Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Factor VIII (FVIII) inhibitors develop as either alloantibodies against exogenous FVIII in patients with congenital hemophilia A after FVIII-replacement therapy or as autoantibodies against endogenous FVIII in previously healthy, nonhemophilic individuals. The predominant immunoglobulin G (IgG) subclass of FVIII inhibitors is IgG(4). The main epitopic regions are known to be located, however, in the A2, A3, and C2 domains. The A2 and A3 epitopes have been identified between amino acid residues 484 and 509 and residues 558 and 565, respectively. Both of these regions are close to the binding sites for activated FIX (FIXa). Two regions have been identified in the C2 domain, one in the amino-terminal portion of the domain (residues 2181-2243) and the other in the carboxy-terminal portion of the domain (residues 2248-2312 and residues 2315-2330). In addition, a crystallographic analysis of a complex of the C2 domain and a human monoclonal IgG(4)(K) Fab revealed that this type of antibody is in direct contact with hydrophobic and basic residues of the membrane-binding surface. Inactivated FVIII is rapidly cleared from the circulation in the presence of inhibitors. The inhibitors also bind to essential FVIII ligand proteins, including von Willebrand factor, FIXa, FXa, and thrombin, and to surface membrane phospholipid. Some type 2 inhibitors interfere with binding to activated protein C.
 ...
PMID:Characterization of factor VIII inhibitors. 1651 28

Factor VIII (fVIII) is the plasma protein that is missing or deficient in hemophilia A. In contrast, elevated levels of fVIII are associated with an increased risk of arterial and venous thrombosis. fVIII is activated by thrombin to form a non-covalently linked A1/A2/A3-C1-C2 heterotrimer. At physiological concentrations, fVIIIa decays as a result of A2 subunit dissociation, which may help regulate the balance between hemostasis and thrombosis. A2 subunit dissociation is faster in human fVIIIa than in porcine fVIIIa, which may represent an evolutionary adaptation associated with the development of the upright posture and venous stasis in the lower extremities. To investigate the basis for the different decay kinetics of human and porcine fVIIIa, hybrid fVIII molecules representing all possible combinations of human and porcine A domains were isolated. The kinetics of fVIIIa decay were measured and fit to a model describing a reversible bimolecular reaction in which the dissociation rate constant, k, and dissociation constant, Kd, were the fitted parameters. Substitution of the porcine A1 domain into human fVIIIa produced a dissociation rate constant indistinguishable from porcine fVIIIa. Subsequently, substitution of the second cupredoxin-like A1 subdomain resulted in a dissociation rate constant similar to porcine fVIIIa, whereas substitution of the first cupredoxin-like A1 subdomain resulted in a dissociation rate constant intermediate between human and porcine fVIIIa. We propose that cupredoxin-like A1 subdomains in fVIII contain inter-species differences that are a result of selective pressure on the dissociation rate constant.
 ...
PMID:A1 subunit-mediated regulation of thrombin-activated factor VIII A2 subunit dissociation. 1651 39

During experimental lung metastasis, tumor cells adhere to the pulmonary microvasculature and activate coagulation via surface-expressed tissue factor (TF), leading to local fibrin deposition and platelet aggregation. While interventional studies have demonstrated great efficacy of anticoagulants and antiplatelet agents in inhibiting metastasis, no information is available on how tumor biology may be affected by congenital bleeding disorders such as hemophilia A. We therefore used a syngeneic model to study experimental metastasis and primary tumor growth in factor VIII (FVIII)-deficient mice. By conventional reverse transcription-polymerase chain reaction, flow cytometry, and one-stage clotting assays, we demonstrated constitutive expression of TF mRNA, antigen, and procoagulant activity in the murine B16F10 melanoma cell line. In hemophilic mice, B16F10 lung metastasis was significantly (P < 0.001) enhanced by a single dose of human FVIII (100 U kg(-1)), suggesting that FVIII played a critical role during the early blood-borne phase of the metastatic cascade. In contrast, lung seeding was significantly (P < 0.05) reduced by lepirudin, a direct thrombin inhibitor, suggesting that thrombin generation contributed to pulmonary metastasis even in the absence of FVIII. Consistent with this finding, intravenous injection of B16F10 cell-evoked laboratory changes of a hemolytic thrombotic microangiopathy and consumptive coagulopathy in both hemophilic and non-hemophilic mice. Subcutaneous implantation of B16F10 cells into mice with hemophilia A gave rise to primary tumors in an exponential growth pattern similar to that observed in non-hemophilic mice. Although TF expression by B16F10 cells may promote thrombin-dependent metastasis in mice with hemophilia A, amplification of coagulation by host FVIII appears to be necessary for maximum lung seeding.
 ...
PMID:Experimental metastasis and primary tumor growth in mice with hemophilia A. 1668 59

