Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two short-lived vitamin K-dependent factors, factor VII and protein C, were measured by both functional and antigenic techniques in 3 hematological conditions known for their risk of hepatotoxicity: Following use of asparaginase and bisantrene, and patients at high risk of hepatic veno-occlusive disease after allogenic bone marrow transplantation for relapse of acute leukemia of accelerated phase of evoluted chronic myelogenic leukemia. In these 3 conditions functionally measured levels of protein C and factor VII, and antigenically measured levels of both these factors proved to be early markers of incipient hepatic involvement. These tests were easy to use routinely were reproducible, and proved to be predictive of veno-occlusive disease in grafted patients at the preconditioning stage. In the follow-up of bone marrow grafted patients plasma markers of endothelial function (von Willebrand's factor, tissue type plasminogen activator, and plasma activity of angiotensin converting enzyme) were significantly altered at the time of overdose with cyclosporin A, probably due to a drug-induced in vivo lesion of the endothelium. In the search for cytoprotective drugs for the prevention of veno-occlusive disease in bone marrow grafted patients prostaglandin E1 (PGE1) was given prior to and for at least 4 weeks after transplantation and proved to be effective by biological criteria (the level of protein C mainly). This deserves further study in a prospective clinical trial of the potential usefulness of PGE1 in preventing liver veno-occlusive disease in bone marrow grafted patients.
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PMID:[Hemostasis tests as markers of hepatic and endothelial toxicity in chemotherapy]. 329 Aug 34

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

In a recent prospective study of allogenic bone marrow transplantation we reported that decreases in factor VII and protein C were predictive markers for high risk of veno-occlusive disease (VOD). In order to determine the relative involvement of endothelial and hepatocyte injury in the genesis of VOD, 34 consecutive patients undergoing autologous bone marrow transplantation (BMT) were studied. Conditioning was performed by chemotherapy alone or associated with total body irradiation (TBI). Protein C and factor VII, the endothelial markers Von Willebrand factor (vWF and t-PA, fibrinogen and fibronectin were measured weekly before and after BMT. Protein C and factor VII were within the normal range before BMT, decreased significantly on day 7 to 73 and 64% respectively (p < .01) and then returned to normal values. Fibrinogen increased to 7 g/l (p < .001) on day 7 but then returned to normal levels. Fibronectin was abnormally high (p < .001) before BMT and decreased thereafter, while vWF increased (p < 0.001) for three consecutive weeks. t-PA was low (p < 0.001) before conditioning but increased thereafter. These results demonstrate the presence of endothelial lesions before BMT and acute hepatic and endothelial lesions after conditioning. Although VOD was never observed in our patients, this complication could well arise from preexisting vascular lesions due to previous chemotherapy and/or from acute hepatocytic injury, which could also be of endothelial origin, after conditioning.
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PMID:Changes in protein C, factor VII and endothelial markers after autologous bone marrow transplantation: possible implications in the pathogenesis of veno-occlusive disease. 833 49

The natural anticoagulants (antithrombin III, protein C, protein S), plasminogen and tissue plasminogen activator antigen (t-PA ag), were measured in 27 consecutive patients following allogeneic BMT. Thrombosis and veno-occlusive disease were not seen in this study. Changes in the levels of these proteins occurred mainly during acute GVHD. There were 14 patients who had no acute GVHD (group I) and 13 patients who had acute GVHD (group II). No changes in antithrombin III (ATIII), protein C, protein S and t-PA levels were found in group II before the appearance of acute GVHD when compared with group I. However, we noted a significant rise in protein S (p = 0.01), antithrombin III (p = 0.001) and t-PA ag (p = 0.0004) levels during acute GVHD. In contrast, protein C levels decreased early in GVHD (p = 0.005), and then increased progressively over the course of a month post-GVHD. No changes in plasminogen levels were observed. These results might reflect activation of and/or damage to endothelial cells during GVHD.
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PMID:Alterations in natural anticoagulant levels during allogeneic bone marrow transplantation: a prospective study in 27 patients. 848 78

We monitored 30 laboratory hemostatic parameters in an attempt to better comprehend alterations in coagulation and fibrinolysis in 10 patients with hematological malignancies subjected to autologous peripheral blood stem cell transplantation (APBSCT). These parameters were assessed before and just after high-dose conditioning chemotherapy, on days 1, 7, 14 and 28. Although, clinical manifestations associated with fibrino-coagulation disorders never occurred, including veno-occlusive disease, a statistically significant increase was seen in 7 of 30 parameters, compared to values seen before conditioning chemotherapy. These were subdivided into early and late phase parameters. The early phase parameters, which increased during the first day after the conditioning chemotherapy was given, then returned to baseline values, included protein C, plasma tissue factor and tissue-plasminogen activator. The late phase parameters, which increased over baseline values during days 7 to 28, included free-protein S, fibrinogen, plasmin-alpha2-plasmin inhibitor complex and soluble-thrombomodulin. The increase of early phase parameters, as produced by the liver and by endothelial cells, may reflect tissue damage by conditioning chemotherapy. Late phase parameters increased in parallel with C-reactive protein, which suggests a correlation with the degree of inflammation, such as the presence of infective disease during neutropenia. These subclinical alterations in coagulation and fibrinolysis which take on a biphasic pattern during the course of APBSCT should be kept in mind by the attending physicians during therapy.
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PMID:Subclinical alterations in coagulation and fibrinolysis in patients undergoing autologous peripheral blood stem cell transplantation. 951 13

