Effect of levothyroxine replacement therapy on coagulation and fibrinolysis in severe hypothyroidism

OBJECTIVE: We previously demonstrated that patients suffering from moderate hypothyroidism were at increased risk of thrombosis contrasting with the bleeding tendency of those presenting severe hypothyroidism. The latter state is associated with hemostatic anomalies including von Willebrand type 1 disease and increased fibrinolytic capacity. With the exception of von Willebrand type 1 disease, reversibility of hemostatic changes is not established after levothyroxine replacement therapy. Therefore our objective was to analyze the reversibility of these anomalies. MATERIALS AND METHODS: We analyzed the impact of levothyroxine treatment on lipid parameters, fibrinogen, platelet count, D-dimers, alpha2 antiplasmin activity, plasminogen activity, tissue plasminogen activator antigen (t-PA Ag), plasminogen activator inhibitor type 1 antigen (PAI-1 Ag) and coagulation factors (factor VIII coagulant, von Willebrand factor antigen, von Willebrand factor and factor IX) in 23 patients with severe hypothyroidism (TSH level > 50 mU/ I). RESULTS: Mean fibrinogen levels increased by 14.2% while t-PA Ag and PAI-1 Ag increased by 42.6 and 69%, respectively, after correction of hypothyroidism. Interestingly, post-treatment PAI-1 Ag levels tended to be higher in patients with normal-high final TSH levels than in patients with normal-low final TSH levels. Our results suggest that normalization of fibrinolysis is obtained after a transient decrease of fibrinolytic activity. We also confirmed the correction of coagulation factor abnormalities upon levothyroxine replacement therapy. CONCLUSIONS: We demonstrated that the coagulation disorders and the hyperfibrinolytic status of severe hypothyroid patients were corrected upon levothyroxine therapy. However, the clinical consequences of the transient decrease of the fibrinolytic activity during the course of TSH normalization need further studies.     

Intra- and postoperative fibrinolysis in patients undergoing cardiopulmonary bypass surgery

The influence of cardiopulmonary bypass (CPB) on fibrinolytic activity was assessed in 100 patients with valvular heart disease or atrial septal defects. Euglobulin fibrinolytic activity (EFA), tissue type plasminogen activator (t-PA) activity, plasminogen activator inhibitor 1 (PAI-1) activity, plasminogen, alpha 2-antiplasmin (alpha 2-AP), fibrinogen degradation products (FDP), and D-dimer were measured pre-, intra-, and postoperatively. There were significant increases in EFA and t-PA activity (p less than 0.002), and decreases in plasminogen and alpha 2-AP (p less than 0.0001) intraoperatively with respect to baseline values. t-PA activity decreased significantly after surgery (p less than 0.002), whereas PAI-1 activity showed a marked increase shortly after operation and on postoperative day 1 (p less than 0.0001). FDP and D-dimer levels were significantly increased both intra- and postoperatively, the latter showing higher values (p less than 0.01 and p less than 0.0001, respectively). This study shows that there is an activation of the fibrinolytic system, as a result of the increased activation of plasminogen and decreased levels of plasmin inhibitors, during CPB surgery followed by a postoperative fibrinolytic shutdown.     

Interactions of tissue-type plasminogen activator with plasma inhibitors and their pharmacologic implications

