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.

Predictive Value of Combined Plasma D-Dimer, SCUBE1, and Right Ventricular Tei Index for the Prognosis of Elderly Patients with Acute Pulmonary Thromboembolism.

Acute pulmonary thromboembolism (APTE) has become a non-negligible clinical concern due to its high mortality and complex symptoms. Early diagnosis and prognostic assessment of APTE are of great significance for the long-term benefits of patients, especially elderly patients. Elderly patients with pulmonary embolism (n = 250) who presented to our hospital from January 2018 to July 2021 were recruited into this study. In addition, 50 healthy elderly people with no history of allergies were selected as the control group. An enzyme-linked immunosorbent assay (ELISA) method was used to determine concentrations of D-dimer and signal peptide-CUB-EGF domain-containing protein-1 (SCUBE1) in their plasma. Right ventricular volume contraction time (ICT), ejection time (ET), and isovolumic relaxation time (IRT) were determined by Doppler ultrasound. Right ventricular Tei index was calculated as (ICT + IRT)/ET. High plasma D-dimer, plasma SCUBE1, and right ventricular Tei index are risk factors for poor prognosis in APTE patients after treatment. Plasma D-dimer, plasma SCUBE1, and right ventricular Tei index have predictive value for poor prognosis in APTE patients. Their combined detection (0.256*DD +0.04*SCUBE1 + 10.188*Tei) can improve the sensitivity and specificity of prediction. There is a predictive value of combined plasma D-dimer, SCUBE1, and right ventricular Tei index for the prognosis of elderly patients with APTE.

Acute Pulmonary Embolism: A Review.

Importance: Pulmonary embolism (PE) is characterized by occlusion of blood flow in a pulmonary artery, typically due to a thrombus that travels from a vein in a lower limb. The incidence of PE is approximately 60 to 120 per 100 000 people per year. Approximately 60 000 to 100 000 patients die from PE each year in the US. Observations: PE should be considered in patients presenting with acute chest pain, shortness of breath, or syncope. The diagnosis is determined by chest imaging. In patients with a systolic blood pressure of at least 90 mm Hg, the following 3 steps can be used to evaluate a patient with possible PE: assessment of the clinical probability of PE, D-dimer testing if indicated, and chest imaging if indicated. The clinical probability of PE can be assessed using a structured score or using clinical gestalt. In patients with a probability of PE that is less than 15%, the presence of 8 clinical characteristics (age <50 years, heart rate <100/min, an oxygen saturation level of > 94%, no recent surgery or trauma, no prior venous thromboembolism event, no hemoptysis, no unilateral leg swelling, and no estrogen use) identifies patients at very low risk of PE in whom no further testing is needed. In patients with low or intermediate clinical probability, a D-dimer level of less than 500 ng/mL is associated with a posttest probability of PE less than 1.85%. In these patients, PE can be excluded without chest imaging. A further refinement of D-dimer threshold is possible in patients aged 50 years and older, and in patients with a low likelihood of PE. Patients with a high probability of PE (ie, >40% probability) should undergo chest imaging, and D-dimer testing is not necessary. In patients with PE and a systolic blood pressure of 90 mm Hg or higher, compared with heparin combined with a vitamin K antagonist such as warfarin followed by warfarin alone, direct oral anticoagulants such as apixaban, edoxaban, rivaroxaban, or dabigatran, are noninferior for treating PE and have a 0.6% lower rate of bleeding. In patients with PE and systolic blood pressure lower than 90 mm Hg, systemic thrombolysis is recommended and is associated with an 1.6% absolute reduction of mortality (from 3.9% to 2.3%). Conclusions and Relevance: In the US, PE affects approximately 370 000 patients per year and may cause approximately 60 000 to 100 000 deaths per year. First-line therapy consists of direct oral anticoagulants such as apixaban, edoxaban, rivaroxaban, or dabigatran, with thrombolysis reserved for patients with systolic blood pressure lower than 90 mm Hg.

