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Septic shock
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Bryan E. Freeman, Michael R. Foley
Although the exact mechanism is unknown, activated protein C possesses both anti-thrombotic and anti-inflammatory properties. As mentioned before, sepsis involves activation of the extrinsic (tissue factor) pathway of the clotting cascade, which leads to overproduction of thrombin. This is the target of APC. Normally protein C, the zymogen of APC, is activated by thrombin. However, there are two aspects of sepsis that cause disruptions in this system. The first problem is that circulating levels of protein C, APC, and protein S (the cofactor for protein C) are decreased. The other issue is that the thrombin:thrombomodulin complex that is usually responsible for the conversion of protein C to APC is also disrupted, which leads to the unregulated production of thrombin. Administration of rhAPC compensates for the lack of naturally created APC and exerts an anti-thrombotic effect by blocking the conversion of factors VIIIa and Va to factors VIII and V, as well as by inhibiting plasminogen activator inhibitor-1 (PAI-1), thereby allowing fibrinolysis to occur. Other mechanisms may be involved as well (17).
Transfusion products
Published in Jennifer Duguid, Lawrence Tim Goodnough, Michael J. Desmond, Transfusion Medicine in Practice, 2020
Recombinant human activated protein C has emerged as a new drug for treating severe sepsis in intensive care patients. Activated protein C is a potent antithrombotic serine protease with substantial anti-inflammatory properties. Pro-inflammatory cytokines released in response to infection can also activate coagulation and inhibit fibrinolysis. A combination of procoagulant and inflammatory stimuli provides a potent mechanism for initiating and perpetuating microvascular injury, intravascular coagulation, inadequate tissue perfusion, and organ failure. Activated protein C inhibits activated factors V and VIII, stimulates fibrinolysis, reduces production of tumour necrosis factor a by monocytes, and reduces interactions between neutrophils and endothelial cells.
Lupus Anticoagulants: Characteristics, Methods of Laboratory Detection and Some Clinical Associations
Published in E. Nigel Harris, Thomas Exner, Graham R. V. Hughes, Ronald A. Asherson, Phospholipid-Binding Antibodies, 2020
Thomas Exner, Douglas Triplett
However, the most likely antithrombotic mechanism compromised by LA may be that involving the “thrombomodulin pathway”. Essentially, thrombin formed and released at a site of injury binds to thrombomodulin present on normal endothelial cells and in this complex catalyzes the activation of protein C. Activated protein C is a potent anticoagulant which shuts off the clotting mechanism by destroying factors Va and Villa. Phospholipid and protein S are cofactors in this process and therefore anti-phospholipid antibodies might be expected to interfere with this particular pathway. A number of investigators claim to have demonstrated antibodies in patients with LA which interfere by binding thrombomodulin or protein S.88,91 (See Chapter 16.)
Effects of anticoagulants on protein C activity
Published in Acta Cardiologica, 2020
Yusuf Ziya Şener, Metin Okşul, Seher Şener
Protein C acts a primary role in fibrinolysis and is synthesised from liver by vitamin K dependent pathways. Warfarin is vitamin K antagonist and inhibits the synthesis of vitamin K dependent clotting factors including factor II, VII, IX, X and the anticoagulant proteins C and S [2]. Novel oral anticoagulants (NOACs) have different mechanism rather than vitamin K antagonists and targets of NOACs are activated factor II (dabigtran) or activated factor X (Rivaroxaban, apixaban, edoxaban [3]. It is well known that warfarin decreases both level and activity of protein C. NOACs also have effects on haemostasis assays and especially clot-based assays can give false results about protein C activity in patients under treatment with NOACs [4]. Heparin also affects the activity of protein C. Protein C is activated by thrombin-thrombomodulin complex and heparin inhibits the effects of thrombin. Activated protein C has its own unique inhibitor, activated protein C inhibitor. Inhibition of activated protein C is stimulated by relatively high levels of heparin (5–10 u/ml) [5].
Pathogenesis of antiphospholipid syndrome: recent insights and emerging concepts
Published in Expert Review of Clinical Immunology, 2019
Karl J. Lackner, Nadine Müller-Calleja
Another interesting recent observation is the observation of an association of antibodies against protein C [81] and tissue factor pathway inhibitor (TFPI) with the severity of thrombosis and the risk of recurrent events in spite of therapeutic anticoagulation [82]. While these antibodies apparently increase the extent of the index-event and the risk for recurrent thrombo-embolic events in both APS and non-APS patients with thrombosis, their frequency and avidity is substantially higher in APS patients than in non-APS patients. Resistance to activated protein C that is aggravated by antibodies to protein C is a well-known risk factor for thrombosis and recurrent events. Also interference with TFPI by autoantibodies is likely to aggravate the prothrombotic state in patients in whom TF plays a major role in the pathogenesis of thrombosis. TF has long been implicated as important player in APS pathogenesis. TF expression and activation of cell surface TF by aPL has been shown and in vivo data further support its role in APS (see above). This may explain the particularly strong association of anti-TFPI in APS compared to non-APS patients [82]. Still enigmatic remains the higher prevalence of these antibodies in APS and their higher avidity. It may reflect a general propensity of APS patients to develop autoimmunity, but further studies into this question are needed.
Ureteral stent-associated infection and sepsis: pathogenesis and prevention: a review
Published in Biofouling, 2019
Kymora B. Scotland, Joey Lo, Thomas Grgic, Dirk Lange
Urosepsis is often treated using broad-spectrum antibiotics (Heidenreich and Thissen 2014). Once urine and blood cultures have been speciated, the antimicrobial coverage can be adjusted and an antibiotic is chosen to directly treat the specific uropathogens involved (Gosciniak et al. 2014; Heidenreich and Thissen 2014). Supportive and adjunctive treatment can also be administered, which includes oxygen, fluid and dialysis therapy, steroids and catecholamines (Gosciniak et al. 2014). Human recombinant activated protein C can also be administered as its anticoagulant properties aid in improving sepsis-induced coagulopathy (Heidenreich and Thissen 2014). Interdisciplinary management, early therapy, infection control, frequent monitoring, balancing fluid and electrolyte levels, and adjustment of irregular coagulation remain crucial challenges for the treatment of urosepsis (Heidenreich and Thissen 2014).