Tissue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal haemoglobinuria

Abstract. Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder thought to arise in a multipotent haemopoietic stem cell. A distinct clinical feature is a tendency to thrombosis, with a particular predilection for the hepatic veins (Budd-Chiari syndrome). We report here on two patients with PNH who developed hepatic vein thrombosis (HVT) and who were treated with tissue plasminogen activator (t-PA). Both patients had a marked clinical and radiological improvement following the t-PA treatment and remain well over 2 years and 6 years after the treatment. This method of thrombolysis for HVT occurring in PNH has only been reported in two previous patients with limited follow-up. We suggest that this therapy is a useful first-line treatment for PNH patients who develop HVT.     

Abnormal fibrinolysis in healthy male cigarette smokers: role of plasminogen activator inhibitors

The extrinsic fibrinolytic system and its response to cigarette smoking was studied in five healthy male smokers 35-45 years old. Tissue plasminogen activator (t-PA) release in response to venous occlusion was intact both at 8:00 A.M. and 3:00 P.M. Acutely smoking two cigarettes neither stimulated fibrinolysis nor changed levels of t-PA or plasminogen activator inhibitors. Functional plasminogen activator inhibitor (PA-I) levels and euglobulin lysis times were higher in the smoking group than in a control group matched for age, sex, and body mass. Antigenic levels of PA-I 1, the PA-I derived from vascular endothelial cells and platelets, were similar in both groups. While smoking did not acutely alter fibrinolysis in chronic smokers, these individuals had a high frequency of abnormal fibrinolysis characterized by high levels of PA-I activity. This abnormality is due to either high specific activity of PA-I 1 or to the presence of other antigenically distinct plasminogen activator inhibitors. Abnormal fibrinolysis may be one mechanism contributing to the thrombotic diathesis of cigarette smokers.     

Regulation of tissue plasminogen activator in sickle cell anemia

Evidence of activation of the clotting system in individuals with sickle cell anemia (SCA) has been observed by several investigators. It has been suggested that the clotting and fibrinolytic systems may play a role in the pathophysiology of vaso-occlusion in SCA. We reported previously evidence of abnormal fibrinolytic activity as reflected in decreased releasable tissue plasminogen activator (t-PA) using a functional assay. We have examined the mechanism of the decreased functional releasable t-PA in individuals with SCA. We studied 12 patients with respect to releasable t-PA, fast acting inhibitor to t-PA (or PAI-1), and immunoreactive or antigenic t-PA. These SCA individuals were at their baseline states and not taking medications known to interfere with the fibrinolytic or clotting systems. We found that the mean releasable t-PA for the SCA individuals was 0.01 IU/ml of plasma with a standard error of mean (SEM) of 0.01. The mean releasable t-PA of 118 healthy normal controls was 0.70 IU/ml with SEM 0.10 (P less than .001). The mean level of fast-acting inhibitor to t-PA in unoccluded circulation of the SCA patients' plasma was 16.5 IU/ml with SEM of 3.54. The mean plasma levels of fast-acting inhibitor to t-PA in 56 healthy controls was 2.56 IU/ml with SEM of 0.29 (P less than .0001). The SCA patients had a mean baseline t-PA antigen level of 5.98 ng/ml with SEM of 1.72. The mean level of t-PA antigen of 78 healthy controls using the same technique was 4.3 ng/ml with SEM of 2.7 (not significant). The mean baseline functional t-PA for SCA individuals was 0.15 IU/ml with SEM 0.01 and the mean baseline functional t-PA for 118 controls was 0.17 IU/ml with SEM 0.10. These data suggest that the mechanism of decreased releasable t-PA in sickle cell anemia is related to an elevation of fast-acting inhibitor to t-PA and that antigenically t-PA is present in normal quantities in the baseline plasma in this population.     

Increased plasminogen activator inhibitor and tissue plasminogen activator levels in subjects with electrocardiographic abnormality indicative of ischaemic heart disease: a cross-sectional study in Norsj?, Sweden.

