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)

Severe microangiopathy resembling thrombotic thrombocytopenic purpura (TTP) has been reported as a complication of acute graft-versus-host disease (aGvHD) in patients receiving cyclosporin (CsA) prophylaxis following allogeneic BMT. In order to analyze the pathophysiological events involved in microangiopathy, a prospective study comparing release of von Willebrand Factor (vWF), t-PA and PAI, as well as TNF alpha and further coagulation parameters was performed in 32 patients. Endothelial damage as the central lesion was confirmed by the close association of vWF and t-PA:Antigen with severity of microangiopathy. t-PA activity, however, was neutralized by a simultaneous rise in PAI. Activation of coagulation in the course of microangiopathy was further confirmed by increased levels of DDimer (DDi), fibrinopeptide A (FPA), beta-thromboglobulin (beta TG) and platelet factor 4 (PF4). As clinical grades of microangiopathy, as well as the release of t-PA:Ag and PAI were correlated with systemic release of TNF alpha our data further support our hypothesis of cytokine induced endothelial damage in clinical complications following allogeneic BMT.
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PMID:Increased levels of tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor (PAI) correlate with tumor necrosis factor alpha (TNF alpha)-release in patients suffering from microangiopathy following allogeneic bone marrow transplantation (BMT). 141 3

Endothelial cell injury is thought to be one of the causative factors in thrombotic thrombocytopenic purpura (TTP). A novel index of endothelial injury, plasma thrombomodulin, was measured in 13 patients with acute TTP. The mean plasma concentration of thrombomodulin was elevated in patients with TTP (34.23 +/- 19.08 ng/ml) as compared with healthy subjects (16.99 +/- 2.63 ng/ml, P less than 0.001). Eight (61.5%) of 13 patients had high thrombomodulin values. Markedly elevated thrombomodulin levels were observed in TTP patients who had suffered from systemic lupus erythematosus, in whom plasma thrombomodulin was still elevated when they achieved remission. Five of these 13 patients with TTP had normal plasma levels of thrombomodulin. In addition, the plasma thrombomodulin concentrations were correlated well with von Willebrand factor antigen and tissue-type plasminogen activator antigen levels, both of which are released from stimulated or damaged endothelial cells. No difference was found in plasma thrombomodulin levels between patients who achieved remission and who did not. These findings suggest that the magnitude of the endothelial damage in TTP is variable among patients and that plasma thrombomodulin has limited clinical relevance to the severity of TTP.
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PMID:Circulating thrombomodulin in thrombotic thrombocytopenic purpura. 165 86

Prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin complexes (TAT), as well as other coagulation and fibrinolysis parameters, were studied in a series of 13 patients affected by thrombotic thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS). Fragment F1 + 2 was found to be increased in all patients at diagnosis (patients' range, 1.21-19.03 nmol/l; normal limits, 0.28-1.08 nmol/l), and remained also higher than normal after treatment with plasma exchange (patients' range, 1.5-4.01 nmol/l). Even though the analysis of fibrinolysis markers did not show a definite state of hypo or hyperfibrinolysis in the systemic circulation, enhanced circulating D-dimer levels (0.53-12.6 micrograms/ml, normal levels of 0.03-0.29 micrograms/ml) indicated that a certain grade of fibrin lysis was present at previously formed thrombi. Plasma PAI-1 activities either on admission (9.2-38.2 U/ml) and after plasma exchange therapy (2.6-38.6 U/ml) showed a behavior irrespective of t-PA:Ag changes, and post-plasmapheresis values remained high only in patients with fatal neurological outcome. Nevertheless, no correlations between clinical and laboratory data could be established useful for the TTP/HUS prognosis. We conclude that increased thrombin generation occurring in damaged areas is appropriately inhibited by antithrombin III in the systemic circulation, avoiding consumption coagulopathy to develop in uncomplicated patients. In addition, fibrinolysis data suggest that elevated PAI-1 may decisively favor the development of microvascular thrombi.
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PMID:Thrombin generation and fibrinolysis in the thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. 151 82

Molecular forms of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA), identified by gel filtration and specific immunoassays, were studied in plasma from subjects with normal and elevated PAI-1 levels before and after in vitro or in vivo addition of t-PA. In normal plasma, PAI-1 occurs in three molecular forms, a Mr greater than 700 KDa inactive form of heterogeneous composition, an active 450 KDa form containing PAI-1/vitronectin complex and an inactive peak at Mr 50 KDa containing free PAI-1. Stimulation of platelets results in a significant increase of the 50 KDA form and a slight increase of the 450 KDa form. Patients with increased PAI activity levels have an increase of both the 450 KDa and the 50 KDa forms, whereas patients with thrombotic thrombocytopenic purpura have an increased 50 KDa form. In normal plasma, collected in the presence or absence of D-Phe-Pro-Arg-CH2Cl, t-PA occurs primarily as a Mr greater than 700 KDa form containing t-PA/PAI-1 complex. Addition of high concentrations of t-PA (70 ng/ml) to plasma in vitro or t-PA injection in vivo, results in t-PA inhibitor complexes, including t-PA/ alpha 2 antiplasmin. It is concluded that in subjects with increased PAI-1 levels in plasma, PAI-1 may occur as high molecular weight complexes with vitronectin of which 450 KDa was the most important part and as a 50 KDa inactive form; t-PA circulates primarily in complex with inhibitors. Thus, some of the molecular interactions between PAI-1, t-PA and vitronectin, previously demonstrated in purified systems in vitro, also occur in plasma.
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PMID:Molecular forms of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) in human plasma. 190 71

