Séquelles perfusionnelles après une embolie pulmonaire : pronostic, prédiction et mécanismes physiopathologiques

Pulmonary vascular sequels after pulmonary embolism: prognosis, prediction and physiopathologyAbstract: Post Pulmonary Embolism (PE) syndrome is not rare after PE: one third of the patients presents residual pulmonary vascular obstruction (RPVO) traducing sequels associated with increased dyspnea and impaired exercise capacity. Some of these patients will suffer PE recurrence or, more rarely, chronic thromboembolic pulmonary hypertension, whose one the diagnosis criteria is persistent perfusion defect. Prognosis value and mechanisms underlying vascular sequels are still unclear. The present work shows that RPVO > 10% after a first PE is associated with an increased risk for venous thromboembolism recurrence (odds ratio 1.9). Secondly, fibrinogen properties were investigated in PE patients. Patients with RPVO >10% presented more monosialiated Bβchain form. Prediction models for RPVO that include fibrinogen analysis were more accurate than those without fibrinogen data; This results highlights the key role of fibrin in the pathophysiology of chronic venous thromboembolism. Interestingly, the present work shows that patient who will present RPVO had an impaired endothelial cells mobilization. Compared to patients without RPVO, patients with RPVO had lower circulating endothelial cells at the acute phase of PE. This endothelial dysfunction is probably triggered by endothelial progenitors that expressed the very low density lipoprotein receptor (VLDLr), implicated in the inhibition of angiogenesis and able to bind the β15-42 N terminal sequence of the fibrin Bβ chain.Au décours d'une première embolie pulmonaire (EP), certains patients présentent un syndrome post EP : un tiers des patients ont une obstruction persistante de la vascularisation pulmonaire, associée à la persistance d'une dyspnée et une limitation des performances à l'effort. Certains patients présenteront une récidive d'EP ou, plus rarement, une hypertension pulmonaire, dont les séquelles perfusionnelles sont un critère diagnostique indispensable. Le rôle et la physiopathologie des séquelles perfusionnelles au cours du syndrome post EP est incomprise. Ce travail a mis en évidence l'existence d'un risque majoré de récidive d'EP (odds ratio 1,9) chez les patients présentant des séquelles perfusionnelles >10% à la vascularisation pulmonaire. L'analyse des propriétés fonctionnelles du fibrinogène purifié à partir du plasma de patients suivis pour une première EP améliore la prédiction de séquelles perfusionnelles confirmant le rôle clé de celui-ci dans la physiopathologie de la maladie. Ainsi, une forte proportion de chaine Bβ porteuse d'un seul résidu acide sialique majore le risque de séquelles. L'étude des cellules endothéliales circulantes à la phase aigüe et après une EP montre que les patients qui développeront des séquelles mobilisent peu de cellules endothéliales, témoignant d'une forte altération des processus de réparation de l'endothélium pulmonaire. L'interaction de la fibrine avec les progéniteurs endothéliaux dans cette anomalie de la régulation est possible : les progéniteurs expriment le récepteur VLDLr dont l'épitope β15-42 de la fibrine est un ligand impliqué dans la régulation du cycle cellulaire et l'inhibition de l'angiogenèse

Pulmonary vascular sequels after pulmonary embolism : prognosis, prediction and physiopathology

