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)

Factor XI (FXI) may be activated in a purified system by thrombin and by autoactivation in the presence of negatively charged substances such as dextran sulfate or sulfatides. The current studies were performed to determine if these processes occur during the coagulation of plasma. FXII--deficient plasma was supplemented with 125I-FXI and clot formation was induced with tissue factor and/or sulfatides. Cleavage of FXI was studied by standard polyacrylamide gel electrophoresis and autoradiography. Activated FXI (FXIa) was detected after 20 minutes of incubation with sulfatides alone and this process was markedly accelerated by the addition of tissue factor (TF). The enhancing effect of TF was blocked by hirudin, which indicated thrombin involvement in FXI activation. The contribution of FXIa to FIX activation in this system was studied using a 3H-FIX activation peptide release assay. Sulfatides increased FIX activation about twofold in plasma induced to clot with TF but had no effect if the plasma was immunodepleted of FXI. FIX activation was also increased in plasma induced to clot with FXa if sulfatides were present. The enhanced generation of FIXa was dependent on FXI and was blocked by hirudin. Some activation was seen in the reactions with sulfatides and hirudin and is likely solely caused by FXI autoactivation. The data indicate that during the coagulation of plasma in the presence of sulfatides, FXI is activated by a mechanism that is thrombin dependent and does not require FXII.
...
PMID:Factor XII-independent activation of factor XI in plasma: effects of sulfatides on tissue factor-induced coagulation. 833 46

The activation of factor XI initiates the intrinsic coagulation pathway. Until recently it was believed that the main activator of factor XI is factor XIIa in conjunction with the cofactor high molecular weight kininogen on a negatively charged surface. Two recent reports have presented evidence that in a purified system factor XI is activatable by thrombin together with the soluble polyanion dextran sulfate. To assess the physiological relevance of these findings we studied the activation of factor XI in normal and factor XII-deficient plasma. We used either kaolin/cephalin or dextran sulfate as a surface for the intrinsic coagulation pathway, tissue factor to generate thrombin via the extrinsic pathway, or the addition of alpha-thrombin directly. 125I-factor XI, added to factor XI-deficient plasma at physiologic concentrations (35 nmol/L), is rapidly cleaved on incubation with kaolin. The kinetics appear to be exponential with half the maximum cleavage at 5 minutes. Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided. Tissue factor (1:500) added to plasma did not induce cleavage of factor XI during a 90-minute incubation, although fibrin formation within 30 seconds indicated that thrombin was generated via the extrinsic pathway. Adding 1 mumol/L alpha-thrombin (equivalent to 50% prothrombin activation) directly to factor XII deficient or normal plasma (with or without kaolin/cephalin/Ca2+ or dextran sulfate) led to instantaneous fibrinogen cleavage, but again no cleavage of factor XI was observable. We conclude that in plasma surroundings factor XI is not activated by thrombin, and that proposals of thrombin initiation of the intrinsic coagulation cascade are not supportable.
...
PMID:Activation of factor XI in plasma is dependent on factor XII. 850 85

Bovine thrombin-induced factor V deficiency was though to be a very rare acquired coagulopathy, with only three documented cases. We report a series of nine patients seen during a period of 32 months; these patients had normal preoperative coagulation profiles, and this unique coagulopathy developed 1 to 2 weeks after cardiovascular operations. The coagulopathy was characterized by a markedly elevated prothrombin time (40.9 +/- 5.8 seconds), an elevated activated partial thromboplastin time (96.3 +/- 12.2 seconds), a study positive for lupus anticoagulation (9/9), and markedly decreased levels of factor V (0.09 +/- 0.03 U/ml) and factor XI (0.04 +/- 0.02 U/ml), respectively. All patients had been exposed to commercially available bovine thrombin during prior cardiovascular or vascular operations and received a second bovine thrombin challenge during the latest procedure. Coagulopathic bleeding developed in four of the nine patients. Bleeding was unrelated to absolute fall in factor V level, but cessation of hemorrhage appeared to correlate with improvement in factor V level. Treatment with vitamin K, fresh frozen plasma, and platelet infusion were all unsuccessful in altering prothrombin time or factor V levels. Intravenous gamma globulin was used in three patients, two of whom were bleeding. All three patients showed a transient increase in factor V levels. Bleeding stopped in one of the two patients; the other continued to bleed and subsequently died. The third patient was treated prophylactically to increase factor V levels in preparation for flap reconstruction of his sternum. His factor V level increased from 0.26 to 0.49 U/ml, and he underwent the procedure without incident. Bovine thrombin-induced factor V deficiency may have been previously unrecognized. This deficiency should be suspected in patients who have undergone redo cardiovascular operations and in whom marked elevations in their prothrombin time occur 7 to 10 days after exposure to bovine thrombin. The resulting coagulopathy, although usually self-limited, has the potential to produce devastating bleeding complications. Intravenous gamma globulin (1 gm/kg during each of 2 days) has been used to increase factor V levels transiently but its role in therapy of this coagulopathy requires further investigation.
...
PMID:Redo cardiac surgery: late bleeding complications from topical thrombin-induced factor V deficiency. 842 48