The physiologic mechanisms that influence plasma levels of von Willebrand factor (vWF) are poorly understood but include race, blood group, age, pregnancy, exercise, and adrenergic and neurohumoral stimuli. Inherited abnormalities in von Willebrand's disease (vWD) are associated with a defect of the vWF gene on chromosome 12, but in some cases, coexistence of impaired response of plasminogen activator and telangiectasia suggests the presence of a regulatory defect or more extensive endothelial perturbation. Three broad types of vWD are recognized; in addition, a platelet-type vWD (pseudo-vWD) is due to an abnormal platelet receptor for vWF. The prevalence of vWD, which is difficult to determine because of variations in severity even within a kindred, is reportedly as high as 1%. In a survey of European patients, the prevalence of treated vWD varied from 4.5 to 24 per million. Preliminary results of an international survey of vWD indicate that about 3% of treated patients have seroconversion to human immunodeficiency virus, 50% of whom have symptoms. Inhibitor of vWF occurs in type III vWD after treatment and is associated with the presence of gene deletions. Acquired vWD may complicate lymphoproliferative and autoimmune disorders, and proteolytic degradation of vWF complicates myeloproliferative disorders. The level of vWF is increased during pregnancy and in vascular and other disorders; it may be involved in the pathogenesis of atherosclerosis. High-molecular-weight multimers of vWF and a cofactor are thought to promote the formation of microthrombi in thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. Thus, study of vWD has shed light on pathogenetic mechanisms in a wide range of disorders.
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PMID:von Willebrand factor: clinical features of inherited and acquired disorders. 207 62

Coagulo-fibrinolytic factors were studied in five patients suffering from thrombotic thrombocytopenic purpura (TTP). The change in coagulation factors in the acute stage was mild compared with that found in disseminated intravascular coagulation (DIC). We observed a slight increase of fibrin-fibrinogen degradation products (FDP) in the plasma of four patients during the acute stage of TTP, but the level of the D-dimer remained within normal variation and was extremely low compared with that in 27 samples from patients with DIC showing the same level of FDP. At the same time, both antigen levels of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were elevated in three of the four patients tested. Although a similar change was recognized in DIC patients' plasma, the elevation of PAI-1 in the acute stage of TTP was far higher than in overt DIC. The antigen levels of t-PA and PAI-1 were normal in remission, and a mild elevation of PAI-1 was detected in one of the three patients during the early stage of TTP relapse. Enzymography revealed the appearance of free t-PA and an increase of a substance with a 110 kD molecule, assumed to be a t-PA and PAI-1 complex, in TTP plasma in the acute stage, but the findings were normal for plasma from cases in remission and the early stage of relapse. Enzymography also showed a decrease of urokinase-type plasminogen activator (u-PA) only in the acute stage of TTP. These changes in the coagulo-fibrinolytic factors in the acute stage of TTP suggest that fibrinogenolysis might be induced by t-PA, released through vascular reaction at an uninvolved area of vascular lesions caused by platelet agglutinates, which would then release large amounts of PAI-1 inhibiting t-PA and u-PA activities at the occlusive lesion.
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PMID:Fibrinogenolysis in thrombotic thrombocytopenic purpura. 250 13

The profile of blood coagulation and fibrinolysis was studied in detail in eight patients with acute thrombotic thrombocytopenic purpura (TTP). In the majority of the patients, fibrinogen, factor XIII, antithrombin III, alpha 2-plasmin inhibitor, plasminogen, and alpha 2-macroglobulin were normal, whereas FDP, plasmin-alpha 2-plasmin inhibitor complex, and tissue-type plasminogen activator antigen were marginally or moderately elevated. Low fibronectin values were observed in four patients. Protein C and C4b-binding protein were nearly normal, whereas total protein S and free protein S were reduced in five and six patients, respectively. A positive correlation was found between total protein S and C4 and between free protein S and C3. von Willebrand factor antigen (vWf:Ag) and ristocetin cofactor (RCof) were either normal or elevated, but RCof/vWf:Ag ratio was decreased in seven patients. Crossed immunoelectrophoresis and sodium dodecyl sulfate (SDS)-agarose gel electrophoresis revealed that the large vWf multimers were either absent from or relatively decreased in all patients except one. In addition, one patient had unusually large vWf multimers, and a low-molecular-weight vWf fragment was apparently observed in three patients. These findings indicate that the intravascular generation of thrombin and plasmin was minimal in TTP and suggest that the alterations of the vWf molecule were caused not only by consumption through its participation in platelet thrombus formation but also by accelerated proteolysis. Low protein S values would be related to the immunological abnormalities underlying TTP.
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PMID:Coagulation studies in thrombotic thrombocytopenic purpura, with special reference to von Willebrand factor and protein S. 252 Dec 76