Au décours d'une première embolie pulmonaire (EP), certains patients présentent un syndrome post EP : un tiers des patients ont une obstruction persistante de la vascularisation pulmonaire, associée à la persistance d'une dyspnée et une limitation des performances à l'effort. Certains patients présenteront une récidive d'EP ou, plus rarement, une hypertension pulmonaire, dont les séquelles perfusionnelles sont un critère diagnostique indispensable. Le rôle et la physiopathologie des séquelles perfusionnelles au cours du syndrome post EP est incomprise. Ce travail a mis en évidence l'existence d'un risque majoré de récidive d'EP (odds ratio 1,9) chez les patients présentant des séquelles perfusionnelles >10% à la vascularisation pulmonaire. L'analyse des propriétés fonctionnelles du fibrinogène purifié à partir du plasma de patients suivis pour une première EP améliore la prédiction de séquelles perfusionnelles confirmant le rôle clé de celui-ci dans la physiopathologie de la maladie. Ainsi, une forte proportion de chaine Bβ porteuse d'un seul résidu acide sialique majore le risque de séquelles. L'étude des cellules endothéliales circulantes à la phase aigüe et après une EP montre que les patients qui développeront des séquelles mobilisent peu de cellules endothéliales, témoignant d'une forte altération des processus de réparation de l'endothélium pulmonaire. L'interaction de la fibrine avec les progéniteurs endothéliaux dans cette anomalie de la régulation est possible : les progéniteurs expriment le récepteur VLDLr dont l'épitope β15-42 de la fibrine est un ligand impliqué dans la régulation du cycle cellulaire et l'inhibition de l'angiogenèse.Pulmonary vascular sequels after pulmonary embolism: prognosis, prediction and physiopathologyAbstract: Post Pulmonary Embolism (PE) syndrome is not rare after PE: one third of the patients presents residual pulmonary vascular obstruction (RPVO) traducing sequels associated with increased dyspnea and impaired exercise capacity. Some of these patients will suffer PE recurrence or, more rarely, chronic thromboembolic pulmonary hypertension, whose one the diagnosis criteria is persistent perfusion defect. Prognosis value and mechanisms underlying vascular sequels are still unclear. The present work shows that RPVO > 10% after a first PE is associated with an increased risk for venous thromboembolism recurrence (odds ratio 1.9). Secondly, fibrinogen properties were investigated in PE patients. Patients with RPVO >10% presented more monosialiated Bβchain form. Prediction models for RPVO that include fibrinogen analysis were more accurate than those without fibrinogen data; This results highlights the key role of fibrin in the pathophysiology of chronic venous thromboembolism. Interestingly, the present work shows that patient who will present RPVO had an impaired endothelial cells mobilization. Compared to patients without RPVO, patients with RPVO had lower circulating endothelial cells at the acute phase of PE. This endothelial dysfunction is probably triggered by endothelial progenitors that expressed the very low density lipoprotein receptor (VLDLr), implicated in the inhibition of angiogenesis and able to bind the β15-42 N terminal sequence of the fibrin Bβ chain

D‐dimer testing in clinical practice in the era of COVID‐19

Abstract D‐dimer is a fragment of crosslinked fibrin resulting from plasmin cleavage of fibrin clots and hence an indirect biomarker of the hemostatic system activation. Early in the coronavirus disease 2019 (COVID‐19) pandemic, several studies described coagulation disorders in affected patients, including high D‐dimer levels. Consequently, D‐dimer has been widely used in not‐yet‐approved indications. Ruling out pulmonary embolism and deep vein thrombosis in patients with low or intermediate clinical suspicion is the main application of D‐dimer. D‐dimer is also used to estimate the risk of venous thromboembolism recurrence and is included in the ISTH algorithm for the diagnosis of disseminated intravascular coagulation. Finally, numerous studies identified high D‐dimer levels as a biomarker of poor prognosis in hospitalized patients with COVID‐19. This report focuses on validated applications of D‐dimer testing in patients with and without COVID‐19

Population pharmacodynamic modeling and simulation of the respiratory effect of acetazolamide in decompensated COPD patients.

Chronic obstructive pulmonary disease (COPD) patients may develop metabolic alkalosis during weaning from mechanical ventilation. Acetazolamide is one of the treatments used to reverse metabolic alkalosis.619 time-respiratory (minute ventilation, tidal volume and respiratory rate) and 207 time-PaCO2 observations were obtained from 68 invasively ventilated COPD patients. We modeled respiratory responses to acetazolamide in mechanically ventilated COPD patients and then simulated the effect of increased amounts of the drug.The effect of acetazolamide on minute ventilation and PaCO2 levels was analyzed using a nonlinear mixed effect model. The effect of different ventilatory modes was assessed on the model. Only slightly increased minute ventilation without decreased PaCO2 levels were observed in response to 250 to 500 mg of acetazolamide administered twice daily. Simulations indicated that higher acetazolamide dosage (>1000 mg daily) was required to significantly increase minute ventilation (P<.001 vs pre-acetazolamide administration). Based on our model, 1000 mg per day of acetazolamide would increase minute ventilation by >0.75 L min(-1) in 60% of the population. The model also predicts that 45% of patients would have a decrease of PaCO2>5 mmHg with doses of 1000 mg per day.Simulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide

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

International audienceCancer-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

International audienceBackground: 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 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 patient