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)

A 29-year-old man with congenital protein C deficiency and acute myocardial infarction is reported. Four hours after the onset of chest pain, he was treated intravenously with tissue-type plasminogen activator. Subsequent coronary angiography revealed only slight stenosis of the left anterior descending coronary artery without any atherosclerosis. The propositus, his brother, and his mother, showed low levels of both protein C activity and antigen, while plasma thrombomodulin levels were normal. His grandfather had died from acute myocardial infarction at 38 years of age. We investigated several other risk factors for arterial thrombosis, including factor VII, fibrinogen, heparin cofactor II, lipoprotein (a), and anticardiolipin antibodies. No other haemostatic abnormalities apart from factor VII hyperactivity were detected in this family. To study the effects of protein C and factor VII on procoagulant activity, prothrombin time was measured after the addition of activated protein C and factor VII to protein C-deficient plasma. The prothrombin time ratio decreased along with an increase in the factor VII level. It also decreased with a decrease in the activated protein C level. These findings indicated that the procoagulant activity of factor VII was enhanced by low protein C levels, suggesting that concomitant factor VII hyperactivity may cause acute myocardial infarction in patients with protein C deficiency.
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PMID:Congenital protein C deficiency and myocardial infarction:concomitant factor VII hyperactivity may play a role in the onset of arterial thrombosis. 144 May 17

This article has summarized known congenital and acquired alterations of hemostasis leading to thrombosis. Decreases in coagulation inhibitors, including antithrombin III, heparin cofactor II, and protein C and protein S, are of major importance in assessing patients with hypercoagulable states or patients with unexplained thrombosis. Newer assays for components of the fibrinolytic system, plasminogen, t-PA and t-PA inhibitor are also now readily available and are important for defining congenital or acquired fibrinolytic defects leading to hypercoagulability and thrombosis. By judicious use of these assays, combined with clinical evaluation, many patients with thrombosis will have an underlying etiologic blood protein defect defined. Delineating reasons for a thrombotic event is of obvious importance for planning long-term prophylactic therapy and for diagnosing and counseling afflicted family members. In this manner, newly found patients can be treated prophylactically before unalterable morbidity or mortality occurs.
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PMID:Hypercoagulability and thrombosis. 145 21

Plasminogen activator inhibitor type 1 (PAI-1), the fast-acting inhibitor of tissue-type plasminogen activator (t-PA) and urokinase (u-PA), is a member of the serpin superfamily of proteins. Both in plasma and in the growth substratum of cultured endothelial cells, PAI-1 is associated with its binding protein vitronectin, resulting in a stabilization of active PAI-1. Recently, it has been demonstrated that the PAI-1-binding site on vitronectin is adjacent to a heparin-binding site (Preissner et al., 1990). Furthermore, it can be deduced that the amino acid residues, proposed to mediate heparin binding in the serpins antithrombin III and heparin cofactor II, are conserved in PAI-1. Consequently, here we have investigated whether PAI-1 also interacts with heparin. At pH 7.4, PAI-1 quantitatively binds to heparin-Sepharose and can be eluted with increasing [NaCl]. Binding of PAI-1 to heparin-Sepharose can be efficiently competed with heparin in solution (IC50, 7 microM). In the presence of heparin, the protease specificity of PAI-1 toward thrombin is substantially increased. This is shown by (i) quenching of thrombin activity of PAI-1 in the presence of heparin and (ii) induction of the formation of SDS-stable complexes between thrombin and PAI-1 by heparin. In a dose response curve, both effects reached a maximum at approximately 1 unit/mL and then diminished again upon further increasing the heparin concentration, strongly suggesting a template mechanism as an explanation for the observed effect. In contrast to vitronectin, heparin does not stabilize the active conformation of PAI-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional interaction of plasminogen activator inhibitor type 1 (PAI-1) and heparin. 170 36