The plasma levels of tissue plasminogen activator (tPA) antigen concentration and plasminogen activator inhibitor (PAI) activity were measured in a random sample of 260 subjects, 30, 40, 50, or 60 years of age. Electrocardiographic Q, ST and/or ST-T changes, suggestive of definite or possible ischaemic heart disease (IHD), were found in 21% of the 50-year-old and 37% of the 60-year-old subjects. As compared to subjects lacking such signs, plasma tPA and PAI levels were significantly increased in the 60-year-old group, and PAI tended to be increased in the 50-year-old group. Previous case-control studies, usually performed at specialized centres and liable to sampling biases, have suggested an association between increased PAI levels and ischaemic heart disease. This cross-sectional population study provides independent data that patients with electrocardiographic signs of IHD have increased levels of both PAI and tPA antigen.     

Evidence for increased levels of plasminogen activator inhibitor and tissue plasminogen activator in plasma of patients with angiographically verified coronary artery disease

We studied 234 consecutive patients who underwent coronary angiography because of severe angina pectoris. Tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI), and lipoprotein Lp(a) were measured in citrated plasma samples. The 214 patients showing significant coronary artery stenosis (greater than 50% reduction of luminal area in any of the great coronary arteries) had higher mean levels of tPA (P less than 0.001) and PAI (P less than 0.01) than a random population sample of similar age. PAI and tPA levels were higher in smokers than in either non-smokers or ex-smokers, and in patients with hypertension tPA was increased. Subjects with blood group A had a higher mean Lp(a) level than subjects with blood group O. There were positive correlations of PAI and tPA levels with serum triglycerides and with body mass index; Lp(a) correlated weakly with plasma fibrinogen concentrations. The findings suggest an impairment of the fibrinolytic system in patients with coronary artery disease, which offers a link between established risk factors and a plausible pathophysiological mechanism, namely thrombus turnover.     

Tissue plasminogen activator and other risk factors as predictors of cardiovascular events in patients with severe angina pectoris

The value of measurements of the fibrinolytic factors, tissue plasminogen activator and plasminogen activator inhibitor, for predicting death and non-fatal cardiovascular events was studied in 213 consecutive patients with angiographically documented coronary artery disease. In the course of 4-year follow-up, 47 patients (22.1%) had at least one cardiovascular event. We found the incidence of cardiovascular events to be positively associated with high tissue plasminogen activator antigen concentration, in addition to previous myocardial infarction, low ejection fraction, hypertension, high body mass index and high triglyceride levels. Cholesterol was not found to be associated with cardiovascular events. A high concentration of tissue plasminogen activator antigen thus implies an increased risk of cardiovascular events in patients with severe angina pectoris.     

肝硬化患者血浆中尿激酶型纤溶酶激活物的检测及其意义

目的 探讨肝硬化患者血浆尿激酶型纤溶酶激活物(uPA)、尿激酶型纤溶酶激活物受体(uPAR)、纤溶酶原激活物抑制剂-1(PAI-1)的变化及其意义。 方法 确诊的72例乙型肝炎后肝硬化患者,Child-pugh分级A级23例(A组),B级29例(B组),C级20例(C组)。6例健康志愿献血者为正常对照组。酶联免疫吸附实验测定血浆uPA、uPAR、PAI-1的变化。并同时检测血透明质酸(HA)、Ⅳ型胶原(C Ⅳ)、Ⅲ型前胶原(PC Ⅲ)、血浆白蛋白、胆红素、凝血酶原时间及其活动度改变。 结果 随着肝硬化的进展,血浆uPA、uPAR、PAI-1逐渐增加,HA、PC Ⅲ也明显增加。Child C组患者血浆uPA、uPAR、PAI-1水平(μg/L)分别为1.88±0.64、4.82±2.02和52.60±16.87,A组分别为1.36±0.43、3.03±1.48和24.09±7.14,B组分别为1.79±0.62、4.80±2.22和41.40±17.52,C组与A、B组比较,t值为2.81～7.38,P值均<0.01。A组血浆uPA与PC Ⅲ呈负相关(r=-0.4785,P<0.05);C组PAI-1与HA呈正相关(r=0.5447,P<0.01)。 结论 肝硬化晚期,虽然血浆uPA、PAI-1增加,但总的效应表现为uPA相对不足,肝基质纤维降解受抑制,血浆uPA、PAI-1与肝硬化发展密切相关。     

