Minimally modified human blood coagulation factor X to bypass direct factor Xa inhibitors.

BACKGROUND: Direct oral factor (F)Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity. OBJECTIVES: The ability of FXa variants to bypass the direct oral FXa inhibitors was assessed. METHODS: Human FXa variants were generated through substitution of phenylalanine 174 (F174) for either alanine, isoleucine, or serine. FXa variants were stably expressed in HEK293 cells and purified to homogeneity using ion-exchange chromatography. RESULTS: F174-substituted human FX variants demonstrated efficacy in restoring thrombin generation in plasma containing direct FXa inhibitors (apixaban, rivaroxaban, edoxaban). Their ability to bypass the anticoagulant effects stems from a significantly reduced sensitivity for the direct FXa inhibitors due to a decrease in binding affinity determined using molecular dynamics simulations and free energy computation. Furthermore, F174 modification resulted in a partial loss of inhibition by tissue factor pathway inhibitor, enhancing the procoagulant effect of F174-substituted FX. Consequently, the F174A- and F174S-substituted FX variants effectively counteracted the effects of 2 widely used anticoagulants, apixaban and rivaroxaban, in plasma of atrial fibrillation and venous thromboembolism patients. CONCLUSION: These human FX variants have the potential to serve as a rescue reversal strategy to overcome the effect of direct FXa inhibitors in case of life-threatening bleeding events or emergency surgical interventions.

Clinical Presentation and Outcomes of Patients With Cancer-Associated Isolated Distal Deep Vein Thrombosis.

PURPOSE: Patients with isolated distal deep vein thrombosis (DVT) have lower rates of adverse outcomes (death, venous thromboembolism [VTE] recurrence or major bleeding) than those with proximal DVT. It is uncertain if such findings are also observed in patients with cancer. METHODS: Using data from the international Registro Informatizado de la Enfermedad TromboEmbolica venosa registry, we compared the risks of adverse outcomes at 90 days (adjusted odds ratio [aOR]; 95% CI) and 1 year (adjusted hazard ratio [aHR; 95% CI]) in 886 patients with cancer-associated distal DVT versus 5,196 patients with cancer-associated proximal DVT and 5,974 patients with non-cancer-associated distal DVT. RESULTS: More than 90% of patients in each group were treated with anticoagulants for at least 90 days. At 90 days, the adjusted risks of death, VTE recurrence, or major bleeding were lower in patients with non-cancer-associated distal DVT than in patients with cancer-associated distal DVT (reference): aOR = 0.16 (0.11-0.22), aOR = 0.34 (0.22-0.54), and aOR = 0.47 (0.27-0.80), respectively. The results were similar at 1-year follow-up: aHR = 0.12 (0.09-0.15), aHR = 0.39 (0.28-0.55), and aHR = 0.51 (0.32-0.82), respectively. Risks of death, VTE recurrence, and major bleeding were not statistically different between patients with cancer-associated proximal versus distal DVT, both at 90 days: aOR = 1.11 (0.91-1.36), aOR = 1.10 (0.76-1.62), and aOR = 1.18 (0.76-1.83), respectively, and 1 year: aHR = 1.01 (0.89-1.15), aHR = 1.02 (0.76-1.35), and aHR = 1.10 (0.76-1.61), respectively. However, more patients with cancer-associated proximal DVT, compared with cancer-associated distal DVT, developed fatal pulmonary embolism (PE) during follow-up: The risk difference was 0.40% (95% CI, 0.23 to 0.58). CONCLUSION: Cancer-associated distal DVT has serious and relatively comparable outcomes compared with cancer-associated proximal DVT. The lower risk of fatal PE from cancer-associated distal DVT needs further investigation.

Anticoagulation and venous thromboembolism in patients aged 90 years and older: Data from the RIETE registry.

