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)

Junin virus, an arenaviridae, is the etiological agent of Argentine hemorrhagic fever. In addition to thrombocytopenia, patients present several alterations in both the blood coagulation and the fibrinolytic system, but diffuse intravascular coagulation could not be demonstrated. To investigate further the activation status of the two systems, levels of thrombin-antithrombin complexes (TAT), prothrombin fragment 1 + 2, protein C, total and free protein S, C4bBP, antithrombin III, t-PA, PAI-1 and D-dimer were measured. Fourteen patients with a confirmed diagnosis of Argentine hemorrhagic fever were included in the study, 2 were severe, 3 moderate and 9 mild clinical cases, but hemorrhages were slight throughout. Blood samples were collected for 6 consecutive days on admission and on remission. At admission TAT and F1 + 2 levels were increased in 13/14 patients, reaching 0.33 nM (0.06-0.87) and 2.16 nM (0.96-6.5), respectively. PC was low in 4 cases, fPS in 6 and tPS in 2, whereas C4bBP and ATIII values were within normal range. t-PA and D-dimer levels were high in 11/14 patients, reaching 20 ng/ml (2.7-106) and 1660 ng/ml (877-3780) respectively, while PAI-1 was considerably increased in the 2 severe cases and normal in the remainder. These results suggest low level though persistent process of blood coagulation and fibrinolysis activation in this viral hemorrhagic disease. We believe these abnormalities may lead to the well described bleeding manifestations in these patients.
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PMID:Early markers of blood coagulation and fibrinolysis activation in Argentine hemorrhagic fever. 766 17

The lysine analogues epsilon-aminocaproic acid (EACA) and trans-4-amino-methyl cyclohexane carboxylic acid (AMCA) are used to prevent excessive bleeding in patients with coagulopathies, such as hemophilia and thrombocytopenia, or in those who have received tissue plasminogen activator (t-PA). However, their relative efficacy in inhibiting lysis of clots that have been formed in the presence of exogenous t-PA or that have been formed and then exposed to exogenous t-PA has not been well characterized. The present study utilized blood from normal volunteers and 125I-fibrinogen in a dilute whole blood clot assay to determine the relative concentrations of lysine analogues required for inhibition of clot lysis induced by exogenous t-PA. AMCA (0.06 mM) and EACA (0.6 mM) were effective in prolonging clot lysis if (1) whole blood clots were formed and then exposed to a lysine analogue and exogenous t-PA or if (2) whole blood clots were formed in the presence of exogenous t-PA and a lysine analogue. However, their inhibitory effect was markedly reduced if clots were formed in the presence of t-PA and then exposed to either of the lysine analogues. The analogues did not inhibit the initial binding of t-PA to fibrin. They did inhibit binding of plasminogen to fibrin as well as the activation of plasminogen by t-PA in the absence of fibrin. The data suggest that lysine analogues, even at low concentrations, reduce the rate of t-PA induced whole blood clot lysis by several mechanisms.
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PMID:Inhibitory effects of lysine analogues on t-PA induced whole blood clot lysis. 807 94

A normally functioning hemostasis system is closely related to liver function. The liver parenchymal cells produce most of the factors and inhibitors of the clotting and fibrinolytic systems, and the RES of the liver greatly aids in the clearance of activation products. Hemostasis defects thus depend on the extent of liver damage. A wide spectrum of defects is found in patients with liver cirrhosis. Owing to impaired protein synthesis, most factors and inhibitors of the clotting and the fibrinolytic systems are markedly reduced. Additionally, abnormal vitamin K-dependent factor and fibrinogen molecules have been encountered. Most patients have hyperfibrinolysis that could be DIC in nature. Thrombocytopenia and thrombocytopathy are also found. Acute or chronic hepatocellular disease may display decreased vitamin K-dependent factor levels, especially factor VII and protein C, with other factors still being normal. If patients go into hepatic failure, the abnormalities resemble those found in liver cirrhosis. Vitamin K deficiency is associated with the production of poorly functioning vitamin K-dependent factors. All other hemostasis parameters are normal. Disturbances associated with liver surgeries again depend on the underlying liver problem. Peritoneovenous shunts (LeVeen) may lead to DIC; bleeding from partially resected liver surfaces is usually a mechanical problem. Severe bleeding is encountered with orthotopic liver transplantation. It is greatly influenced by the activation of the fibrinolytic system. This occurs during the anhepatic phase and during the reperfusion phase. The hyperfibrinolysis is mediated by an intense release of t-PA. Antifibrinolytic drugs, if used cautiously, have markedly reduced bleeding and thus reduced need for blood and blood product substitution.
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PMID:Coagulation defects in liver disease. 817 Feb 58