To delineate interactions of infused tissue-type plasminogen activator (t-PA) with inhibitors in plasma and their impact on fibrinolytic activity, serial plasma samples from patients with acute myocardial infarction and from normal rabbits given infusions of t-PA were assayed for t-PA antigen, activity of "fast acting" plasminogen activator inhibitor (PAI-1), and the presence and nature of t-PA-inhibitor complexes. In patients, endogenous t-PA circulated predominantly as a 100 kilodalton (kDa) complex with PAI-1, as verified by immunoprecipitation. During infusions, t-PA circulated not only as free t-PA (55 kDa) but also in complexes with PAI-1 (100 kDa), alpha 2-antiplasmin (110 kDa), and C1-esterase inhibitor (170 kDa). After termination of infusions, levels of free t-PA declined, while inhibitor complexes remained prominent. Free PAI-1 activity, assayed spectrophotometrically, was markedly elevated in the 24 hr interval after infusion of t-PA in 47% of patients with infarction. The specific activity of t-PA during infusions was 0.4 IU/ng or greater. However, during the 3 hr interval after infusions in patients, specific activity declined in association with prominence of t-PA complexes, predominantly with PAI-1. Infusions of t-PA in normal rabbits did not result in reactive increases in PAI-1 activity or in the t-PA-PAI-1 complex. After infusions, t-PA was associated predominantly with alpha 2-antiplasmin and C1-esterase inhibitor rather than PAI-1. t-PA inhibitor complexes were seen despite immediate acidification of whole blood, indicating that they were present in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fibrinolysis during liver transplantation in humans: role of tissue- type plasminogen activator

Human liver transplantation is frequently associated with a coagulopathy and bleeding diathesis developing during the anhepatic phase of surgery. The hemostatic defect has been attributed in part to accelerated fibrinolysis. In this study we evaluated changes in specific blood fibrinolytic parameters occurring in eight adult patients undergoing first-time orthotopic liver transplantation. Five of the eight patients experienced moderate to severe systemic fibrinolysis as reflected by alpha 2-antiplasmin consumption and fibrinogen degradation with the concomitant appearance of fibrin(ogen) degradation products. In association with these changes, an increase in tissue-type plasminogen activator (t-PA) activity and t-PA antigen levels was also observed. Fibrinolysis was most pronounced during the anhepatic phase of surgery and decreased after revascularization of the grafted liver. Three additional patients who underwent the same procedure manifested much less evidence of systemic fibrinolytic activation and had minimal elevation of t-PA antigen levels or activity. Urokinase-type plasminogen activator levels, although elevated in three patients, were disassociated from increased t-PA levels and concomitant systemic fibrinolysis. The operative course of those patients developing t-PA-associated fibrinolysis was characterized by shock, acidosis, generalized bleeding, and a need for substantially greater blood product support during surgery. These findings suggest that the observed fibrinolytic defect is related to increased circulating plasma levels of t-PA, presumably resulting from a combination of increased intravascular release and decreased hepatic clearance of t-PA. These observations may have implications for intraoperative therapy for the transplant-related coagulopathy and its associated bleeding.     

老年前列腺癌患者去势后性激素水平变化及对凝血和纤溶系统的影响

目的探讨老年前列腺癌患者去势后性激素水平变化及对血液凝血和纤溶系统活性的影响。方法27例早期前列腺癌经手术去势的患者作为研究组,39例非前列腺癌老年患者作为正常对照组。分别测定黄体生成素(LH)、卵泡刺激素(FSH)、总睾酮(TT)、游离睾酮(FT)、雌激素(E2)、部分凝血酶原时间(PT)、活化部分凝血酶时间(APTT)、纤维蛋白原(Fib)、凝血酶原活动度(PA)、纤溶酶原(PLG)活性、α2-抗纤溶酶(α2-PI)活性、抗凝血酶-Ⅲ(AT-Ⅲ)活性、二磷酸腺苷(ADP)活性、D-二聚体(DD)含量、血小板聚集率和黏附率、组织型纤溶酶原激活剂(t-PA)及组织型纤溶酶原激活剂抑制物(PAI-1)抗原浓度。结果研究组中患者TT、FT、E2水平显著降低,E2降低幅度小于TT,LH、FSH、FT/TT、E2/TT显著升高;PT、APTT显著缩短,Fib及DD含量显著增加,血小板聚集率、黏附率及ADP活性均显著升高,PLG、α2-PI活性显著增强,t-PA抗原含量及t-PA/PAI-1显著下降,PAI-1含量显著增加。AT-Ⅲ活性无显著变化。结论前列腺癌患者去势后性激素比例严重失调;血小板活性及血液凝血活性显著增强,纤溶活性显著抑制,提示去势患者存在发生动脉硬化的高度危险性。     

