Activated factor xiia

Human coagulation factor XIIa (FXIIa) is a trypsin-like serine protease that is involved in pathologic thrombosis. As a potential target for designing safe anticoagulants, FXIIa has received a great deal of interest in recent years. In the present study, we employed virtual high-throughput screening of 500,064 compounds within Enamine database to acquire the most potential inhibitors of FXIIa. Subsequently, 18 compounds with significant binding energy (from -65.195 to -15.726 kcal/mol) were selected, and their ADMET properties were predicted to select representative inhibitors...

Kinase inhibitors can pose bleeding risks as platelet signaling evolves during clotting. Using microfluidics (200 s-1 wall shear rate) to perfuse Factor XIIa-inhibited or thrombin-inhibited whole blood (WB) over collagen ± tissue factor (TF), we explored the potency of the Src family kinase (SFK) inhibitor dasatinib or the spleen tyrosine kinase (Syk) inhibitor GS-9973 present at clot initiation or added after 90 s (via rapid switch to inhibitor-pretreated WB). When initially present, dasatinib potently inhibited platelet deposition on collagen (no TF)...

C1-inhibitor (C1-INH) is an important regulator of the complement, coagulation, fibrinolytic and contact systems. The quantity of protease/C1-INH complexes in the blood is proportional to the level of the in vivo activation of these four cascade-like plasma enzyme systems. Parallel determination of C1-INH-containing activation complexes could be important to understand the regulatory role of C1-INH in diseases such as hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE). We developed in-house ELISAs to measure the concentration of complexes of C1-INH formed with active proteases: C1r, C1s, MASP-1, MASP-2, plasma kallikrein, factor XIIa, factor XIa, and thrombin, as well as to determine total and functionally active C1-INH...

Cardiovascular disease, including stroke, myocardial infarction, and venous thromboembolism, is one of the leading causes of morbidity and mortality worldwide. Excessive coagulation may cause vascular occlusion in arteries and veins eventually leading to thrombotic diseases. Studies in recent years suggest that coagulation factors are involved in these pathological mechanisms. Factors XIa (FXIa), XIIa (FXIIa), and plasma kallikrein (PKa) of the contact system of coagulation appear to contribute to thrombosis while playing a limited role in hemostasis...

Hereditary angioedema (HAE) types I and II are characterized by functional C1 inhibitor (fC1-INH) deficiency which results in bradykinin overproduction. Sensitive, specific and robust methods to quantitate fC1-INH in human samples are required for diagnosing HAE and/or to measure pharmacodynamic activity of C1-INH drugs in clinical studies. To date, three methods have been reported in literature to measure fC1-INH: conventional chromogenic assay measuring residual C1-esterase activity, and immunoassays based on functional binding to either activated complement C1s or Factor XIIa/kallikrein...

BACKGROUND: The complement and coagulation systems share an evolutionary origin with many components showing structural homology. Certain components, including complement factor H (FH) and coagulation factor XII (FXII), have separately been shown to have auxiliary activities across the two systems. OBJECTIVES: The interaction between FXII and FH was investigated. METHODS: Using enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) complex formation between different FXII forms and FH was investigated...

BACKGROUND: Chronic spontaneous urticaria (CSU) is characterized by recurrent itchy weals and/or angioedema and is believed to be driven by mast cell activation. It was shown that excessive mast cell activation during anaphylaxis initiates contact activation, resulting in bradykinin release. Evidence for bradykinin release was never demonstrated in CSU. OBJECTIVE: To study biomarkers of bradykinin release in CSU. METHODS: Plasma samples of CSU patients were collected during routine visits at the outpatient clinic...

BACKGROUND: Thrombosis represents as the prime contributor to the burden of diseases, worldwide. Conventional anticoagulants for thrombosis therapy have a common bleeding side effect. Bioactive peptides are studied to be an effective alternative for currently available therapeutic drugs. OBJECTIVE: In this study, VITPOR AI peptide, a previously reported coagulation FXIIa inhibitor from Nori (Porphyra yezoensis), was assessed for its inhibitory activity against FXIIa and its in vivo mode of action...

BACKGROUND: Exposure of blood to polyanionic artificial surfaces, for example, during cardiopulmonary bypass (CPB), induces a highly procoagulant condition requiring strong anticoagulation. Unfractionated heparin (UFH) is currently used during CPB but can lead to serious bleeding complications or development of a hypercoagulable state culminating in life-threatening thrombosis, highlighting the need for safer antithrombotics. Ixodes ricinus contact phase inhibitor (Ir-CPI) is a protein expressed by I...

Factor XII (FXII) is the zymogen of serine protease, factor XIIa (FXIIa). FXIIa enzymatic activities have been extensively studied and FXIIa inhibition is emerging as a promising target to treat or prevent thrombosis without creating a hemostatic defect. FXII and plasma prekallikrein reciprocally activate each other and result in liberation of bradykinin. Due to its unique structure among coagulation factors, FXII exerts mitogenic activity in endothelial and smooth muscle cells, indicating that zymogen FXII has activities independent of its protease function...