Utilidad diagnóstica del dímero-D en el tromboembolismo pulmonar de pacientes COVID-19 / DiagnosticutilityofD-dimerin pulmonarythromboembolism in COVID-19 patients

Resumen Introducción: El aumento de la concentración de dímero-D en pacientes COVID-19 se ha asociado a mayor gravedad y peor pronóstico; sin embargo, su rol en predecir el diagnóstico de tromboembolismo pulmonar (TEP), aún es incierto. Objetivo: Evaluar la utilidad del dímero-D plasmático en el diagnóstico de TEP en pacientes con COVID-19. Pacientes y Métodos: Estudio observacional analítico. Se incluyó a pacientes COVID-19 que tenían una angiotomografía computada de tórax (AngioTAC). Se registraron datos clínicos, niveles plasmáticos de dímero-D de ingreso y previo al momento de realizar la AngioTAC. Se identificó la presencia o ausencia de TEP. Resultados: Se incluyeron 163 pacientes; 37(23%) presentaron TEP. Al comparar la serie de pacientes con TEP versus sin TEP, no se encontraron diferencias significativas en características clínicas, ni mortalidad. Hubo diferencias significativas en el nivel plasmático del dímero-D previo a realizar la AngioTAC (3.929 versus 1.912 μg/L; p = 0,005). El área bajo la curva ROC del dímero-D para TEPfue de 0,65. El mejor punto de corte del dímero-D fue de 2.000 μg/L, con una baja sensibilidad y valor predictivo positivo. El valor de corte con el mejor valor predictivo negativo (VPN)fue de 900 μg/L (96%), el cual fue mejor que la estrategia de corte de dímero D ajustado por edad (VPN 90%). Conclusión: La capacidad discriminativa del dímero D para diagnosticar TEP fue baja. En cambio, el dímero D mantiene un alto valor predictivo negativo para descartar TEP, el cual es mayor al valor descrito clásicamente en los pacientes no COVID.

Introduction: Increased D-dimer concentration in COVID-19 patients has been associated with greater severity and worse prognosis; however its role in predicting the diagnosis of pulmonary thromboembolism (PTE), is still uncertain. Objective: To evaluate the usefulness of plasma D-dimer in the diagnosis of PTE in patients with COVID-19. Method: Analytical observational study. COVID-19 patients who had a chest computed tomography angiography (CTA) were included. Clinical data, Ddimer plasma levels on admission and prior to CTA were recorded. The presence or absence of PTE was identified. Results: 163 patients were included, 37 (23%) presented PTE. After comparing the series of patients with PTE versus the series without PTE, no significant differences were found in clinical characteristics or mortality. There were significant differences in the plasma level of D-dimer prior to performing CTA (3,929 μg/L versus. 1,912 μg/L; p = 0.005). The area under the D-dimer ROC curve for PTEprediction was 0.65. The best D-dimer cutoffpoint was 2.000μg/L, with a low sensitivity and positivepredictive value. The cutoff value with the best negativepredictive value (NPV) was 900 μg/L (96%), which was better than the age-adjusted D-dimer cutoff strategy (NPV 90%). Conclusion: The discriminative ability of D-dimer to diagnose PTE was low. In contrast, D-dimer maintains a high negative predictive value to rule out PTE, which is higher than the value classically described in non-COVID patients.

Predictors of Prolonged Hospital Stay in Patients with Acute Pulmonary Thromboembolism- A Hospital Based Cohort Study.

AIMS AND OBJECTIVES: Patients with pulmonary thromboembolism (PTE) are commonly admitted to hospital and generally have a prolonged hospital stay in this part of the world. We aimed to determine different clinical and laboratory parameters that are associated with prolonged hospital stay in our set-up and to analyse effectiveness of Pulmonary Embolism Severity Index (PESI) score as a predictor of prolonged hospital stay in patients with PTE. MATERIALS AND METHODS: It was a hospital based observational prospective study. Confirmed cases of PTE defined as patients with evidence of thrombus on CT pulmonary angiogram (CTPA) were included in this study. Depending on the length of hospital stay, patients were divided into two cohorts: Shorter Hospital stay (less than mean i.e., < 10 Days) and Prolonged Hospital stay (longer than mean i.e., ≥ 10 Days). Logistic regression analysis was done to identify predictors of prolonged hospital stay. RESULTS: 150 patients were included in the study with 67 patients (44.67%) having shorter hospital stay (<10 days) and 83 patients (55.33%) having prolonged hospital stay (≥10 days). On multivariate regression analysis, parameters that were found to be statistically significant were hypotension at presentation, decreased level of consciousness, pco2 < 30 mmHg, presence of S1Q3T3 pattern on electrocardiogram (ECG) and high risk PESI (class III-V). CONCLUSION: PESI class can be effectively used to predict prolonged hospital stay in patients with pulmonary embolism. Patients with hypotension at presentation, decreased level of consciousness, pco2 less than 30 mmHg, and S1Q3T3 on ECG are more likely to have prolonged hospital stay in our healthcare setup.