Expression of urokinase-type plasminogen activator receptor and plasminogen activator inhibitor-1 in gastric cancer

In gastric cancer, the urokinase-type plasminogen activator (uPA) system plays important roles in invasion and metastasis, processes which entail proteolysis and adhesion. Both the urokinasetype plasminogen activator receptor (uPAR) and the plasminogen activator inhibitor-1 (PAI-1) are thought to be important factors in this system. To clarify the relationship between these two factors and gastric cancer invasiveness, we evaluated the expression of uPAR and PAI-1 in 91 cases of gastric cancer by immunohistochemistry and in situ hybridization. Urokinase-type plasminogen activator receptor-mRNA, PAI-1-mRNA, uPAR and PAI-1 protein were diffusely distributed in the cytoplasm of the cancer cells and concentrated at invasive foci. Urokinase-type plasminogen activator receptor protein expression correlated with lymphatic, venous invasion (P<.01) and lymph node metastasis (P<0.05); uPAR-mRNA expression correlated with lymphatic, venous invasion and lymph node metastasis (P<0.05). Plasminogen activator inhibitor-1 protein expression correlated with lymphatic, venous invasion, lymph node metastasis and depth of invasion (P<0.01); PAI-1-mRNA expression was linked to lymphatic, venous invasion (P<0.01), lymph node metastasis and depth of invasion (P<0.05). This suggests that the proteolytic activity of uPAR and the cellular motility of PAI-1 in gastric cancer cells may determine penetration of lymphatic and blood vessels, whereby lymph node metastasis may be promoted and that the promotion of cellular motility by PAI-1 may influence the depth of cancer invasion.     

Protection by α2-macroglobulin of tissue plasminogen activator against inhibition by plasminogen activator inhibitor-1

Tissue plasminogen activator (tPA) is widely used in the treatment of acute myocardial infarction (MI). However, its thrombolytic efficacy does not correlate with the dose administered. The interactions between tPA, α2-macroglobulin (α2-M), and plasminogen activator inhibitor-1 (PAI-1) were investigated both in vitro and in patients undergoing tPA therapy for MI in an attempt to identify variables that might affect the clinical efficacy of tPA.
Purified α2-M (5.4 mg/ml) protected 16.0% or 22.4% of tPA (12.5 IU/ml) activity from inhibition by PAI-1 at 4 or 8 IU/ml in vitro . Of nine patients treated with 5–20 mega IU of tPA for MI, the plasma activity of tPA remained increased for 15–30 min after the cessation of infusion in eight; the patient who failed to exhibit a persistent increase in tPA activity had a low plasma concentration of α2-M. Total tPA activity, derived from the area under the activity-versus-time curve (AUC), showed a significant inverse correlation with the ratio of the plasma PAI-1 activity to the plasma α2-M concentration. Total tPA activity did not correlate with plasma PAI-1 activity or plasma α2-M concentration alone. Results suggest that α2-M, by binding to tPA, protects the latter against inhibition by PAI-1.     

Tissue plasminogen activator in refractory unstable angina. A randomized double-blind placebo-controlled trial in patients with refractory unstable angina and subsequent angioplasty