BACKGROUND: Age is a major risk factor for venous thromboembolism (VTE), yet patients aged ≥90 years are under-represented in clinical trials of anticoagulant therapy. The objectives were to describe and compare patient clinical characteristics, treatments, and outcomes (VTE recurrence, bleeding, and mortality) during the first 3 months of anticoagulation between VTE patients aged ≥90 years and those aged <90 years. METHODS: We analyzed data from the Registro Informatizado Enfermedad TromboEmbὀlica (RIETE), an ongoing global observational registry of patients with objectively confirmed acute VTE. RESULTS: From January 2001 to October 2022, 96,701 patients were registered in RIETE, of whom 3262 (3.4%) were aged ≥90 years. Patients aged ≥90 years were less likely to be men, and to have experienced cancer or recent surgery, but more likely to manifest immobility, chronic heart failure, anemia, renal insufficiency, or dementia than those aged <90 years. Most (99.6%) patients aged ≥90 years were receiving anticoagulant therapy. During the first 3 months, 26 patients aged ≥90 years developed VTE recurrences, 116 experienced major bleeding, and 564 died. Among patients initially presenting with pulmonary embolism (PE), deaths due to PE exceeded those due to fatal bleeding (76 vs. 19). Among those initially presenting with isolated deep-vein thrombosis (DVT), it was the reverse (2 vs. 11 deaths). CONCLUSIONS: In patients aged ≥90 years, the difference in the outcome of anticoagulant treatment depending on the initial presentation of VTE could suggest a need for different management approaches. Clinical trials evaluating the optimal duration of anticoagulation according to initial VTE presentation are warranted to limit excess deaths in this particular population.

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.

Inhibition of Factor XI: A New Era in the Treatment of Venous Thromboembolism in Cancer Patients?

Direct oral anticoagulants against activated factor X and thrombin were the last milestone in thrombosis treatment. Step by step, they replaced antivitamin K and heparins in most of their therapeutic indications. As effective as the previous anticoagulant, the decreased but persistent risk of bleeding while using direct oral anticoagulants has created space for new therapeutics aiming to provide the same efficacy with better safety. On this basis, drug targeting factor XI emerged as an option. In particular, cancer patients might be one of the populations that will most benefit from this technical advance. In this review, after a brief presentation of the different factor IX inhibitors, we explore the potential benefit of this new treatment for cancer patients.

Assessment of bleeding risk in cancer patients treated with anticoagulants for venous thromboembolic events.

Introduction: Anticoagulant is the cornerstone of the management of VTE at the cost of a non-negligible risk of bleeding. Reliable and validated clinical tools to predict thromboembolic and hemorrhagic events are crucial for individualized decision-making for the type and duration of anticoagulant treatment. We evaluate the available risk models in real life cancer patients with VTE. The objectives of the study were to describe the bleeding of cancer patients with VTE and to evaluate the performance of the different bleeding models to predict the risk of bleeding during a 6-month follow-up. Materials and Methods: VTE-diagnosed patient's demographic and clinical characteristics, treatment regimens and outcomes for up to 6 months were collected. The primary endpoint was the occurrence of a major bleeding (MB) or a clinically relevant non major bleeding (CRNMB) event, categorized according to the ISTH criteria. Results: During the 6-months follow-up period, 26 out of 110 included patients (26.7%) experienced a bleeding event, with 3 recurrences of bleeding. Out of the 29 bleeding events, 19 events were CRNMB and 10 MB. One patient died because of a MB. Bleeding occurred in 27 % of the patients treated with DOACs and 22% of the patients treated with LMWH. Most of the bleedings were gastrointestinal (9 events, 31%); 26.9% of the bleedings occurred in patient with colorectal cancer and 19.6% in patients with lung cancer. In our cohort, none of the 10 RAMs used in our study were able to distinguish cancer patients with a low risk of bleeding, from all bleeding or non-bleeding patients. The Nieto et al. RAM had the best overall performance (C-statistic = 0.730, 95% CI (0.619-0.840)). However, it classified 1 out of 5 patients with major bleeding in the low risk of bleeding group. The rest of the RAMs showed a suboptimal result, with a range of C-statistic between 0.489, 95%CI (0.360-0.617)) and 0.532, 95%CI (0.406-0.658)). Conclusions: The management of CAT patients is challenging due to a higher risk of both recurrent VTE and bleeding events, as compared with non-cancer patients with VTE. None of the existing RAMs was able to consistently identify patients with risk of anticoagulant associated bleeding events.

Diagnostic Approach for Venous Thromboembolism in Cancer Patients.