The Predictor Potential Role of the Glucose to Potassium Ratio in the Diagnostic Differentiation of Massive and Non-Massive Pulmonary Embolism.

OBJECTIVE: Acute pulmonary embolism (PE) is one of the main causes of death and has a course as massive (MPE) or non-massive (NMPE). The study investigates the indicator potential of Glucose to Potassium ratio (GPR) in the differential diagnosis of MPE and NMPE. MATERIALS AND METHODS: The study was designed as a retrospective cross-sectional clinical cohort in patients with PE. A total of 111 participants enrolled in the research separating two groups: MPE (n:54) and NMPE (n:67). The GPR was calculated by dividing serum glucose by potassium levels and its results were compared with D-Dimer, Pulmonary Artery Pressure (PAP), and C-Reactive Protein Test (CRP). RESULTS: D-Dimer was measured as 6.5 ± 5.7 µg/L in the MPE and found higher than the NMPE (3.9 ± 5.2 µg/L) (P = .019). CRP (100 ± 83.5 to 30.9 ± 42.7 mg/L; P = .0001) and PAP (49.5 ± 11.9 to 34.8 ± 7.3 mmHg; P = .0001) were found increased in the MPE. GPR strongly increased in the MPE (30.7 ± 7.5 to 24.9 ± 4.3; P = .0003) in line with CRP, D-Dimer and PAP. GPR showed a stronger diagnostic value (AUC: 0.733; P = .00001; Sensitivity:72%; Spesifity:70%; Cut-off: 26.5). PAP and GPR showed significant efficiency on occurrence of the MPE according to the binary logistic regression. CONCLUSION: The GPR, as a novel and cheap marker, can be useful for diagnostic differentiation of MPE from NMPE, but weaker than PAP and better than D-dimer. TYPE OF STUDY AND LEVEL OF EVIDENCE: Level-II, Retrospective clinical cohort study.

Dysregulation of Biomarkers of Hemostatic Activation and Inflammatory Processes are Associated with Adverse Outcomes in Pulmonary Embolism.

INTRODUCTION: The pathophysiology of pulmonary embolism (PE) represents complex, multifactorial processes involving blood cells, vascular endothelium, and the activation of inflammatory pathways. Platelet (P), endothelial (E), and leukocyte (L)-selectin molecules may play an important role in PE pathophysiology. We aimed to profile the biomarkers of inflammation, including selectins in PE patients, and compare them to healthy individuals. MATERIALS AND METHODS: 100 acute PE patients and 50 controls were included in this case control study. ELISA methods were used to quantify levels of selectins, inflammatory, and hemostatic biomarkers. RESULTS: In PE patients, levels of selectin molecules as compared to controls convey increased P-selectin levels (95 ng/mL vs 40 ng/mL, p < .0001) and decreased L-selectin levels (1468 ng/mL vs 1934 ng/mL, p < .0001). Significant correlations were found between selectins and Plasminogen Activating Inhibitor-1 (PAI-1), Tumor Necrosis Factor-a (TNFa), and D-dimer. Fold change between selectins and controls is compared to other biomarkers, illustrating degrees of change comparable to TNFa, alpha-2-antiplasmin, and microparticles. L-selectin levels are inversely associated with all-cause-mortality in PE patients, (p = .040). CONCLUSION: These studies suggest that various thrombo-inflammatory biomarkers are elevated in PE patients. Furthermore, L-selectin levels are inversely associated with mortality outcomes.

A Feasibility Study on the Identification of Potential Biomarkers in Pulmonary Embolism Using Proteomic Analysis.

Acute pulmonary embolism (PE) is a common emergency with a high morbidity and mortality. Most clinical presentations are non-specific and there is a lack of suitable biomarkers for PE. For example, the traditional D-dimer tests shows a rather high sensitivity for PE, but yet a rather low positive predictive value due to its lack of specificity. Research on novel biomarkers for PE is thus of interest to improve early diagnostics and reduce the number of unnecessary computed tomography pulmonary angiogram (CTPA) scans performed. In this study we evaluate the feasibility to use label-free quantitative proteomics to discover potential biomarkers for acute PE and to monitor changes in proteins levels in PE patients over time. Blood was collected from 8 patients with CTPA verified PE and from 8 patients presenting with same symptoms but with a negative CTPA. The samples were analyzed by liquid chromatography-mass spectrometry and thirteen protein concentrations were found to be significantly changed in PE patients compared to the CTPA negative controls. This exploratory study shows that proteomic analysis can be used to identify potential biomarkers for PE as well as to monitor changes of protein levels over time.The complement proteins play a part in PE but further studies are needed to clarify their specific role in the pathophysiological process and to look for more specific proteins.

