Coagulopathy of Acute Sepsis

Coagulopathy is common in acute sepsis and may range from subclinical activation of blood coagulation (hypercoagulability), which may contribute to venous thromboembolism, to acute disseminated intravascular coagulation, characterized by widespread microvascular thrombosis and consumption of platelets and coagulation proteins, eventually causing bleeding. The key event underlying this life-threatening complication is the overwhelming inflammatory host response to the pathogen leading to the overexpression of inflammatory mediators. The latter, along with the microorganism and its derivatives drive the major changes responsible for massive thrombin formation and fibrin deposition: (1) aberrant expression of tissue factor mainly by monocytes-macrophages, (2) impairment of anticoagulant pathways, orchestrated by dysfunctional endothelial cells (ECs), and (3) suppression of fibrinolysis because of the overproduction of plasminogen activator inhibitor-1 by ECs and thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor. Neutrophils and other cells, upon activation or death, release nuclear materials (neutrophil extracellular traps and/or their components such as histones, DNA, lysosomal enzymes, and High Mobility Group Box-1), which have toxic, proinflammatory and prothrombotic properties thus contributing to clotting dysregulation. The ensuing microvascular thrombosis–ischemia significantly contributes to tissue injury and multiple organ dysfunction syndromes. These insights into the pathogenesis of sepsis-associated coagulopathy may have implications for the development of new diagnostic and therapeutic tools

Sepsis-Associated Disseminated Intravascular Coagulation and Thromboembolic Disease

Sepsis is almost invariably associated with haemostatic abnormalities ranging from subclinical activation of blood coagulation (hypercoagulability), which may contribute to localized venous thromboembolism, to acute disseminated intravascular coagulation (DIC), characterized by massive thrombin formation and widespread microvascular thrombosis, partly responsible of the multiple organ dysfunction syndrome (MODS), and subsequent consumption of platelets and coagulation proteins causing, in most severe cases, bleeding manifestations. There is general agreement that the key event underlying this life-threatening sepsis complication is the overwhelming inflammatory host response to the infectious agent leading to the overexpression of inflammatory mediators. Mechanistically, the latter, together with the micro-organism and its derivatives, causes DIC by 1) up-regulation of procoagulant molecules, primarily tissue factor (TF), which is produced mainly by stimulated monocytes-macrophages and by specific cells in target tissues; 2) impairment of physiological anticoagulant pathways (antithrombin, protein C pathway, tissue factor pathway inhibitor), which is orchestrated mainly by dysfunctional endothelial cells (ECs); and 3) suppression of fibrinolysis due to increased plasminogen activator inhibitor-1 (PAI-1) by ECs and likely also to thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor (TAFI). Notably, clotting enzymes non only lead to microvascular thrombosis but can also elicit cellular responses that amplify the inflammatory reactions. Inflammatory mediators can also cause, directly or indirectly, cell apoptosis or necrosis and recent evidence indicates that products released from dead cells, such as nuclear proteins (particularly extracellular histones), are able to propagate further inflammation, coagulation, cell death and MODS. These insights into the pathogenetic mechanisms of DIC and MODS may have important implications for the development of new therapeutic agents that could be potentially useful particularly for the management of severe sepsis

Histones differentially modulate the anticoagulant and profibrinolytic activities of heparin, heparin derivatives and dabigatran.

The antithrombin activity of unfractionated heparin (UFH) is offset by extracellular histones, which, along with DNA, represent a novel mediator of thrombosis and a structural component of thrombi. Here, we systematically evaluated the effect of histones, DNA, and histone-DNA complexes on the anticoagulant and profibrinolytic activities of UFH, its derivatives enoxaparin and fondaparinux, and the direct thrombin inhibitor dabigatran. Thrombin generation was assessed by calibrated automated thrombinography, inhibition of factor Xa and thrombin by synthetic substrates, tissue plasminogen activator–mediated clot lysis by turbidimetry, and thrombinactivatable fibrinolysis inhibitor (TAFI) activation by a functional assay. Histones alone delayed coagulation and slightly stimulated fibrinolysis. The anticoagulant activity of UFH and enoxaparin was markedly inhibited by histones, whereas that of fondaparinux was enhanced. Histones neutralized both the anti-Xa and anti-IIa activities of UFH and preferentially blocked the anti-IIa activity of enoxaparin. The anti-Xa activity of fondaparinux was not influenced by histones when analyzed by chromogenic substrates, but was potentiated in a plasma prothrombinase assay. Histones inhibited the profibrinolytic activity of UFH and enoxaparin and enhanced that of fondaparinux by acting on the modulation of TAFI activation by anticoagulants. Histone H1 was mainly responsible for these effects. Histone-DNA complexes, as well as intact neutrophil extracellular traps, impaired the activities of UFH, enoxaparin, and fondaparinux. Dabigatran was not noticeably affected by histones and/or DNA, whatever the assay performed. In conclusion, histones and DNA present in the forming clot may variably influence the antithrombotic activities of anticoagulants, suggesting a potential therapeutic advantage of dabigatran and fondaparinux over heparin

Flow-diverter treatment for renal artery aneurysms: One-year follow-up of a multicentric preliminary experience

PURPOSERenal artery aneurysms (RAAs) are rare in the general population, although the true incidence and natural history remain elusive. Conventional endovascular therapies such as coil embolization or covered stent graft may cause sidebranches occlusion, leading to organ infarction. Flow-diverters (FD) have been firstly designed to treat cerebrovascular aneurysms, but their use may be useful to treat complex RAAs presenting sidebraches arising from aneurysmal sac. To evaluate mid-term follow-up (FUP) safety and efficacy of FD during treatment of complex RAAs.METHODSBetween November 2019 and April 2020, 7 RAAs were identified in 7 patients (4 men, 3 women; age range 55-82 years; median 67 years) and treated by FD. Procedural details, complications, morbidity and mortality, aneurysm occlusion and segmental artery patency were retrospectively reviewed. Twelve months computed tomography angiography (CTA) FUP was evaluated for all cases.RESULTDeployment of FD was successful in all cases. One intraprocedural technical complication was encountered with one FD felt down into aneurism sac which requiring additional telescopic stenting. One case at 3 months CTA FUP presented same complication, requiring same rescue technique. At 12 months CTA FUP 5 cases of size shrinkage and 2 cases of stable size were documented. No rescue surgery or major intraprocedural or mid-term FUP complication was seen.CONCLUSIONComplex RAAs with two or more sidebranches can be safely treated by FD. FD efficacy for RAA needs a further validation at long term FUP by additional large prospective studies

Fisiologia dell'Emostasi

In condizioni fisiologiche il sangue circola sotto pressione positiva in un circuito virtualmente chiuso, l'albero vascolare, mantenendo la sua fluidità grazie soprattutto al contatto con le cellule endoteliali che rivestono i vasi. L’endotelio non è una semplice barriera che isola le piastrine e gli altri fattori del sistema emostatico dai costituenti "trombogenici" dei tessuti sottoendoteliali, ma svolge un ruolo attivo nel mantenere la normale omeostasi vascolare attraverso la costante produzione di numerose molecole ad attività antitrombotica

MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES www.mjhid.org ISSN 2035-3006 Review article Sepsis-Associated Associated Disseminated Intravascular Coagulation and Thromboembolic

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