To evaluate the effect of recombinant tissue plasminogen activator(alteplase) on the clinical course, angiographic changes andthe outcome of subsequent coronary angioplasty, 36 patientswith angina at rest, despite bedrest and medical treatment includingheparin, and with concomitant ECG changes, were studied. Afterdiagnostic angiography, patients were randomized to receiveeither alteplase 100mg in 3 h (19 patients), or placebo (17patients). The mean interval between qual anginal episode andinitial angiography was 10 and 9 h for the alteplase and placebogroup, respectively. Angiography was repeated and angioplastywas performed within 24 hours. Between the first and the second angiogram, five patients inthe alteplase and seven in the placebo group had recurrent ischaemicepisodes, while four alteplase and three placebo patients showedsigns of myocardial necrosis (creatine kinase (CK) rise twicethe upper limit for normal). Intracoronary clots were recognizedin three alteplase patients and one placebo patient at the firstangiograrn, while two alteplase patients and one placebo patientshowed total occlusion of the ischaemic-related vessel. Afterinfusion, thrombi were present in four alteplase patients andone placebo patient, and total occlusion in three alteplasepatients and one placebo patient. Quantitative coronary angiographyshowed no change in the percentage diameter stenosis of theischae, nia-related segment after drug infusion, (alteplase67±16 to 69±16%; placebo 65±11 to 63±12%).Angioplasty was successful in 14 of 19 alteplase and 14 of 16placebo patients. Three patients after alteplase and two placebopatients developed myocardial necrosis during percutaneous transluminalcoronary angioplasty (PTCA) and one alteplase patient requiredurgent bypass surgery. Minor bleeding complications were observedin six alteplase patients before the second angiogram and infive alteplase patients and one placebo patient after PTCA.One patient after alteplase developed a fatal retroperitonealhaemorrhage. In patients with unstable angina refractory to medical treatment,including heparin, alteplase has no beneficial effect on theseverity of coronary stenosis, on the clinical course, or onthe success of a subsequent angioplasty procedure. Thus thrombolytictherapy with alteplase for unstable angina cannot be recommendedon the basis of this investigation.     

Plasma concentration of endogenous tissue plasminogen activator and the occurrence of future cardiovascular events

Data from recent prospective studies of hemostasis and thrombosis indicate that the plasma concentration of endogenous tissue-type plasminogen activator (tPA) is often elevated years in advance of a first arterial occlusion. Specifically, among healthy subjects with no prior cardiovascular disease, the risk of future myocardial infarction and stroke appears to be three to four times higher among subjects with high baseline levels of tPA antigen as compared to subjects with lower levels. Whether this relationship represents activation of the endogenous fibrinolytic system in response to the presence of preclinical atherosclerosis or is a reflection of elevated concentrations of local plasminogen activator inhibitors is currently unresolved. However, cross-sectional data indicate that the plasma concentration of tPA antigen is related to several traditional atherosclerotic risk factors, including HDL cholesterol, findings that further support a direct relationship between endogenous tPA and vascular risk. In concert with data concerning the primary inhibitors of plasminogen activation, it has been hypothesized that the endogenous fibrinolytic system varies within the general population such that certain individuals are prone to thrombosis, whereas others may be prone to hemorrhage. Thus, observations regarding fibrinolytic activation and inhibition raise the possibility that assessment of the intrinsic fibrinolytic system may prove useful in identifying individuals at increased risk for vascular thrombosis. In addition, available findings suggest that therapeutic agents capable of favorably shifting the net fibrinolytic balance may provide a new strategy for cardiovascular disease prevention.     

Tissue plasminogen activator in refractory unstable angina. A randomized double-blind placebo-controlled trial in patients with refractory unstable angina and subsequent angioplasty.

To evaluate the effect of recombinant tissue plasminogen activator (alteplase) on the clinical course, angiographic changes and the outcome of subsequent coronary angioplasty, 36 patients with angina at rest, despite bedrest and medical treatment including heparin, and with concomitant ECG changes, were studied. After diagnostic angiography, patients were randomized to receive either alteplase 100 mg in 3 h (19 patients), or placebo (17 patients). The mean interval between qualifying anginal episode and initial angiography was 10 and 9 h for the alteplase and placebo group, respectively. Angiography was repeated and angioplasty was performed within 24 hours. Between the first and the second angiogram, five patients in the alteplase and seven in the placebo group had recurrent ischaemic episodes, while four alteplase and three placebo patients showed signs of myocardial necrosis (creatine kinase (CK) rise greater than or equal to twice the upper limit for normal). Intracoronary clots were recognized in three alteplase patients and one placebo patient at the first angiogram, while two alteplase patients and one placebo patient showed total occlusion of the ischaemic-related vessel. After infusion, thrombi were present in four alteplase patients and one placebo patient, and total occlusion in three alteplase patients and one placebo patient. Quantitative coronary angiography showed no change in the percentage diameter stenosis of the ischaemia-related segment after drug infusion, (alteplase 67 +/- 16 to 69 +/- 16%; placebo 65 +/- 11 to 63 +/- 12%). Angioplasty was successful in 14 of 19 alteplase and 14 of 16 placebo patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of octreotide on epidermal growth factor receptor,tissue plasminogen activator,and plasminogen activator inhibitor during intraperitoneal adhesion formation

