Serum PLA2R antibody as a predictive biomarker for venous thromboembolism risk in primary membranous nephropathy / El anticuerpo PLA2R sérico como biomarcador predictivo del riesgo de tromboembolia venosa en la nefropatía membranosa primaria

Background Patients with nephrotic syndrome are at high risk of venous thromboembolism (VTE), especially for primary membranous nephropathy (PMN). The phospholipase A2 receptor (PLA2R) is a marker of primary membranous nephropathy activity. This study investigated the predictive value of PLA2R antibodies in PMN for VTE.Methods In this retrospective study, we included 97 PMN patients and evaluated the predictive value of serum PLA2R antibodies for VTE risk. Lower extremity venous ultrasound, renal vein ultrasound, or spiral computed tomography pulmonary arteriography were used to assess VTE events. Serum anti-PLA2R antibodies were detected by enzyme-linked immunosorbent assay (ELISA). The risk of VTE was stratified according to serum albumin levels. Results Twenty PMN patients (21%) had thromboembolic events. Eight (15%) of patients with serum albumin >25g/l developed VTE, 6 of whom were positive for serum PLA2R antibodies. Positive serum PLA2R antibodies were significantly associated with VTE events in patients with serum albumin >25g/l (p=0.01). Age, sex, blood creatinine, serum albumin, and 24-h urine protein levels were not statistically different between the two groups. Kaplan–Meier analysis using the log-rank test revealed anti-PLA2R positive membranous nephropathy patients had more probability of VTE events than anti-PLA2R negative patients. Univariate Cox proportional hazards analysis revealed that lnPLA2R-Ab is an unfavorable predictor for VTE events in patients with serum albumin >25g/l (hazard ratio (HR) 2.1, p=0.01). Conclusions The PLA2R antibody was a risk predictor for thromboembolic events in patients with primary membranous nephropathy with serum albumin >25g/l (AU)

Antecedentes Los pacientes con síndrome nefrótico presentan un alto riesgo de tromboembolia venosa (TEV), especialmente en el caso de la nefropatía membranosa primaria (NMP). El receptor de fosfolipasa A2 (PLA2R) es un marcador de la actividad de la NMP. Este estudio investigó el valor predictivo de los anticuerpos PLA2R en NMP para TEV. Métodos En este estudio retrospectivo, se incluyeron 97 pacientes con NMP y se evaluó el valor predictivo de los anticuerpos PLA2R en suero para el riesgo de TEV. Se utilizaron la ecografía venosa de las extremidades inferiores, la ecografía de la vena renal o la arteriografía pulmonar por tomografía computarizada en espiral para evaluar los episodios de TEV. Los anticuerpos séricos anti-PLA2R se detectaron mediante un ensayo inmunoenzimático (ELISA). El riesgo de TEV se estratificó en función de los niveles de albúmina sérica. Resultados Veinte pacientes con NMP (21%) presentaron episodios tromboembólicos. Ocho (15%) de los pacientes con albúmina sérica>25g/l desarrollaron TEV, 6 de los cuales fueron positivos para anticuerpos PLA2R séricos. La positividad de los anticuerpos PLA2R séricos se asoció significativamente con episodios de TEV en pacientes con albúmina sérica>25g/l (p=0,01). La edad, el sexo, la creatinina en sangre, la albúmina sérica y los niveles de proteínas en orina de 24h no fueron estadísticamente diferentes entre los 2 grupos. El análisis de Kaplan-Meier mediante la prueba de rangos logarítmicos reveló que los pacientes con nefropatía membranosa positivos para anti-PLA2R tenían más probabilidad de sufrir TEV que los pacientes negativos para anti-PLA2R. El análisis univariante de riesgos proporcionales de Cox reveló que ln PLA2R-Ab es un predictor desfavorable de episodios de TEV en pacientes con albúmina sérica>25g/l (hazard ratio 2,1; p=0,01). Conclusiones El anticuerpo PLA2R fue un predictor de riesgo de episodios tromboembólicos en pacientes con NMP con albúmina sérica>25g/l (AU)

Unveiling the diagnostic enigma of D-dimer testing in cancer patients: Current evidence and areas of application.