Venous thromboembolic disease (VTE) is a common complication in cancer patients. The currently recommended VTE diagnostic approach involves a step-by-step algorithm, which is based on the assessment of clinical probability, D-dimer measurement, and/or diagnostic imaging. While this diagnostic strategy is well validated and efficient in the noncancer population, its use in cancer patients is less satisfactory. Cancer patients often present nonspecific VTE symptoms resulting in less discriminatory power of the proposed clinical prediction rules. Furthermore, D-dimer levels are often increased because of a hypercoagulable state associated with the tumor process. Consequently, the vast majority of patients require imaging tests. In order to improve VTE exclusion in cancer patients, several approaches have been developed. The first approach consists of ordering imaging tests to all patients, despite overexposing a population known to have mostly multiple comorbidities to radiations and contrast products. The second approach consists of new diagnostic algorithms based on clinical probability assessment with different D-dimer thresholds, e.g., the YEARS algorithm, which shows promise in improving the diagnosis of PE in cancer patients. The third approach uses an adjusted D-dimer threshold, to age, pretest probability, clinical criteria, or other criteria. These different diagnostic strategies have not been compared head-to-head. In conclusion, despite having several proposed diagnostic approaches to diagnose VTE in cancer patients, we still lack a dedicated diagnostic algorithm specific for this population.

Temporary inferior vena cava filters factors associated with non-removal.

OBJECTIVES: Inferior vena cava filter (IVCF) placement is indicated when there is a deep vein thrombosis and/or a pulmonary embolism and a contraindication of anticoagulation. Due to the increased risk of recurrent deep venous thrombosis when left in place, IVCF removal is indicated once anticoagulant treatment can be reintroduced. However, many temporary IVCF are not removed. We aimed to analyze the removal rate and predictors of filter non-removal in a university hospital setting. METHODS: We collected all the data of consecutive patients who had a retrievable IVCF inserted at the Saint-Etienne University Hospital (France) between April 2012 and November 2019. Rates of filter removal were calculated. We analyzed patient characteristics to assess factors associated with filter non-removal, particularly in patients without a definitive filter indication. The exclusion of this last category of patients allowed us to calculate an adjusted removal rate. RESULTS: The overall removal rate of IVCF was 40.5% (IC 95% 35.6-45.6), and the adjusted removal rate was 62.9 % (IC 95% 56.6-69.2%). No major complications were noted. Advanced age (p < 0.0001) and cancer presence (p < 0.003) were statistically significant predictors of patients not being requested to make a removal attempt. CONCLUSIONS: Although most of the filters placed are for therapeutic indications validated by scientific societies, the removal rate in this setting remains suboptimal. The major factors influencing IVCF removal rate are advanced age and cancer presence. KEY POINTS: • Most vena cava filters are placed for therapeutic indications validated by scientific societies. • Vena cava filter removal rates in this setting remain suboptimal. • Major factors influencing IVCF removal rate are advanced age and cancer presence.

Occurrence of Major Local Lower Limb Events in Type 2 Diabetic Patients with Lower Extremity Arterial Disease: Impact of Metformin.

BACKGROUNDS: Patients with type 2 diabetes mellitus (T2DM) are particularly at risk of developing major adverse cardiovascular events (MACE) and peripheral artery disease (PAD) due to an acceleration of the atherosclerotic process linked to hyperglycemia and inflammation with a greater risk of local complications. We aimed to identify the predictive factors for major adverse limb events (MALE) in T2DM patients with PAD to manage modifiable factors at an early stage. METHODS: This is a prospective study in which T2DM patients with PAD were included from November 2017 to May 2018 and followed over 12 months. The predictive factors for the onset of MALE, MACE, and death from all causes have been identified. RESULTS: A total of 100 patients were included; 37% of the patients developed a MALE. After multivariate analysis, metformin was associated with a decrease of MALE (odds ratio (OR) = 0.26; 95% confidence interval (CI) [0.10; 0.68]; P = 0.007), and a history of the treatment of intravenous iloprost was associated with an increased risk of MALE (OR = 5.70; 95% CI [1.31; 31.93]; P = 0.029). Regular physical activity was associated with a decreased risk of MACE (OR = 0.07; 95% CI [0; 0.44]; P = 0.021). A history of stroke and a history of venous thromboembolism were associated with an increased all-cause mortality risk with OR = 3.68; 95% CI [1.17; 11.5]; P = 0.025 and OR = 3.78; 95% CI [1.16; 12.3]; P = 0.027. CONCLUSIONS: Metformin is protective against local complications in people with diabetes with PAD and should be prescribed to diabetic patients with PAD at an early stage.