Infusion of the thrombolytic agents streptokinase (SK, 666 units/kg per minute for 60 minutes) and tissue-type plasminogen activator (t-PA, 10 micrograms/kg per minute for 15 minutes) in rabbits induced a significant hypotension and decrease in platelet count that were completely prevented by treatment with platelet-activating factor (PAF) receptor antagonists SDZ 63-675 and WEB 2170. PAF synthesis by vascular tissue was suggested by its extraction from blood-free heart and aorta of rabbits treated in vivo with SK or t-PA but not of control rabbits. In contrast, PAF was not detected in peripheral blood. Ex vivo studies on platelet aggregation response to ADP and PAF performed on platelet-rich plasma obtained before and after SK and t-PA infusion demonstrated an early hyperaggregable phase, abrogated by PAF receptor antagonists and followed by reduced sensitivity of platelets to PAF. The ED50 values for the aggregation of washed rabbit platelets induced by PAF but not thrombin were significantly increased at 60 and 120 minutes after SK and t-PA infusion, suggesting a specific desensitization of platelets to PAF. In contrast to PAF receptor antagonists, aspirin did not significantly modify the hypotension and the platelet hyperaggregability induced by SK or t-PA or the platelet hypoaggregability induced by t-PA. Thrombocytopenia induced by t-PA, but not by SK, was partially prevented by aspirin. The effect of SK, t-PA, and plasmin on the aggregation of washed platelets from untreated rabbits and from humans was also studied. Whereas SK and t-PA were inactive, plasmin induced dose-dependent platelet aggregation that was inhibited by platelet pretreatment with PAF receptor antagonists. In conclusion, the effect of PAF receptor antagonists observed in the present experimental model suggests that the hypotension and activation of platelets induced by SK and t-PA infusion are mediated by PAF.
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PMID:Role of platelet-activating factor in hypotension and platelet activation induced by infusion of thrombolytic agents in rabbits. 838 25

Primary hypercoagulable states are hereditary disorders that result in arterial and venous thromboses. The purpose of this report is to present three patients with hypercoagulable states, and offer current guidelines for diagnosis and treatment. Primary hypercoagulable disorders such as antithrombin III, protein C and protein S deficiencies, fibrinolytic disorders such as decreased plasminogen levels and plasminogen activator deficiency, and antiphospholipid syndromes such as anticariolipin antibody and lupus anticoagulants will be reviewed. We will emphasize clinical characteristics that should prompt evaluation for hypercoagulation, appropriate laboratory tests for hypercoagulable disorders, and treatment. Other secondary and recently investigated hypercoagulable disorders, including heparin-associated thrombocytopenia, homocystinemia, lipoprotein (a), plasminogen activator inhibitor, and factor V Leiden, will also be reviewed.
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PMID:The surgical implications of primary hypercoagulable states. 904 71

