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Coagulation Theory, Principles, and Concepts
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
factor IX circulates as a single-chain glycoprotein with four distinct structural domains. These include the Gla domain (calcium binding γ-carboxyglutamic acid region), two epidermal growth factor regions, an activation peptide, and the catalytic site. The activation of factor IX to produce factor IXa is a two-step process. The single-chain zymogen is first cleaved to produce a two-chain molecule in which the chains are connected by disulfide bonds. This intermediate is functionally inactive until a second cleavage occurs, which releases the activation peptide (41). This sequence can be modified by using Russell’s viper venom. Russell’s viper venom cleaves at a slightly different initial site, which produces a factor IXa with an activity of about half that of normally activated factor XIa. In certain mutations of factor IX, normal activation produces a similar product and in some individuals leads to hemophilia.
Briefing Therapeutic Approaches in Anticoagulant, Thrombolytic, and Antiplatelet Therapy
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Vitamin K antagonists inhibit the enzyme vitamin K epoxide reductase, which uses vitamin K to modify several coagulation zymogens (factor VII, factor IX, factor X and prothrombin). Therefore, antithrombotic effect is a consequence of their inhibition of the vitamin K-dependent post-translational γ-carboxylation of glutamic acid (Gla) residues in the previously mentioned procoagulant zymogens. γ-carboxyglutamic acid residues (a specific domain) are an essential requirement for these proteins for permitting the binding of procoagulants to phospholipid surfaces and hence proper assembly into the active tenase and prothrombinase complexes. Deficiency of Gla domains turns FVIIa, FIXa, FXa, and thrombin into physiologically very poor procoagulants. These antagonists are used for long-term anticoagulant therapy. These inhibitors were introduced more than 50 years ago and still in clinical use today. Vitamin K antagonists are Warfarin and its analogs, such as phenprocoumon, acenocoumarol, and dicumarol (Figure 7.5).
Anti-inflammatory, Anti-allergic, Antipyretic, Antinociceptive, Antithrombotic, and Anti-coagulant Activities of Seaweeds and their Extracts
Published in Leonel Pereira, Therapeutic and Nutritional Uses of Algae, 2018
TF is constitutively present on cell membranes within and around the vessels and serves as the cell surface receptor for serine protease factor VIIa. Carboxylated GLA domain of factor VIIa binds to negatively charged phospholipids in the presence of calcium. Binding of VIIa to negatively charged phospholipids greatly enhances the protein-protein binding of VIIa to TF. Upon a vessel injury, tissue factor, normally found outside of blood vessels, is exposed to the blood where it forms a catalytic complex with factor VIIa activating factor IX and catalyzing the conversion of inactive protease factor X into active protease factor Xa (Spronk et al. 2003, Mirzaahmadi et al. 2011).
Factor IX(a) inhibitors: an updated patent review (2003-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Daniel K. Afosah, Edward Ofori, Madhusoodanan Mottamal, Rami A. Al-Horani
FIX is a vitamin K-dependent protein that is biosynthesized by hepatocytes as a precursor of a serine protease, FIXa [58]. It is biosynthesized as a precursor protein of 461 amino acids. During the biosynthesis, several posttranslational modifications take place resulting in a single chain of 415 residues and an average molecular weight of 57 kD [59]. Structurally, FIX possesses an N-terminal Gla domain (residues 1–40), a short hydrophobic stack (residues 41–46), two epidermal growth factor (EGF)-like domains (EGF1: residues 47–83, and EGF2: residues 88–127, that are linked by residues 84–87), an activation peptide (residues 146–180), and a C-terminal protease domain (residues 181–415) [60,61]. The Gla domain and EGF1 domain contain several binding sites for calcium ions. The zymogen FIX is activated to the enzyme FIXa by either the TF/FVIIa/calcium ion complex or FXIa/calcium ion [58], and that is by proteolytically cleaving the two peptide bonds at Arg145–Ala146 and Arg180–Val181, along with the release of a 35-residue activation peptide [59]. The resulting active protease i.e. FIXa contains a light chain (residues 1–145) and a heavy chain (residues 181–415) held together by a disulfide bond. The light chain consists of the Gla domain, EGF1 domain, and EGF2 domain, while the heavy chain contains the serine protease domain with the catalytic triad of Ser365 (chymotrypsin numbering 195), His221 (57), and Asp269 (102) [58]. The structure of FIXa is illustrated in Figure 4.
