[New anticoagulants in 2024: Development of factor XI and XIa inhibitors]. / Les nouveaux anticoagulants en 2024 : développement des inhibiteurs du facteur XI et du XIa.

Thrombosis remains one of the leading causes of death in the world. The history of anticoagulation has evolved considerably from non-specific drugs (i.e., heparins and vitamin K antagonists, VKA) to agents that directly target specific coagulation factors (i.e., argatroban, fondaparinux and direct oral anticoagulants, DOAC). Since the last decade, DOAC are widely used in clinical practice because of their ease to use, their favorable pharmacological profile and the fact that they do not require monitoring. However, despite having a better safety profile than vitamin K antagonist, their bleeding risk is not negligible. New anticoagulants targeting the contact phase of coagulation are currently being developed and could make it possible to prevent the risk of thrombosis without impairing hemostasis. Epidemiological and preclinical data on FXI deficiency make FXI a promising therapeutic target. The aim of this review is to summarize the results of the various clinical trials available that focus on FXI/FXIa inhibition, and to highlight the challenges that this new therapeutic class of anticoagulants will face.

Acute phase determinant of post-thrombotic syndrome: A review of the literature.

BACKGROUND: Post-thrombotic syndrome (PTS) is the main long-term complication of deep vein thrombosis (DVT). Several therapies are being evaluated to prevent or to treat PTS. Identifying the patients most likely to benefit from these therapies presents a significant challenge. OBJECTIVES: The objective of this review was to identify risk factors for PTS during the acute phase of DVT. ELIGIBILITY CRITERIA: We searched the PubMed and Cochrane databases for studies published between January 2000 and January 2021, including randomized clinical trials, meta-analyses, systematic reviews and observational studies. RESULTS: Risk factors for PTS such as proximal location of DVT, obesity, chronic venous disease, history of DVT are associated with higher risk of PTS. On the initial ultrasound-Doppler, a high thrombotic burden appears to be a predictor of PTS. Among the evaluated biomarkers, some inflammatory markers such as ICAM-1, MMP-1 and MMP-8 appear to be associated with a higher risk of developing PTS. Coagulation disorders are not associated with risk of developing PTS. Role of endothelial biomarkers in predicting PTS has been poorly explored. Lastly, vitamin K antagonist was associated with a higher risk of developing PTS when compared to direct oral anticoagulants and low molecular weight heparin. CONCLUSIONS: Several risk factors during the acute phase of VTE are associated with an increased risk of developing PTS. There is a high-unmet medical need to identify potential biomarkers for early detection of patients at risk of developing PTS after VTE. Inflammatory and endothelial biomarkers should be explored in larger prospective studies to identify populations that could benefit from new therapies.

Perioperative management of venous recanalization in a patient with inherited antithrombin deficiency: case report.

Background: Inherited antithrombin (AT) deficiency (ATD) is a severe thrombophilia causing venous thromboembolism, which can be complicated by postthrombotic syndrome (PTS). Venous recanalization, used to treat PTS, often requires a temporary withdrawal of anticoagulant therapy. In ATD patients, there is a risk of insufficient perioperative anticoagulation due to altered heparin response. Key Clinical Question: There is no consensus on how to manage perioperative anticoagulation in ATD patients. Clinical Approach: Warfarin-unfractionated heparin transition could be a more reliable strategy than low-molecular-weight heparin transition because unfractionated heparin anti-Xa activity not only reflects heparin-bound AT but also AT's activity, which correlates strongly with therapeutic anticoagulation. Biological monitoring could thus decrease the number of plasma-derived AT supplementation. Conclusion: This study describes a successful perioperative management of anticoagulation for venous recanalization that could be suggested to type 1 ATD patients with PTS.

Is there a role for the laboratory monitoring in the management of specific antidotes of direct oral anticoagulants?

