Biomedical subjects
Publications and source records attributed to M T Sartori.
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To determine whether fibrinolytic testing predicts recurrent venous thrombosis, we have performed a prospective cohort study in which 303 patients with a first episode of venous thromboembolism underwent comprehensive fibrinolytic testing while receiving oral anticoagulants, and after anticoagulants had been discontinued. They were then followed for up to 3 years for recurrent venous thrombosis. No systematic differences in the levels or activity of type 1 plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (tPA) or euglobulin clot lysis times were detected between patients who did, or did not, suffer recurrent thrombosis. There were also no differences in these variables when patients whose initial thrombosis was idiopathic were compared to patients whose thrombosis occurred in the setting of a known thrombotic risk factor. Based on these results, neither measuring fibrinolytic parameters in patients with venous thromboembolism, nor modification of treatment based on the results of such testing, are justified. Our study also confirms that patients with idiopathic venous thromboembolism have a high risk of recurrence.
As PAI-1, a cardiovascular risk factor linked to insulin-resistance, may be influenced by a 4G/5G gene polymorphism in disease states, we studied both PAI-1 plasma concentration (PAI-1:Ag) and 4G/5G polymorphism, and their relationship with anthropometric and endocrinemetabolic parameters in 93 obese patients and 79 lean normal subjects. In obese patients PAI-1:Ag levels were significantly increased, namely in males and in those with central obesity, and tightly related to the insulin-resistance parameters. In obese patients the 4G/5G polymorphism was a determinant of PAI-1:Ag levels, which were highest in 4G/4G, intermediate in 4G/5G and lowest in 5G/5G genotype carriers. PAI-1:Ag levels were significantly associated with most of anthropometric and endocrine-metabolic parameters only in 4G allele obese carriers. Moreover, only in patients with central obesity was the relationship between genotype and PAI-1 concentration maintained, with the highest levels in the 4G/4G patients. In each genotype subset of patients with central, but not peripheral, obesity PAI-1:Ag levels were significantly increased compared to their lean counterparts. In conclusion, the 4G/5G polymorphism may influence PAI-1 expression in obesity, with a crucial role in central but not peripheral adiposity. Since subjects with central obesity are at high risk for cardiovascular disease, the effects of the 4G/5G polymorphism on PAI-1 concentration may further enhance this risk.
BACKGROUND: Long-term steroid immunosuppression has been associated with the prothrombotic state observed in renal transplant (RT) patients, in whom both hypercoagulability due to an increase of von Willebrand factor/factor VIII complex, and impaired fibrinolysis due to PAI-1 excess have been demonstrated. Our aim was to investigate the effect of steroid withdrawal on fibrinolytic capacity in a group of RT patients. METHODS: The fibrinolytic study was performed in 28 RT patients under stable immunosuppression therapy with cyclosporine, azathioprine, and methylprednisolone; only 12 of these patients could repeat the study 6 months after steroid withdrawal. Euglobulin lysis time (ELT), tissue plasminogen activator activity (t-PA:act) and antigen (t-PA:Ag), PAI-1 activity (PAI-1:act), and antigen (PAI-1:Ag) were assayed on blood samples drawn before and 20 min after the venous occlusion test (VO). RESULTS: An hypofibrinolytic state due to a significant increase in PAI-1 levels was confirmed in RT patients receiving triple immunosuppression therapy. RT patient who stayed off steroids showed a significant shortening of ELT both before (P=0.01) and 20' after VO (P=0.005) at the 6-month control. Moreover, after steroid withdrawal, PAI-1:Ag levels decreased significantly (P=0.002) and normalized; in a similar manner PAI-1:act levels also showed a significant decrease both before (P=0.001), and after VO (P=0.0001). The prevalence of RT patients with impaired fibrinolytic capacity was as high as 83.3% during steroid treatment, and dropped to 16.7% after steroid withdrawal. CONCLUSIONS: Our findings confirm that steroid withdrawal may normalize impaired fibrinolytic capacity in RT patients; this improvement may further contribute to reduce the thrombotic risk associated with renal transplantation.