BACKGROUND: Cancer is a well-known risk factor for venous thromboembolism (VTE). A combined strategy of D-dimer testing and clinical pre-test probability is usually used to exclude VTE. However, its effectiveness is diminished in cancer patients due to reduced specificity, ultimately leading to a decreased clinical utility. This review article seeks to provide a comprehensive summary of how to interpret D-dimer testing in cancer patients. METHODS: In accordance with PRISMA standards, literature pertaining to the diagnostic and prognostic significance of D-dimer testing in cancer patients was carefully chosen from reputable sources such as PubMed and the Cochrane databases. RESULTS: D-dimers have not only a diagnostic value in ruling out VTE but can also serve as an aid for rule-in if their values exceed 10-times the upper limit of normal. This threshold allows a diagnosis of VTE in cancer patients with a positive predictive value of more than 80%. Moreover, elevated D-dimers carry important prognostic information and are associated with VTE reoccurrence. A gradual increase in risk for all-cause death suggests that VTE is also an indicator of biologically more aggressive cancer types and advanced cancer stages. Considering the lack of standardization for D-dimer assays, it is essential for clinicians to carefully consider the variations in assay performance and the specific test characteristics of their institution. CONCLUSIONS: Standardizing D-dimer assays and developing modified pretest probability models specifically for cancer patients, along with adjusted cut-off values for D-dimer testing, could significantly enhance the accuracy and effectiveness of VTE diagnosis in this population.

Plasma levels of coagulation factors VIII and IX and risk of venous thromboembolism: Systematic review and meta-analysis.

INTRODUCTION: The associations of plasma factor VIII (FVIII) and factor IX (FIX) levels with risk of venous thromboembolism (VTE) are not well defined. We performed a systematic review and meta-analysis of these associations. METHODS: Random effects inverse-variance weighted meta-analysis was used to estimate pooled odds ratios for comparisons across equal quartiles of the distributions and 90 % thresholds (higher versus lower), and for testing linear trends. RESULTS: Among 15 studies (5327 cases) the pooled odds ratio of VTE for the fourth versus first quarter was 3.92 (95 % confidence interval 1.61, 5.29) for FVIII level; and among 7 studies (3498 cases) 1.57 (1.32, 1.87) for FIX level. Comparing factor levels above, versus below, the 90th percentile, the estimated pooled odds ratios were 3.00 (2.10, 4.30) for FVIII; 1.77 (1.22, 2.56) for FIX; and 4.56 (2.73, 7.63) for both FVIII and FIX considered jointly. CONCLUSIONS: We confirm increases in risk of VTE across population distributions of FVIII and FIX levels. Levels above the 90th percentile have almost twice the risk for FIX level compared to levels below; three-fold risk for FVIII level; and almost five-fold risk for both FVIII and FIX levels elevated.

Impact of the von Willebrand factor-ADAMTS-13 axis on the risk of future venous thromboembolism.

BACKGROUND: von Willebrand factor (VWF) and its cleaving protease, ADAMTS-13, form a pivotal axis that regulates hemostasis. However, the role of the VWF-ADAMTS-13 axis in the risk of future venous thromboembolism (VTE) is unknown. OBJECTIVES: To investigate whether plasma ADAMTS-13 levels and an imbalance with VWF levels, assessed as the VWF/ADAMTS-13 ratio, are associated with the risk of future VTE. PATIENTS/METHODS: A population-based nested case-control study, comprising 383 incident VTE cases and 780 age- and sex-matched controls, was derived from the Tromsø study cohort (1994-2007). Antigen levels of ADAMTS-13 and VWF were measured in plasma samples obtained at cohort baseline. Odds ratios (ORs) with 95% CIs were estimated according to quartile cutoffs of ADAMTS-13 and VWF/ADAMTS-13 ratio determined in controls. RESULTS: In age- and sex-adjusted analysis, ADAMTS-13 levels were inversely associated with the VTE risk, with an OR of 1.40 (95% CI, 0.99-1.99) for the lowest vs highest quartiles. The VWF/ADAMTS-13 ratio was linearly associated with the VTE risk (P for trend = .001), with an OR of 1.70 (95% CI, 1.19-2.43) for the highest vs lowest quartiles, and the association was particularly pronounced for unprovoked VTE (OR, 2.81; 95% CI, 1.65-4.81). The ORs were only slightly attenuated after additional adjustments for body mass index and C-reactive protein. CONCLUSIONS: Lowered ADAMTS-13 levels and an imbalance between ADAMTS-13 and VWF levels, reflected by an increased VWF/ADAMTS-13 ratio, were associated with an increased risk of future VTE. Our findings suggest that the VWF-ADAMTS-13 axis is involved in the pathogenesis of VTE.

