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Proteinase Inhibitors: An Overview of their Structure and Possible Function in the Acute Phase
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
In humans, the animal whose serpins have been studied in most detail, the inhibitory members can be divided into those that regulate coagulation (ATIII, PN-1, and protein C inhibitor), fibrinolysis (α2-antiplasmin, PAIs), complement (C1 inhibitor), and inflammatory proteinases (α1-PI, α1-ACT). It is highly significant that almost all of the inhibitors that regulate these systems are serpins, and we presume that the superfamily has diverged to fulfill required regulatory roles during the evolution of vertebrate hemostatic systems. In keeping with the scope of this chapter, we concentrate on α1-PI and α1-ACT, since they are the main acute phase serpins. Although related genes, possible pseudogenes, have been identified,89 it is currently thought that humans express only one α1-PI and one α1-ACT. The function of α1-PI is to regulate the extracellular activity of neutrophil elastase, while the function of α1-ACT appears to be to regulate neutrophil cathepsin G and, possibly, mast cell chymases.2,90
Observations on the Fibrinolytic Response in Two Models of the Baboon in Response to E.Coli: Consumptive and Thrombotic Coagulopathies
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
What are the specifics of this model and what is the evidence supporting the concept shown in Figure 2? Table 1 and Figure 3 summarize the experimental data gathered from this model thus far. Table 1 shows that infusion of factor XaPC/PS on the one hand is followed by generation of thrombin-antithrombin complexes (TAT), but only a limited decrease (consumption) of fibrinogen, no decrease (sequestration) of platelets, or increase of t-PA or plasmin-antiplasmin complexes (PAP) in plasma. On the other hand this infusion of factor XaPC/PS is followed by the appearance of activated protein C/inhibitor complexes together with evidence that factor Va but not factor V is cleaved and inactivated by activated protein C.16 These results suggest that the protein C anticoagulant system is activated and engaged, and that it has attenuated what otherwise would be an uncompensated coagulopathic response. Infusion of factor XaPC/PS with anti-protein C antibody (anti-protein C), however, is followed by appearance of larger amounts of TAT complexes, unrestricted consumption of fibrinogen and sequestration of platelets, and larger amounts of t-PA and PAP complexes.16 Under these circumstances no activated protein C/inhibitor complexes appear, and there is cleavage and inactivation of both factor Va and factor V by plasmin. This suggests that, in the absence of the endogenous protein C system, the coagulant/fibrinolytic response to factor XaPC/PS is uncompensated.
Protein C and Protein S
Published in Hau C. Kwaan, Meyer M. Samama, Clinical Thrombosis, 2019
Mujais et al.32 examined protein C levels in patients on hemodialysis. Protein C amidolytic activity was significantly lower in the 18 uremic subjects than in healthy controls (78 vs. 102%, p <0.001). Within the uremic group, those with repeated vascular access clotting and with large heparin requirements during dialysis had the lowest levels of protein C activity. Similar to the findings of Cosio et al.31 protein C antigen was within the normal range. The authors suggested that low-grade intravascular coagulation in the uremic patients was responsible for the activation and clearance of protein C in these subjects. Alternatively, increased levels of protein C inhibitor might have been present.
Molecular therapeutics of hemophilia A and B
Published in Expert Review of Hematology, 2022
Jie Gong, Hao-Lin Wang, Lung-Ji Chang
Protein C, a vitamin K-dependent serine protease, is encoded by the PROC gene. When converted to APC, protein C is an important anticoagulant regulator and key enzyme in the blood coagulation pathway that inactivates FVa and FVIIIa [99]. FVIIIa is proteolytically inactivated by cleaving susceptible bonds at residues Arg336-Met337 and Arg562-Gly563 (Figure 3) [100]. The region containing residue amino acid 390–404 in APC is essential for anticoagulant activity which interacts with FVa or FVIIIa [101]. Inhibition of APC is the latest novel therapeutic strategy for bleeding disorders. The principle is to inhibit APC, which leads to proteolytic degradation of FVa, resulting in dampening of the intrinsic amplification pathway. Endogenous inhibitors of APC include Protein C inhibitor and α1-antitrypsin, both belong to the serpin family [102]. Polderdijk et al. have reported a mutant of serpin, which enhances the reactivity and specificity of APC and restores hemostasis in hemophilia mice.
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].
Current and emerging biologics for the treatment of hemophilia
Published in Expert Opinion on Biological Therapy, 2019
Giancarlo Castaman, Silvia Linari
Thrombin is the central serine protease in the coagulation cascade, executing several critical reactions as the cleavage of fibrinogen to generate insoluble fibrin and activation of platelets via cleavage of two protease activated receptors (PAR1 and PAR4) [29]. Moreover, thrombin activates both FXI, which then activates FIX, and cofactors VIII and V [30]. This has historically been called the ‘intrinsic pathway’ of coagulation, but it is more appropriate to consider it as a positive feedback loop. Ultimately thrombin plays an important role in down regulation of the coagulation by binding to thrombomodulin on endothelial cells and then activating protein C (APC) [31]. Coagulation is kept localized at the vessel wound by inhibitors that inactivate procoagulantfactors. The procoagulant cofactors FVa and FVIIIa are inactivated by activated protein C (APC) and its cofactor protein S (PS). The procoagulant proteases thrombin, FXa, FIXa and FXIa are inhibited by antithrombin (AT) in plasma and by that highly active bound to heparan sulfate on endothelial cells. AT is the most important inhibitor belonging to the serpin family, as well heparin cofactor II (thrombin inhibitor), protein Z-dependent protease-inhibitor (FXa inhibitor), protein C inhibitor (APC inhibitor) and C1-inhibitor (FXIa inhibitor).