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

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

Severe thrombotic alterations, such as veno-occlusive disease of the liver, may occur in the early phase following high-dose chemoradiotherapy and BMT. In this study, performed in patients with hematological malignancies subjected to allogeneic (10 cases) and autologous (20 cases) BMT, we have monitored laboratory hemostatic parameters to better understand the pathogenetic mechanism of thrombosis and particularly of veno-occlusive disease. Prothrombin time, activated partial thromboplastin time, plasma fibrinogen, markers of hypercoagulability (thrombin-antithrombin complex and prothrombin fragment F1+2); natural anticoagulants (protein C, protein S and antithrombin) together with fibrinolytic parameters (plasminogen, alpha 2-antiplasmin, tissue-plasminogen activator, plasminogen activator inhibitor and D-dimer) were assessed before transplant, on day 0 and weekly for 1 month thereafter. A hypercoagulability state, not related to an impairment of the anticoagulant and fibrinolytic systems, was documented before and after autologous and allogeneic transplant. Two patients developed veno-occlusive disease: they did not show any difference from the other patients before transplant while they presented a decrease of the natural anticoagulants along with altered fibrinolytic parameters only at the clinical onset of veno-occlusive disease. In conclusion, in this study a state of marked hypercoagulability was documented in BMT patients and the hemostatic laboratory parameters evaluated were not able to predict the occurrence of the thrombotic complications.
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PMID:Hypercoagulability in patients undergoing autologous or allogeneic BMT for hematological malignancies. 824 85

Hepatic veno-occlusive disease (VOD) is a major complication after bone marrow transplantation (BMT). Its prediction, diagnosis and treatment remain unclear. Examination was made of changes in hemostatic parameters in patients with or without VOD after BMT. Twenty-seven children were studied following BMT. Eight of them developed VOD. Tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), thrombomodulin (TM), von Willebrand factor (vWF), factor VII, fibrinogen (FBG), FDP, D-dimer (D-D), plasminogen (PLG), thrombin-antithrombin III (TAT), alpha 2-plasmin inhibitor/plasmin complex (PIC), antithrombin III (AT-III), protein C, N-terminal propeptide for type III procollagen (P-III-P), were measured weekly from pre-BMT to day 28 after BMT. In VOD patients, t-PA and PAI-1 significantly increased (P < 0.05) and FBG significantly fell during the post-transplant period (P < 0.05). Significantly low AT-III and PLG were also noted before VOD (P < 0.05). There were no changes in other hemostatic parameters. t-PA, PAI-1 and FBG would thus appear useful markers for the diagnosis of VOD, and AT-III and PLG, predictive markers for VOD. The coagulation-fibrinolysis system following endothelial cell damage may contribute to the onset of VOD.
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PMID:Changes in hemostatic parameters in hepatic veno-occlusive disease following bone marrow transplantation. 915 66

Alterations of the coagulation system that may lead to coagulation activation and thrombosis are common sequelae after allogeneic bone marrow transplantation (BMT). We performed prophylactic anticoagulation by low dose heparin (50 units/kg/day) and substitution of antithrombin (AT) concentrate to sustain plasma levels above 90% of pooled normal human plasma. Conventional tests for plasmatic hemostasis and substitution of AT concentrate were recorded for 50 patients until day +50 after BMT. Incidence of sepsis, graft-versus-host-disease [GVHD], capillary leakage syndrome [CLS] and veno-occlusive disease of the liver [VOD] were investigated and compared with the results of patients without any of these complications. Patients with proven sepsis (n = 6) showed decreased activity of AT, and a prolonged activated partial thromboplastin time (aPTT), while fibrinogen levels were slightly increased. This constellation was interpreted as mild to moderate activation of the humoral coagulation cascade. Patients with VOD (n = 10) showed an increased consumption of AT concentrate at day +7 followed by a decrease of prothrombin time, of clotting factors II and VII, and a prolongation of aPTT at days +11 to +18 after BMT. This suggests, that activation of coagulation precedes decreased synthesis of coagulation factors. Patients with CLS (n = 15) or GVHD > or = II degree (n = 14) showed no major alterations of coagulation parameters. In conclusion, after BMT, two types of coagulopathy were observed: (i) an activation of the coagulation cascade (i.e. sepsis and VOD) which was followed by (ii) a diminished synthesis of coagulation factors (VOD). In order to perform timely therapeutic interventions in the coagulation system in patients with sepsis and/or VOD it appears to be important to assess the clinical value of parameters for early detection of coagulation activation as thrombin-AT complexes, D-dimers and F1 + 2 fragments.
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PMID:Humoral coagulation and early complications after allogeneic bone marrow transplantation. 929 52