[Clinical characteristics and presentation form in patients with venous thromboembolism and negative or weakly positive D-dimer]. / Características clínicas y forma de presentación en pacientes con enfermedad tromboembólica venosa y dímero-D negativo o débilmente positivo.

INTRODUCTION: D-dimer has a high negative predictive value for the diagnosis of venous thromboembolic disease (VTE). However, VTE has been reported in the presence of normal D-dimer values. METHODS: This is a prospective observational study in patients with VTE from Hospital Gregorio Marañón between 2001 and 2022, comparing the characteristics of clinical presentation based on D-dimer levels (<500 ng/mL vs. ≥500 ng/mL). RESULTS: A total of 2582 patients were found, 333 patients (12.9%) presented negative or weakly positive D-dimer levels. They were significantly younger (57.9 vs. 65.3 years), with a lower prevalence of comorbidities (ischemic heart disease, dementia, and chronic kidney disease), and a greater family history of VTE (8.4% vs. 5.2%) and thrombophilia (11.7% vs. 7.8%). They presented significantly less dyspnea (57.6% vs. 75.4%), syncope (3% vs. 13.5%), less thrombotic load, elevated NT-pro-BNP (22.0% vs. 48.2%), and right ventricle dilatation (8.1% vs. 30.0%). CONCLUSION: Patients with VTE and low D-dimer levels at diagnosis were younger, with milder clinical presentation and lower thrombotic load; but they presented a higher prevalence of thrombophilia and a family history of VTE.

Evaluation of DOAC Dipstick Test for Detecting Direct Oral Anticoagulants in Urine Compared with a Clinically Relevant Plasma Threshold Concentration.

Measuring direct oral anticoagulant (DOAC) concentrations might be necessary in certain clinical situations but is not routinely performed. The DOAC Dipstick is a new rapid test for detecting DOACs in urine. The aim of this study was to evaluate the possible uses and limitations of the DOAC Dipstick and to compare visual analysis and DOASENSE Reader analysis of DOAC Dipstick pads. Plasma and urine samples were collected from 23 patients taking DOACs. DOAC concentrations in plasma and urine were measured by chromogenic substrate assays and in urine also by the DOAC Dipstick. Plasma concentrations were dichotomized at a threshold of ≥30 ng/mL. Patient samples were compared with samples from control individuals not using anticoagulants (n = 10) and with DOASENSE control urines. The Combur-10 test was used to measure parameters that may affect urine color and hence the interpretation of the DOAC Dipstick result. DOAC Dipstick test results were positive in 21/23 patient urine samples at a plasma DOAC concentration of ≥30 ng/mL and in 2/23 patient urine samples at a plasma DOAC concentration of <30 ng/mL. Inter-observer agreement was above 90% for visual analysis of patient urine samples and was 100% for DOASENSE Reader analysis of patient urines and for analysis of control group urines and DOASENSE control urines. Abnormalities in urine color detected by the Combur-10 test did not affect the DOAC Dipstick results. DOAC Dipstick detects DOACs in urine at a plasma threshold of ≥30 ng/mL. Positive DOAC Dipstick results should be confirmed by measuring DOAC plasma concentration.

Thrombin Generation in Cardiac Versus Noncardiac Surgical Cohorts.

BACKGROUND: Bleeding can be a significant problem after cardiac surgery. As a result, venous thromboembolism (VTE) or anticoagulation or both following mechanical valve implantation are often delayed in these patients. The calibrated automated thrombin (CAT) generation assay has become the gold standard to evaluate thrombin generation, a critical step in clot formation independent of other hemostatic processes (eg, platelet activation, fibrin cross-linking, and fibrinolysis), and is increasingly used to examine thrombotic and hemorrhagic outcomes. No study has currently used this assay to compare the thrombin generation profiles of cardiac surgical patients to noncardiac surgical patients. We hypothesize that noncardiac patients may be less prone to postoperative changes in thrombin generation. METHODS: A prospective, observational, cohort study was undertaken using blood samples from 50 cardiac and 50 noncardiac surgical patients preoperatively, immediately postoperatively, and on postoperative days 1 to 4. Platelet-poor plasma samples were obtained from patients preoperatively, on arrival to the postanesthesia care unit (PACU) or intensive care unit (ICU), and daily on postoperative days 1 to 4 if patients remained inpatient. Samples were evaluated for CAT measurements. Patient and surgical procedure characteristics were obtained from the electronic medical record. RESULTS: The primary outcome variable, median endogenous thrombin potential (ETP), measured in nanomolar × minutes (nM × min), was decreased 100% in cardiac surgical versus 2% in noncardiac patients (P < .001). All parameters of thrombin generation were similarly depressed. Cardiac (versus noncardiac) surgical type was associated with -76.5% difference of percent change in ETP on multivariable regression analysis (95% confidence interval [CI], -87.4 to -65.5; P value <.001). CONCLUSIONS: Cardiac surgical patients exhibit a profound decrease in thrombin generation postoperatively compared with noncardiac surgical patients evaluated by this study. Hemodilution and coagulation factor depletion likely contribute to this decreased thrombin generation after cardiac surgery.