Platelet calcium signaling by G-protein coupled and ITAM-linked receptors regulating anoctamin-6 and procoagulant activity
Published in Platelets, 2021
Delia I. Fernández, Marijke J. E. Kuijpers, Johan W. M. Heemskerk
As indicated before, a condition par excellence that induces anoctamin-6 mediated PS exposure and procoagulant activity is the activation of platelets by collagen plus thrombin (next to Ca2+ ionophore), resulting in ‘supramaximal’ high Ca2+ rises [5,87]. These high-Ca2+ PS-exposing platelets are furthermore characterized by a calpain-mediated cleavage and inactivation of integrin αIIbβ3 [88], the extracellular cleavage of GPVI and GPIbα [89], and a greatly enhanced binding ability of Gla-domain containing coagulation factors [18,90]. This assembly of coagulation factors causes a magnitude increase in the formation of factor Xa (tenase complex) and thrombin (prothrombinase complex) at the platelet surface, thereby strongly enhancing thrombin generation and the clotting process [1,52,91]. Since the ballooned PS-exposing platelets can collect a surrounding protein (fibrin) coat, they were also designated as COAT platelets (COllagen And Thrombin) [92,93]. Given the major morphological changes of the ballooned platelets, it is not a surprise that anoctamin-6 has a strong regulatory effect on the platelet neo-N-terminal and phospho-proteomes upon collagen/thrombin activation [86]. With the risk of popularizing, for these non-dead platelets, the term ‘zombie’ might be more appropriate than ‘necrotic.’
Effects of bisphenol A and S on blood coagulation: in vivo, in vitro and in silico approaches in toxicodynamic
Published in Toxicology Mechanisms and Methods, 2021
Artur Paes Chagas, Beatriz Pereira Peixoto, Bianca Barros da Costa, Thamyris Almeida Moreira, Leonardo Paes Cinelli, Leandro Louback da Silva, Leandro Miranda-Alves, Clemilson Berto-Junior
Human FVII is a vitamin K-dependent factor with distinct subdomains: a gamma-carboxyglutamic acid-rich domain (GLA domain, from residue 1 to 38), a short hydrophobic domain (39–45), two epidermal growth factor (EGF)-like domain (47–84 and 85–131) and a C-terminal serine protease domain (from 153 to 406) (Vadivel and Bajaj 2012). It may be activated by other coagulation factors such as FXa, FIXa and FVIIa, which in turns lead to a cleavage between ARG152 and ILE153, activating the enzyme (Prasad and Sen 2018). It becomes necessary to measure how much BPA and BPS can interact with activated FVII. Therefore, in silico approach rises as a great opportunity to explore interaction between FVIIa and bisphenols, although, as the in vivo assay was performed in zebrafish and in vitro assays were performed in human samples, an alignment should be performed first to help validating our findings. Alignment displayed a relatively low identity (49%) and high gaps (211) which could be explained by the use of only the heavy chain of human FVIIa and the entire zebrafish protein, since this was the portion used for docking experiments and was available for human (https://www.ncbi.nlm.nih.gov/protein/1JBU_H) but not for zebrafish in NCBI website. However, the same amino acids residues required for redocking validation and for docking studies were present at the same position in zebrafish and human sequences: position 236(H) is HIS57, 381(D) is ASP189, 382(S) is SER190, 387(S) is SER195, 406(S) is SER214, 407(W) is TRP215, 410(G) is GLY219 and 411(C) is CYS220 [22], which encouraged us to step to docking simulations.