Hepatic veno-occlusive disease (VOD) of the liver is a common complication following high-dose cytotoxic therapy for bone marrow transplantation (BMT). The major pathological changes are seen in centrilobular (zone 3) hepatocytes and adjacent endothelium. Glutathione (GSH) becomes depleted following chemotherapy and experimental evidence suggests reduced levels predispose to centrilobular hepatocyte and endothelial cell injury. Animal studies have shown that glutamine infusions can maintain GSH levels and protect against free radical injury. We have prospectively studied the effect of glutamine supplementation during BMT. Thirty-four patients undergoing BMT were randomised to receive either glycl-L-glutamine (n = 18) or an isonitrogenous mixture of non-essential amino acids (n = 16). Glutamine was shown to significantly preserve protein C (days +4 and +7, P < 0.05) and albumin levels (days 0 and +4, P < 0.02). Markers of thrombin and plasmin generation (thrombin-antithrombin, prothrombin fragment F1+2 and plasmin-antiplasmin levels) were not significantly changed between the two groups. These findings suggest that glutamine preserves hepatic function but does not alter thrombin or plasmin generation during BMT. Previous studies have shown reductions in protein C, albumin, factor X and factor VII levels post BMT. Falling protein C levels have been shown to be predictive of severe VOD. These data suggest a role for glutamine in the protection of hepatic function following BMT.
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PMID:Parenteral glutamine protects hepatic function during bone marrow transplantation. 972 Jul 43

The objective of the present study was to analyze whether veno-occlusive disease (VOD) is based on specific findings or whether this syndrome is the exacerbation of changes in hemostatic parameters that develop following hematopoietic stem cell transplantation (HSCT). 40 patients undergoing HSCT were enrolled (6 allogeneic bone marrow transplantation and 34 peripheral stem cell rescue-2 allogeneic, 32 autologous). Measurements of hemostatic parameters (endothelial, hypercoagulability and fibrinolytic markers) were obtained prior to chemotherapy and weekly thereafter for 3 weeks. The incidence of VOD was 15%. HSCT showed a state of moderate hypercoagulability (increase of thrombin-antithrombin complex and fibrinogen, and decrease of Factor VII, Protein C, and antithrombin-III), probably as a consequence of marked endothelial damage (increase of von Willebrand Factor and tissue plasminogen activator). All these alterations create a potentially prothrombotic state, more pronounced in VOD. The decreasing incidence of VOD and the moderate disease in all patients suggest that increasing improvements in transplant strategies have reduced the risk and severity of a syndrome that at the beginning of the transplantation era was a leading cause of morbidity/mortality.
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PMID:Is veno-occlusive disease a specific syndrome or the exacerbation of physiopathologic hemostatic changes in hematopoietic stem cell transplantation (HSCT)? 1097 71

Hepatic veno-occlusive disease (VOD) is a major complication after hematopoietic stem cell transplantation (HSCT). Aetiological determinants, diagnosis and treatment remain unclear. Changes in coagulation-fibrinolysis parameters and N-terminal propeptide for type III procollagen (P-III-P) have been studied in patients with or without VOD after HSCT. We prospectively measured protein C activity, tissue plasminogen activator (t-PA), antithrombin III (AT-III), plasminogen activity (PLG), thrombin-antithrombin III (TAT), alpha2-plasmin inhibitor (alpha2-PI),fibrinogen (Fbg) and P-III-P in 44 consecutive adult patients undergoing allogeneic HSCT. Each parameter was determined before conditioning, on day 0 of HSCT and weekly for 5 weeks. Five of the 44 patients developed VOD at a median post HSCT of day 3 (range, day 3 to 12). On repeated analysis of variance (ANOVA), there were significant differences between patients with and without VOD in P-III-P (P < 0.0001), protein C (P < 0.0001), t-PA (P < 0.0001), PLG (P < 0.0001), AT-III(P < 0.0001), Fbg (P < 0.0001), alpha2-PI (P = 0.0002). Levels of P-III-P were significantly higher in patients with VOD than without VOD, before preparative chemotherapy (P < 0.005) and on days 0 and 7 (P < 0.001). On day 0, levels of t-PA were significantly higher in patients with VOD than without VOD (P < 0.05). On day 7, levels of protein C were significantly lower in patients with VOD than without VOD (P < 0.01). On day 0, there were trends of differences (P = 0.0515) between patients with and without VOD in the levels of protein C. These results suggest P-III-P, t-PA and protein C are predictive markers for VOD after HSCT in adults. Moreover, the serum P-III-P level before start of conditioning might indicate patients at risk for developing VOD.
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PMID:Predictive markers for hepatic veno-occlusive disease after hematopoietic stem cell transplantation in adults: a prospective single center study. 1108 89

Hemostatic parameters were examined in 39 patients who underwent allogeneic bone marrow transplantation (BMT). Twenty-six patients survived and 13 patients died within 6 months after BMT. The main causes of death were acute graft-versus-host disease (GVHD: n=6), veno-occlusive disease (VOD: n=2), and thrombotic microangiopathy (TMA: n=2). Plasma levels of D-dimer and thrombomodulin (TM) were significantly elevated in the non-survivor group. Plasma levels of soluble fibrin (SF) and Fas were significantly elevated in the non-survivor group at 1 to 4 weeks after BMT. Plasma levels of thrombin-antithrombin complex (TAT), D-dimer, and tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPA-PAI-1 complex) were significantly elevated in patients with complications after BMT. Plasma levels of TAT, D-dimer, and tPA-PAI-1 complex were significantly elevated in patients with GVHD. These results suggest that abnormalities of hemostatic parameters might predict poor outcomes or complications in patients with BMT.
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PMID:Hemostatic abnormalities and changes following bone marrow transplantation. 1549 20