The recent observation that coagulation factor XI is activated by the serine protease thrombin indicates that factor XI may play a role in sustaining the haemostatic process by activating factor IX, after coagulation has been initiated by the factor VIIa/tissue factor catalytic complex. Since negatively charged substances, such as dextran sulphate or sulphatides, have been shown to enhance the activation of factor XI by thrombin, we investigated the effect of glycosaminoglycans on this reaction. A 60-fold enhancement in activation was observed in the presence of heparin and more modest increases were seen with dermatan sulphate and chondroitin sulphates A and C. The increase in activation was greater if Zn2+ was included in the reactions with glycosaminoglycans. The combination of heparin or chondroitin sulphate C and Zn2+ supported factor XI autoactivation in addition to factor XI activation by thrombin; an effect noted previously only with dextran sulphate.
...
PMID:Effects of glycosaminoglycans on factor XI activation by thrombin. 845 45

Various hemostatic abnormalities have been reported and excess activation of coagulation factors, such as prothrombin, factor VII, factor IX, and factor XI, have been detected in thrombotic diseases states by various assay systems. We recently developed the enzyme-linked differential immunoassay for activated factor XI-alpha 1 antitrypsin complex (FXIa-alpha 1 AT) and applied it with other assays for activated factors such as thrombin-antithrombin III complex (TAT) to detect the hypercoagulable state in clinical samples. In patients with DIC, the FXIa-alpha 1 AT level in plasma increased before onset of DIC. In patients with non-insulin-dependent diabetes mellitus, FXIa-alpha 1AT and TAT levels were increased in the patient plasma. FXIa-alpha 1AT was related to the severity of urinary albumin excretion, whereas TAT was not. Plasma FXIa-alpha 1AT levels were significantly increased in patients with angiographically proven coronary artery disease, and showed a positive correlation with TAT, fibrinogen, and Lp(a). Evaluation of activated coagulation factor provides useful information on the diagnosis of thrombotic disease.
...
PMID:[Activated coagulation factors in various thrombotic diseases]. 856 28

The variable bleeding tendency associated with a genetic deficiency of factor XI (FXI) and the lack of bleeding disorders in individuals with a genetic deficiency of factor XII (FXII) suggest an alternative mechanism for FXI activation in vivo. Recently, thrombin has been shown to activate FXI. However, in plasma this activation has been shown to occur only with exogenous FXI and a non-physiological cofactor (sulphatides), and the occurrence of this reaction in a plasma environment has been questioned. Using recently developed sensitive assays for FXIa-inhibitor complexes we found thrombin-mediated and FXII-dependent activation of endogenous FXI in plasma in the presence of heparan sulphate, heparin, dermatan sulphate or dextran sulphate. Using heparan sulphate, which is present in the human vascular system, activation of about 1-2% of plasma FXI was observed, however, only after addition of very high amounts (500 nmol/l) of human alpha-thrombin to FXII-deficient plasma (at a 1 to 4 final dilution). We conclude that endogenous FXI in plasma can be activated by thrombin in the presence of various glycosaminoglycans, including the physiological compounds heparan sulphate and dermatan sulphate, but only at very high concentrations of thrombin, corresponding to 100% prothrombin activation in undiluted plasma.
...
PMID:Thrombin-mediated activation of endogenous factor XI in plasma in the presence of physiological glycosaminoglycans occurs only with high concentrations of thrombin. 860 18

Previously we defined a binding site for high molecular weight kininogen (HK) in the A1 domain of factor XI (FXI). Since thrombin can activate FXI and HK inhibits the activation of FXI by thrombin, we have identified a thrombin binding site in FXI. Both the recombinant A1 domain (Glu1-Ser90) and a synthetic peptide (Phe56-Ser86) containing the HK binding site inhibited FXI activation by thrombin. Both a monoclonal antibody, 5F7, recognizing the A1 domain, and the rA1 domain were shown to be competitive inhibitors of thrombin-catalyzed FXI activation. The peptides Ala45-Arg54 and Val59-Arg70 acted synergistically to inhibit FXI activation by thrombin. Mutant rA1 domain constructs (Val64 --> Ala and Ile77 --> Ala), which do not inhibit FXI binding to HK, retain full capacity to inhibit FXI activation by thrombin. The peptide Ala45-Arg54 inhibited thrombin-catalyzed FXI activation, whereas it had no effect on FXI binding to HK. In contrast, the peptide Asn72-Leu83 (which inhibited FXI binding to HK) did not inhibit FXI activation by thrombin. Thus, a thrombin binding site exists in the A1 domain of FXI spanning residues Ala45-Arg70 that is contiguous with but separate and distinct from the HK binding site. These sites may regulate which ligand is bound to FXI and through which pathway FXI is activated.
...
PMID:A binding site for thrombin in the apple 1 domain of factor XI. 863 76