Tissue-type plasminogen activator and its inhibitor (PAI-1) in plasma in cases of non-insulin-dependent diabetes mellitus (NIDDM)

Parameters of fibrinolysis, including plasminogen, alpha 2 plasmin-inhibitor (alpha 2 PI), tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigens, and fibrinogen were assayed in 53 patients (28 women and 27 men; mean age: 64 years, age range: 32-87 years) with non-insulin-dependent diabetes mellitus (NIDDM). The control group was similarly aged (mean age: 60.4 years, age range: 38-81). The levels of t-PA and t-PA/PAI-1 ratio of the diabetic group (mean +/- SD; 9.8 +/- 4.3 ng/ml, 0.94 +/- 0.47, respectively) were significantly higher than that of the control group (5.5 +/- 2.5 ng/ml, 0.51 +/- 0.23, respectively). The increased levels of t-PA antigen and t-PA/PAI-1 ratio in diabetics mean that free t-PA has been released. However, there was no significant difference in the level of PAI-1 between the diabetic group (12.9 +/- 6.4 ng/ml) and the control group (12.1 +/- 5.6 ng/ml). Levels of fibrinogen, plasminogen and alpha 2 PI in plasma were not different in the two groups. Duration of the disease, levels of glycosylated hemoglobin, differences in treatment and presense of diabetic nephropathy or retinopathy did not affect the fibrinolytic parameters. The levels of fibrinogen was higher in those with nephropathy than in the diabetics without nephropathy and retinopathy (p less than 0.05). There were no significant differences in the levels of t-PA, t-PA/PAI-1 ratio and PAI-1 between younger (less than 65 years) and older (65 years or more) subjects, in either the control or diabetic groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pathogenesis of accelerated fibrinolysis in hepatosplenic schistosomiasis.

Seventy patients with different stages of hepatosplenic schistosomiasis and 18 non-bilharzial normal controls were studied. Plasminogen, plasminogen activators (PA), tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), alpha 2-antiplasmin (alpha 2-AP), plasminogen activator inhibitor (PAI), fibrinogen/fibrin degradation products (FDP) and D-dimer were determined to elucidate the role of plasminogen activators and inhibitors in the pathogenesis of accelerated fibrinolysis in schistosomiasis. There was a progressive increase in the levels of PA, t-PA, u-PA, FDP and D-dimer indicating enhanced fibrinolytic activity with advancing disease. In addition, there was progressive decrease of plasminogen, alpha 2-AP and PAI levels which might be due to decreased hepatic synthesis and/or increased peripheral consumption. These findings suggest that the pathogenesis of accelerated fibrinolysis in schistosomiasis is multifactorial, but may be due to the progressive increase in the levels of plasminogen activators. In addition, the increase of FDP and D-dimer levels are evidence of secondary fibrinolysis following thrombin generation.     

A lifelong bleeding disorder associated with a deficiency of plasminogen activator inhibitor type 1

A 36-year-old patient was investigated for a lifelong history of epistaxis and delayed bleeding after minor surgeries. Deficiencies or abnormalities of the coagulation system, of platelet function, or of factor XIII and alpha-2-antiplasmin were excluded. Consistently, however, over a period of 7 years, a high basal euglobulin fibrinolytic activity was observed that was characterized by a high tissue-type plasminogen activator (t-PA) activity, normal t-PA antigen, and undetectable plasminogen activator inhibitor type-1 (PAI-1) antigen and activity. The high specific activity of t-PA (640,000 IU/mg) and the minimal amounts of t-PA/PAI-1 complexes detected by fibrin zymography suggest that in this patient all t-PA was active. This is in striking contrast to normal plasma, where the majority of t-PA is complexed to PAI-1. Thus, in this patient, a severe deficiency of PAI-1 is associated with a delayed type bleeding tendency. Our observation underscores the importance of plasma PAI-1 for the stabilization of the hemostatic plug.     