Key issues in the management of patients with hemophilia include a thorough understanding of the mechanisms of blood coagulation and the complications that follow recurrent joint bleeding. Monoclonal antibodies are powerful tools for dissecting the intrinsic coagulation pathway and deriving reagents that could lead, on the long term, to the identification of molecules that enhance, or perhaps even replace factor (F) VIII concentrates in the management of hemophilia A. In recent in vitro experiments, it was demonstrated that plasmatic thrombin generation and intrinsic FX activation was enhanced by each of two FIXa-specific monoclonal antibodies, one of which had FIXa-agonistic activity only, whereas the other enhanced the activity of the intrinsic FX-activating complex (FVIIIa/FIXa) by at least two distinct mechanisms. Hemophilic synovitis, an inflammatory and proliferative disorder in patients with hemophilia, is the result of bleeding into joints and can lead to debilitating arthritis and chronic arthropathy. A major causative factor in the development of hemophilic synovitis is blood-derived iron deposited in joints. FVIII-deficient knockout mice with trauma-induced hemarthrosis serve as a model system for hemophilic synovitis, reproducing the histological features observed in patients. In addition, this animal model recapitulates the observations made in vitro with synovial cell cultures stimulated by iron. These in vitro experiments suggested a role for iron as an agent capable of inducing proliferation and oncogene expression by human and murine synovial fibroblasts. A better understanding of iron-regulated pathways and oncogene expression may lay the groundwork for targeted molecular interventions in hemophilic synovitis.
 ...
PMID:Future aspects of hemophilia research and care. 1680 34

The synthesis and evaluation of inhibitors of activated protein C (aPC) are reported. This serine protease is partly responsible for the degradation of factor VIIIa, involved in the regulation of bleeding in hemophilia A. Benzamidine-containing derivatives were found to be potent aPC inhibitors, some of them showing selectivity against the procoagulant protease thrombin. Moreover, compound 1 significantly restored the generation of thrombin in hemophiliac plasma.
 ...
PMID:Low molecular weight activated protein C inhibitors as a potential treatment for hemophilic disorders. 1691 94

Several lines of evidence have shown that antibody responses to coagulation factor VIII (FVIII) in patients with hemophilia A depend on the help of activated CD4(+) T cells. The primary activation of CD4(+) T cells requires interaction with mature dendritic cells (DCs) that present antigenic peptides in the context of MHC class II and express costimulatory molecules. Maturation of DCs requires danger signals provided by exogenous or endogenous stimuli such as pathogen-derived products or inflammatory cytokines. We asked the question whether FVIII itself, FVIII complexed with von Willebrand factor (VWF) or thrombin-activated FVIII contain danger signals for human DCs that induce the upregulation of costimulatory molecules or the expression of proinflammatory cytokines necessary for effective activation of CD4(+) T cells. Human peripheral monocytes were differentiated into DCs. FVIII, thrombin-activated FVIII, VWF, VWF-FVIII, lipopolysaccharide (LPS), LPS + FVIII, LPS + VWF or LPS + FVIII-VWF were added either on day 0 or on day 5 of differentiation cultures. Differentiation markers, cytokines in cell culture supernatants and the capacity of DCs to stimulate autologous and allogeneic T cells were analysed after seven days of differentiation cultures. Our results indicate that neither FVIII, thrombin-activated FVIII, VWF nor a complex of FVIII and VWF modulate the maturation of human DCs or their capacity to stimulate autologous or allogeneic T cells. We conclude that neither of these proteins present danger signals to human DCs.
 ...
PMID:Recombinant factor VIII and factor VIII-von Willebrand factor complex do not present danger signals for human dendritic cells. 1695 72

Inhibitors against replacement clotting factors occur in approximately 30%-40% of patients with hemophilia A and 1.5%-3% of patients with hemophilia B. In this group of patients, bleeding events are best treated with bypassing agents. Recombinant activated factor VII (rFVIIa) has become the first-line agent in treating surgical and non-surgical bleeding in many centres with efficacy at standard 90 microg/kg doses approaching 90%. The greater efficacy is associated with early initiation of treatment, as well as, possibly larger doses of rFVIIa. A higher concentration appears to be essential in initiating an adequate thrombin burst, which results in a stable clot. Higher dosage regimens, home therapy and continuous infusion regimens are continuously evolving as we strive to define optimal dosing strategies in hemophilia patients. rFVIIa has been a remarkably safe agent for hemophiliacs but with high dosages being advocated and older patients being given such doses outside a trial setting, thromboembolic events remain a concern.
 ...
PMID:Recombinant activated clotting factor VII (rFVIIa) in the treatment of surgical and spontaneous bleeding episodes in hemophilic patients. 1732 97