High-density lipoproteins (HDL) can bind and neutralize lipopolysaccharides (LPS) in vitro and in vivo. HDL can also affect fibrinolytic activity and can directly influence platelet function by reducing platelet aggregation. In this study, the effects of reconstituted HDL (rHDL) on LPS-induced coagulation, fibrinolysis and platelet activation in humans were investigated. In a double-blind, randomized, placebo-controlled, cross-over study, eight healthy male volunteers were injected with LPS (4 ng/kg) on two occasions, once in conjunction with rHDL (40 mg/kg, given as a 4 h infusion starting 3.5 h prior to LPS injection), and once in conjunction with placebo. rHDL significantly reduced LPS-induced activation of coagulation (plasma levels of prothrombin fragment F1 + 2) and fibrinolysis (plasma levels of tissue type plasminogen activator antigen, t-PA). No effect was observed on LPS-induced inhibition of the fibrinolytic pathway (PAI-1) or on the transient thrombocytopenia elicited by LPS. Furthermore, rHDL treatment significantly enhanced the inhibition of collagen-stimulated inhibition of platelet aggregation during endotoxemia, but had no such effect on arachidonate-stimulated platelet aggregation. rHDL treatment per se also reduced collagen-induced platelet aggregation. These results indicate that rHDL modifies the procoagulant state associated with endotoxemia.
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PMID:Differential effects of reconstituted high-density lipoprotein on coagulation, fibrinolysis and platelet activation during human endotoxemia. 915 86

Few studies of activated protein C resistance (APCR) and thromboembolism in childhood have been published. In the majority of childhood thromboses reported, the factor V Leiden mutation was associated with venous thromboses; however, one case report and three studies described arterial thromboembolism in infants and children due to the common mutation in the factor V gene. In one neonate purpura fulminans occurred, and heparin-induced thrombocytopenia type II was additionally documented. Two case reports and seven of nine studies reported associated clinical conditions together with inherited coagulation disorders. In three studies homozygous patients were mentioned. There are few studies describing the interaction between APCR and coagulation or the fibrinolytic system in symptomatic and nonsymptomatic infants. Compared with healthy brothers or sisters and a healthy age-matched control group, thrombin generation, D-dimer, PAI-1 activity, and t-PA antigen were found clearly elevated in children with APCR. In addition, infants and children with the Arg506-to-Gln mutation in the factor V gene showed significantly increased thrombomodulin concentrations along with normal protein C activities compared with relatives and healthy controls. No difference was recorded in these studies between heterozygous infants and children without vascular occlusion and patients who previously had suffered from thromboembolism. Until long-term data are available for the treatment of patients with APCR, such children should be treated in the same way as patients with deficiencies of protein C, protein S, or antithrombin.
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PMID:APC resistance in childhood thromboembolism: diagnosis and clinical aspects. 925 6

We have previously demonstrated a low-affinity (0.8 microM, non-covalent complex formation between high-molecular-mass kininogen (HK) and plasminogen (Plg) which prevented Plg interaction with glioma and endothelial cells. We have now extended our previous observations by exploring the potential complex formation between Plg and low-molecular-mass kininogen (LK) and between LK and HK with Plg cleaved with human neutrophil elastase (HNE). Plg cleavage by HNE (PlgHNE) yielded kringles 1-3, kringle 4 and mini-plasminogen. PlgHNE was subjected to SDS/PAGE under non-reducing conditions, followed by western blotting, and incubated with either 125I-HK or 125I-LK. Autoradiograms revealed that 125I-HK bound to miniplasminogen and to kringles 1-3 but not to kringle 4 and the presence of 10 mM 6-aminohexanoic acid (Ahx) disrupted only the interaction with kringles 1-3. In contrast, 125I-LK bound to miniplasminogen but not to kringles 1-3 or 4 and Ahx had no effect at all. The complex formation of either HK (0.67 microM) or LK (3 microM) with Plg (1.5 microM) did not affect its conversion to plasmin by tissue plasminogen activator (t-PA) (10 U/ml) in the presence of a tissue plasminogen stimulator (0.14 microM). However, the rate of conversion of plasminogen to plasmin by t-PA was affected when platelets were added to the reaction mixture. Since HK (0.83 microM) has been shown to inhibit plasmin-induced platelet aggregation, we investigated whether this inhibitory property is found within the heavy chain shared by HK and LK. We found that LK inhibited plasmin-induced platelet aggregation, but a 4-fold molar excess was required when compared to HK. Compared to plasmin, 3-5-fold molar excess of miniplasmin is required to induce platelet aggregation, indicating the important role of kringles 1-3 for plasmin interactions with these cells. These results indicate that HK and LK-mediated inhibition of plasmin-induced platelet aggregation is likely due to complex formation with kringle 5 without interfering with plasmin's active site. We found an additional interaction between HK and kringles 1-3 enhancing the inhibitory effect, presumably by interfering with plasmin's interaction with platelets. This HK and LK-associated modulation of plasmin-induced platelet aggregation may serve as a template to develop synthetic peptides as novel therapeutic agents to prevent some of the plasmin-associated thrombocytopenia seen during thrombolytic therapy.
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PMID:High-molecular-mass and low-molecular-mass kininogens block plasmin-induced platelet aggregation by forming a complex with kringle 5 of plasminogen/plasmin. 942 7