Complexing of tissue plasminogen activator with PAI-1, alpha 2-macroglobulin, and C1-inhibitor: studies in patients with defibrination and a fibrinolytic state after electroshock or complicated labor.

Release of tissue plasminogen activator (t-PA) and its interaction with plasma protease inhibitors were studied in two patients with massive defibrination, one after electroshock and soft tissue injury and the other after complicated labor; both had very severe hemorrhage. Large quantities of free t-PA were present in the circulation for several hours. Complexes of t-PA with plasminogen activator inhibitor 1 (PAI-1), alpha 2-macroglobulin and C1-inhibitor were also observed. PAI-1 antigen rose dramatically in both patients, and complexes of t-PA with PAI-1 rose rapidly during the period of observation. In contrast, the complexes of t-PA with alpha 2-macroglobulin and C1-inhibitor, present initially, persisted for short periods only and disappeared when free t-PA disappeared from the circulation. Plasmin was generated initially, as indicated by the presence of plasmin-alpha 2-antiplasmin complexes. Plasma concentrations of alpha 2-macroglobulin, C1-inhibitor, antithrombin III, and alpha 2-antiplasmin were severely depleted initially, but rapidly returned to normal. The observations demonstrate that there is a major release of t-PA in such defibrinating patients, that there is a role for protease inhibitors other than PAI-1 in the regulation of endogenous t-PA, and indicate the great rapidity with which such free t-PA is complexed and cleared.     

Profound imbalance of pro-fibrinolytic and anti-fibrinolytic factors (tissue plasminogen activator and plasminogen activator inhibitor type 1) and severe bleeding diathesis in a patient with cirrhosis: correction by liver transplantation.

A 49-year-old male with alcoholic cirrhosis suffered several spontaneous, life-threatening, deep muscle bleeding episodes. Laboratory evaluation indicated excessive fibrinolysis with low plasminogen, low alpha2-antiplasmin, undetectable plasminogen activator inhibitor type 1 (PAI-1) activity, high tissue plasminogen activator (t-PA) activity and high t-PA antigen. Treatment with oral anti-fibrinolytic agents prevented further bleeding episodes. Decompensated cirrhosis eventually necessitated orthotopic liver transplantation. Post-operatively, the patient did not require oral anti-fibrinolytic agents, and there were no significant bleeding events. Circulating PAI-1 activity, t-PA activity and antigen normalized by 3 months post transplant. In short, the profound bleeding diathesis, as well as the imbalance in t-PA and PAI-1 levels, corrected after liver transplantation. Recognition of such patients is important, because the bleeding diathesis is an indication rather than a contraindication for orthotopic liver transplantation.     

Tissue plasminogen activator, plasminogen activator inhibitor, and other parameters of fibrinolysis in the early stages of taurocholate acute pancreatitis in rats.

It is well known that fibrinolytic activity in the early stages of acute experimental pancreatitis (AEP) as assessed by euglobulin lysis time (ELT) is depressed. The aim of this study was to evaluate changes in the fibrinolytic system in the early stages of taurocholate AEP in rats. Tissue plasminogen activator (t-PA) activity, plasminogen activator inhibitor 1 (PAI-1) activity, plasminogen, alpha 1 proteinase inhibitor (alpha 1 PI), alpha 2 antiplasmin (alpha 2 AP), antithrombin III (AT III), fibrinogen, and ELT were measured 0.5, 1, 3, and 6 h after the induction of taurocholate AEP in rats, as well as in sham-operated animals and the control group, which was not submitted to any operation. T-PA activity decreased significantly after 3 and 6 h of AEP; PAI activity had a time course reverse to t-PA and was parallel to alpha 1 PI activity. ELT was slightly prolonged after 0.5, 1, and 3 h, whereas alpha 2 AP activity and plasminogen levels increased significantly; AT III activity was increased after 1 h in comparison to control group. Sham operation caused nonsignificant changes in fibrinolysis. Increase of PAI activity and decrease of t-PA could be a reasonable explanation for inhibited plasma euglobulin fibrinolytic activity noted in the early period of AEP.     