Much progress has recently been made in understanding the biochemistry and physiology of endogenous fibrinolysis. As a result, a better understanding of the mechanisms and clinical consequences of disordered fibrinolysis has emerged. Increased fibrinolytic activity is an uncommon but important cause of hemorrhagic disease. Congenital disorders of fibrinolysis which cause bleeding include increased plasma plasminogen activator activity and deficiency of alpha-2 antiplasmin. Acquired disorders associated with increased fibrinolytic activity and bleeding include liver cirrhosis, amyloidosis, acute promyelocytic leukemia, some solid tumors, and certain snake envenomation syndromes. Increased fibrinolysis is important to recognize because epsilon-aminocaproic acid (EACA) may be required to prevent or control bleeding. Diminished fibrinolytic activity has been associated with a variety of thrombotic disorders, but a direct cause-and-effect relationship has yet to be established. Congenital abnormalities of fibrinolysis associated with thrombosis include plasminogen deficiency, decreased endothelial generation of plasminogen activator activity, and certain abnormal fibrinogens. Thrombosis in these disorders is effectively managed with warfarin. Diminished fibrinolysis has also been reported in "idiopathic" venous thrombosis, oral contraceptive-induced and post-operative venous thrombosis, coronary artery disease, cerebrovascular disease, systemic lupus erythematosus, and thrombotic thrombocytopenic purpura, but the significance of abnormal fibrinolysis in these disorders is uncertain. Large, prospective studies of fibrinolytic variables as risk factors for vascular and thrombotic disease are needed to determine whether pharmacologic augmentation of impaired fibrinolysis could be useful in the prevention or treatment of these disorders.
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PMID:Clinical disorders of fibrinolysis: a critical review. 252 71

We examined red cell fragmentation syndrome (RCFS) induced by mitomycin C (MMC) (13 patients), by thrombotic thrombocytopenic purpura (TTP) (17 patients), and by disseminated intravascular coagulation (DIC) (15 patients). Plasma cytokine levels were increased in the TTP and DIC patients, but not in those whose RCFS was induced by MMC, suggesting that the activation of the immune system plays an important role in the pathogenesis of RCFS due to TTP and DIC but did not in RCFS due to MMC. Plasma thrombomodulin, tissue type plasminogen activator, and plasminogen activator inhibitor-I levels were increased in all RCFS patients, suggesting that RCFS, whether MMC induced, or due to TTP or DIC, might be associated with vascular endothelial cell injury. In TTP, von Willebrand factor (vWF) antigen and high molecular weight vWF multimer levels were reduced, possibly as a result of microthrombus consumption. The hemostatic data in this study showed that the TTP patients were in a hypercoagulable state without hyperfibrinolysis, and that DIC patients were in both a hypercoagulable and a hyperfibrinolytic state, whereas hemostatic abnormalities were slight in patients with MMC induced RCFS. These findings suggest that vascular endothelial cell injuries might be associated with RCFS, and that those injuries in MMC-induced RCFS might not be related to microthrombi or an activated immune system.
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PMID:Hemostatic abnormalities and increased vascular endothelial cell markers in patients with red cell fragmentation syndrome induced by mitomycin C. 748 97

We found that patients with thrombotic thrombocytopenic purpura (TTP) have significantly elevated plasma thrombin antithrombin III complex (TAT) and FDP-D-dimer levels, while the plasmin-alpha 2 plasmin inhibitor complex (PIC) level was only slightly increased. The tissue-type plasminogen activator (t-PA) level was increased, but it was well correlated with the plasminogen activator inhibitor-I (PAI-I) level. These findings suggest that hypercoagulable and hypofibrinolytic states coexist in these patients, in contrast to patients with disseminated intravascular coagulation, who exhibit coexisting hypercoagulable and hyperfibrinolytic states. Levels of vascular endothelial cell markers, such as PAI-I, thrombomodulin (TM), and t-PA, were increased at the onset of TTP, but the level of von Willebrand factor (vWF) antigen was not increased. The outcome in TTP patients was correlated with plasma t-PA and TM levels but not with TAT or PIC. These results suggest that vascular endothelial cell markers, such as TM and t-PA, are released from injured or stimulated endothelial cells, reflecting the degree of vascular endothelial damage, and that the main factor in the pathogenesis of TTP is vascular endothelial cell injury.
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PMID:Increased levels of vascular endothelial cell markers in thrombotic thrombocytopenic purpura. 826 13


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