To investigate the involvement of heparin cofactor II (HC II) in fibrinolytic system, endothelial cells from human umbilical vein were cultured in the presence of HC II or antithrombin III (AT III) combined with or without thrombin. Although AT III significantly inhibited thrombin-induced increase in tissue plasminogen activator antigen (t-PA:Ag) release, HC II did not exhibit such a suppressive effect. In contrast, in the presence of dermatan sulfate, HC II inhibited thrombin stimulation of t-PA:Ag release more strongly than AT III did. The release of plasminogen activator inhibitor-1 antigen (PAI-1:Ag) was also stimulated by thrombin; this stimulation was inhibited only by the combination of HC II and dermatan sulfate. Comparatively high concentrations of HC II significantly suppressed thrombin stimulation of t-PA:Ag and PAI-1:Ag release but did not cause an obvious change of both release in the absence of thrombin. Based on these results, it was suggested that HC II may inhibit an increase in fibrinolytic activity mediated by thrombin-stimulated endothelial cells in the liquid phase through a suppression of thrombin stimulation of t-PA:Ag release, when plasma is exposed to vascular smooth muscle cells or fibroblasts which synthesize a significant amount of dermatan sulfate.
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PMID:Heparin cofactor II inhibits thrombin-stimulated release of tissue plasminogen activator from cultured human endothelial cells in the presence of dermatan sulfate. 212 37

Lupus anticoagulants (LA) are IgG or IgM antibodies against phospholipids which in vivo represent an important thrombophilic factor despite their in vitro anticoagulant activity. We investigated the fibrinolytic system of 20 patients with connective tissue disease and positive LA, compared to a control group of 24 age- and disease-matched patients without LA. There was no statistically significant difference of alpha 2-antiplasmin, plasminogen, fibrinogen, t-PA activity, D-dimers and heparin cofactor II, between the two groups. Although t-PA was uniformly low in both groups, plasminogen activator inhibitor activity (PAI) was significantly higher in LA cases (p less than 0.001). Increased PAI levels represent an inhibitory factor of the fibrinolytic defense mechanism, which together with other functional deviations may contribute to the thrombophilic tendency of LA patients.
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PMID:Impaired fibrinolysis as an essential contribution to thrombosis in patients with lupus anticoagulant. 250 94

During a survey of four month's duration the following parameters were determined in 43 healthy blood donors (22 males, 21 females; mean age 29 years/20-49/): plasminogen activity, plasminogen concentration, alpha 2-antiplasmin (alpha 2-AP) activity, alpha 2-AP concentration, tissue type plasminogen activator (t-PA) activity, t-PA concentration, plasminogen activator inhibitor--I (PAI-I) activity, AT III activity, AT III concentration and heparin cofactor II (HC II) activity. Normal values including standard deviation (x +/- 2s) were: plasminogen activity: 96.3% (65.9-126.8), plasminogen concentration: 12.2 mg/dl (7.7-16.8), alpha 2-AP activity: 99.9% (83.8-116), alpha 2-AP concentration: 108.1% (84.5-131.8), t-PA activity: 0.85 IU/l (0.0-1.92), t-PA concentration: 10.3 ng/ml (2.5-18.1), PAI-I activity: 15.2 AU/ml, AT III activity: 111.4% (87.8-134.9), AT III concentration: 31.6 mg/dl (24.2-39.1) and HC II activity: 110.7% (81.4-140.0). Concerning plasminogen values no sex related difference could be stated. Women who were smokers and used oral contraceptives tended to present elevated t-PA activity levels due to a lower activity of PAI-I, although this tendency was not significant. Determining concentration and activity of components in the fibrinolytic system plays an important part in the diagnosis, therapy and prognosis of thrombophilic disorders.
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PMID:Reference values and variability of plasminogen in healthy blood donors and its relation to parameters of the fibrinolytic system. 312 9

We investigated the relationship between fasting insulin level and various hemostatic factors, including fibrinolytic factors (active plasminogen activator inhibitor-1 (PAI-1), tissue type plasminogen activator (tPA)-PAI-1 complex, plasmin-alpha 2-plasmin inhibitor (PIC), and D-dimer), coagulation factors (activated factor VII, factor VII coagulant activity and antigen, factor VIII, factor X, and fibrinogen), coagulation inhibitors (antithrombin III, heparin cofactor II, and protein C), and an acute phase marker (sialic acid) in 102 healthy individuals aged > or = 75 years (46 men and 56 women). Active PAI-1 levels had a significant negative correlation with PIC levels (r = -0.342, P = 0.0006), indicating that PAI-1 influences in vivo fibrinolytic activity in the very elderly. Gender differences were found in the relationship between insulin and hemostatic abnormalities, with the insulin level being positively correlated with coagulation factors in men (factor VIII activity: r = 0.422, P < 0.01; factor VII activity: r = 0.386, P < 0.01) and with hypofibrinolysis in women (active PAI-1: r = 0.549, P < 0.0001). Insulin levels were positively correlated with the levels of factor VII antigen and factor VII activity in men (P < 0.01), but there was no correlation with activated factor VII levels. The fasting insulin level was also correlated with the levels of heparin cofactor II and sialic acid in men (P < 0.05). However, other hemostatic factors were not related to the insulin level in either sex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Gender differences of disturbed hemostasis related to fasting insulin level in healthy very elderly Japanese aged > or = 75 years. 757 76