The effects of TNF alpha inhibition on plasma fibrinolytic balance in patients with chronic inflammatory rheumatical disorders

OBJECTIVE: Recent studies support an inflammatory basis for atherosclerosis. Patients with chronic inflammatory rheumatical disorders are at increased risk for cardiovascular events, and this can be partially attributed to the inhibition of fibrinolytic system. TNF a inhibitors such as infliximab are shown to retard the progression of inflammatory arthritides. In this study, we investigated the effects of infliximab on plasma fibrinolytic parameters. METHODS: Thirteen patients (7 female, 6 male; mean age: 44 +/- 11 years) with a clinical indication for infliximab (rheumatoid arthritis (RA) (n = 8), ankylosing spondylitis (AS) (n = 5)) were selected. Plasma plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (t-PA) antigens (Ag) and high sensitive C-reactive protein (hs-CRP) levels were measured during low salt intake at baseline. All patients received infliximab (Remicaide, i.v. infusion, 3 mg/kg). Plasma PAI-1 Ag, t-PA Ag and hs-CRP were measured during low salt intake at the end of 2 weeks. All samples were collected at 9 AM. Antigen levels were determined using a 2-site enzyme-linked immunosorbent assay. RESULTS: Patients experienced significant improvement in disease related activity scores after infliximab treatment. DAS score (for rheumatoid arthritis) and BASDAI index (for ankylosing spondylitis) decreased significantly after treatment (p = 0.01 and p = 0.04 respectively). Infliximab significantly reduced the marker of inflammation (hs-CRP) (8.3 +/- 3.9 vs. 4 +/- 4.1 mg/L, p < 0.01). Plasma PAI-1 antigen (64.7 +/- 26.9 vs. 40 +/- 31.1 ng/ml, p = 0.03) and PAI-1/t-PA ratio (10.8 +/- 5.9 vs. 6.6 +/- 3.8, p = 0.02) were significantly lower after the treatment. In contrast, plasma t-PA levels were unchanged (9.4 +/- 4.4 vs. 9.0 +/- 4.3 ng/ml, p = 0.73). CONCLUSION: This study provides evidence that TNF alpha inhibition with infliximab decreases PAI-1 Ag level and PAI-1/t-PA ratio, and hence activates fibrinolytic system in patients with chronic inflammatory disorders.     

Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products.

Several investigators have reported that tumor necrosis factor (TNF) can alter the production of plasminogen activator type-1 (PAI-1) and plasminogen activators (PAs) by endothelial cells in vitro. We have examined the in vivo effects of recombinant human TNF administration on fibrinolysis as assessed by parameters in plasma during a 24-hour period of continuous TNF infusion to 17 cancer patients with active disease. The plasma levels of PAI activity increased sevenfold after 3 and 24 hours of TNF infusion. This was the result of an increase of PAI-1 antigen; PAI-2 antigen was not detectable. Plasma concentrations of tissue-type PA (t-PA) antigen increased twofold to fivefold after 3 and 24 hours of TNF infusion, whereas urokinase-type PA antigen levels in plasma remained unaltered. After 3 hours of TNF infusion the plasma levels of alpha 2-antiplasmin were slightly decreased, 5% on average, suggesting that fibrinolysis continued. After 24 hours of TNF infusion a highly significant increase in fibrin- plus fibrinogen-degradation products, and separately of fibrin degradation products and fibrinogen degradation products, was found. This indicates that fibrinolysis persisted, at least partly, in the presence of high levels of PAI activity. Whereas PAI-1 production increased, t-PA production by human endothelial cells in vitro remains unaltered or even decreases on TNF addition. It has been shown previously that TNF infusion in our patients results in thrombin and fibrin generation. Therefore, it is possible that thrombin, not TNF, is the actual stimulus for t-PA production in our patients. We speculate that fibrin is formed during TNF infusions and that plasmin is generated by t-PA action immediately on the initial formation of (soluble) fibrin molecules. Such a process may explain the generation of degradation products of both fibrin and fibrinogen during infusion of TNF in patients.     

