperative DVT in SCI patients, D-dimer having the highest diagnostic value. When the above risk factors occur, clinicians need to be vigilant and take appropriate prevention and treatment measures.

Antithrombin III Levels and Outcomes Among Patients With Trauma.

Importance: Patients with trauma exhibit a complex balance of coagulopathy manifested by both bleeding and thrombosis. Antithrombin III is a plasma protein that functions as an important regulator of coagulation. Previous studies have found a high incidence of antithrombin III deficiency among patients with trauma. Objective: To assess whether changes in antithrombin III activity are associated with thrombohemorrhagic complications among patients with trauma. Design, Setting, and Participants: This cohort study was conducted from December 2, 2015, to March 24, 2017, at a level I trauma center. A total of 292 patients with trauma were followed up from their arrival through 6 days from admission. Data, including quantification of antithrombin III activity, were collected for these patients. Thromboprophylaxis strategy; hemorrhage, deep vein thrombosis (DVT), and pulmonary embolism screenings; and follow-up evaluations were conducted per institutional protocols. Data analyses were performed from September 28, 2023, to June 4, 2024. Main Outcomes and Measures: The primary study outcome measurements were associations between antithrombin III levels and outcomes among patients with trauma, including ventilator-free days, hospital-free days, intensive care unit (ICU)-free days, hemorrhage, venous thromboembolic events, and mortality. Results: The 292 patients had a mean (SD) age of 54.4 (19.0) years and included 211 men (72.2%). Patients with an antithrombin III deficiency had fewer mean (SD) ventilator-free days (27.8 [5.1] vs 29.6 [1.4]; P = .0003), hospital-free days (20.3 [8.2] vs 24.0 [5.7]; P = 1.37 × 10-6), and ICU-free days (25.7 [4.9] vs 27.7 [2.3]; P = 9.38 × 10-6) compared with patients without a deficiency. Antithrombin III deficiency was also associated with greater rates of progressive intracranial hemorrhage (21.1% [28 of 133] vs 6.3% [10 of 159]; P = .0003) and thrombocytopenia (24.8% [33 of 133] vs 5.0% [8 of 159]; P = 1.94 × 10-6). Although antithrombin III deficiency was not significantly associated with DVT, patients who developed a DVT had a more precipitous decrease in antithrombin III levels that were significantly lower than patients who did not develop a DVT. Conclusions and Relevance: In this cohort study of patients with trauma, antithrombin III deficiency was associated with greater injury severity, increased hemorrhage, and increased mortality, as well as fewer ventilator-free, hospital-free, and ICU-free days. Although this was an associative study, these data suggest that antithrombin III levels may be useful in the risk assessment of patients with trauma.

Plasma levels of complement components C5 and C9 are associated with thrombin generation.

BACKGROUND: The thrombin generation assay (TGA) evaluates the potential of plasma to generate thrombin over time, providing a global picture of an individual's hemostatic balance. OBJECTIVES: This study aimed to identify novel biological determinants of thrombin generation using a multiomics approach. METHODS: Associations between TGA parameters and plasma levels of 377 antibodies targeting 236 candidate proteins for cardiovascular risk were tested using multiple linear regression analysis in 770 individuals with venous thrombosis from the Marseille Thrombosis Association (MARTHA) study. Proteins associated with at least 3 TGA parameters were selected for validation in an independent population of 536 healthy individuals (Etablissement Français du Sang Alpes-Méditerranée [EFS-AM]). Proteins with strongest associations in both groups underwent additional genetic analyses and in vitro experiments. RESULTS: Eighteen proteins were associated (P < 1.33 × 10⁻4) with at least 3 TGA parameters in MARTHA, among which 13 demonstrated a similar pattern of associations in EFS-AM. Complement proteins C5 and C9 had the strongest associations in both groups. Ex vivo supplementation of platelet-poor plasma with purified C9 protein had a significant dose-dependent effect on TGA parameters. No effect was observed with purified C5. Several single nucleotide polymorphisms associated with C5 and C9 plasma levels were identified, with the strongest association for the C5 missense variant rs17611, which was associated with a decrease in C5 levels, endogenous thrombin potential, and peak in MARTHA. No association of this variant with TGA parameters was observed in EFS-AM. CONCLUSION: This study identified complement proteins C5 and C9 as potential determinants of thrombin generation. Further studies are warranted to establish causality and elucidate the underlying mechanisms.

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.