An MRI Radiomics Approach to Predict the Hypercoagulable Status of Gliomas.

Venous thromboembolic events are frequent complications of Glioblastoma Multiforme (GBM) and low-grade gliomas (LGGs). The overexpression of tissue factor (TF) plays an essential role in the local hypercoagulable phenotype that underlies these complications. Our aim was to build an MRI radiomics model for the non-invasive exploration of the hypercoagulable status of LGG/GBM. Radiogenomics data from The Cancer Genome Atlas (TCGA) and REMBRANDT (Repository for molecular BRAin Neoplasia DaTa) cohorts were used. A logistic regression model (Radscore) was built in order to identify the top 20% TF-expressing tumors, considered to be at high thromboembolic risk. The most contributive MRI radiomics features from LGG/GBM linked to high TF were identified in TCGA using Least Absolute Shrinkage and Selection Operator (LASSO) regression. A logistic regression model was built, whose performance was analyzed with ROC in the TCGA/training and REMBRANDT/validation cohorts: AUC = 0.87 [CI95: 0.81-0.94, p < 0.0001] and AUC = 0.78 [CI95: 0.56-1.00, p = 0.02], respectively. In agreement with the key role of the coagulation cascade in gliomas, LGG patients with a high Radscore had lower overall and disease-free survival. The Radscore was linked to the presence of specific genomic alterations, the composition of the tumor coagulome and the tumor immune infiltrate. Our findings suggest that a non-invasive assessment of the hypercoagulable status of LGG/GBM is possible with MRI radiomics.

Cancer-associated thrombosis: How many patients seen in clinical practice would be eligible for a direct oral anticoagulant randomized controlled trial?

Based on the results of randomized clinical trials (RCT) assessing direct oral anticoagulants (DOACs) for the treatment of patients with cancer-associated thrombosis (CAT), DOACs have been proposed as alternative to low molecular weight heparin by several international guidelines. However, the proportion of CAT patients who would have not been eligible for such trials is currently unknown. Our primary aim was to assess the proportion of patients seen in clinical practice for acute CAT who would not have been eligible for CARAVAGGIO or HOKUSAI-VTE RCT. Secondary aim was to describe patients outcomes according to eligibility. In a multicenter, observational study, all patients consecutively admitted from January 2017 to December 2019 for an acute CAT event were retrospectively analyzed. Patients were classified according to the presence or absence of non-inclusion criteria for CARAVAGGIO or HOKUSAI-VTE RCT. Event free survival during a 6-month follow-up were analyzed as secondary endpoints. Among the 302 patients (women: 53 %, mean age: 67.9 ± 13.2) analyzed, 138 (46 %) for HOKUSAI-VTE cancer and 161 (53 %) for CARAVAGGIO met one or more non-inclusion criteria. Main criteria were upper limb and unsual site thrombosis (n = 63, 18.5 %), anemia/thrombopenia (n = 43, 14.2 %), brain tumors (n = 33, 10.9 %), ECOG PS >2 (n = 28, 9.3 %), severe renal failure (n = 16, 5.3 %). At 6 months, the event-free survival rate was not statistically different between the two groups. Almost half of CAT patients would have not been able to participate to a modern DOAC RCT. Evaluation of DOACs safety and efficacy in this subset of patients deserves further research.

Annexin-V positive extracellular vesicles level is increased in severe COVID-19 disease.

Objectives: To evaluate extracellular vesicles levels in a cohort of SARS-CoV-2's patients hospitalized in an intensive care unit with and without COVID-19 associated thromboembolic events. Methods: In this study, we aim to assess endothelial and platelet membrane-derived extracellular vesicles levels in a cohort of SARS-CoV-2 patients with and without COVID-19-associated thromboembolic events who were hospitalized in an intensive care unit. Annexin-V positive extracellular vesicles levels were prospectively assessed by flow cytometry in one hundred twenty-three critically ill adults diagnosed with acute respiratory distress syndrome associated with a SARS-CoV-2 infection, ten adults diagnosed for moderate SARS-CoV-2 infection and 25 healthy volunteers. Results: On our critically ill patients, thirty-four patients (27.6%) had a thromboembolic event, Fifty-three (43%) died. Endothelial and platelet membrane-derived extracellular vesicles were drastically increased in SARS-CoV-2 patients hospitalized in the ICU compared to healthy volunteers. Moreover a slighty higher small/large ratio for platelets membrane-derived extracellular vesicles in patients was linked to thrombo-embolic events. Conclusion: A comparison between total annexin-V positive extracellular vesicles levels in severe and moderate SARS-CoV-2 infection and healthy controls showed a significant increase in patients with severe infection and their sizes could be considered as biomarkers of SARS-CoV-2 associated thrombo-embolic events.

Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial.

Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients. Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707). Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034). Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens. Funding: French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole.

Contemporary Minimally Invasive Surgery for TASC-D Aorto-Iliac Lesions: Analysis of Outcomes and Risk Factors for Primary and Secondary Patency.

BACKGROUND: For complex extensive TASC-II D lesions, the standard of care remains conventional surgery. Nevertheless, guidelines tend to broaden endovascular surgery indications in expert centers for patients at high surgical risk with TASC-II D lesions. Due to the increasing use of endovascular surgery in this setting, we planned to evaluate the patency rate of this approach. METHODS: We conducted a retrospective study in a tertiary center. All patients treated for symptomatic peripheral arterial disease (PAD) with classified D lesions according to the TASC-II classification and requiring management of the aortoiliac bifurcation were retrospectively included between January 1, 2007 and December 31, 2017. The type of surgical approach was classified as a pure percutaneous approach or hybrid surgery. The main objective was to describe long-term patency results. The secondary objectives were to identify risk factors for loss of patency and long-term complications. The primary outcomes were primary patency, primary-assisted patency, and secondary patency at 5 years of follow-up. RESULTS: One hundred and thirty-six patients were included. For the overall population, the primary, primary-assisted, and secondary patency proportions at 5 years were 71.6% (95% confidence interval (CI) 63.2-81%), 82.1% (95% CI 74.9-89.3%), 96.3% (95% CI 92-100%), respectively. For primary patency, there was a significant difference in favor of the covered stent group at 36 months (P < 0.01) and 60 months (P = 0.037). In a multivariate model, only CS and age were associated with a better primary patency (hazard ratio (HR) 0.36, CI 95% [0.15-0.83], P = 0.0193 and an HR 0.07, 95% CI [0.05-0.09], P = 0.005, respectively). The overall rate of perioperative complications was 11%. CONCLUSIONS: We report that endovascular and hybrid surgery are safe and effective in the management of TASC-D complex aortoiliac lesions in mid to long-term follow-up. Short-term and long-term complications were all considered as minor.

Venous Thrombosis Recurrence After Catheter-Related Upper Extremity Deep Venous Thrombosis in Cancer Patients: A Retrospective Analysis.

Long-term indwelling central venous catheters (CVC) are frequently used to secure vascular access to deliver injectable treatment. Catheter-related thrombosis (CRT) occurs in approximately 2-6% of cancer patients. We conducted a single-center retrospective study to assess the rate of venous thromboembolism (VTE) recurrence in cancer patients; 200 patients were included. Mean age was 56 ± 15.15 years, median follow-up duration was 16.5 [range: 10-36] months. The incidence of recurrence was estimated using Gray's method for competing risk with death as the competing event of VTE. Recurrent VTE occurred in 25.5% of patients with a median occurrence time of 6.5 [range: 5-11.25] months. In case of recurrence, 94.6% of patients were treated for cancer and 80.4% of them received anticoagulants; 4 major bleeds and 17 non-major bleeds occurred during follow-up. In multivariate analysis, previous VTE (Hazard Ratio (HR) 2.48 (95% CI 1.42-4.32) and presence of CVC (HR 5.56 (95% CI 1.96-15.75) were significant recurrence risk factors. After a first episode of CRT, 25.5% of patients experienced VTE recurrence as UEDVT in 30 cases (55.5%), PE in 17 cases (31.5%), and DVT in 7 cases (13%), mostly during anticoagulation therapy. Anticoagulation therapy does not avoid CRT in case of cancer and must be balanced with hemorrhagic risk.

The coagulome of oral squamous cell carcinoma: examining the role and regulation of coagulation in oral cancers using a systems approach.

PURPOSE OF REVIEW: Solid tumors often establish a locally hypercoagulant state that promotes vascular complications, such as venous thromboembolism (VTE). Oral squamous cell carcinoma (OSCC) is associated with a broad range of hemostatic complications. Although VTE rarely occurs in ambulatory patients with OSCC, the coagulation cascade is typically activated by surgical resection and local hemorrhage. We present the recent progress in the understanding of the role and regulation of coagulation in OSCC. RECENT FINDINGS: Application of systems biology, using bulk tumor and single cell genomic analyses, unveiled the landscape of the tumor coagulome. Of all tumor types, OSCC express the highest mRNA levels of F3 and PLAU, the genes that encode the tissue factor (TF) and urokinase-type plasminogen activator (uPA), the key regulators of coagulation and fibrinolysis, respectively. It also brought to light the intimate and reciprocal regulation between coagulation/fibrinolysis and the tumor microenvironment (TME). SUMMARY: OSCC have a specific coagulome, with consequences that likely extend beyond the vascular risk. We discuss the attractive possibility that biomarkers of the coagulation cascade might reflect some important characteristics of the TME, offering new opportunities to better understand the impact of surgical procedures, better predict their oncological outcome and improve current therapeutic approaches.