The clinical significance of ultra-high D-dimer levels.

OBJECTIVE: Plasma D-dimer levels >5000 ng/mL are encountered in a number of conditions other than venous thromboembolism (VTE). Recent studies have used plasma D-dimer levels as a prognostic indicator for coronavirus disease 2019 (COVID-19) infection. The implications of abnormal levels are less clear for patients diagnosed with COVID-19 with a baseline elevation in plasma D-dimer levels. In the present study, we reviewed the occurrence of plasma D-dimer levels >5000 ng/mL and investigated the clinical significance of this finding before the onset of the COVID-19 pandemic. METHODS: Inpatient records for a 4-year period were screened for laboratory results of plasma D-dimer levels >5000 ng/mL. The patient data were reviewed for the clinical identifiers commonly associated with elevated plasma D-dimer levels, including VTE, cancer, sepsis, pneumonia, other infection, bleeding, and trauma. The patients were then categorized into groups stratified by the plasma D-dimer level to allow for comparisons between the various clinical diagnoses. RESULTS: A total of 671 patients were included in the present study. VTE was the most common diagnosis for patients with a plasma D-dimer level >5000 ng/mL, followed by cancer and pneumonia. Multiple clinical diagnoses were present in 61% of the patients. No clear cause for the ultra-high plasma D-dimer level could be identified in 11.3% of the patients. Among the patients lacking a clinical diagnosis at discharge, mortality was 24% in the 5000- to 10,000-ng/mL group, 28.6% in the 10,000- to 15,000-ng/mL group, and 75% in the >15,000-ng/mL group. CONCLUSIONS: VTE, cancer, and pneumonia were frequently present when ultra-high plasma D-dimer levels were encountered, and mortality was high when the levels were >15,000 ng/mL. The results from our study from a pre-COVID-19 patient population suggest that ultra-high plasma D-dimer levels indicate the presence of severe underlying disease. This should be considered when using the plasma D-dimer level as a screening tool or prognostic indicator for COVID-19 infection.

Evaluation of procoagulant imbalance in Cushing's syndrome after short- and long-term remission of disease.

OBJECTIVE: Patients with Cushing's syndrome (CS) are at high risk of venous thromboembolism related to a hypercoagulability due to procoagulant imbalance. However, whether these alterations are reversible after disease remission is still unclear. The endogenous thrombin potential (ETP) measured with and without the addition of thrombomodulin provides a global representation of coagulation and previous data confirmed hypercoagulable profile in patients with active hypercortisolism. Aim of this study was to assess the short- and long-term modification of ETP in patients with CS after disease remission. DESIGN AND METHODS: Nineteen patients with CS for whom surgical remission was achieved, were prospectively evaluated for clinical characteristics, cortisol secretion profile and ETP at different time points: (i) before surgical intervention; (ii) after 6 months and (iii) 5 years from the time of persistent remission. Nineteen healthy subjects matched for age and gender were also evaluated as control group. RESULTS: Before surgery, patients showed higher ETP-ratio (with/without thrombomodulin) than controls (0.62 ± 0.09-vs-0.56 ± 0.09, p = 0.034). No significant correlation between ETP-ratio and cortisol secretion was found. 6 months after remission, ETP-ratio was still significantly increased compared to controls (0.64 ± 0.09-vs-0.56 ± 0.09, p = 0.01), but was similar to baseline (0.64 ± 0.09-vs-0.62 ± 0.09, p = 0.87). At 5 years, ETP-ratio showed a significant decrease (0.55 ± 0.14-vs-0.62 ± 0.09, p = 0.02) and was comparable to controls (0.55 ± 0.14-vs-0.56 ± 0.09, p = 0.7). CONCLUSIONS: Plasma hypercoagulability detected in patients with active hypercortisolism persists at short-term evaluation and seems to be completely reversible after long-term remission of disease. These data, as part of a whole evaluation of thrombotic risk, can contribute to make appropriate therapeutic choice in these patients.

