Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that some human antiphospholipid Abs (aPL) in patients with the antiphospholipid syndrome (APS) bind to the homologous enzymatic domains of thrombin and the activated coagulation factor X (FXa). Moreover, some of the reactive Abs are prothrombotic and interfere with inactivation of thrombin and FXa by antithrombin (AT). Considering the enzymatic domain of activated coagulation factor IX (FIXa) is homologous to those of thrombin and FXa, we hypothesized that some aPLs in APS bind to FIXa and hinder AT inactivation of FIXa. To test this hypothesis, we searched for IgG anti-FIXa Abs in APS patients. Once the concerned Abs were found, we studied the effects of the Ab on FIXa inactivation by AT. We found that 10 of 12 patient-derived monoclonal IgG aPLs bound to FIXa and that IgG anti-FIXa Abs in APS patients were significantly higher than those in normal controls (p < 0.0001). Using the mean + 3 SD of 30 normal controls as the cutoff, the IgG anti-FIXa Abs were present in 11 of 38 (28.9%) APS patients. Importantly, 4 of 10 FIXa-reactive monoclonal aPLs (including the B2 mAb generated against beta(2)-glycoprotein I significantly hindered AT inactivation of FIXa. More importantly, IgG from two positive plasma samples were found to interfere with AT inactivation of FIXa. In conclusion, IgG anti-FIXa Ab occurred in approximately 30% of APS patients and could interfere with AT inactivation of FIXa. Because FIXa is an upstream procoagulant factor, impaired AT regulation of FIXa might contribute more toward thrombosis than the dysregulation of the downstream FXa and thrombin.
...
PMID:Novel autoantibodies against the activated coagulation factor IX (FIXa) in the antiphospholipid syndrome that interpose the FIXa regulation by antithrombin. 1915 17

Antiphospholipid syndrome is an important cause of recurrent thrombotic events. The pathogenesis of the thrombosis remains unclear, but it has been suggested that anti-phospholipid Abs, which are laboratory markers for the disease and include species capable of binding to vascular endothelial cells, play an important role. We hypothesized that these anti-endothelial Abs promote thrombosis through interference with clearance of dying cells. We show that healthy endothelial cell monolayers effectively remove apoptotic endothelial cells, but this clearance is markedly inhibited by serum or IgG from patients with antiphospholipid syndrome and anti-endothelial Abs. In addition, patient sera or IgG opsonize apoptotic endothelial cells and cause enhanced Fc-mediated uptake by professional phagocytes. Importantly, the delayed clearance of apoptotic cells by healthy endothelial cells and the enhanced Fc-mediated macrophage uptake each result in procoagulant consequences, as judged by increased thrombin generation. The effects on apoptotic cell clearance were reproduced by a mAb derived from a patient with antiphospholipid syndrome, which binds to endothelial cells and is thrombogenic in experimental models. Taken together, our data support a novel, dual mechanism by which anti-endothelial Abs are prothrombotic in antiphospholipid syndrome by inhibiting removal of procoagulant apoptotic cells and by diverting their clearance to provoke inflammatory and prothrombotic changes in professional phagocytes.
...
PMID:Anti-endothelial antibodies interfere in apoptotic cell clearance and promote thrombosis in patients with antiphospholipid syndrome. 1915 25

Circulating antiphospholipid antibodies (aPL) are associated with central nervous system dysfunction in antiphospholipid syndrome (APS) patients and in a mouse model of APS. We propose a logical pathway of how experimental APS (eAPS) causes brain dysfunction: binding of the antibodies to the brain endothelium evoking microthrombosis, endothelial dysfunction, and IgG leakage through the blood-brain barrier (BBB), then secondary inflammatory cell spread around blood vessels and production of cytokines by these inflammatory cells leading to further disruption of the BBB. The diffuse brain endothelial dysfunction would result in extravasation of serum proteins including APS IgG and activated thrombin, which may induce the behavioral changes observed in the APS mice. We have collected data from the mouse eAPS model which supports this hypothesis. Elucidating the mechanism of the pathogenicity of aPL in vitro and in vivo will serve as a much needed basis for developing new therapeutic modalities in this important disorder.
...
PMID:The pathogenesis of neural injury in animal models of the antiphospholipid syndrome. 1955 16