Circulating MicroRNAs for Diagnosis of Acute Pulmonary Embolism: Still a Long Way to Go.

Venous thromboembolism (VTE) represents the third most frequent cause of acute cardiovascular syndrome. Among VTE, acute pulmonary embolism (APE) is the most life-threatening complication. Due to the low specificity of symptoms clinical diagnosis of APE may be sometimes very difficult. Accordingly, the latest European guidelines only suggest clinical prediction tests for diagnosis of APE, eventually associated with D-dimer, a biomarker burdened by a very low specificity. A growing body of evidence is highlighting the role of miRNAs in hemostasis and thrombosis. Due to their partial inheritance and susceptibility to the environmental factors, miRNAs are increasingly described as active modifiers of the classical Virchow's triad. Clinical evidence on deep venous thrombosis reported specific miRNA signatures associated to thrombosis development, organization, recanalization, and resolution. Conversely, data of miRNA profiling as a predictor/diagnostic marker of APE are still preliminary. Here, we have summarized clinical evidence on the potential role of miRNA in diagnosis of APE. Despite some intriguing insight, miRNA assay is still far from any potential clinical application. Especially, the small sample size of cohorts likely represents the major limitation of published studies, so that extensive analysis of miRNA profiles with a machine learning approach are warranted in the next future. In addition, the cost-benefit ratio of miRNA assay still has a negative impact on their clinical application and routinely test.

Development and Validation of a Nomogram for Predicting the Long-Term Survival in Patients With Chronic Thromboembolic Pulmonary Hypertension.

There remains a lack of prognosis models for patients with chronic thromboembolic pulmonary hypertension (CTEPH). This study aims to develop a nomogram predicting 3-, 5-, and 7-year survival in patients with CTEPH and verify the prognostic model. Patients with CTEPH diagnosed in Fuwai Hospital were enrolled consecutively between May 2013 and May 2019. Among them, 70% were randomly split into a training set and the other 30% as a validation set for external validation. Cox proportional hazards model was used to identify the potential survival-related factors which were candidate variables for the establishment of nomogram and the final model was internally validated by the bootstrap method. A total of 350 patients were included in the final analysis and the median follow-up period of the whole cohort was 51.2 months. Multivariate analysis of Cox proportional hazards regression showed body mass index, mean right atrial pressure, N-terminal pro-brain natriuretic peptide (per 500 ng/ml increase in concentration), presence of anemia, and main treatment choice were the independent risk factors of mortality. The nomogram demonstrated good discrimination with the corrected C-index of 0.82 in the training set, and the C-index of 0.80 (95% CI: 0.70 to 0.91) in the external validation set. The calibration plots also showed a good agreement between predicted and actual survival in both training and validation sets. In conclusion, we developed an easy-to-use nomogram with good apparent performance using 5 readily available variables, which may help physicians to identify CTEPH patients at high risk for poor prognosis and implement medical interventions.

Age adjusted D-dimer cutoffs for pulmonary embolism in a geriatric population utilizing a D-dimer unit assay.