Using a Simple Prescription Gap to Determine Warfarin Discontinuation Can Lead to Substantial Misclassification.

BACKGROUND: Warfarin remains widely used and a key comparator in studies of other direct oral anticoagulants. As longer-than-needed warfarin prescriptions are often provided to allow for dosing adjustments according to international normalized ratios (INRs), the common practice of using a short allowable gap between dispensings to define warfarin discontinuation may lead to substantial misclassification of warfarin exposure. We aimed to quantify such misclassification and determine the optimal algorithm to define warfarin discontinuation. METHODS: We linked Medicare claims data from 2007 to 2014 with a multicenter electronic health records system. The study cohort comprised patients ≥65 years with atrial fibrillation and venous thromboembolism initiating warfarin. We compared results when defining warfarin discontinuation by (1) different gaps (3, 7, 14, 30, and 60 days) between dispensings and (2) having a gap ≤60 days or bridging larger gaps if there was INR ordering at least every 42 days (60_INR). Discontinuation was considered misclassified if there was an INR ≥2 within 7 days after the discontinuation date. RESULTS: Among 3,229 patients, a shorter gap resulted in a shorter mean follow-up time (82, 95, 117, 159, 196, and 259 days for gaps of 3, 7, 14, 30, 60, and 60_INR, respectively; p < 0.001). Incorporating INR (60_INR) can reduce misclassification of warfarin discontinuation from 68 to 4% (p < 0.001). The on-treatment risk estimation of clinical endpoints varied significantly by discontinuation definitions. CONCLUSION: Using a short gap between warfarin dispensings to define discontinuation may lead to substantial misclassification, which can be improved by incorporating intervening INR codes.

Activated Factor XI is Increased in Plasma in Response to Surgical Trauma but not to Recombinant Activated FVII-Induced Thrombin Formation.

AIM: Feedback activation of factor XI (FXI) by thrombin is believed to play a critical role in the amplification phase of thrombin generation and to contribute to thrombosis development and hemostasis. However, the activation of FXI by thrombin has been shown in vitro to require a cofactor. In this study, the role of thrombin in activated FXI (FXIa) formation in vivo is investigated. METHODS: The study population comprised probands in whom coagulation activation was triggered by low-dose (15 µg/kg) recombinant activated factor VII (rFVIIa, n=89), of whom 34 with (VTE+) and 45 without a history of venous thromboembolism (VTE-), and patients undergoing major orthopedic surgeries (n=45). FXIa was quantified via an enzyme capture assay using a monoclonal FXI-specific antibody. Thrombin formation was monitored using an oligonucleotide-based enzyme capture assay and the thrombin activation markers prothrombin fragment 1＋2 (F1＋2) and thrombin-antithrombin complex (TAT). RESULTS: In the rFVIIa cohort, FXIa and thrombin remained below their lower limit of quantification of 3.48 and 1.06 pmol/L, respectively. By contrast, during the surgeries, median FXIa levels increased from 3.69 pmol/L pre-operatively to 9.41 pmol/L mid-operatively (P=4·10-4) and remained significantly elevated 24 h thereafter, with 9.38 pmol/L (P=0.001). Peak levels of F1+2 were comparable in the VTE+, VTE-, and surgery cohort (235, 268, and 253 pmol/L), whereas peak TAT levels were higher in the surgery cohort (53.1, 33.9, and 147.6 pmol/L). CONCLUSIONS: Under in vivo conditions, the activation of FXI requires specific local features that are present at the wounded site including potential cofactors of thrombin.

Comparison of the in vitro clot-capturing efficiencies of commercially available retrievable inferior vena cava filters.

