Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the clinical significance of the venous occlusion (VO) test on patients with systemic lupus erythematosus (SLE) with or without circulating lupus anticoagulant (LA) concerning whether changes in the blood coagulation and fibrinolysis system in vivo subsequent to VO reflect mechanical stimulation of the endothelium or presence/development of endothelial damage. The tissue plasminogen activator antigen (tPA:Ag) before VO was much lower in the LA-positive patients than in the LA-negative ones (p < 0.01) and the von Willebrand factor antigen (VWF:Ag) pre-VO was significantly higher in the patient group, regardless of LA status, than in the control group (p < 0.01). But the mean increment in tPA:Ag and VWF:Ag post-VO, when expressed as the percentage of the baseline level, showed no appreciable difference between LA-positive and -negative groups. Thrombomodulin (TM) basically, on the other hand, was higher in the patients of either LA status than in the controls (p < 0.01) with a significant post-VO increase in the SLE group, which was more marked in the LA-positive patients, against no substantial change in the controls (p < 0.01). It is known that tPA and VWF:Ag are released simply as a result of endothelial stimulation and that the release of TM is preceded by endothelial damage. Based on the present results, we may well conclude that (1) the endothelium is functionally intact in SLE patients, (2) an injury of the endothelium, possibly as a consequence of vasculitis, preexists in LA-positive patients, and thus to measure the TM response to VO would offer a helpful tool in diagnosing the preexisting endothelial damage in these clinical settings.
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PMID:Clinical significance of the venous occlusion test on systemic lupus erythematosus patients with a focus on changes in blood levels of tissue plasminogen activator, von Willebrand factor antigen, and thrombomodulin. 132 22

Livedoid vasculitis, a hyalinizing vasculopathy, is characterized by extensive formation of microthrombi and deposition of fibrin in the middermal vessels, which result in epidermal infarction, ulceration, and formation of stellate scars. In a prospective study of nonhealing ulcers in patients with livedoid vasculitis, we found a high incidence of anticardiolipin antibodies, lupus anticoagulants, increased levels of plasminogen activator inhibitor, and low levels of endogenous tissue plasminogen activator (t-PA) activity. This procoagulant tendency and decreased fibrinolysis may provide an explanation for the occlusive vasculopathy often noted in biopsy specimens from these patients. On the basis of these findings, we proposed that fibrinolysis with recombinant t-PA would lyse microvascular thrombi, restore circulation, and promote wound healing. In six patients who had nonhealing ulcers caused by livedoid vasculitis and in whom numerous conventional therapies had failed, low-dose t-PA (10 mg) was administered intravenously during a 4-hour period daily for 14 days. Five of the six patients had dramatic improvement; almost complete healing of the ulcers occurred during hospitalization, and tissue oxygenation, as measured by transcutaneous oximetry, increased. The one treatment failure was due to rethrombosis of the microvasculature; this patient was subsequently re-treated but with concurrent anticoagulation, and her leg ulcers healed. We conclude that daily administration of a low dose of t-PA is safe and effective treatment for nonhealing ulcers due to occlusive vasculopathy.
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PMID:Tissue plasminogen activator for treatment of livedoid vasculitis. 143 47

Increased thrombogenesis observed in systemic lupus erythematosus (SLE) is derived from multiple mechanisms, including: Enhanced coagulation factor VIII:VWf activity, lupus anticoagulants, anti-phospholipid antibodies, acquired deficiencies of natural anti-thrombotic mechanisms (protein C, protein S, anti-thrombin III), and impaired fibrinolytic mechanisms. We studied the fibrinolytic mechanisms of 18 patients with systemic lupus erythematosus, selected carefully to avoid other possible causes of abnormalities in the fibrinolytic activity. Despite the fact that the euglobulin lysis time in steady state was normal in all instances, disturbances in the tissue plasminogen activator/plasminogen activator inhibitor (TPA/PAI) system were found in all SLE patients: TPA activity was undetectable in all cases, whereas it was above 0.4 IU/ml in a control group. In 72 percent of patients, the undetectable TPA activity was correlated with abnormally high PAI activity; PAI levels were normal in all members of the control group, their mean value being 0.74 versus 8.63 IU/ml for SLE patients (P less than .01). Coagulation protein C deficiency was found in 3 patients (17%). Even though within normal range, fibrinogen levels were significantly higher in SLE than in normal controls (219 versus 192 mg/dl, P less than .01) and plasminogen levels were significantly higher in SLE than in controls (117 versus 78.2%, P less than .01). Cross-linked fibrin derivatives (D-D dimers) were negative in all patients with SLE. Sixty-eight percent of SLE patients had high levels of antiphospholipid antibodies, but no correlation with the disturbances of the TPA/PAI system was found. It is concluded that most patients with SLE display severe abnormalities in the TPA/PAI anti-thrombotic system and that these abnormalities may be related to the lupus thrombophilia, apparently multifactorial in its origin.
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PMID:Disturbances in the tissue plasminogen activator/plasminogen activator inhibitor (TPA/PAI) system in systemic lupus erythematosus. 190 23