Is the Calcium Score Useful for Rheumatoid Arthritis Patients at Low or Intermediate Cardiovascular Risk?

Cardiovascular disease, particularly myocardial infarction, is the leading cause of death of rheumatoid arthritis (RA) patients. The usefulness of the coronary artery calcification score (CACS), determined using cardiac computed-tomography (CT)-scan images, was assessed as a part of a cardiovascular work-up of RA patients at low or intermediate cardiovascular disease risk. This descriptive, cross-sectional, single-center study was conducted on patients with stable RA or that which is in remission. Each patient's work-up included a collection of cardiovascular risk factors, laboratory analyses, an electrocardiogram, a supra-aortic trunks (SATs) echo-Doppler test and a cardiac CT scan. The primary endpoint was to determine the frequency of patients with a CACS > 100, indicating notable atherosclerosis. Fifty patients were analyzed: mean ± standard deviation age was 53.7 ± 7.5 years, 82% women. The CACS exceeded 100 in 12 (24%) patients (11 were at intermediate risk) and 2 of them underwent angioplasty for silent myocardial ischemia. Cardiovascular risk was reclassified from intermediate to high for 5 patients. Age according to sex and smoking status were significantly associated with that increase; no association was found with RA characteristics or treatments.

Adjusting D-dimer to Lung Disease Extent to Exclude Pulmonary Embolism in COVID-19 Patients (Co-LEAD).

OBJECTIVE: D-dimer measurement is a safe tool to exclude pulmonary embolism (PE), but its specificity decreases in coronavirus disease 2019 (COVID-19) patients. Our aim was to derive a new algorithm with a specific D-dimer threshold for COVID-19 patients. METHODS: We conducted a French multicenter, retrospective cohort study among 774 COVID-19 patients with suspected PE. D-dimer threshold adjusted to extent of lung damage found on computed tomography (CT) was derived in a patient set (n = 337), and its safety assessed in an independent validation set (n = 337). RESULTS: According to receiver operating characteristic curves, in the derivation set, D-dimer safely excluded PE, with one false negative, when using a 900 ng/mL threshold when lung damage extent was <50% and 1,700 ng/mL when lung damage extent was ≥50%. In the derivation set, the algorithm sensitivity was 98.2% (95% confidence interval [CI]: 94.7-100.0) and its specificity 28.4% (95% CI: 24.1-32.3). The negative likelihood ratio (NLR) was 0.06 (95% CI: 0.01-0.44) and the area under the curve (AUC) was 0.63 (95% CI: 0.60-0.67). In the validation set, sensitivity and specificity were 96.7% (95% CI: 88.7-99.6) and 39.2% (95% CI: 32.2-46.1), respectively. The NLR was 0.08 (95% CI; 0.02-0.33), and the AUC did not differ from that of the derivation set (0.68, 95% CI: 0.64-0.72, p = 0.097). Using the Co-LEAD algorithm, 76 among 250 (30.4%) COVID-19 patients with suspected PE could have been managed without CT pulmonary angiography (CTPA) and 88 patients would have required two CTs. CONCLUSION: The Co-LEAD algorithm could safely exclude PE, and could reduce the use of CTPA in COVID-19 patients. Further prospective studies need to validate this strategy.

JAK2 allele burden is correlated with a risk of venous but not arterial thrombosis.

BACKGROUND: Thrombosis is the main complication in myeloproliferative neoplasms (MPN). A JAK2V617F mutation has been shown to be a risk factor for thrombosis. The implication of other risk factors alongside a mutation allele burden needs to be clarified (Trifa et al., 2018; Borowczyk et al., 2015). OBJECTIVE: Our aim was to investigate the role of the JAK2 mutation allele burden in the risk of cardiovascular events (CVE) and/or venous thrombosis (VTE) in a cohort of patients with confirmed MPN, as well as in patients without confirmed MPN. METHODS: We restrospectively included all consecutive patients who were positive for JAK2V617F seen by our unit between December 2008 and September 2016. Inclusion criteria were a positive test for the JAK2V617F mutation, with at least 1% allele burden, with or without confirmed MPN. RESULTS: We included 239 patients of median age 71 years [60-81], followed-up for a median of 82.8 months [41.08-146.88]. For JAK2V617F positive patients having an allele burden superior to 50% the cumulative incidence of VTE was significantly higher than for those with an allele burden inferior to 50% (HR 3.11 95% CI [1.10-8.76] p = 0.031). The cumulative incidence of VTE was also higher in patients with obesity (HR 4.58 95% CI [1.33-15.8] p = 0.016). There was no significant association between a JAK2V617F allele burden and arterial thrombosis (manifesting as CVE). Previous VTE was also associated with a higher cumulative incidence of recurrence during follow-up HR 3.22 95% CI [1.17-8.81] p = 0.0231. CONCLUSION: We show that a JAK2V617F allele burden is associated with risk of VTE but not with CVE.