Background . Intraperitoneal adhesions remain a problem after abdominal surgery. Octreotide has been proved to be able to reduce the number, strength, and extent of fibrous bands at and away from the anastomotic site in an animal model of rats with intestinal resection and reanastomosis. The aim of the present study was to investigate whether epidermal growth factor receptor (EGF-R), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI) are involved in this process. Methods. Laparotomy with intestinal resection and reanastomosis was performed on 60 male Wistar rats. All rats were randomly assigned to five groups: receiving no medication (control; C), normal saline (NS), octreotide solution peritoneal irrigation (Oc), octreotide intramuscular injection (IM), and Oc plus octreotide intramuscular injection (Oc + IM). The concentrations of serum EGF-R, plasma tPA, PAI-1, and PAI-2, and the strength of wound healing were measured. Results. The serum EGF-R concentration showed no significant change from the preoperative level in the C and NS groups 7 and 14 days after the abdominal surgery. However, it decreased significantly on postoperative days 7 and 14 in groups Oc, IM, and Oc + IM (P < 0.05). The plasma tPA concentrations were significantly higher than the preoperative level in all groups of rats on postoperative day 7. The levels were higher in groups Oc, IM, and Oc + IM than in group C or group NS at that time (P < 0.05). On postoperative day 14, the plasma tPA concentrations had returned to the preoperative level in group C and group NS. However, the concentrations in groups Oc, IM, and Oc + IM still remained at a significantly higher level than the concentrations in group C and group NS. The plasma PAI-1 and PAI-2 concentrations showed no significant difference from the preoperative level in group C and group NS on days 7 and 14 after the abdominal surgery. However, the concentrations in groups Oc, IM, and Oc + IM on postoperative days 7 and 14 were markedly lower than those in groups C and NS (P < 0.05). The wound strength was significantly greater on day 14 than on day 7 in all groups. Conclusions. In the rats with octreotide irrigation, the EGF-R level was decreased, the plasma tPA concentration was higher, and the plasma PAI-1 and PAI-2 concentrations were lower when compared with values in group C and group NS rats on days 7 and 14 after surgery. The data suggest that EGF-R, tPA, PAI-1, and PAI-2 are all involved in the mechanism of octreotide's action in reducing adhesion formation. Received: February 25, 2002 / Accepted: November 22, 2002 RID="*" ID="*" Reprint requests to: H.-S. Lai Acknowledgments. This study was supported by a National Science Council Grant (NSC87-2314-B-002-352), and a National Taiwan University Hospital Grant (NTUH. 89S1509)     

Hypofibrinolysis in patients with hypercoagulability: The roles of urokinase and of plasminogen activator inhibitor

The prevalence of abnormalities of fibrinolysis in patients with venous thromboembolism is as yet unknown. Defined abnormalities include congenital dysfunction and deficiency of plasminogen, and probably impaired plasminogen activation secondary to elevated levels of plasminogen activator inhibitor type 1 (PAI-1) or to impaired release of tissue plasminogen activator (tPA). In this preliminary study, we analyzed plasma samples from 21 patients for whom an investigation for possible thrombophilia was requested. Twenty of the patients had venous thromboembolism, and one had arterial thrombosis at an early age. Two patients had deficiency of protein C or protein S, but no other recognized biochemical disturbances related to thrombophilia were identified. Patient samples and plasma from 25 normal controls were assayed for tPA activity, PAI-1 activity, and urokinase (uPA) activity and antigen. tPA activity and antigen were not significantly different in patients than in controls. PAI-1 activity was significantly greater in patients (P < 0.0001). uPA activity was not different in the two groups. However, uPA antigen was significantly reduced in patients compared to controls (P = 0.001). These data suggest that hypofibrinolysis leading to a risk of thrombosis may be caused not only by elevated PAI-1 activity but also by reduced total uPA concentration. © 1993 Wiley-Liss, Inc.     