BACKGROUND: Age adjusted serum d-dimer (AADD) with clinical decision rules have been utilized to rule out pulmonary embolism (PE) in low-risk patients; however, its use in the geriatric population has been questioned and the use of d-dimer unit (DDU) assay is uncommon. OBJECTIVE: The present study aims to compare the test characteristics of the AADD (age × 5) measured in DDU with the standard cutoff (DDU < 250) and study hospital laboratory's d-dimer cutoff (DDU < 600) in geriatric patients presenting with suspected PE. METHODS: This retrospective study enrolled patients ≥65 years old with suspected PE and d-dimer performed between January 1, 2019 and December 31, 2019 who presented to the emergency department (ED). Charts were reviewed for CTA chest and ventilation perfusion imaging results for PE. Diagnostic parameters for each cutoff were calculated for the primary outcome. RESULTS: 510 patients were included, 20 with PE. There was no significant difference between the sensitivities of AADD (100%, 95% CI: 80-100), standard cutoff (100%, 95% CI: 80-100), and hospital cutoff (90%, 95% CI: 66.9-98.2). The hospital cutoff specificity (22.7%, 95% CI: 17.1-29.3) was significantly greater than the AADD (13.4%, 95% CI: 9.1-19.2) and standard cutoff (10.8%, 95% CI: 7.0-16.3) specificities. CONCLUSIONS: In geriatric patients presenting to the ED with suspected PE, the AADD measured in DDUs maintained sensitivity with improved specificity compared to standard cutoff. In this population, the AADD would have safely reduced imaging by 19% without missing any PEs. AADD remains a valid tool with high sensitivity and negative predictive value in ruling out PE in geriatric patients.

Risk assessment in pulmonary hypertension based on routinely measured laboratory parameters.

BACKGROUND: γ-glutamyl transferase (GGT), the aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, and the neutrophil-to-lymphocyte ratio (NLR) are prognostic biomarkers in several cardiovascular diseases, but their relevance in pulmonary hypertension (PH) is not fully understood. We aimed to assess their prognostic value in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). METHODS: We retrospectively analyzed 731 incident patients with idiopathic PAH or CTEPH who entered the Giessen PH registry during 1993-2019. A risk stratification score based on GGT, AST/ALT ratio, and NLR tertiles was compared with a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) risk stratification scheme. Associations with survival were evaluated using Kaplan-Meier and Cox regression analyses. External validation was performed in 311 patients with various types of PAH or CTEPH from a second German center. RESULTS: GGT levels, AST/ALT, and NLR independently predicted mortality at baseline and during follow-up. The scoring system based on these biomarkers predicted mortality at baseline and during follow-up (both log-rank p < 0.001; hazard ratio [95% confidence interval], high vs low risk: baseline, 7.6 [3.9, 15.0]; follow-up, 13.3 [4.8, 37.1]). Five-year survival of low, intermediate, and high risk groups was 92%, 76%, and 51%, respectively, at baseline and 95%, 78%, and 50%, respectively, during follow-up. Our scoring system showed characteristics comparable to the ESC/ERS scheme, and predicted mortality in the validation cohort. CONCLUSION: GGT, AST/ALT, and NLR were reliable prognostic biomarkers at baseline and during follow-up, with predictive power comparable to the gold standard for risk stratification.

Fibrinogen ß chain and FXIII polymorphisms affect fibrin clot properties in acute pulmonary embolism.

BACKGROUND: Prothrombotic fibrin clot properties, including increased clot density, are in part genetically determined. We investigated whether fibrinogen alpha-chain gene (FGA) c.991A>G (rs6050), fibrinogen beta chain gene (FGB) -455G>A (rs1800790) and factor XIII gene (F13) c.103G>T (rs5985) polymorphisms affect plasma fibrin clot properties in patients with acute pulmonary embolism (PE). METHODS: As many as 126 normotensive patients with PE, free of cancer, were genotyped by TaqMan assay. Fibrin clot permeability (Ks ), clot lysis time (CLT) and endogenous thrombin potential (ETP) were assessed on admission. RESULTS: The minor allele frequencies were as follows: FGA rs6050 (n = 62, 0.31), FGB rs1800790 (n = 40, 0.17) and F13 rs5985 (n = 49, 0.23). There were no differences related to any of the polymorphisms with regard to demographic, clinical and laboratory data, except for fibrinogen concentration, which was higher in carriers of F13 rs5985 polymorphism (p = .024), and PE combined with deep-vein thrombosis, which was less prevalent in FGB rs1800790 polymorphism carriers (p = .004). Carriers of FGB rs1800790 A allele and F13 rs5985 T allele had lower Ks , prolonged CLT and higher ETP compared with major homozygotes (all p < .05). After adjustment for fibrinogen, all differences remained significant (all p < .01). There were no associations between the FGA rs6050 polymorphism and Ks , CLT or ETP. CONCLUSION: Our study showed that FGB rs1800790 and F13 rs5985 polymorphisms contribute to the prothrombotic fibrin clot phenotype and these effects are strong enough to be observed in the acute phase of PE.

Isoprostane-8 and GDF-15 as novel markers of post-PE syndrome: Relation with prothrombotic factors.