Molecular Landscape of the Coagulome of Oral Squamous Cell Carcinoma.

BACKGROUND: Hemostatic complications, ranging from thromboembolism to bleeding, are a significant source of morbidity and mortality in cancer patients. The tumor coagulome represents the multiple genes and proteins that locally contribute to the equilibrium between coagulation and fibrinolysis. We aimed to study the coagulome of Oral Squamous Cell Carcinoma (OSCC) and examine its link to the tumor microenvironment (TME). METHODS: We used data from bulk tumor DNA/RNA-seq (The Cancer Genome Atlas), single-cell RNA-seq data and OSCC cells in culture. RESULTS: Among all tumor types, OSCC was identified as the tumor with the highest mRNA expression levels of F3 (Tissue Factor, TF) and PLAU (urokinase type-plasminogen activator, uPA). Great inter- and intra-tumor heterogeneity were observed. Single-cell analyses showed the coexistence of subpopulations of pro-coagulant and pro-fibrinolytic cancer cells within individual tumors. Interestingly, OSCC with high F3 expressed higher levels of the key immune checkpoint molecules CD274/PD-L1, PDCD1LG2/PD-L2 and CD80, especially in tumor dendritic cells. In vitro studies confirmed the particularity of the OSCC coagulome and suggested that thrombin exerts indirect effects on OSCC cells. CONCLUSIONS: OSCC presents a specific coagulome. Further studies examining a possible negative modulation of the tumor's adaptive immune response by the coagulation process are warranted.

Under-Prescription of Medical Treatment for Peripheral Artery Disease in the Under 50s: A Retrospective Study.

Peripheral artery disease (PAD) is a common cause of morbidity and mortality; however, data on its etiology and evolution in patients under 50 years old are scarce. Therefore, we performed a retrospective analysis of data from medical records, including cardiovascular risk factors, etiology, medical and surgical treatment, and follow-up. We included all patients with PAD aged between 18 and 50 years attending our university hospital between 2005 and 2015. Of the 87 patients included, 32 (36%) were women. Smoking was acknowledged by 81 patients (93%), and 37 had dyslipidemia (42.5%). Median follow-up was 24 months (10-59). Recurrence occurred in 41 patients (47.1%), all active smokers, with a median delay of 14 months (7-47). Acute limb ischemia at diagnosis was significantly associated with major amputation, odds ratio (OR) 5.95 (95%CI 1.41-40.90, P = .029), which was needed by 11 patients (12.6%). Treatments included antiplatelet therapy (76; 87.4%), statins (67; 77%), and anti-hypertensives (60; 69%), and 29 (32.1%) patients benefited from vascular rehabilitation. This cohort of relatively young patients with PAD showed a high level of symptom recurrence. Atherosclerosis was the most common etiology. Our study revealed that medical treatment is often under-prescribed in this age group and needs to be improved.

Women and Pregnancy in Thromboangiitis Obliterans.

Data regarding women and thromboangiitis obliterans (TAO) are conflicted, and a few cases of pregnancy have been described. We aimed to describe the interplay between TAO and pregnancies. Among 224 TAO patients, 22.8% were women. Demographic data, clinical manifestations, and outcomes were similar between men and women. Twenty-one (41.2%) women had 48 pregnancies. Thirty-six (75%) pregnancies with on term and complication free delivery occurred. None of the patients experienced a disease flare of TAO during pregnancy. TAO does not seem to affect pregnancy complications, and pregnancy does not seem to interfere with the course of TAO.

A pan-cancer analysis of the human tumor coagulome and its link to the tumor immune microenvironment.