Disorders of coagulation in children often prove challenging to the medical care team. The aims of this study were to assess the spectrum and prevalence of coagulation disorders among children attending Mansoura University Children Hospital (MUCH), Mansoura, Egypt. A total of 105 pediatric patients were referred to MUCH. They were divided into two groups: congenital coagulation disorders (75 cases, age 45.36 +/- 48.59 months), and acquired coagulation disorders (30 cases, age 56.13 +/- 61.61 months). All patients were subjected to thorough history taking including the nature of bleeding, family, past history, mode of inheritance, and detailed physical findings. Hemostatic tests included: platelet count, bleeding time (BT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT). Specific tests in the congenital group include assay of coagulation factors according to each disorder, Von Willebrand factor assay, ristocetin aggregation test, APTT mixing study for detection of inhibitors in complicated hemophilia cases, F VIII C to VWAg ratio with cut off 0.7 for detection of carriers in some hemophilia A families. Congenital disorders constituted 71.4% of the studied cases vs. 28.6% for acquired disorders. Hemophilia A (42.85%), hemophilia B (14.28%) and liver diseases (14.28%) represented the majority of the studied cases. Mild and moderate cases of hemophilia A and B are more frequent than severe cases in both types. Male sex is more frequent than female in the congenital group (94.7 vs. 5.3%, P < 0.001). Direct correlation existed between factor level assay and severity of hemophilia (r = 0.73, P = 0.006). Three mothers and one sister were identified as carrier out of four families. Anti-clotting factors inhibitor was detected in 18.2% of patients with hemophilia A and in 9.1% with hemophilia B. In conclusion, our study found that hemophilias are the most prevalent congenital coagulation disorders among children. Attention must be given for detection of hemophilia carriers and inhibitors of clotting factors.
 ...
PMID:Coagulation disorders and inhibitors of coagulation in children from Mansoura, Egypt. 1765 57

Mathematical modelling has become a powerful tool to quickly test a series of hypotheses and predict outcomes prior to performing the actual experiments. Here, we present the use of mathematical modelling in simulating the biochemical reactions of the coagulation cascade, up to thrombin formation. This model is used to examine thrombin generation in the normal plasma state, as well as in the absence of individual factors VIII, IX, and XI. Each of the latter states represents a hemophilic state in blood (hemophilia A, B, and C, respectively), and when combined resemble the situation in the avascular ovarian follicular fluid system. Model results indicate a much lower thrombin production in the absence of factors VIII, IX, or XI, matching the clinical bleeding outcomes in such patients. Furthermore, results from varying the severity of the factor deficiencies qualitatively match the expected outcomes.
 ...
PMID:Modelling the effect of amplification pathway factors on thrombin generation: A comparison of hemophilias. 1829 17

Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is structurally similar to human plasma-derived coagulation factor VIIa, but is manufactured using DNA biotechnology. Recombinant factor VIIa interacts with thrombin-activated platelets to produce a thrombin burst leading to accelerated fibrin clot formation localized to the site of vascular injury. It is approved in many countries for use as an intravenous hemostatic agent in patients with congenital hemophilia with inhibitors, and also for acquired hemophilia, factor VII deficiency, and Glanzmann thrombasthenia in some countries. Studies have shown it to be effective and generally well tolerated when used intravenously to treat bleeding episodes or provide hemostatic cover during surgery in patients with congenital hemophilia with inhibitors, acquired hemophilia, factor VII deficiency or Glanzmann thrombasthenia. Based on available data, its efficacy in terms of patient-assessed response may be similar to that of activated prothrombin complex concentrate (aPCC), but treatment with a single 270 microg/kg dose of recombinant factor VIIa might reduce the need for rescue therapy compared with aPCC. Recombinant factor VIIa is not immunogenic in patients with hemophilia, does not produce an anamnestic response in hemophilia patients with inhibitors, and has very low thrombogenicity. It is recommended in guidelines as the treatment of choice for bleeds in patients with hemophilia B with high-responding inhibitors and for patients with factor VII deficiency, and is also a first-line therapeutic option for high-responder hemophilia A patients with inhibitors and those with acquired hemophilia. Cost data from pharmacoeconomic analyses support its use in hemophilia patients with inhibitors. Thus, recombinant factor VIIa is a valuable treatment option for patients with these rare, but potentially serious, bleeding disorders.
 ...
PMID:Recombinant factor VIIa (eptacog alfa): a review of its use in congenital hemophilia with inhibitors, acquired hemophilia, and other congenital bleeding disorders. 1834 9


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>