BACKGROUND: Post-pulmonary embolism (PE) syndrome occurs in up to 50% of PE patients. The pathophysiology of this syndrome is obscure. OBJECTIVE: We investigated whether enhanced oxidative stress and prothrombotic state may be involved in post-PE syndrome. METHODS: We studied 101 normotensive noncancer PE patients (aged 56.5 ± 13.9 years) on admission, after 5-7 days and after a 3-month anticoagulation, mostly with rivaroxaban. A marker of oxidative stress, 8-isoprostane, endogenous thrombin potential, fibrinolysis proteins, clot lysis time (CLT) and fibrin clot permeability (Ks ), along with PE biomarkers, were determined. RESULTS: Patients who developed the post-PE syndrome (n = 31, 30.7%) had at baseline 77.6% higher N-terminal brain natriuretic propeptide and 46.8% higher growth differentiation factor 15, along with 14.1% longer CLT associated with 34.4% higher plasminogen activator inhibitor-1 as compared to subjects without post-PE syndrome (all P < .05). After 5-7 days, only hypofibrinolysis was noted in post-PE syndrome patients. When measured at 3 months, prolonged CLT and reduced Ks were observed in post-PE syndrome patients, accompanied by 23.8% higher growth differentiation factor 15 and 35.8% higher plasminogen activator inhibitor-1 (all P < .05). 8-isoprostane levels ≥108 pg/ml (odds ratio=4.36; 95% confidence interval 1.63-12.27) and growth differentiation factor 15 ≥ 1529 pg/ml (odds ratio=3.89; 95% confidence interval 1.29-12.16) measured at 3 months were associated with higher risk of developing post-PE syndrome. CONCLUSIONS: Enhanced oxidative stress and prothrombotic fibrin clot properties could be involved in the pathogenesis of the post-PE syndrome. Elevated growth differentiation factor 15 assessed at 3 months might be a new biomarker of this syndrome.

Enoxaparin titrated by anti-Xa levels reduces venous thromboembolism in trauma patients.

BACKGROUND: Trauma is a major risk factor for the development of a venous thromboembolism (VTE). After observing higher than expected VTE rates within our center's Trauma Quality Improvement Program data, we instituted a change in our VTE prophylaxis protocol, moving to enoxaparin dosing titrated by anti-Xa levels. We hypothesized that this intervention would lower our symptomatic VTE rates. METHODS: Adult trauma patients at a single institution meeting National Trauma Data Standard criteria from April 2015 to September 2019 were examined with regards to VTE chemoprophylaxis regimen and VTE incidence. Two groups of patients were identified based on VTE protocol-those who received enoxaparin 30 mg twice daily without routine anti-Xa levels ("pre") versus those who received enoxaparin 40 mg twice daily with dose titrated by serial anti-Xa levels ("post"). Univariate and multivariate analyses were performed to define statistically significant differences in VTE incidence between the two cohorts. RESULTS: There were 1698 patients within the "pre" group and 1406 patients within the "post" group. The two groups were essentially the same in terms of demographics and risk factors for bleeding or thrombosis. There was a statistically significant reduction in VTE rate (p = 0.01) and deep vein thrombosis rate (p = 0.01) but no significant reduction in pulmonary embolism rate (p = 0.21) after implementation of the anti-Xa titration protocol. Risk-adjusted Trauma Quality Improvement Program data showed an improvement in rate of symptomatic pulmonary embolism from fifth decile to first decile. CONCLUSION: A protocol titrating prophylactic enoxaparin dose based on anti-Xa levels reduced VTE rates. Implementation of this type of protocol requires diligence from the physician and pharmacist team. Further research will investigate the impact of protocol compliance and time to appropriate anti-Xa level on incidence of VTE. LEVEL OF EVIDENCE: Therapeutic/care management, Level IV.

TNF-α and HMGB1: New Biomarkers of Acute Pulmonary Embolism.