Blood coagulation and fibrinolysis in patients with hyperthyroidism

Several papers concerning abnormalities of blood coagulation and fibrinolysis during hyperthyroidism, have been published. Increased von Willebrand Factor (vWF) activity and high fibrinogen levels have been reported. However, there is controversy concerning the presence of a hypercoagulable state in hyperthyroidism. We investigated various hemostatic parameters in 41 hyperthyroid patients and compared them to 20 euthyroid controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors V, VII, VIII, IX and X activities, vWF, antithrombin III (AT III), protein C, protein S, tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor-1 (PAI-1), as well as common lipid variables, were measured. The relationships between serum thyroid hormones and these hemostatic parameters were examined. Compared with control subjects, fibrinogen, factor IX, vWF, AT III and PAI-1 were significantly increased in patients (p<0.05, p<0.0001, p<0.05, p<0.01 and p<0.0001; respectively), whereas factor X and t-PA were decreased (p<0.05). We showed that free T4 (FT3) levels were correlated with factor VIII activity (r=0.35, p<0.05). FT4, FT3 and TSH did not correlate with fibrinogen, vWF, AT III, t-PA, or PAI-1. AT III was inversely correlated with factor VII activity (r=-0.48, p<0.01). Protein C and S were correlated with vWF levels (r=0.58, p<0.0001; r=0.55, p<0.0001, respectively). Protein C was inversely correlated with t-PA (r=-0.39, p<0.01). There was a negative correlation between triglycerides, LDL-C and F X (r=-0.45, p<0.05; r=-64, p<0.01, respectively). Mean platelet volume (MPV) was correlated with anti-thyroid peroxidase (TPO) antibodies (in Graves'disease) and F IX activity (r=0.57, p<0.05 and r=0.39, p<0.05; respectively). We found important differences in the coagulatory /fibrinolytic parameters between the hyperthyroid patients and healthy controls. Hyperthyroid patients may experience vascular endothelial dysfunction and decreased fibrinolytic activity in blood. This endothelial activation may represent a situation with a higher thromboembolic potential.     

Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit

Disseminated thrombotic processes in the microcirculation are considered to be an important cause of multiple organ failure in septic patients. Fibrinolysis is one endogenous mechanism protecting the circulation from overwhelming thrombosis. Therefore, we looked for alterations of fibrinolytic parameters (tissue plasminogen activator (t-PA), tissue plasminogen activator inhibitor (PAI), D-dimer, euglobulin-clot-lysis-time (ECLT), plasminogen, alpha 2-antiplasmin) and of some coagulation parameters (prothrombin time, fibrinogen, platelets, antithrombin III, protein C, factor XII) in clearly defined septic patients and for the relations of these values to the severity of the disease (APACHE II-score). An increase in D-dimer and t-PA-antigen was registered in all patients, while factor XII and plasminogen were decreased, indicating an activated fibrinolysis. In contrast the systemic fibrinolytic capacity of the blood was strongly inhibited: t-PA-activity was not detectable, PAI-function was elevated, the ECLT was prolonged and alpha 2-antiplasmin was normal. Coagulation was moderately activated: the platelets, antithrombin III and protein C were decreased, the prothrombin time was prolonged and fibrinogen was normal. The changes in t-PA-antigen, PAI-function, factor XII, prothrombin time and antithrombin III were significantly related to the APACHE II-score of the patients. We conclude that the activation of coagulation is accompanied by an activation of fibrinolysis in the microcirculation, but that systemically the increased inhibitors of fibrinolysis (PAI, alpha 2-antiplasmin) induce a decrease of the fibrinolytic capacity of the blood. The severity of the disease determines the extent of the alterations.     