Given the growing number of patients receiving direct oral anticoagulant (DOAC), patients requiring rapid neutralization is also increasing in case of major bleedings or urgent surgery/procedures. Idarucizumab is commercialized as a specific antidote to dabigatran while andexanet alfa has gained the Food and Drug Administration and the European Medicines Agency approval as an oral anti-factor Xa inhibitors antidote. Other antidotes or hemostatic agents are still under preclinical or clinical development, the most advanced being ciraparantag. DOAC plasma levels measurement allows to appropriately select patient for antidote administration and may prevent unnecessary prescription of expensive molecules in some acute clinical settings. However, these tests might be inconclusive after some antidote administration, namely andexanet alfa and ciraparantag. The benefit of laboratory monitoring following DOAC reversal remains unclear. Here, we sought to provide an overview of the key studies evaluating the safety and efficacy of DOAC reversal using the most developed/commercialized specific antidotes, to discuss the potential role of the laboratory monitoring in the management of patients receiving DOAC specific antidotes and to highlight the areas that deserve further investigations in order to establish the exact role of laboratory monitoring in the appropriate management of DOAC specific antidotes.

Challenges in the Monitoring of Therapeutic Plasma Exchange during Acute Heparin-Induced Thrombocytopenia in Adults under ECMO.

Therapeutic plasma exchange (TPE) has been proposed to remove heparin-induced thrombocytopenia (HIT) antibodies before planned thoracic surgery in patients with acute HIT and to allow brief re-exposure to heparin during surgery. In patients on extracorporeal membrane oxygenation (ECMO), simultaneous administration of TPE and alternative nonheparin anticoagulant therapies is challenging. We report 2 patients on ECMO with acute HIT who underwent repeated TPE to enable cardiothoracic surgery with the use of heparin. In both cases, serial monitoring of HIT antibody titer and heparin-induced platelet activation assay (HIPA) was performed. The effect of adding exogenous platelet factor 4 (PF4) in the HIPA was also tested. Negative anti-PF4/H IgG levels were achieved after 5 and 3 TPE sessions, respectively and patients could beneficiate from surgery with brief heparin re-exposure without any thrombotic complication. Negative HIPA results were obtained before negative anti-PF4/H IgG in one patient but remained positive in the other despite very low antibody titers. The addition of PF4 in HIPA led to more contrasted results for the two patients. Serial HIT screening including immunological and functional assays is necessary to closely monitor TPE in acute HIT patients on ECMO who require surgery. The addition of PF4 in HIPA could help detect clinically relevant platelet-activating antibodies and guide re-exposure to heparin.

VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients.

BACKGROUND: Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is characterized by persistent clinical symptoms following COVID-19. OBJECTIVE: To correlate biomarkers of endothelial dysfunction with persistent clinical symptoms and pulmonary function defects at distance from COVID-19. METHODS: Consecutive patients with long COVID-19 suspicion were enrolled. A panel of endothelial biomarkers was measured in each patient during clinical evaluation and pulmonary function test (PFT). RESULTS: The study included 137 PASC patients, mostly male (68%), with a median age of 55 years. A total of 194 PFTs were performed between months 3 and 24 after an episode of SARS-CoV-2 infection. We compared biomarkers evaluated in PASC patients with 20 healthy volunteers (HVs) and acute hospitalized COVID-19 patients (n = 88). The study found that angiogenesis-related biomarkers and von Willebrand factor (VWF) levels were increased in PASC patients compared to HVs without increased inflammatory or platelet activation markers. Moreover, VEGF-A and VWF were associated with persistent lung CT scan lesions and impaired diffusing capacity of the lungs for carbon monoxide (DLCO) measurement. By employing a Cox proportional hazards model adjusted for age, sex, and body mass index, we further confirmed the accuracy of VEGF-A and VWF. Following adjustment, VEGF-A emerged as the most significant predictive factor associated with persistent lung CT scan lesions and impaired DLCO measurement. CONCLUSION: VEGF-A is a relevant predictive factor for DLCO impairment and radiological sequelae in PASC. Beyond being a biomarker, we hypothesize that the persistence of angiogenic disorders may contribute to long COVID symptoms.

Intraoperative argatroban vessel irrigation during microsurgical anastomosis in heparin-induced thrombocytopenia patients: About two cases.

Patients with heparin-induced thrombocytopenia or confirmed allergies to heparin have a contraindication to heparin therapy, which poses a problem for intraoperative free flap irrigation in reconstruction. The use of argatroban as an alternative to heparin allowed us to perform a free flap for leg salvage and a deep inferior epigastric perforator flap for breast reconstruction without microvascular complication, with a 0.01 mg/mL solution. We reported two cases of using an alternative treatment to heparin in an emergency and planned surgeries for vessel irrigation during microsurgical anastomosis reconstruction without microvascular complications, suggesting the reliability and effectiveness of its use in case of contraindication to heparin.