Bleeding is a rare manifestation of antiphospholipid syndrome, unless associated with reduced clotting factors or severe thrombocytopenia. Accurate assessment of the autoantibodies in plasma is very important since the autoantibodies can lead to bleeding or thrombosis. The objective of the present study was to define the inhibitors causing reduced clotting activity in a patient with antiphospholipids antibodies and to assess the potential of thrombin generation assay to assist in establishment of optimal treatment in case of major bleeding. Levels of clotting factors as well as inhibitors to factors II, V, VII, VIII, IX, X and XI were defined. For detection of inhibitors to prothrombin crossed immunoelectrophoresis was used. IgG was purified by commercial protein A column. Thrombin generation was measured using a fluorometric assay in platelet-poor and platelet-rich plasma. Inhibitors toward the activity of factors V, VII, VIII, IX, X and XI were defined and also an inhibitor to prothrombin antigen. No thrombin generation was induced in the patient's plasma by recalcification even in the presence of recombinant factor VIIa or factor VIII inhibitor bypassing activity. In contrast, addition of platelets from either donor or patient or synthetic phospholipids normalized the thrombin generation. The thrombin generation model showed that the addition of platelets and no recombinant factor VIIa or factor VIII inhibitor bypassing activity would correct thrombin generation in vitro. On this basis, platelet concentrates were administered to a patient with bleeding caused by lupus anticoagulant and low clotting factors activity.
...
PMID:Thrombin generation assay as a possible tool for assessment of reduced activity of clotting factors induced by antiphospholipid antibodies and in-vitro evaluation of treatment options. 1973 Feb 46

Among the heterogeneous antiphospholipid antibodies, many studies suggest that those directed to beta2-glycoprotein I (beta2GPI) are the major pathogenic antibodies in antiphospholipid syndrome (APS). They have been shown to activate the coagulation pathway via several mechanisms, activate platelets via thrombin formation, and suppress fibrinolysis. Additionally, we propose another possible mechanism that involves certain chemokines and results in platelet activation. This hypothesis is based on the observations that anti-beta2GPI antibodies stimulated monocytes to secrete inflammatory cytokines such as IL-1beta and TNF-alpha, which in turn stimulated vascular endothelial cells to express chemokines such as CX3CL1 and CCL5. CX3CL1 increased the ability of normal platelets to adhere to collagen at a high shear rate, while CCL5 induced platelet aggregation. Expression of tissue factor, IL-1beta, and TNF-alpha by monocytes stimulated with anti-beta2GPI antibodies, as well as CX3CL1 and CCL5 by vascular endothelial cells stimulated with IL-1beta or TNF-alpha were all suppressed by the NF-kappaB-specific inhibitor DHMEQ. These results suggest that the NF-kappaB pathway may be a potential therapeutic target relating to both the coagulation pathway and platelet activity.
...
PMID:Possible involvement of chemokine-induced platelet activation in thrombophilic diathesis of antiphospholipid syndrome. 1975 42

Microparticles (MPs) are blebs released from cellular surfaces during activation/apoptosis. They are procoagulant, pro-inflammatory and could contribute to pathogenesis of deep venous thrombosis (DVT). This study compared the number, cellular origin and procoagulant activity of MPs on DVT patients in different clinical situations: at diagnosis (n = 9, 5F/4M; mean age = 41.11), 1-3 years after warfarin withdrawal (n = 10, 7F/3M; mean age = 32.90), associated to antiphospholipid syndrome (APS; n = 11, 9F/2M; mean age = 33.82), or asymptomatic carriers of Factor V Leiden (FVL; n = 7, 7F/0M; mean age = 34.00) vs healthy controls (CTR). The quantification and characterization were performed by flow cytometry using CD235, CD61, CD45, CD31, CD14, CD45, anti-TF and Annexin V. The plasmatic procoagulant activity was investigated by prothrombin fragment 1 + 2 (F1 + 2) determination. The MPs procoagulant activity was analyzed by D-dimer (DD2) and Thrombin Generation Test (TGT) on a healthy pool of plasmas adjusted or not by their number (10,000 MPs). The MPs percentages were not different between the groups, but absolute number was increased in patients 1-3 years after warfarin withdrawal vs CTR (P = 0.02). There was no difference of the MPs cellular origin comparing patients to controls. TGT using 10,000 MPs was lower on these patients (P = 0.01). APS patients showed a reduction of plasmatic procoagulant activity (P = 0.004), but they were under warfarin therapy. DD2 in the presence of MPs, independently of its number, was higher in patients with DVT at diagnosis (P < 0.0001). MPs of patients with spontaneous DVT at diagnosis can promote coagulation activation demonstrated by increased DD2. Even the increased MPs from patients 1-3 years after thrombotic episode generated lower amount of thrombin, they can have a protective effect by activation of Protein C anticoagulant pathway.
...
PMID:Microparticles in deep venous thrombosis, antiphospholipid syndrome and Factor V Leiden. 1981 Dec 20