Human plasma contains an inhibitor of tissue factor-initiated coagulation known as the lipoprotein-associated coagulation inhibitor (LACI) or also known as the extrinsic pathway inhibitor (EPI). A competitive fluorescent immunoassay was developed to measure the plasma concentration of LACI in samples from normal individuals and patients with a variety of diseases. The LACI concentration in an adult control population varied from 60% to 160% of the mean with a mean value corresponding to 89 ng/mL or 2.25 nmol/L. Plasma LACI levels were not decreased in patients with severe chronic hepatic failure, warfarin therapy, primary pulmonary hypertension, thrombosis, or the lupus anticoagulant. Plasma LACI antigen was decreased in some, but not all patients with gram-negative bacteremia and evidence for disseminated intravascular coagulation. Plasma LACI levels were elevated in women undergoing the early stages of labor (29%), in patients receiving intravenous tissue-type plasminogen activator (45%), and in patients receiving intravenous heparin (375%). A radioligand blot of the pre- and post-heparin plasma samples shows the increase to be in a 40-Kd form of LACI. Very low levels of plasma LACI antigen were found in patients with homozygous abetalipoproteinemia and hypobetalipoproteinemia, diseases associated with low plasma levels of apolipoprotein B containing lipoproteins. Following the injection of heparin into one patient with homozygous abetalipoproteinemia, the plasma LACI antigen level increased to a level comparable with that in normal individuals after heparin treatment.
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PMID:Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. 207 76

The coagulation system can be considered as a balance in which clotting and fibrinolysis have to be in a state of equilibrium. Increased fibrin formation or decreased fibrinolysis can predispose to thromboembolic diseases. Derailments in the clotting system leading to thrombosis center around the regulatory mechanisms, antithrombin III, protein C, protein S and possibly heparin cofactor II. Many cases of congenital or acquired deficiencies or abnormalities or antithrombin III, protein C and S have been described, all predisposing to thrombotic events. Alterations of the fibrinolytic system can also be associated with thromboembolisms. In particular, abnormalities of plasminogen, tissue plasminogen activator release and elevated tissue plasminogen activator inhibitor levels seem to be associated with thromboses. Conceivably also factor XIIa (Hageman factor) and prekallikrein deficiencies, when associated with thrombosis, exert their mechanism through the fibrinolytic system. Finally, about 50% of patients with lupus anticoagulant seem to suffer from thromboembolic disorders. The pathophysiology of this particular association is not known with certainty. Undoubtedly, there will be more disturbances discovered in the hemostasis system that are associated with increased intravascular fibrin formation. The understanding of these derailments is at this time only in its earliest stages of development.
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PMID:Pathophysiology of thrombophilic states. 246 10

We retrospectively evaluated 66 patients younger than 40 years of age who presented with acute nonhemorrhagic cerebral infarction (n = 63) or transient ischemic attacks (n = 3) to determine the possible etiology and long-term outcome at a mean follow-up interval of 3 years after initial presentation. A probable cause for the stroke was identified in 24 patients (36%); this group included one woman with a history of recurrent spontaneous abortions and a positive test for the presence of the lupus anticoagulant. We performed detailed hemostatic investigations at follow-up in 38 (90%) of the remaining 42 patients in whom the cause of the stroke was unknown or uncertain; results of the basic hemostatic screening tests (including that for fibrinogen) were uniformly normal. All 38 patients demonstrated a normal fibrinolytic response as measured by tissue plasminogen activator release to a standard venous occlusion stress test; concentration of the inhibitor of tissue plasminogen activator was not increased. No abnormalities in the concentrations of the inhibitory proteins C or S or antithrombin III were identified, and none of the 38 patients had evidence of a lupus anticoagulant. Neurologic recovery was complete or the residual disability mild in 46 of 59 (78%) patients. Overall prognosis was excellent and independent of whether a precipitating factor for the stroke could be identified.
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PMID:Etiology, prognosis, and hemostatic function after cerebral infarction in young adults. 249 81