OBJECTIVE: Solid tumors often establish a procoagulable state that can lead to venous thromboembolism (VTE). Although some of the key genes involved in this process are known, no previous study has compared the "coagulome", i.e., the expression of coagulation/fibrinolysis genes, across different primary tumor types. It is also unclear whether the coagulome is associated with specific characteristics of the tumor microenvironment (TME). We aimed to address this question. METHODS: We analyzed the expression of the genes F3, PLAU, PLAT, PLAUR, SERPINB2, and SERPINE1 in 32 cancer types using data from The Cancer Genome Atlas (TCGA) and other freely available resources. RESULTS: We identified specific expression patterns of procoagulant and fibrinolytic genes. The expression of the Tissue Factor (F3) was found to be tumor type dependent, with the highest expression in glioblastoma (GBM), a highly procoagulable tumor type. Conversely, high expression of the fibrinolysis gene cluster PLAU, PLAUR, SERPINE1 was consistently linked to the characteristics of the TME (monocytic infiltration) and high expression of important checkpoints of the immune response, such as PD-L2 and CD276/B7-H3. CONCLUSION: These tumor-specific patterns of expression might partially explain the differences in VTE risk among tumor types. We propose that biomarkers of coagulation fibrinolysis might provide valuable information about the TME in cancer patients.

Thrombotic Complications in Venous Malformations: Are There Differences Between Facial and Other Localizations?

Venous thrombosis (VT) is a frequent complication in venous malformations (VM) in relation with blood stasis and localized intravascular coagulopathy (LIC). Our aim was to describe the clinical characteristics and the treatment of patients with facial and non facial VM with VT. We implemented an observational retrospective study of patients with VM followed between 2002 and 2017. We compared features of facial and non facial VM. Descriptive and bivariate statistics were computed and the P value was set at 0.05. Fifty patients were included between 2002 and 2017. 24 of them were women (44%). The median age of the patients at diagnosis was 16,5 [8-31] years. The median follow up was 2 [2; 4] years. In non facial VM venous thrombosis occurred in 12 cases. In facial VM, 3 patients had thrombotic complication (15%). We demonstrate no difference of VT between facial VM and other localization. No patients had clinical risk factors for VT at diagnosis. Our study showed that VT is a frequent complication of VM and its proportion is not different between facial and non facial VM. Studies are needed to confirm the role of LIC in VT in VM, particularly in facial VM.

Did the Clinical Spectrum of Thromboangiitis Obliterans Change in the Past 40 Years?

Thromboangiitis obliterans (TAO) is an inflammatory disease that usually affects small and medium-sized arteries in the upper and lower limbs of young smokers. Previous studies showed that the spectrum TAO has changed in the 80s: the male-to-female ratio decreased, older patients were diagnosed, and upper limb involvement was more common. The aim of our study was to assess the changing clinical spectrum of TAO in France during the past 40 years. All consecutive patients fulfilling TAO's criteria between January 1967 and January 2016 were retrospectively included in 3 departments of internal medicine. We compared TAO features in patients diagnosed before and after 2002; 141 (77.5%) men and 41 (22.5%) women were included. Patients diagnosed after 2002 were older (37 [31-39] vs 34 [29-35] years P = .03), had a more frequent isolated upper limb involvement (34.3% vs 7.8% P = .001), and less frequent isolated lower limb involvement (55.7% vs 74.5%, P < .001). The clinical spectrum of TAO has changed in France since the beginning of the 21st century.

Long-Term Outcome and Prognostic Factors of Complications in Thromboangiitis Obliterans (Buerger's Disease): A Multicenter Study of 224 Patients.

Background Data regarding long-term outcome of patients with thromboangiitis obliterans are lacking and most series come from India and Japan. In this study, we assess long-term outcome and prognostic factors in a large cohort of thromboangiitis obliterans. Methods and Results Retrospective multicenter study of characteristics and outcomes of 224 thromboangiitis obliterans patients fulfilling Papa's criteria were analyzed. Factors associated with vascular events and amputations were identified. The median age at diagnosis was 38.5 (32-46) years, 51 (23.8%) patients were female, and 81.7% were whites. After a mean follow-up of 5.7 years, vascular events were observed in 58.9%, amputations in 21.4%, and death in 1.4%. The 5-, 10-, and 15-year vascular event-free survival and amputation-free survival were 41% and 85%, 23% and 74%, and 19% and 66%, respectively. Ethnic group (nonwhite) (hazard ratio 2.35 [1.30-4.27] P=0.005) and limb infection at diagnosis (hazard ratio 3.29 [1.02-10.6] P=0.045) were independent factors of vascular event-free survival. Factor associated with amputation was limb infection (hazard ratio 12.1 [3.5-42.1], P<0.001). Patients who stopped their tobacco consumption had lower risk of amputation ( P=0.001) than those who continued. Conclusions This nationwide study shows that 34% of thromboangiitis obliterans patients will experience an amputation within 15 years from diagnosis. We identified high-risk patients for vascular complications and amputations.