Intra-atrial tissue plasminogen activator infusion for prosthetic valve thrombosis.

Thrombosis is a well-known and life-threatening complication of prosthetic mechanical valves. Therapy typically requires medical thrombolysis or surgical thrombectomy/valve replacement. We report the case of a thrombosed atrioventricular valve in a young boy with complex congenital heart disease, which was successfully treated with direct intra-atrial infusion of recombinant tissue plasminogen activator after failed attempts at systemic therapy. We present this treatment as an alternative to conventional medical therapy.     

组织型纤溶酶原激活剂及其抑制剂与肺血栓栓塞症

肺血栓栓塞症（PTE）的发病与机体的纤溶和凝血系统功能密切相关。组织型纤溶酶原激活物（t-PA）及其抑制物（PAI-1）因调节机体的纤溶系统而在静脉血栓形成及栓塞性疾病的发病机制中发挥重要作用,因此,本文对t—PA和PAI-1与PTE的关系作如下综述。     

Treatment of prosthetic tricuspid valve thrombosis with recombinant tissue-type plasminogen activator

Recombinant tissue-type plasminogen activator (rt-PA) was admministeredintravenously to a 64-years old female with thrombotic malfunctionof a Björk–Shiley prosthetic tricuspid valve. 150mg of single-chain rt-PA was infused over 8 hours followed byan additional dose of 50 mg over the next 8 hours. At the endof the first infusion, restoration of normal valve functionwas demonstrated by fluoroscopic and echo-Doppler examinations.Mild systemic activation of the fibrinolytic system occurred,with a decrease of fibrinogen and ₂-antiplasmin to 53% and 33%,respectively, of the preinfusion value at the nadir.     

Clinical significance of urokinase-type plasminogen activator activity in hepatocellular carcinoma

BACKGROUND AND METHODS: The plasminogen activation system plays a crucial role in the process of cancer invasion and metastasis. To evaluate the most effective factor in the invasion, metastasis and prognosis of hepatocellular carcinoma (HCC), we examined urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor (PAI)-1, PAI-2 and uPA activity by enzyme-linked immunosorbent assays (ELISA) in HCC tissues obtained from 46 patients. The results were compared with the patients' clinicopathological features and prognoses. RESULTS: Of the clinicopathological features, only histological portal involvement or intrahepatic metastasis, or both (INV), was significantly correlated to the disease-free survival rates (DFS; P < 0.05). The levels of uPA, PAI-1 and PAI-2 antigens were significantly associated with INV and histological grade. The DFS was not different, however, between cases with uPA, PAI-1 and PAI-2 values above and below the median. The high levels of uPA activity were closely related to INV (P < 0.001), and the activity gradually raised histological grades (P < 0.0001). The DFS was significantly different between patients with uPA activity below and above the median (0.70 ng/mL; P = 0.0092); it was also significantly different between such patients without INV (P < 0.05). CONCLUSIONS: Urokinase-type plasminogen activator activity may be the most sensitive factor affecting HCC invasion in the plasminogen activation system and a strong predictor for the recurrence of HCC. We suggest that cases with uPA activity of more than 0.70 ng/mL should be carefully followed up for possible HCC recurrence.     

Treatment of prosthetic tricuspid valve thrombosis with recombinant tissue-type plasminogen activator

Recombinant tissue-type plasminogen activator (rt-PA) was admministeredintravenously to a 64-years old female with thrombotic malfunctionof a Björk–Shiley prosthetic tricuspid valve. 150mg of single-chain rt-PA was infused over 8 hours followed byan additional dose of 50 mg over the next 8 hours. At the endof the first infusion, restoration of normal valve functionwas demonstrated by fluoroscopic and echo-Doppler examinations.Mild systemic activation of the fibrinolytic system occurred,with a decrease of fibrinogen and ₂-antiplasmin to 53% and 33%,respectively, of the preinfusion value at the nadir.