OBJECTIVE: We compared the in vitro clot-capturing efficiencies (CCEs) of commercially available retrievable inferior vena cava (IVC) filters. METHODS: Four types of commercially available retrievable IVC filters were included in the present study: Denali (BD, Franklin Lakes, NJ), OptEase (Cordis Corp, Hialeah, Fla), Celect (Cook Medical, Bloomington, Ind), and Option (Argon Medical Devices, Frisco, Tex). The CCE of each IVC filter for 10 different size clots, ranging from 2 mm × 10 mm to 6 mm × 20 mm, was analyzed using a venous flow simulator. RESULTS: When ≥4 × 10-mm clots were used, the CCEs were 100% for all four types of IVC filters in a 20-mm-diameter simulated IVC filter. However, when ≤3 × 20-mm clots were used, the CCEs were significantly different among the four types of filters in a 20-mm-diameter simulated IVC, with the Denali showing the highest CCE, followed by the OptEase, Celect, and Option. When ≥6 × 10-mm clots were used, the CCEs were 100% for all four types of IVC filters in the 25-mm-diameter simulated IVC. However, when ≤5 × 20-mm clots were used, the CCEs were significantly different among the four types of filters in the 25-mm-diameter simulated IVC, with the Denali showing the highest CCE. When ≤5 × 10-mm clots were used, the CCEs were significantly lower in the 25-mm-diameter simulated IVC than in the 20-mm-diameter simulated IVC for all four types of IVC filters, with Option showing the greatest change in CCEs, followed by the Celect, OptEase, and Denali. CONCLUSIONS: The CCEs were significantly different among the four IVC filters and were significantly lower for the smaller size clots than for the larger size clots and for the larger diameter simulated IVC than for the smaller diameter simulated IVC.

Supraprophylactic Anti-Factor Xa Levels Are Associated with Major Bleeding in Neurosurgery Patients Receiving Prophylactic Enoxaparin.

BACKGROUND: Prior studies demonstrated reduced risk for venous thromboembolism (VTE) in neurosurgical patients secondary to prophylaxis with both heparin and low-molecular-weight heparin. The ability to monitor low-molecular-weight heparin by obtaining anti-factor Xa (anti-Xa) serum levels provides an opportunity to evaluate safety and efficacy. The aim of this study was to describe characteristics of patients who have anti-Xa levels outside of the goal range (0.2-0.4/0.5 IU/mL) and investigate incidence of major bleeding and VTE. METHODS: A single-center, retrospective, observational study was conducted on neurosurgical patients receiving enoxaparin for VTE prophylaxis between August 2019 and December 2020. Significance testing was conducted via Fisher exact test and independent samples t test. RESULTS: The study included 85 patients. Patients were less likely to have an anti-Xa level in the goal range if they were male, had a higher weight, or were morbidly obese. Three neuroendovascular patients (3.5%) experienced a major bleed. Serum anti-Xa levels were significantly higher in patients who experienced major bleeds compared with patients who did not (0.45 ± 0.16 IU/mL vs. 0.28 ± 0.09 IU/mL, P = 0.003). Patients with a supraprophylactic anti-Xa level (>0.5 IU/mL) were more likely to experience a major bleed (P = 0.005). One VTE event occurred: the patient experienced a pulmonary embolism with anti-Xa level at goal. CONCLUSIONS: Anti-Xa-guided enoxaparin dosing for VTE prophylaxis in neurosurgical patients may help prevent major bleeding. These data suggest that a higher anti-Xa level may predispose patients to major bleeding. Further evaluation is needed to identify the goal anti-Xa level for VTE prophylaxis in this population.

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.

Using a low-molecular weight heparin-calibrated anti-factor Xa assay to assess the concentration of apixaban and rivaroxaban.

INTRODUCTION: Direct oral anticoagulant (DOAC)-inhibiting factor Xa (FXa-DOAC) are being increasingly used as prophylaxis of venous thromboembolism and for prevention of stroke in patients with atrial fibrillation. In contrast to vitamin K antagonists, DOACs do not require monitoring in general. However, it is sometimes of value in the acute setting, for instance when considering a reversal agent in uncontrolled bleeding in patients on DOAC. METHODS: We evaluated if a low-molecular weight heparin (LMWH)-calibrated anti-factor Xa assay could be used to estimate FXa-DOAC concentration in the concentration range <100 ng/mL by spiking known concentrations of FXa-DOAC and from those result calculate the FXa-DOAC concentration from the response of the LMWH assay. This procedure was then evaluated by comparing the result with a drug-calibrated chromogenic assay and liquid chromatography tandem mass spectrometry (LC-MS/MS) on clinical plasma samples from patients treated with apixaban or rivaroxaban. RESULTS: Although the measuring range was narrower for the LMWH-calibrated assay, concentrations recalculated from the LMWH assay was comparable with those measured by the drug-calibrated method when compared with LC-MS/MS. CONCLUSION: We suggest that an LMWH-calibrated anti-factor Xa assay can be used after characterization of the response of FXa-DOACs to give guidance on the concentration of apixaban and rivaroxaban. Shorter turnaround time than LC-MS/MS and the greater availability than drug-calibrated chromogenic assays could make this a valuable option in the acute setting.