Haemostasis is a delicate balance between procoagulant and anticoagulant processes. In the human body usually anticoagulant mechanisms prevail over procoagulant mechanisms, thereby preventing a prothrombotic state. The antiphospholipid syndrome is an example in which this balance is shifted to a more prothrombotic state due to the presence of antiphospholipid antibodies. One of the most extensively proposed pathogenic mechanisms within the antiphospholipid syndrome is the inhibition of protein C by antiphospholipid antibodies. Antiphospholipid antibodies have been described to have different actions on the protein C pathway, for example decreasing protein C and/or S plasma levels, inducing increased resistance against activated protein C and lowering thrombin levels (resulting in an impaired protein C activation). This review briefly discusses the actions of protein C in human body but mainly focuses on the effects of antiphospholipid antibodies on the protein C pathway that have been described in literature.
...
PMID:Antiphospholipid antibodies and the protein C pathway. 2035 76

The most common neurological manifestations of antiphospholipid syndrome (APS) in all age-groups include stroke and transient ischemic attacks due to arterial thromboses and cerebral ischemia. Antiphospholipid antibodies may cause additional non-criteria neurological impairments through vascular, neuroinflammatory and direct neuronal effects. Anti-aggregant or anticoagulant therapies are indicated for APS-related ischemic strokes. Treatment regimens for asymptomatic antibody-positive patients and those with refractory or recurrent disease remain controversial. There is scant literature on the epidemiology and therapy of neurological APS manifestations in pediatric patients. Assessments of modifiable cardiovascular and inherited thrombophilia risk factors are essential in patients with APS. There may be a role for novel neuroimaging modalities in quantifying APS-related microstructural brain damage. The clinical utility of statins, antimalarials, angiotensin-converting enzyme inhibitors, and thrombin inhibitors warrant further research.
...
PMID:Antiphospholipid syndrome and the brain in pediatric and adult patients. 2035 78

Antiphospholipid syndrome patients with recurrent miscarriage have an impairment in fibrinolysis demonstrated by prolonged clot lysis time (CLT) that cannot be attributed to differences in thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels. Patients with unexplained recurrent miscarriage have an impairment in fibrinolysis demonstrated by increased CLT, that can be at least partly explained by higher TAFI antigen levels.
...
PMID:Thrombin activatable fibrinolysis inhibitor and clot lysis time in women with recurrent miscarriage associated with the antiphospholipid syndrome. 2037 10

It is generally accepted that the major autoantigen for antiphospholipid antibodies (aPL) in the antiphospholipid syndrome (APS) is beta(2)-glycoprotein I (beta(2)GPI). However, a recent study has revealed that some aPL bind to certain conformational epitope(s) on beta(2)GPI shared by the homologous enzymatic domains of several serine proteases involved in hemostasis and fibrinolysis. Importantly, some serine protease-reactive aPL correspondingly hinder anticoagulant regulation and resolution of clots. These results extend several early findings of aPL binding to other coagulation factors and provide a new perspective about some aPL in terms of binding specificities and related functional properties in promoting thrombosis. Moreover, a recent immunological and pathological study of a panel of human IgG monoclonal aPL showed that aPL with strong binding to thrombin promote in vivo venous thrombosis and leukocyte adherence, suggesting that aPL reactivity with thrombin may be a good predictor for pathogenic potentials of aPL.
...
PMID:Antibodies to serine proteases in the antiphospholipid syndrome. 2042 33


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

---