OBJECTIVE: Inflammatory mediators have been implicated in the pathophysiology of acute pulmonary embolism (PE). However, the role of inflammatory mediator activation in the development of pulmonary embolism remains elusive. Here, we determined the reliability of the plasma levels of inflammatory markers tumor necrosis factor-alpha (TNF-α) and high mobility histone 1 (HMGB1) as diagnostic biomarkers of PE. METHODS: Eighty-seven patients with PE and ninety-two healthy adults were enrolled. Plasma levels of TNF-α and HMGB1 were measured before and after anticoagulation treatment using conventional commercialized ELISA. RESULTS: The mean concentrations of plasma TNF-α and HMGB1 in patients with PE before anticoagulation treatment were 3.36- and 2.54-fold higher than those in controls (p<0.0001), respectively. Similar results were obtained in patients with PE before anticoagulation treatment, in which plasma levels of TNF-α and HMGB1 were 3.99- and 1.99-fold higher (p<0.0001), respectively, than in PE patients after anticoagulation treatment. Among the two potential markers, TNF-α performed best in distinguishing patients with PE from controls. A significant positive correlation was found between the two markers' concentrations. CONCLUSIONS: These findings suggest that the plasma levels of TNF-α and HMGB1 may serve as potential biomarkers for PE.

Predictive value of D-dimer and analysis of risk factors in pregnant women with suspected pulmonary embolism after cesarean section.

BACKGROUND: Acute pulmonary embolism (PE) is one of the leading causes of maternal mortality, and cesarean section is an established independent risk factor for PE. The diagnostic utility of D-dimer for PE in non-pregnant women has been well-established, but its role in women with suspected PE after cesarean section is unclear. Furthermore, the optimal threshold level in this patient population is unknown. Traditional D-dimer levels have low diagnostic specificity, resulting in many pregnant women being exposed to potentially harmful radiation despite negative diagnostic imaging results. This research aimed to optimize the clinical threshold for D-dimer to improve specificity while ensuring high sensitivity and to identify risk factors for PE after cesarean section. METHODS: This retrospective study of 289 women who underwent diagnostic imaging (ventilation/perfusion [V/Q] or computed tomographic pulmonary angiography [CTPA]) for suspected acute PE after cesarean delivery from 2010 to 2021 was conducted. Clinical data and laboratory indicators within 24 h postpartum including D-dimer levels were collected for analyses. RESULTS: The final analysis included 125 patients, among whom 33 were diagnosed with acute PE (incidence of 11.42%, 95% confidence interval 7.7-15.1). The receiver operating characteristic curve analysis suggested that a D-dimer cut-off value of 800 ng/mL had specificity of 25.26% and sensitivity of 100% for detecting PE. The cut-off value was adjusted to 1000 ng/mL with a specificity of 34.74% and a sensitivity of 96.67%. Using a D-dimer cut-off value of 800 ng/mL (instead of the conventional value of 500 ng/mL) increased the number of patients excluded from suspected PE from 9.6 to 18.4% without additional false-negative results. Of note, a history of known thrombophilia was significantly more common in patients with PE than in those without (P < 0.05). No other independent risk factors were noted in our study. CONCLUSIONS: The D-dimer cut-off value of 800 ng/mL ensures high sensitivity and increases specificity compared to the conventional threshold of 500 ng/mL. Utilizing this higher threshold can reduce the number of unnecessary CT and subsequently unnecessary radiation exposure, in women after cesarean delivery. Prospective studies should also be conducted to verify these results.

Effect of a Diagnostic Strategy Using an Elevated and Age-Adjusted D-Dimer Threshold on Thromboembolic Events in Emergency Department Patients With Suspected Pulmonary Embolism: A Randomized Clinical Trial.