Coagulation factor XI is a glycoprotein of the contact factor system. Its deficiency is associated with a highly variable bleeding tendency, thus a role in relation to hemostasis appears to exist. However, the importance of factor XI for stimulating intrinsic coagulation in vivo has not yet been determined. To study the procoagulant effects of human factor XIa in vivo, we infused the purified enzyme into normal chimpanzees (100 micrograms) in the absence or presence of the thrombin inhibitor rec-hirudin (1.0 mg/kg loading dose plus 0.3 mg/kg body wt continuous infusion). Factor XIa elicited an immediate activation of factors IX, X, and prothrombin, as measured by their respective activation fragments. However, whereas the activation of factors IX and X was immediate and shortlasting, (peak increments of 6- and 1.4-fold of baseline at 5 minutes after injection), the conversion of prothrombin gradually increased, reaching a summit of 6-fold baseline values after 60 min, and remaining elevated during the course of the experiments. Thrombin-antithrombin complexes also remained elevated during the study period. In the presence of hirudin, the initial activation of factors IX, X, and prothrombin was unchanged, however the further increment in prothrombin fragment F1 + 2 was markedly inhibited. These results demonstrate that factor XIa is a potential agonist of the intrinsic cascade in vivo, which activity is enhanced in the presence of thrombin.
...
PMID:Factor XIa induced activation of the intrinsic cascade in vivo. 870 5

That factor XI has a role in normal blood coagulation is evidenced by the fact that patients with deficiency are prone to excessive bleeding after haemostatic challenge. The role of factor XI in physiological processes has become clearer since the discovery that it is activated by thrombin; this fact has contributed to a revised model of blood coagulation. Factor XI deficiency is particularly common in Ashkenazi Jews. Bleeding is typically provoked by surgery in areas of increased fibrinolysis, and is not restricted to individuals with severe deficiency. The bleeding tendency is variable and the reasons for this are not fully understood, although in severe deficiency there is some correlation between phenotype and genotype. The factor XI gene is 23 kb long, and two mutations are responsible for most factor XI deficiency in the Ashkenazi population. A total of 13 mutations have thus far been published. Factor XI deficient patients may need specific therapy to cover surgery and dental extractions. Although a factor XI concentrate is available there have been recent reports of coagulation activation and thrombosis indicating that it should be used cautiously. Fresh frozen plasma may be an acceptable alternative in some situations.
...
PMID:Factor XI deficiency. 880 May 10

Fibrin-bound thrombin is protected from inactivation by antithrombin III, while its coagulant potential is retained. In the presence of heparin, ternary complexes between thrombin, fibrin and heparin are formed. In these complexes the coagulant activity of thrombin is retained, whereas the anticoagulant activity of fibrin-bound heparin is neutralized. The limited effectiveness of heparin in the prevention of both venous thrombosis and coronary reocclusion is probably related to the protective effect of fibrin on the inactivation of thrombin by anti-thrombin III. Recently, it has been shown that factor XI can be activated by thrombin, resulting in the generation of additional thrombin via the intrinsic pathway. This additional thrombin is capable of stabilizing the clot by protecting it from fibrinolysis. We studied the effect of heparin on the activation of factor XI by fibrin-bound thrombin. First, we used fibrin monomers coupled to Sepharose to which thrombin and unfractionated heparin (UFH) were bound. Factor XI activation by thrombin was the same in the presence of fibrin-Sepharose or control-Sepharose. The addition of heparin (0.1 U/ml) resulted in a 91 and 15-fold enhancement in the presence of control-Sepharose and fibrin-Sepharose, respectively. Next, we added complexes of heparin, thrombin and fibrin monomer to factor XII and XI double-deficient plasma in the presence or absence of a reconstituting amount of factor XI. In the presence of factor XI, additional fibrin formation was observed indicating that factor XI activation by thrombin in complex with fibrin and heparin can take place in plasma. We then studied the effect of other heparin-like anticoagulants on the thrombin-mediated factor XI activation. UFH enhanced thrombin-mediated factor XI activation 68-fold, LMWH (low molecular weight heparin, Fragmin) 12-fold, danaparoid (Orgaran) 3-fold, while the pentasaccharide ORG 31540 did not result in an enhancement. Binding studies of these anticoagulants to fibrin-Sepharose showed that LMWH bound with approximately the same affinity as UFH, while danaparoid and the pentasaccharide did not bind to fibrin. We conclude that fibrin-bound thrombin is capable of factor XI activation. Furthermore, heparin bound in a complex with fibrin can act as a cofactor for this activation. This factor XI activation capacity may play a role in the limited effectiveness of heparin. Provided that thrombin-mediated factor XI activation plays an important role in vivo, danaparoid and especially the pentasaccharide may be better anticoagulants than UFH and LMWH.
...
PMID:Effect of heparin on the activation of factor XI by fibrin-bound thrombin. 888 69


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

---