Pulmonary Embolism in the Cancer Associated Thrombosis Landscape.

In cancer patients, pulmonary embolism (PE) is the second leading cause of death after the cancer itself, most likely because of difficulties in diagnosing the disease due to its nonclassical presentation. The risk of PE recurrence and possibly the case-fatality rate depends on whether the patient presents a symptomatic PE, an unsuspected PE, a subsegmental PE, or a catheter-related PE. Choosing the best therapeutic option is challenging and should consider the risk of both the recurrence of thrombosis and the occurrence of bleeding. The purpose of this review is to provide an overview of the clinical characteristics and the treatment of cancer-associated PE, which could benefit clinicians to better manage the deadliest form of thrombosis associated with cancer. After a brief presentation of the epidemiological data, we will present the current attitude towards the diagnosis and the management of cancer patients with PE. Finally, we will discuss the perspectives of how the medical community can improve the management of this severe medical condition.

Factor XI Inhibition for the Prevention of Venous Thromboembolism: An Update on Current Evidence and Future perspectives.

During the past decade, emergence of direct oral anticoagulants (DOACs) has drastically improved the prevention of thrombosis. However, several unmet needs prevail in the field of thrombosis prevention, even in the DOACs' era. The use of DOACs is still constrained and the drugs cannot be administered in every clinical scenario, such as an increased anticoagulant-associated bleeding risk, particularly in some specific populations (cancer - notably those with gastrointestinal or genitourinary cancer - and frail patients), the impossibility to be used in certain patients (eg, end-stage kidney failure during hemodialysis, pregnancy and breastfeeding), and their lack of efficacy in certain clinical scenarios (eg, mechanical heart valves, triple-positive antiphospholipid syndrome). Efforts to find a factor that upon antagonization prevents thrombosis but spares haemostasis have resulted in the identification of coagulation factor XI (FXI) as a therapeutic target. After briefly recapitulating the role of factor XI in the balance of haemostasis, we propose a narrative review of the key data published to date with compounds targeting factor XI to prevent thrombosis as well as the main ongoing clinical studies, opening up prospects for improving the care of patients requiring thrombosis prevention.

In Search of the Appropriate Anticoagulant-Associated Bleeding Risk Assessment Model for Cancer-Associated Thrombosis Patients.

Patients with venous thromboembolism events (VTE) in the context of cancer should receive anticoagulants as long as the cancer is active. Therefore, a tailor-made anticoagulation strategy should rely on an individualized risk assessment model (RAM) of recurrent VTE and anticoagulant-associated bleeding. The aim of this review is to investigate the applicability of the currently available RAMs for anticoagulant-associated bleeding after VTE in the CAT population and to provide new insights on how we can succeed in developing a new anticoagulant-associated bleeding RAM for the current medical care of CAT patients. A systematic search for peer-reviewed publications was performed in PubMed. Studies, including systematic reviews, were eligible if they comprised patients with VTE and used a design for developing a prediction model, score, or other prognostic tools for anticoagulant-associated bleeding during anticoagulant treatment. Out of 15 RAMs, just the CAT-BLEED was developed for CAT patients and none of the presented RAMs developed for the VTE general population were externally validated in a population of CAT patients. The current review illustrates the limitations of the available RAMs for anticoagulant-associated bleeding in CAT patients. The development of a RAM for bleeding risk assessment in patients with CAT is warranted.

Evolutionary Adaptations in Pseudonaja Textilis Venom Factor X Induce Zymogen Activity and Resistance to the Intrinsic Tenase Complex.