Various coagulation abnormalities were reported in HIV-infected patients. Cases of severe thrombocytopenia were first observed in contaminated homosexual males, as well as prolonged APTT due to the presence of lupus-like anticoagulant with a frequency in the range 8 to 70% of the studied patients. Even if lupus anticoagulant could be evidenced in asymptomatic patients, it frequently occurred during acute opportunistic infections such as Pneumocystis carinii. More recently, increased prevalence of protein S and heparin cofactor II deficiency, two physiological coagulation inhibitors were demonstrated in HIV-infected patients. The same applied for hypoalbuminemia-related fibrin polymerization defects which induced prolonged thrombin and reptilase clotting times. Abnormalities of the fibrinolytic system were also reported, such as increased levels of both tissue-type plasminogen activator and type 1 plasminogen activator inhibitor or decreased levels of histidine-rich glycoprotein. Even if the acute phase response could play a key-role, the pathogenesis of these abnormalities is not fully understood, so far. In addition, their clinical consequences have not been extensively investigated, but hemorrhage appeared to be uncommon. Moreover, D-dimer levels were found increased in HIV-infected patients, suggesting that HIV-infection might be associated with a so-called prethrombotic state, which could lead to clinical thrombosis in some HIV-infected patients (2%).
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PMID:[Hemostasis and human immunodeficiency virus (HIV) infection]. 975 40

Heparin-induced thrombocytopenia (HIT), a well recognized complication of heparin administration, is associated with thrombotic complications. An immunologic mechanism is believed to be responsible for the thrombocytopenia, but the cause of thrombosis is not fully understood. We report a histological and immunohistochemical study of thrombosed vessels in surgically removed ischemic tissues in patients with HIT complicated by gangrene of the lower limbs. Tissue sections were studied by: (1) hematoxylin and eosin staining and immunoperoxidase staining using a monoclonal antibody against platelet surface glycoprotein Ib(GPIb) for the identification of platelets, and (2) polyclonal antibodies against tissue-type plasminogen activator (tPA) and factor VIII for the identification of endothelial cells. We observed small arteries occluded by multiple small platelet thrombi surrounded by proliferative endothelial cells. In addition, depositions of IgG, IgA, and IgM were found in the occluded arteries. We postulate that the endothelial cell hyperplasia is caused by immunologic injury to endothelial cells as a result of immunoglobulin deposition, and by various mitogens derived from the activated platelets in the thrombi. Such endothelial cell hyperplasia is a major contributory factor, in addition to the microthrombi, of the occlusive vasculature in this disease.
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PMID:Endothelial cell hyperplasia contributes to thrombosis in heparin-induced thrombocytopenia. 1035 48


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