Clinical pharmacology in patients with evolving myocardial infarction of tissue-type plasminogen activator produced by recombinant DNA technology

This study was performed to characterize selected pharmacologic properties and effects on the fibrinolytic system of tissue-type plasminogen activator synthesized by recombinant DNA technology (rt-PA) in 12 patients treated for coronary thrombosis. rt-PA was infused parenterally (by the intracoronary route in four patients and intravenously in eight) in doses of 8.3, 12.5, or 16.7 micrograms/kg/min for 30 to 60 min, yielding a total dosage of 20 to 40 mg/patient. The drug induced coronary thrombolysis in 10 of the 12 patients treated (83%), including six of the eight given rt-PA intravenously. No bleeding complications were encountered. Serial blood samples were obtained before, during, and after infusion of rt-PA and analyzed for t-PA antigen (i.e., immunoassayable rt-PA protein), functional fibrinolytic activity attributable to rt-PA, fibrinogen, plasminogen, alpha 2-antiplasmin, fibrinogen degradation products, prothrombin time, activated partial thromboplastin time, and protamine-corrected thrombin time. Pretreatment plasma t-PA antigen levels averaged 16.5 +/- 5(SD) ng/ml. Peak plasma values were generally proportional to dose, averaging 3330 +/- 1201 ng/ml. Approximately 90% of peak level was reached in 30 min, with a plateau at peak reached within 40 min. Functional t-PA activity increased monotonically in a comparable fashion. Curves for disappearance of both t-PA antigen and functional activity from plasma were monoexponential for at least two half-lives (r = .99 for both) and were concordant. The observed half-lives were similar, averaging 8.3 and 9.1 min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of haemostatic and fibrinolytic markers in patients with Cushing's syndrome and in patients with adrenal incidentaloma.

It is known that either chronic glucocorticoid administration or endogenous hypercortisolism frequently induce an hypercoagulable condition. Since little is known about the evaluation of markers of haemostatic and fibrinolytic systems in other adrenal disorders, we studied plasminogen activator inhibitor (PAI-1), tissue-plasminogen activator (t-PA), fibrinogen and von Willebrand factor antigen (vWF-Ag) levels in 11 patients with Cushing's syndrome and in 12 patients with adrenal incidentaloma. In patients with Cushing's syndrome mean PAI-1, t-PA and vWF-Ag levels did not significantly differ from those found in 50 age- and sex-matched controls, while mean fibrinogen levels were significantly higher in patients (337.0+/-39.1 mg/dl) than in normal subjects (278.9+/-8.4 mg/dl). Patients with adrenal incidentaloma showed PAI-1, t-PA and vWF-Ag mean levels superimposable to those in controls, while fibrinogen (319.7+/-27.9 mg/dl) was slightly, although not significantly, higher than in normals. Considering the limits of normal values (as mean+/-2 SD) obtained in the control group, high PAI-1 levels were found in 2 patients with Cushing's syndrome and in 3 patients with incidentaloma. An elevation of fibrinogen levels was found in 3 patients with Cushing's syndrome and in 3 with incidentaloma. Increased vWF-Ag levels were found only in 1 patient with Cushing's syndrome. An increased t-PA level was occasionally observed only in the patient with adrenal carcinoma. On the whole, an alteration of at least one of haemostatic and fibrinolytic parameters was detected in 55% of the patients with Cushing's syndrome and in 42% of those with adrenal incidentaloma. In conclusion, early alterations of coagulation and fibrinolytic systems may be found in some patients with adrenal disorders, thus suggesting the opportunity of an accurate follow-up in order to identify possible risk factors for cardiovascular disease and thromboembolism.     

Coagulation, fibrinolytic, and inhibitory proteins in acute myocardial infarction and angina pectoris.