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

We investigated the effect of plasma and serum from 10 subjects with the lupus anticoagulant and thrombosis and 9 normal subjects on the secretion of tissue-type plasminogen activator (t-PA) and its rapid inhibitor (type 1 plasminogen activator inhibitor, or PAI-1) by cultured human endothelial cells. Confluent monolayers of human umbilical vein endothelial cells were incubated for 48 hours with plasma or serum diluted ten-fold in serum-free endothelial cell growth medium, and the secretion of t-PA and PAI-1 measured by enzyme-linked immunosorbent assay. No consistent differences in mean t-PA and PAI-1 release were found between cells exposed to normal plasma or serum and plasma or serum from subjects with the lupus anticoagulant and thrombosis. No plasma or serum sample produced consistent inhibition of t-PA release or stimulation of PAI-1 release (defined as t-PA levels less than the mean minus two standard deviations for normal subjects, and PAI-1 levels greater than the mean plus two standard deviations for normal subjects, respectively). These findings do not support a role for altered endothelial fibrinolytic activity in the pathogenesis of thrombosis in subjects with the lupus anticoagulant, and are consistent with previous observations that these subjects have normal fibrinolytic activity in vivo.
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PMID:Effect of the lupus anticoagulant on endothelial fibrinolytic activity in vitro. 250 1

In systemic lupus erythematosus (SLE) the lupus anticoagulant is known to be associated with thrombosis. However, this anticoagulant only occurs in a small percentage of patients. Histopathological studies suggest a more generalized thrombotic tendency with platelets and fibrin within the microvasculature. Fibrinogen is elevated in SLE and this may lead to the fibrin deposition described. We wondered if decreased fibrinolysis contributed to this and we infused desamino D-arginine vasopressin (DDAVP) into ten patients with SLE and eight controls. DDAVP stimulates endothelial production of plasminogen activator (PA) and factor VIII. Baseline results showed a significant decrease in PA activity with a concomitant increase in fibrinogen in SLE. The t-PA and inhibitor levels were normal but factor VIII was increased. After infusion of DDAVP, results indicated that, despite baseline results, SLE patients were able to respond to stimulation and the increase in PA activity produced a decrease in plasma fibrinogen levels. These findings may have therapeutic implications.
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PMID:Fibrinolysis in systemic lupus erythematosus: effect of desamino D-arginine vasopressin infusion. 311 77

Fibrinolysis was evaluated in 16 women with SLE, who were divided into three groups of increasing disease severity according to their past history, and in 10 normal subjects. Fibrinolysis parameters assessed were tissue-type plasminogen activator (t-PA) activity in plasma and in euglobulin fractions and rapid plasminogen activator inhibitor activity. All parameters were evaluated before and after venous occlusion to assess endothelial cell t-PA release in response to localized anoxia. Markers of deficient fibrinolysis were persistently undetectable t-PA activity and increased rapid plasminogen activator inhibitor activity after venous occlusion. Defective fibrinolysis was correlated with disease severity; it was noted only in patients with severe or moderate disease and in no patients with mild disease or in controls. Fibrinolysis abnormalities were independent of disease activity, suggesting that vascular endothelium injuries occurring during flare-ups persist during inactive phases of the disease. No correlation was found between fibrinolysis abnormalities and disease duration, corticosteroid administration, or the presence of lupus anticoagulant or anticardiolipin antibodies. These data support the hypothesis of parallelism between the severity of vascular injuries, suggested by deficient fibrinolysis, and the severity of clinical manifestations in SLE.
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PMID:Fibrinolysis abnormalities in systemic lupus erythematosus and their relation to vasculitis. 312 85


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