Plasminogen activator inhibitor 1 is known to be elevated in patients with hepatic VOD after intensive chemotherapy. To re-establish endogenous fibrinolysis and to inhibit thrombin formation, we used non-APC (zymogen) to normalize PAI-1 levels. As a consequence of thrombin formation inhibition and the consecutive inhibition of the coagulation cascade, this treatment is expected to reduce the elevated D-dimer level. Six pediatric stem cell recipients with moderate or severe VOD after busulfan or total body irradiation conditioning regimen are reported here who were therapy-refractory to defibrotide or rt-PA therapy. All patients had low levels of PC activity (16-39%). The administration of PC (60-240 IU/kg) led to a rapid and sustained rise in PC activity (target level >80%) with near normalization of prothrombin and partial thromboplastin time in all patients. Elevated PAI-1 levels declined. Five of the six patients showed a good clinical response with prompt resolution of clinical, sonographic, and laboratory signs of hepatic blood flow obstruction, while one patient with severe VOD, as well as concomitant liver GVHD and CMV disease, had a slow but detectable response to PC therapy. All patients survived.
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PMID:Favorable response of pediatric stem cell recipients to human protein C concentrate substitution for veno-occlusive disease. 1723 23

Fibrinolytic activity has been shown to be reduced in many vascular diseases, including hepatic veno-occlusive disease after stem cell transplantation, a microangiopathy characterized by sinusoidal endothelial cell injury. Defibrotide is a polydisperse oligonucleotide with antithrombotic, profibrinolytic, anti-ischemic, and antiadhesive properties. Numerous clinical studies have shown promising activity of defibrotide in the treatment and prevention of veno-occlusive disease, with minimal toxicity. In corollary laboratory studies, defibrotide has been shown to decrease plasminogen activator inhibitor-1, increase tissue plasminogen activator levels, and increase overall plasma fibrinolytic activity in patients. Plasmin, a potent and nonspecific serine protease, plays a pivotal role in fibrinolysis by virtue of its ability to effectively degrade fibrin clots. In this study, defibrotide increases the activity of plasmin in hydrolyzing its substrate in a dose-dependent and length-dependent manner. Similar concentration-dependent effects of defibrotide were observed when plasmin was generated by tissue plasminogen activator or urokinase activation of plasminogen. In contrast, defibrotide had no direct effect on the activation of plasminogen to plasmin. Defibrotide was also able to enhance the activity of plasmin in degrading fibrin clot formed from fibrinogen, plasminogen, and thrombin. This effect was also concentration-dependent and directly correlated with the enzymatic activity of plasmin. This study therefore demonstrates that defibrotide is capable of enhancing the activity of plasmin and so contributes to its fibrinolytic activity. Taken together, these results support the effect of defibrotide in restoring the fibrinolytic vascular phenotype, in microangiopathic conditions such as veno-occlusive disease.
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PMID:The fibrinolytic mechanism of defibrotide: effect of defibrotide on plasmin activity. 1980 7

Prediction of veno-occlusive disease (VOD), its precise diagnosis, and treatment have been the subject of various studies, but still remain unclear. Our goal was to investigate the levels of activated coagulation and fibrinolysis markers and natural anticoagulants in pediatric patients with VOD after hematopoietic stem cell transplantation (HSCT). We investigated 47 pediatric patients: 20 with neuroblastoma, 17 with leukemias, and 10 with lymphomas and measured the values of antithrombin (AT), protein C (PC), fibrinogen (FI), thrombin AT complex, prothrombin fragments 1+2 (F1+2), and D-dimer from day -7 to day +30 post-HSCT. Patients were monitored for the occurrence of VOD, and it occurred in 10 patients at a median post-HSCT day of 17.5 (range: 2 to 28 d). In the VOD group, at baseline the levels of FI were significantly lower, and on days +7 and +14 a relevant difference existed in F1+2 levels. The levels of PC were significantly lower on day +14. Logistic multivariate regression analysis between the groups showed significantly different D-dimer levels on day +14. On day +30, the levels of PC, AT, and F1+2 were different between these 2 groups of patients. The levels of D-dimer and F1+2 were increased, and PC and FI decreased before the clinical onset of VOD. The parameter differences may have a predictive value in VOD onset, which makes them candidates to be routinely monitored in patients after HSCT.
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PMID:Veno-occlusive disease in pediatric patients after hematopoietic stem cell transplantation: relevance of activated coagulation and fibrinolysis markers and natural anticoagulants. 2133 67


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