Prospective assessment of the frequency of and risk factors for bleeding events in patients treated with cefazolin.

PURPOSE: Major bleedings have been described with cefazolin. The objective was to determine the frequency of bleeding events in cefazolin-treated patients and to identify risk factors for these complications. METHODS: Monocenter prospective observational study of all consecutive cefazolin-treated patients. Patients benefited from a daily clinical assessment of bleedings and a twice-a-week blood sampling including hemostasis. Bleedings were classified according to the International Society on Thrombosis and Hemostasis classification: major, clinically relevant non-major bleedings (CRNMB) and minor bleedings. RESULTS: From September 2019 to July 2020, 120 patients were included, with a mean age of 59.4 (± 20.7) years; 70% of them (84/120) were men. At least 1 CRNMB or major bleeding were observed in 10% of the patients (12/120). Compared to patients with no or minor bleeding, patients with CRNMB or major bleeding were, upon start of cefazolin, more frequently hospitalized in an intensive care unit (7/12, 58.3%, vs. 12/108, 11.1%, P < 0.001, respectively) and receiving vitamin K antagonists (4/12, 33.3%, vs. 8/108, 7.4%, P = 0.019, respectively). After multivariate analysis, patients receiving vitamin K antagonists the day prior bleeding and/or treated for endocarditis were factors associated with an increased risk of CRNMB or major bleeding (odd ratio 1.36, confidence interval 95%, 1.06-1.76, P = 0.020 and 1.30, 1.06-1.61, P = 0.015, respectively). CONCLUSIONS: Bleeding events associated with cefazolin treatment are frequent. Close clinical monitoring should be performed for patients treated for endocarditis and/or receiving vitamin K antagonists. Hemostasis work-up could be restricted to these patients.

Cancer-Associated Thrombosis on Bevacizumab: Risk of Recurrence and Bleeding When Bevacizumab Is Stopped or Continued.

Cancer-associated thrombosis (CAT) is a common complication during cancer, with complex management due to an increased risk of both recurrence and bleeding. Bevacizumab is an effective anti-angiogenic treatment but increases the risk of bleeding and potentially the risk of venous thromboembolism (VTE). The aim of this study was to evaluate the efficacy and safety of anticoagulant therapy in patients with CAT receiving bevacizumab, according to the continuation or discontinuation of bevacizumab. In a retrospective multicenter study, patients receiving anticoagulant for CAT occurring under bevacizumab therapy were included. The primary endpoint combined recurrent VTE and/or major or clinically relevant non-major bleeding. Among the 162 patients included, bevacizumab was discontinued in 70 (43.2%) patients and continued in 92 (56.8%) patients. After a median follow-up of 318 days, 21 (30.0%) patients in the discontinuation group experienced VTE recurrence or major or clinically relevant non-major bleeding, compared to 27 (29.3%) in the continuation group. The analysis of survival following the first event showed no significant difference between the groups in uni- or multivariate analysis (p = 0.19). The primary endpoint was not influenced by the duration of bevacizumab exposure. These results suggest that the efficacy and safety of anticoagulant therapy in patients with CAT receiving bevacizumab is not modified regardless of whether bevacizumab is continued or discontinued.

Recovery of Endothelium-dependent vascular relaxation impairment in convalescent COVID-19 patients: Insight from a pilot study.

BACKGROUND: Endothelial dysfunction is a key-feature in acute COVID-19. However, follow-up data regarding endothelial dysfunction and injury after COVID-19 infection are lacking. We aimed to investigate the changes in endothelium-dependent vasorelaxation at baseline and four months after hospital discharge in COVID-19 patients. METHODS: Twenty COVID-19 patients were compared to 24 healthy controls. Clinical and morphological data were collected after hospital admission for SARS-CoV-2 infection and reactive hyperaemia index (RHI) measurement was performed with a delay between 24 and 48 h after hospital admission and four months after hospital discharge in the outpatient clinics. Blood tests including inflammatory markers and measurement of post-occlusive vasorelaxation by digital peripheral arterial tonometry were performed at both visits. RESULTS: At baseline, COVID-19 patients exhibited reduced RHI compared to controls (p < 0.001), in line with an endothelial dysfunction. At four months follow-up, there was a 51% increase in the RHI (1.69 ± 0.32 to 2.51 ± 0.91; p < 0.01) in favor of endothelium-dependent vascular relaxation recovery. RHI changes were positively correlated with baseline C-reactive protein (r = 0.68; p = 0.02). Compared to COVID-19 patients with a decrease in RHI, COVID-19 patients with an increase in RHI beyond the day-to-day variability (i.e. >11%) had less severe systemic inflammation at baseline. CONCLUSION: Convalescent COVID-19 patients showed a recovery of systemic artery endothelial dysfunction, in particular patients with lower inflammation at baseline. Further studies are needed to decipher the interplay between inflammation and endothelial dysfunction in COVID-19 patients.