Importance: Uncontrolled studies suggest that pulmonary embolism (PE) can be safely ruled out using the YEARS rule, a diagnostic strategy that uses varying D-dimer thresholds. Objective: To prospectively validate the safety of a strategy that combines the YEARS rule with the pulmonary embolism rule-out criteria (PERC) rule and an age-adjusted D-dimer threshold. Design, Settings, and Participants: A cluster-randomized, crossover, noninferiority trial in 18 emergency departments (EDs) in France and Spain. Patients (N = 1414) who had a low clinical risk of PE not excluded by the PERC rule or a subjective clinical intermediate risk of PE were included from October 2019 to June 2020, and followed up until October 2020. Interventions: Each center was randomized for the sequence of intervention periods. In the intervention period (726 patients), PE was excluded without chest imaging in patients with no YEARS criteria and a D-dimer level less than 1000 ng/mL and in patients with 1 or more YEARS criteria and a D-dimer level less than the age-adjusted threshold (500 ng/mL if age <50 years or age in years × 10 in patients ≥50 years). In the control period (688 patients), PE was excluded without chest imaging if the D-dimer level was less than the age-adjusted threshold. Main Outcomes and Measures: The primary end point was venous thromboembolism (VTE) at 3 months. The noninferiority margin was set at 1.35%. There were 8 secondary end points, including chest imaging, ED length of stay, hospital admission, nonindicated anticoagulation treatment, all-cause death, and all-cause readmission at 3 months. Results: Of the 1414 included patients (mean age, 55 years; 58% female), 1217 (86%) were analyzed in the per-protocol analysis. PE was diagnosed in the ED in 100 patients (7.1%). At 3 months, VTE was diagnosed in 1 patient in the intervention group (0.15% [95% CI, 0.0% to 0.86%]) vs 5 patients in the control group (0.80% [95% CI, 0.26% to 1.86%]) (adjusted difference, -0.64% [1-sided 97.5% CI, -∞ to 0.21%], within the noninferiority margin). Of the 6 analyzed secondary end points, only 2 showed a statistically significant difference in the intervention group compared with the control group: chest imaging (30.4% vs 40.0%; adjusted difference, -8.7% [95% CI, -13.8% to -3.5%]) and ED median length of stay (6 hours [IQR, 4 to 8 hours] vs 6 hours [IQR, 5 to 9 hours]; adjusted difference, -1.6 hours [95% CI, -2.3 to -0.9]). Conclusions and Relevance: Among ED patients with suspected PE, the use of the YEARS rule combined with the age-adjusted D-dimer threshold in PERC-positive patients, compared with a conventional diagnostic strategy, did not result in an inferior rate of thromboembolic events. Trial Registration: ClinicalTrials.gov Identifier: NCT04032769.

Correlation between serum factor VIII:C levels and deep vein thrombosis following gynecological surgery.

Deep vein thrombosis (DVT) is common in patients following gynecological surgery. Coagulation factor VIII (FVIII) is an important part of the human coagulation system, and FVIII:C is a component of FVIII with anticoagulant activity. 800 patients who underwent gynecological surgery were enrolled. General clinical data were harvested, and pre - and postoperative serum FVIII levels were determined. Lower-extremity ultrasound examination and/or postoperative pulmonary angiography were performed. Related data were analyzed statistically. DVT was the first manifestation of venous thromboembolism in all cases. There were a total of 46 cases, and the incidence of DVT was 5.8%. Progression to pulmonary embolism was confirmed in 16 cases, with an incidence of 2.0%. The independent risk factors for DVT after gynecological surgery were postoperative FVIII:C levels (odds ratio [OR] = 1.01), age (OR = 6.57), and operation time ≥3 hours (OR = 2.90) (P < 0.05). When the FVIII:C level was greater than the 75th centile (≥150 IU/dL), the risk of DVT was 2.99 times higher than that below the 25th centile (<100 IU/dL) (P < 0.05). When combined with the risk factor of operation time ≥3 hours, the risk increased to 3.17 times (P = 0.10). When combined with age ≥60 years, the risk was significantly increased, reaching 12.0 times (P < 0.05). Serum FVIII:C levels are an independent risk factor for DVT after gynecological surgery. Higher levels increase the risk of DVT after gynecological surgery, and they may have a dose-dependent relationship. A synergistic effect exists in combination with other risk factors, which further increases the risk.

Utility of Blood Cellular Indices in the Risk Stratification of Patients Presenting with Acute Pulmonary Embolism.

Pulmonary embolism (PE) clinical manifestations vary widely, and that scope is not fully captured by current all-cause mortality risk models. PE is associated with inflammatory, coagulation, and hemostatic imbalances so blood cellular indices may be prognostically useful. Complete blood count (CBC) data may improve current risk models like the simplified pulmonary embolism severity index (sPESI) for all-cause mortality, offering greater accuracy and analytic ability. Acute PE patients (n = 228) with confirmatory diagnostic imaging were followed for all-cause mortality. Blood cellular indices were assessed for association to all-cause mortality and were supplemented into sPESI using multivariate logistic regression. Multiple blood cellular indices were found to be significantly associated with all-cause mortality in acute PE. sPESI including red cell distribution width, hematocrit and neutrophil-lymphocyte ratio had better predictive ability as compared to sPESI alone (AUC: 0.852 vs 0.754). Blood cellular indices contribute an inflammatory and hemodynamic perspective not currently included in sPESI. CBC with differential is a widely used, low-cost test that can augment current risk stratification tools for all-cause mortality in acute PE patients.