The acute and chronic effects on blood coagulation and fibrinolysis of a new molecular weight dermatan sulphate (Desmin 370) have been investigated in a double blind, placebo-controlled cross over study in 12 healthy volunteers. The compound (100 and 200 mg) was injected IM and the expected heparin cofactor II potentiating effect, reflecting dermatan sulphate activity, peaked after 2 h and was still detectable after 9 h. Surprisingly for this type of compound, a substantial increase in anti-Xa activity also appeared and lasted up to 12 h in the absence of a significant change in aPTT. The bovine-thrombin time was not changed, while human-thrombin times were slightly, albeit non-significantly, prolonged. The activity of t-PA was increased 6h after the higher dose, but the overall pattern of fibrinolytic activities did not suggest any important change after drug treatment in comparison to placebo. No residual or cumulative effect on any of the investigated parameters was detectable 24 h after the injection on the 4th and 8th days during repeated daily administration. Parallel in vitro and in vivo investigations showed that the unexpected anti-Xa effect was not attributable to contamination by traces of low molecular weight heparin. Desmin 370, a low molecular weight dermatan sulphate that potentiates heparin cofactor II and also inhibits Factor Xa, deserves clinical evaluation as an antithrombotic agent.
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PMID:Acute and chronic effects of a new low molecular weight dermatan sulphate (Desmin 370) on blood coagulation and fibrinolysis in healthy subjects. 786 77

We examined the effects of thrombin on tissue-type plasminogen activator (t-PA) release and t-PA mRNA levels in cultured human fetal lung fibroblast cells, IMR-90. The secretion of t-PA was increased by thrombin in a dose- and time-dependent manner, but it was not affected by inactivated thrombin with diisopropylfluorophosphate (DFP). Both antithrombin III (ATIII) and heparin cofactor II (HCII), plasma inhibitors to thrombin, inhibited thrombin-induced t-PA release. The thrombin-induced t-PA secretion was preceded by an increase of the steady state level of t-PA-specific mRNA in the cells, suggesting that thrombin activates t-PA gene expression. The t-PA mRNA expression induced by thrombin was completely blocked by pretreatment of the cells with an inhibitor of translation, cycloheximide (CHX). These results suggest that the effect of thrombin on t-PA expression is mediated through its proteolytic activity and the biosynthesis of transcription factor(s).
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PMID:Thrombin regulation of tissue-type plasminogen activator synthesis in cultured human fetal lung fibroblasts. 813 5

This article has stressed the common hereditary and acquired blood protein defects associated with thrombosis. The commonest hereditary defects appear to be antithrombin, protein C, and protein S deficiency, and the commonest acquired defects are anticardiolipin antibodies and the lupus anticoagulant. Therefore these are the defects that should first be looked for in an individual with unexplained thrombosis. If these commoner defects are not found, the rarer defects, including HC-II, plasminogen or t-PA deficiency, dysfibrinogenemia, or elevated PAI-1, should next be sought. The incidence of activated protein C cofactor deficiency is not yet clear but may also represent a common defect. Likewise, PAI-1 defects may, with time, be shown to be quite common. The importance of finding these defects has significant implications for therapy of the individual patient and for institution of family studies to identify, inform, and possibly treat others at risk. It is expected that as knowledge of hemostasis expands, more hereditary and acquired defects, such as elevated lipoprotein (a) or defects of extrinsic (tissue factor) pathway inhibitor may be associated with enhanced risks of thrombosis.
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PMID:Hypercoagulability and thrombosis. 817 Feb 63


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