Development of new anticoagulant in 2023: Prime time for anti-factor XI and XIa inhibitors.

Thrombosis remains one of the leading causes of death in the world. The history of anticoagulation has evolved considerably from non-specific drugs (i.e., heparins and vitamin K antagonists, VKA) to agents that directly target specific coagulation factors (i.e., argatroban, fondaparinux and direct oral anticoagulants, DOAC). Since the last decade, DOAC are widely used in clinical practice because of their ease to use with favorable pharmacological profile and not requiring monitoring, particularly for venous thromboembolism treatment and prevention and stroke prevention in atrial fibrillation. However, despite having a better safety profile than VKA, their bleeding risk is not negligible. Therefore, research is underway to develop new anticoagulant therapies with a better safety profile. One of these news approaches to reduce the risk of bleeding is to target the coagulation in the intrinsic pathway, in particular the contact activation, with the ultimate goal of preventing thrombosis without impairing hemostasis. Based on epidemiological data with patients with inherited factor XI (FXI) deficiency and preclinical studies, FXI emerged as the most promising candidate target separating hemostasis from thrombosis. This review summaries the role of FXI and FXIa in hemostasis, provides evidence of initial success with FXI pathway inhibitors in clinical trials (such as IONIS-FXIRx, fesomersen, osocimab, abelacimab, milvexian, asundexian or xisomab 3G3) and highlights the opportunities and challenges for this next generation of anticoagulants.

Improving Autologous Fat Grafting in Regenerative Surgery through Stem Cell-Assisted Lipotransfer.

Autologous fat transplantation -i.e., lipofilling- has become a promising and popular technique in aesthetic and reconstructive surgery with several application such as breast reconstruction, facial and hand rejuvenation. However, the use of this technology is still limited due to an unpredictable and low graft survival rate (which ranges from 25%-80%). A systematic literature review was performed by thoroughly searching 12 terms using the PubMed database. The objective of this study is to present the current evidence for the efficacy of adjuvant regenerative strategies and cellular factors, which have been tested to improve fat graft retention. We present the main results (fat retention rate, histological analysis for pre-clinical studies and satisfaction/ complication for clinical studies) obtained from the studies of the three main fat grafting enrichment techniques: platelet-rich plasma (PRP), the stromal vascular fraction (SVF) and adipose-derived stem cells (ADSCs) and discuss the promising role of recent angiogenic cell enrichment that could induce early vascularization of fat graft. All in all, adding stem or progenitor cells to autologous fat transplantation might become a new concept in lipofilling. New preclinical models should be used to find mechanisms able to increase fat retention, assure safety and transfer these technologies to a good manufacturing practice (GMP) compliant facility, to manufacture an advanced therapy medicinal product (ATMP).

Fibrin monomers evaluation during hospitalization for COVID-19 is a predictive marker of in-hospital mortality.