BACKGROUND: Inorganic polyphosphate modulates the contact pathway of blood clotting, which is implicated in thrombosis and inflammation. Polyphosphate polymer lengths are highly variable, with shorter polymers (approximately 60-100 phosphates) secreted from human platelets, and longer polymers (up to thousands of phosphates) in microbes. We previously reported that optimal triggering of clotting via the contact pathway requires very long polyphosphates, although the impact of shorter polyphosphate polymers on individual proteolytic reactions of the contact pathway was not interrogated...

Coagulation factor XII (FXII) is a key initiator of the contact pathway, which contributes to inflammatory pathways. FXII circulates as a zymogen, which when auto-activated forms factor XIIa (FXIIa). Here, the production of the recombinant FXIIa protease domain (βFXIIaHis ) with yields of ∼1-2 mg per litre of insect-cell culture is reported. A second construct utilized an N-terminal maltose-binding protein (MBP) fusion (MBP-βFXIIaHis ). Crystal structures were determined of MBP-βFXIIaHis in complex with the inhibitor D-Phe-Pro-Arg chloromethyl ketone (PPACK) and of βFXIIaHis in isolation...

Pentamidine is bis-oxybenzamidine-based antiprotozoal drug. The parenteral use of pentamidine appears to affect the processes of blood coagulation and/or fibrinolysis resulting in rare but potentially life-threatening blood clot formation. Pentamidine was also found to cause disseminated intravascular coagulation syndrome. To investigate the potential underlying molecular mechanism(s) of pentamidine's effects on coagulation and fibrinolysis, we studied its effects on clotting times in normal and deficient human plasmas...

Protease inhibitors have been reported rarely from the leech Hirudinaria manillensis . In this study, we purified a novel protease inhibitor (bdellin-HM-2) with anticoagulant properties from H. manillensis . With a molecular weight of 1.4x104 , bdellin-HM-2 was also characterized with three intra-molecular disulfide bridges at the N-terminus and multiple HHXDD and HXDD motifs at the C-terminus. cDNA cloning revealed that the putative nucleotide-encoding protein of bdellin-HM-2 contained 132 amino acids and was encoded by a 399 bp open reading frame (ORF)...

Thrombosis represents a major cause of morbidity and mortality around the world. Peptides isolated from natural sources have been proven to have anticoagulant and antithrombotic properties. VITPOR AI, a 16-mer peptide, isolated from Porphyra yezoensis was reported to have anticoagulant property. In this study, the coagulation factor XIIa activity in the presence of VITPOR AI was determined. Molecular modelling was performed to investigate the interaction between peptide and FXIIa. The structure of the peptide was predicted using PEP-FOLD3 server and simulated by molecular dynamics (MD) using GROMACS package...

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Although portal vein thrombosis (PVT) commonly occurs in patients with hepatocellular carcinoma (HCC), the hypercoagulability mechanism in patients with HCC is not entirely clear. Recently, tumor-induced formation of neutrophil extracellular traps (NET) has been shown to trigger contact system activation, and contact system activation has been shown to be a new mechanism of thrombosis. Therefore, we investigated whether contact system activation and NET formation occurred in relation to PVT in HCC patients...

Neutrophils can release extracellular traps (NETs) in infectious, inflammatory and thrombotic diseases. NETs have been detected in deep vein thrombosis, atherothrombosis, stroke, disseminated intravascular coagulation and trauma. We have previously shown that haemodynamic forces trigger rapid NETosis within sterile occlusive thrombi in vitro. Here, we tested the effects of thrombin, fibrin and fibrinolysis on shear-induced NETosis by imaging NETs with Sytox Green during microfluidic perfusion of factor XIIa-inhibited or thrombin-inhibited human whole blood over fibrillar collagen (±tissue factor)...

Objective- Factor XI (FXI) contributes to thrombotic disease while playing a limited role in normal hemostasis. We generated a unique, humanized anti-FXI antibody, AB023, which blocks factor XIIa-mediated FXI activation without inhibiting FXI activation by thrombin or the procoagulant function of FXIa. We sought to confirm the antithrombotic activity of AB023 in a baboon thrombosis model and to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adult subjects. Approach and Results- In a primate model of acute vascular graft thrombosis, AB023 reduced platelet and fibrin accumulation within the grafts by >75%...

Snake venom serine proteases (SVSPs) are enzymes that are capable of interfering in various parts of the blood coagulation cascade, which makes them interesting candidates for the development of new therapeutic drugs. Herein, we isolated and characterized Moojase, a potent coagulant enzyme from Bothrops moojeni snake venom. The toxin was isolated from the crude venom using a two-step chromatographic procedure. Moojase is a glycoprotein with N-linked glycans, molecular mass of 30.3 kDa and acidic character (pI 5...