BACKGROUND AND METHOD: The role of thrombus formation in the pathogenesis of acute myocardial infarction (AMI) and unstable angina pectoris has been well established. However, comprehensive and systematic studies of the blood coagulation, fibrinolytic, and inhibitory proteins are not available in patients with these conditions. Fourteen patients with AMI, 10 patients with angina pectoris, and 32 normal volunteers were studied. Plasma antigen concentrations and/or activities of high-molecular-weight kininogen (HMWK), fibrinogen, fibronectin, plasminogen, D-dimer, tissue plasminogen activator (t-PA), alpha 2-antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, protein C, total and free protein S, antithrombin III (AT-III), von Willebrand factor (vWF), factors (F) XII, XI, IX, VIII, VII, X, V, II, and XIII, and plasma antiplasmin activity were measured using appropriate functional or immunologic assays. RESULTS: The AMI group showed a significant reduction in F XII activity, F XII activity-to-concentration ratio, and HMWK concentration. In addition, the AMI patients exhibited a significant elevation of plasma F XI activity, F IX concentration, and F IX activity, and vWF, fibrinogen, D-dimer, and t-PA concentrations. This was associated with significant reductions in F V, F II, and AT-III activity-to-concentration ratio. Many of the changes observed in AMI patients were also present in patients with angina pectoris. Furthermore, the latter group exhibited an elevation of F VIII activity, alpha 2-macroglobulin activity, and alpha 1-antitrypsin concentration and a significant reduction of antiplasmin activity despite a normal alpha 2-antiplasmin concentration. CONCLUSIONS: The observed reduction of the plasma F XII activity-to-antigen concentration ratio combined with a reduced HMWK concentration suggests intrinsic pathway activation, while the elevation of the D-dimer concentration indicates thrombin generation and fibrin formation and degradation in the AMI group. The latter changes were also present in patients with angina pectoris. Both AMI and angina groups showed several other abnormalities of the coagulation, fibrinolytic, and inhibitory systems. The results suggest the presence of a prothrombotic state associated with the activation of coagulation and fibrinolytic systems in patients with acute myocardial ischemia or infarction.     

Diurnal variation of tissue-type plasminogen activator and its rapid inhibitor (PAI-1)

Previous studies have shown that overall fibrinolytic activity in blood follows a diurnal rhythm with a peak in the morning and a trough in the evening. The purpose of this study was to determine which fibrinolytic factor(s) was responsible for this diurnal rhythm. Resting and postvenous occlusion tissue-type plasminogen activator (t-PA) activity, resting t-PA antigen, and resting plasminogen activator inhibitor 1 (PAI-1) activity were measured in the morning and evening in 33 healthy men (mean age, 31 years) and in 15 patients (mean age, 57 years) with previous myocardial infarction or unstable angina. PAI-1 activity and t-PA antigen were significantly higher (p less than 0.01) in the morning compared with the evening in controls and patients. In contrast, resting t-PA activity was significantly lower in the morning (p less than 0.01) in both groups and was inversely correlated with PAI-1 activity (r = -0.57, p less than 0.0001). Postvenous occlusion t-PA activity and t-PA capacity were not significantly different between morning and evening in either group. Because t-PA antigen levels and PAI-1 activity were highest in the morning, the variation in t-PA activity was probably not due to decreased secretion of t-PA but instead to changes in the secretion of PAI-1. Our findings indicate that diurnal variations in PAI-1 activity may reduce fibrinolytic activity in the morning in healthy individuals and in patients with coronary artery disease.     

Fibrinolytic response to venous occlusion in patients with homozygous sickle cell disease

The fibrinolytic potential was evaluated in 37 patients with homozygous sickle cell disease and compared to a control group of 30 age- and sex-matched healthy volunteers. In all individuals, the euglobulin clot lysis time and plasma antigen levels of t-PA and PAI-1 were measured before and after venous occlusion (v.o) for 10 min. The global fibrinolytic activity was normal in 4 patients (good responders to v.o), while it was decreased in 33 patients (poor responders to v.o). Among the latter, 22 patients had significantly increased baseline levels of PAI-1 Ag (82.6 ± 27.5 ng/ml, p < 0.001) and a normal release of t-PA Ag after v.o. In contrast, 11 patients had basal values of PAI-1 Ag comparable to those in controls with a defective release of t-PA Ag after v.o (11.4 ± 5.2 ng/ml, p < 0.01). These data provide evidence for reduced fibrinolytic capacity resulting from either increased basal levels of PAI-1 or defective release of t-PA.