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.

Downregulation of microRNA-200c-3p alleviates the aggravation of venous thromboembolism by targeting serpin family C member 1.

Venous thromboembolism (VTE) is the third most prevalent cardiovascular complication. Increasing studies have demonstrated that some microRNAs (miRNAs) are aberrantly expressed in VTE and play crucial roles in mediating the development of VTE. Therefore, our study intends to explore the detailed function and molecular mechanism of miR-200c-3p in VTE progression. In our research, VTE rat models were first established via inferior vena cava (IVC) ligation and the time-dependent effects of IVC ligation on thrombus formation were discovered. The results of reverse transcription quantitative polymerase-chain reaction (RT-qPCR) and western blotting showed that serpin family C member 1 (SERPINC1) was downregulated in VTE rat models and showed an inverse correlation with thrombus load. MiRNA target prediction tools and luciferase reporter assay confirmed SERPINC1 as a target for miR-200c-3p. VTE rats were injected with miR-200c-3p inhibitor for 24 h to investigate whether miR-200c-3p knockdown influences thrombus formation in vivo. Histological examination through hematoxylin-eosin staining revealed that miR-200c-3p downregulation markedly inhibited the formation of thrombus in IVC of rats. Additionally, miR-200c-3p was upregulated while SERPINC1 was downregulated in serum and inferior vena cava of VTE rats as well as in plasma of patients with VTE. Linear regression analysis demonstrated that miR-200c-3p expression was negatively correlated to SERPINC1 expression in VTE rats and patients with VTE. Our study determines the previously unelucidated function of miR-200c-3p in VTE, which might provide a potential novel insight for the treatment of VTE.

Is There a Predictive Value of High Mean Platelet Volume in Early Diagnosis of Venous Thromboembolism?

BACKGROUND: Venous thromboembolism (VTE) is a serious disease, which demands a fast accurate diagnosis to begin suitable treatment. It presents a major problem in the emergency department (ED), and its confirmation requires adequate evaluation. OBJECTIVES: To evaluate a potential role of mean platelet volume (MPV) in differentiating VTE from other potential diagnosis in patients with suspected VTE. METHODS: We conducted a retrospective case-controlled study of 440 consecutive patients who presented to the ED of our hospital with clinical VTE, but only 316 with proven VTE. A control group was composed of patients (124) who presented with clinical VTE but without proven VTE. We checked the MPV value in all 440 patients and the correlation with VTE occurrence in the study group vs. control group. RESULTS: Statistical analysis of the acquired results indicated that MPV value could not aid in determining the difference of real VTE vs. patients with VTE-like clinical picture presenting to the ED. We found an inverse correlation between MPV value and proven VTE, in contrast to most researchers who have studied the same issue. CONCLUSIONS: Although MPV can be a useful diagnostic marker in many diseases, we found no definite association between low MPV and VTE.

Platelet GPVI (Glycoprotein VI) and Thrombotic Complications in the Venous System.

The immunoglobulin receptor GPVI (glycoprotein VI) is selectively expressed on megakaryocytes and platelets and is currently recognized as a receptor for not only collagen but also a variety of plasma and vascular proteins, including fibrin, fibrinogen, laminin, fibronectin, and galectin-3. Deficiency of GPVI is protective in mouse models of experimental thrombosis, pulmonary thromboembolism as well as in thromboinflammation, suggesting a role of GPVI in arterial and venous thrombus formation. In humans, platelet GPVI deficiency is associated with a mild bleeding phenotype, whereas a common variant rs1613662 in the GP6 gene is considered a risk factor for venous thromboembolism. However, preclinical studies on the inhibition of GPVI-ligand interactions are focused on arterial thrombotic complications. In this review we discuss the emerging evidence for GPVI in venous thrombus formation and leukocyte-dependent thromboinflammation, extending to venous thromboembolism, pulmonary thromboembolism, and cancer metastasis. We also recapitulate indications for circulating soluble GPVI as a biomarker of thrombosis-related complications. Collectively, we conclude that the current evidence suggests that platelet GPVI is also a suitable cotarget in the prevention of venous thrombosis due to its role in thrombus consolidation and platelet-leukocyte complex formation.