The venom of the Australian snake Pseudonaja textilis comprises powerful prothrombin activators consisting of factor X (v-ptFX)- and factor V-like proteins. While all vertebrate liver-expressed factor X (FX) homologs, including that of P. textilis, comprise an activation peptide of approximately 45 to 65 residues, the activation peptide of v-ptFX is significantly shortened to 27 residues. In this study, we demonstrate that exchanging the human FX activation peptide for the snake venom ortholog impedes proteolytic cleavage by the intrinsic factor VIIIa-factor IXa tenase complex. Furthermore, our findings indicate that the human FX activation peptide comprises an essential binding site for the intrinsic tenase complex. Conversely, incorporation of FX into the extrinsic tissue factor-factor VIIa tenase complex is completely dependent on exosite-mediated interactions. Remarkably, the shortened activation peptide allows for factor V-dependent prothrombin conversion while in the zymogen state. This indicates that the active site of FX molecules comprising the v-ptFX activation peptide partially matures upon assembly into a premature prothrombinase complex. Taken together, the shortened activation peptide is one of the remarkable characteristics of v-ptFX that has been modified from its original form, thereby transforming FX into a powerful procoagulant protein. Moreover, these results shed new light on the structural requirements for serine protease activation and indicate that catalytic activity can be obtained without formation of the characteristic Ile16-Asp194 salt bridge via modification of the activation peptide.

Pain assessment and factors influencing pain during bone marrow aspiration: A prospective study.

Although bone marrow aspiration (BMA) is still considered a painful procedure, pain level remains poorly documented. We therefore conducted a prospective study intended to evaluate pain level in adult patients undergoing BMA at the sternal or iliac crest site to identify factors associated with pain. We enrolled a total of 448 patients who underwent 461 BMA and asked those patients to score their pain intensity after BMA using numerical pain rating scale (NPRS). The following factors: level of anxiety, quality of the information given to the patient, operator's experience, and bone texture were recorded using a standardized questionnaire. The median NPRS score was 3.5 (IQR [2.0; 5.0]) the sternal site (n = 405) was associated with an increased median NPRS score (3.5 [2.0; 5.0]) compared to the iliac crest (n = 56, 2.5 [1.0; 4.0]; p<0.0001). For those patients who underwent sternal BMA, the median NPRS score was significantly lower when using lidocaine infiltration (p = 0.0159) as compared with no anesthetic use. Additionally there was no significant effect of anesthetic cream found. After multivariate analysis, the model of NPRS score at the sternal site included patient anxiety (p<0.0001) and the use of lidocaine infiltration (0.0378). This study underlines the usefulness of a comprehensive management including pain relief and efforts to reduce anxiety including appropriate information given to the patient during BMA.

[Towards a better use of midazolam in end of life: A survey in a department of medical oncology]. / Appel à une meilleure utilisation du midazolam en fin de vie : évaluation des pratiques professionnelles dans un service d'oncologie médicale.

INTRODUCTION: At the end of life of cancer patients, sedation is sometimes needed, in order to palliate unbearable symptoms that other treatments fail to relieve. Midazolam is currently recommended for sedation and its prescription is guided by national guidelines. The aim of the present study was to evaluate the practices of midazolam prescription in a department of medical oncology and to compare the results with French national recommendations in order to improve the midazolam use in case of sedation. METHODS: We conducted a retrospective survey studying midazolam prescriptions in patients who died between 2014 and 2015 in the medical oncology department. Compliance rates with recommendations were reviewed. RESULTS: A total of 99 medical files were analyzed. Fifty-three patients received midazolam: 64.4% for refractory symptoms, 22% for anxiolyse, 10.2% for acute respiratory distress syndrome. When reported, the titration indications and modalities systematically conformed to guidelines. In case of sedation for refractory symptoms, adherence to guidelines was 76% regarding the family information, 63% regarding the patient information, 61% regarding the collegial nature of the initiation decision, 34% regarding the titration achievement and 5% regarding the pluridisciplinary nature of the initiation decision. CONCLUSION: Although limited justifications in midazolam prescriptions could have resulted in an overestimate of sedation and in an underestimate of titrations, current guideline are not enough applied in routine, especially regarding the necessity of a pluridisciplinary decision-making. A list of requirements before midazolam initiation is suggested, to increase the adherence to guidelines. Our results highlight the necessity of a better midazolam use in life-end sedations.