Paramagnetic Contrast Agents
Michel M. J. Modo, Jeff W. M. Bulte in Molecular and Cellular MR Imaging, 2007
The development of Gd-based agents responsive to Factor XIII transglutaminase activity has been tackled independently by Weissleder’s79 and Neeman’s80 groups. Factor XIII is a key player in the final stages of blood coagulation, as it catalyzes the formation of a covalent bond between the glutamine residue in one fibrin chain and the e-amino group of a lysine residue in a different chain. Thus, this transglutaminase reaction causes the formation of the fibrin network. A fibrinogen-specific peptide sequence, extracted from α2-antiplasmin (α2AP), the primary inhibitor of plasmin-mediated fibrinolysis, was used. Thus, this peptide functionalized with Gd-DTPA cross-links with fibrin to an extent that depends on the local concentration of Factor XIII. Factor XIII activity is relevant to many pathologies, such as thrombotic disorder, coronary artery disease, myocardial infarction, and cerebrovascular diseases. Moreover, elevated activity of transglutaminase was shown at the boundaries of invading tumors, in association with angiogenesis.
t-PA in Fibrin Dissolution and Hemostasis
Cornelis Kluft in Tissue-Type Plasminogen Activator (t-PA): Physiological and Clinical Aspects, 1988
Fibronectin circulates in plasma and is provided by platelets. Upon clot formation it becomes incorporated into the clot, and it is crosslinked to fibrin by activated factor XIII.143,145 Immobilized plasma fibronectin has been shown to bind t-PA, specifically one chain t-PA; soluble fibronectin did not compete effectively for the binding.15 The specific effect of fibronectin immobilized on plastic suggests exposure of a cryptic site in the molecule by the immobilization. Whether this site is exposed also when fibronectin is bound to fibrin, or whether the site becomes exposed upon proteolytic modification of the component, remains to be established. It further remains to be established whether fibrin-bound fibronectin stimulates the plasminogen activation. A recent study using two-chain t-PA demonstrated a moderate stimulation of Lys-plasminogen activation by soluble fibronectin.146 Only minimal plasmin formation was observed for t-PA activation of glu-plasminogen on adsorbed fibronectin by others; the t-PA was not defined.147
Acquired Circulating Anticoagulants Other than Lupus Anticoagulants
E. Nigel Harris, Thomas Exner, Graham R. V. Hughes, Ronald A. Asherson in Phospholipid-Binding Antibodies, 2020
Clinically more important inhibitors of the fibrin(ogen) phase of the clotting mechanism are those directed against factor XIII and its activation by thrombin. It is well known that deficiency of factor XIII leads to poor wound healing and recurrent hemorrhage. Therefore, antibodies directed against the factor XIII cross-linking of fibrin might be expected to be similarly complicated. These inhibitors have been classified by Lorand into three categories.116 Type 1 interferes with the activation of factor XIII and induces a severe bleeding tendency.117 Type 2 inhibits activated factor XIII and may cause serious hemorrhage. Type 3 blocks the reactivity of the fibrin substrate towards factor XIII and the clinical manifestations are less severe.118 Several of these cases have been in patients who have taken isoniazid.3 One has been reported as part of a lupus-like syndrome following practolol therapy.119
Current and emerging biologics for the treatment of hemophilia
Published in Expert Opinion on Biological Therapy, 2019
Giancarlo Castaman, Silvia Linari
An injured blood vessel also exposes membrane-bound tissue factor (TF) in the extravascular tissue to traces of activated factor VII (FVIIa) that are always present in the plasma [26]. By binding to TF, FVIIa becomes a potent activator of factor X (FX) and initiates the path to the earliest production of thrombin catalyzing the activation of both FIX and FX [27]. This activation pathway is historically termed the extrinsic pathway of coagulation. Although this ‘TF pathway’ is quickly shut down by a specific inhibitor (tissue factor pathway inhibitor, TFPI), coagulation accelerates to a rapid pace because nascent thrombin activates factors V, VIII and XI to produce additional thrombin. Moreover, FIXa also activates FX, in the presence of its cofactor FVIIIa. FXa, also in presence of its cofactor FVa, then activates prothrombin to generate thrombin [28]. Interaction among the procoagulant proteins is facilitated by platelet activation, which transforms the platelet surface into a platform for the assembly of coagulant complexes. When thrombin cleaves two small peptides from fibrinogen, fibrin monomers are formed and begin to polymerize. Fibrin polymers become cross-linked by activated factor XIII (FXIIIa) with stable clot generation and achievement of hemostasis.
Improving fibrinolysis in venous thromboembolism: impact of fibrin structure
Published in Expert Review of Hematology, 2019
The key role of the fibrinolytic system is to dissolve fibrin within thrombi by plasmin, in order to maintain vascular patency. Fibrin is produced from fibrinogen by the cleavage of two sets of amino-terminal peptides, fibrinopeptides A and B from the Aa- and Bb-chains, respectively, by thrombin, exposing binding sites in the E-region (knobs) that interact with polymerization pockets (holes) in each of the D-regions. The subsequent formation of fibrin protofibrils then leads to their lateral aggregation and the generation of fibrin fibers, supported by interactions of the αC-regions [1,2]. The fibrin α- and γ-chains are cross-linked by thrombin-activated factor XIII (FXIIIa), which improves mechanical properties and increases clot resistance to fibrinolysis. Fibrinolysis could be considered the complex process of plasmin generation by plasminogen activators, and the subsequent digestion of fibrin by plasmin [3]. The main enzyme involved is plasmin, a serine protease derived from its inactive precursor, plasminogen, through the action of its activators. Plasmin also cleaves several other substrates, including extracellular matrix proteins, and activates some proteases and growth factors, being involved in wound healing, inflammation, and angiogenesis.
Inflammatory and immune response genes: A genetic analysis of inhibitor development in Iranian hemophilia A patients
Published in Pediatric Hematology and Oncology, 2019
Niloofar Naderi, Hossein Yousefi, Sahar Mollazadeh, Afsaneh Seyed Mikaeili, Masoumeh Keshavarz Norouzpour, Mohammad Jazebi, Seyedeh Somayeh Moazezi Nekooi Asl, Ali Namvar, Alireza Azizi Saraji, Elnaz Agi, Azam Bolhassani
Our data demonstrated that only polymorphisms in F13A1, DOCK2, and MAPK9 genes were associated with the risk of developing FVIII inhibitors in Iranian HA patients. Their relationship with inhibitor development may be correlated with their function. The F13A1 gene encodes the coagulation factor XIII A subunit which is essential for normal blood clotting and the pathogenesis of inflammatory and autoimmune conditions. DOCK2 is dedicator of Cytokinesis 2 which is expressed in hematopoietic cells and peripheral blood leukocytes. MAPK9 acts as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development [17, 24].