Background: Coagulopathy is one of the main triggers of severity and worsening of Coronavirus disease 2019 (COVID-19) particularly in critically ill patients. D-dimer has been widely used to detect COVID-19 coagulation disorders and has been correlated with outcomes such as disease severity and in-hospital mortality. Involvement of other fibrin degradation products, particularly fibrin monomers (FM), remains an ongoing question. Methods: We performed a monocentric study of adult patients with COVID-19, who were admitted either in the medical ward (MW) or in the intensive care unit (ICU) and who had FM measurements performed on them during the first wave of COVID-19 outbreak. We analyzed the positivity of FM levels (FM > 7 µg/mL) to assess the ability of FM monitoring during the first days of hospitalization to predict COVID-19 outcomes. Results: In our cohort, 935 FM measurements were performed in 246 patients during their first 9 days of hospitalization. During patient follow-up, the FM levels were higher in patients admitted directly to the ICU than in those admitted to the MW. Moreover, we observed significantly increased levels of FM in patients when the data were stratified for in-hospital mortality. At hospital admission, only 27 (11%) patients displayed a positive value for FM; this subgroup did not differ from other patients in terms of severity (indicated by ICU referral at admission) or in-hospital mortality. When analyzing FM positivity in the first 9 days of hospitalization, we found that 37% of patients had positive FM at least once during hospitalization and these patients had increased in-hospital mortality (p = 0.001). Thus, we used non-adjusted Kaplan-Meier curves for in-hospital mortality according to FM positivity during hospitalization and we observed a statistically significant difference for in-hospital mortality (hazard ratio = 1.48, 95% CI: 1.25-1.76, p < 0.001). However, we compared the AUC of FM positivity associated with a ratio of D-dimer >70% and found that this combined receiver operating characteristic (ROC) curve was superior to the FM positivity ROC curve alone. Conclusion: Monitoring of FM positivity in hospitalized patients with COVID-19 could be a reliable and helpful tool to predict the worsening condition and mortality of COVID-19.

Platelet activation and coronavirus disease 2019 mortality: Insights from coagulopathy, antiplatelet therapy and inflammation.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with an inflammatory cytokine burst and a prothrombotic coagulopathy. Platelets may contribute to microthrombosis, and constitute a therapeutic target in COVID-19 therapy. AIM: To assess if platelet activation influences mortality in COVID-19. METHODS: We explored two cohorts of patients with COVID-19. Cohort A included 208 ambulatory and hospitalized patients with varying clinical severities and non-COVID patients as controls, in whom plasma concentrations of the soluble platelet activation biomarkers CD40 ligand (sCD40L) and P-selectin (sP-sel) were quantified within the first 48hours following hospitalization. Cohort B was a multicentre cohort of 2878 patients initially admitted to a medical ward. In both cohorts, the primary outcome was in-hospital mortality. RESULTS: In cohort A, median circulating concentrations of sCD40L and sP-sel were only increased in the 89 critical patients compared with non-COVID controls: sP-sel 40,059 (interquartile range 26,876-54,678)pg/mL; sCD40L 1914 (interquartile range 1410-2367)pg/mL (P<0.001 for both). A strong association existed between sP-sel concentration and in-hospital mortality (Kaplan-Meier log-rank P=0.004). However, in a Cox model considering biomarkers of immunothrombosis, sP-sel was no longer associated with mortality, in contrast to coagulopathy evaluated with D-dimer concentration (hazard ratio 4.86, 95% confidence interval 1.64-12.50). Moreover, in cohort B, a Cox model adjusted for co-morbidities suggested that prehospitalization antiplatelet agents had no significant impact on in-hospital mortality (hazard ratio 1.05, 95% CI 0.80-1.37; P=0.73). CONCLUSIONS: Although we observed an association between excessive biomarkers of platelet activation and in-hospital mortality, our findings rather suggest that coagulopathy is more central in driving disease progression, which may explain why prehospitalization antiplatelet drugs were not a protective factor against mortality in our multicentre cohort.

Cangrelor for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia: it is not so easy.

Anticoagulation management for cardiopulmonary bypass (CPB) is challenging in patients with acute heparin-induced thrombocytopenia (HIT). The strategy of combining cangrelor intraoperatively with heparin for CPB anticoagulation is of increasing interest but exposes to specific unresolved problems. We report the case of a patient requiring surgical pulmonary embolectomy for pulmonary embolism at the very acute phase of HIT, with a high titre of anti-PF4/heparin antibodies and severe thrombocytopenia. For CPB management, cangrelor was administered in combination with heparin prescribed and monitored as usual. Surgery was successfully performed, but postoperatively, the patient developed a new thrombotic event. We discussed the specific problems associated with such strategy, including the dose of cangrelor and its monitoring, the management of the cell-saver, the risk of heparin rebound and the risk of platelet transfusion. These issues must be addressed before considering the combination of cangrelor and unfractionated heparin as a standard of care for CBP.