Severe veno-occlusive disease (VOD), characterised by elevated serum bilirubin levels, is a known complication in the first 3 weeks after peripheral blood stem cell transplantation (PBSCT). Severe VOD is associated with capillary leakage and multiple organ dysfunction and leads to high mortality. We report a 17-year-old male, who developed VOD with capillary leakage (CL) after allogeneic PBSCT. The patient presented with a maximum serum bilirubin of 25.4 mg/dl, weight gain (10% of baseline weight), generalized edema, cardiovascular insufficiency, complement activation, jaundice and a decreased AT and protein C functional activity. After VOD and CL were diagnosed the patient was treated with recombinant human plasminogen activator (rt-PA) and C1 esterase-inhibitor concentrate (C1-INH-C). The clinical symptoms resolved and the patient's status stabilized. The patient was in an adequate clinical state 5 months after transplantation. We noted that the combined therapy with rt-PA and C1-INH-C in this high-risk situation led to a resolution of VOD with CL.
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PMID:Hepatic veno-occlusive disease with severe capillary leakage after peripheral stem cell transplantation: treatment with recombinant plasminogen activator and C1-esterase inhibitor concentrate. 961 90

Hepatic veno-occlusive disease (VOD) is the most common of the regimen-related toxicities accompanying stem cell transplantation (SCT). Despite aggressive therapies, including the combination of tissue plasminogen activator (t-PA) and heparin, severe VOD is almost uniformly fatal. Defibrotide (DF) is a polydeoxyribonucleotide with activity in several vascular disorders and, unlike t-PA and heparin, produces no systemic anticoagulant effects. Nineteen patients who developed severe VOD after SCT were treated with DF on a compassionate-use basis. Patients had clinically established VOD and met risk criteria predicting progression and fatality. At the initiation of DF, all 19 patients had evidence of multiorgan dysfunction; median bilirubin was 22.3 mg/dL, 12 patients had renal insufficiency (5 dialysis dependent), 14 required oxygen supplementation, and encephalopathy was present in 8 patients. Beginning a median of 6 days after diagnosis of VOD, DF was administered intravenously in doses ranging from 5 to 60 mg/kg/d for a planned minimum course of 14 days. In no case was DF discontinued for attributable toxicity. No severe hemorrhage related to DF administration was observed. Resolution of VOD (bilirubin <2 mg/dL with improvement in other symptoms and signs) was seen in 8 patients (42%). Six of 8 responders survived past day +100, contrasted with the 2% predicted survival reported in comparable patients. The observed response rate, survival to day +100, and absence of significant DF treatment-associated toxicity are compelling and warrant further evaluation.
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PMID:Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. 968 Mar 39

There are few reports about the occurrence of hepatic VOD after BMT for severe aplastic anemia (SAA). We prospectively studied 17 patients with SAA after allogeneic BMT for the occurrence and severity of VOD. Plasma levels of protein C, protein S, antithrombin III, vWF, t-PA and PAI-1 were determined before preparative chemotherapy, on the day of marrow infusion, and on days 7, 14 and 21. VOD occurred in seven patients (41.2%) at a median of day 1 (range, day -2 to 15). Five had mild, and two moderate VOD. Platelet transfusion requirements were higher in the patients with VOD. The plasma levels of natural anticoagulants such as protein C, free protein S and antithrombin III decreased significantly on day 0 from the baseline levels. Plasma levels of t-PA, PAI-1 and vWF increased significantly in the early post-transplant period compared to the baseline levels. The mean plasma levels of t-PA on day 7 (P = 0.016) and PAI-1 on days 0 and 7 (P = 0.016, 0.032) were higher in the patients with VOD. In summary, we observed hypercoagulability and a high incidence of VOD after allogeneic BMT for SAA. Levels of t-PA and PAI-1 were significantly higher in the patients with VOD after BMT.
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PMID:Veno-occlusive disease of the liver after allogeneic bone marrow transplantation for severe aplastic anemia. 1104 68

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

Defibrotide (DF), a polydeoxyribonucleotide with antithrombotic properties, has recently proven effective in patients with severe hepatic veno-occlusive disease (VOD), a life-threatening complication of high-dose chemo/radiotherapy regimens for stem cell transplantation. To understand the mechanism of its beneficial effect, we studied the impact of DF on the expression of tissue factor (TF) and fibrinolytic proteins (PAI-1 and t-PA) on endothelial cells. The in vitro response to DF of two types of human endothelial cells (ECs) of different origins, that is from macrovascular (HUVEC) and microvascular (HMEC-1 cell line) beds, was evaluated in the presence or absence of a proinflammatory stimulus (ie bacterial endotoxin, LPS). The results show that DF was able to significantly reduce the LPS-induced TF expression by HMEC-1, and less prominently by HUVEC. In addition, DF importantly influenced the fibrinolytic properties of both HMEC-1 and HUVEC. Specifically, it dose-dependently counteracted the LPS-induced increase in PAI-1 levels and decrease in t-PA activity expression. It also significantly incremented t-PA antigen in resting EC. Decreasing the procoagulant activity and increasing the fibrinolytic potential of EC favors an anticoagulant phenotype of the endothelium, which may protect from fibrin deposition and vascular occlusion.
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PMID:Defibrotide reduces procoagulant activity and increases fibrinolytic properties of endothelial cells. 1288 53


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