Combined plasminogen deficiency and resistance to activated protein C defect (factor V Leiden) have been described in a few families and associated with a variable occurrence of thrombotic events. Here we describe a new family with thrombophilia and the presence of hypoplasminogenemia and factor V Leiden mutation. In addition, a brief review of the literature is presented. Nine patients belonging to this kindred underwent coagulation study for hereditary thrombophilia, which included plasminogen antigen and activity assays, an activated protein C resistance test, and genetic analysis for factor V Leiden mutation and for prothrombin variant 20210A. The proposita, a 40-year-old asymptomatic female with a family history of thrombotic diathesis, was affected by heterozygous plasminogen deficiency. Hypoplasminogenemia was found also in her two sisters, in one instance associated with factor V Leiden mutation. The mother was the putative carrier of hypoplasminogenemia, but she refused to be studied. The symptomatic father was heterozygous for factor V Leiden mutation, but presented with normal plasminogen levels. Among the available siblings investigated from the paternal side, resistance to activated protein C due to factor V Leiden mutation was found in three patients, one of whom experienced venous thromboembolism. Another uncle with a history of thrombotic disease showed no coagulation abnormalities. These findings together with the data from literature confirm the role of factor V Leiden as an independent risk factor for venous thromboembolism, whereas isolated hypoplasminogenemia does not seem to increase the risk for thrombosis. There is no clear evidence that the coinheritance of these two defects may be associated with an additional risk for thrombosis compared with the presence of factor V Leiden mutation alone.
BACKGROUND: Plasma homocyst(e)ine levels (pHo) can be a risk marker for cardiovascular diseases. Different factors affect pHo, but it remains unclear whether pHo are genetically determined and whether they are related to other risk markers, such as the angiotensin I converting enzyme (ACE) and the plasminogen activator inhibitor type-1 (PAI-1). METHODS: We measured fasting pHo, plasma levels of ACE (pACE), and PAI-1 antigen (PAI-1:ag) in 60 pairs of healthy monozygotic (MZ) and dizygotic (DZ) normotensive twins. Twin zygosity was determined with polymerase chain reaction analysis of informative minisatellite markers. pHo data were first analyzed with TWINAN90 to obtain estimates of genetic variance and heritability and then examined jointly in a path analysis. RESULTS: Thirty-one twins were MZ and 29 DZ. The mean pHo were 10.48 +/- 4.07 mumol/L (95% confidence interval, 9.73-11.24 mumol/L). Two pairs had to be excluded from further analysis because of overt hyperhomocyst(e)inemia resulting from concomitant drug treatment. Highly statistically significant intraclass correlation coefficients were observed both in MZ (r = 0.421; P = 0.008) and in DZ (r = 0.488; P = 0.004). Because all tests of genetic variance and heritability were not significant, the hypothesis of genetic variance and heritability of pHo was rejected. The preferred model of a likelihood-based analysis included an additive genetic influence (A), a common environmental influence (C), and an individually unique environmental influence (E), accounting for 8%, 39%, and 53%, of pHo variance, respectively. No relationship between pHo and pACE or PAI-1:ag was detected. CONCLUSIONS: These data do not support the contention that normal-to-borderline elevated pHo of healthy subjects are heritable and under major genetic influence. They suggest that E and C are far more important than A in determining pHo variance. Furthermore, they provide no evidence of a relationship of pHo with pACE and PAI-1:ag.
We investigated whether plasma levels of the plasminogen activator inhibitor type 1 antigen (PAI-1:Ag) are genetically determined in monozygotic (MZ) and dizygotic (DZ) twins. Twenty-five pairs of healthy twins underwent measurements of PAI-1:Ag and other variables, including body mass index, mean blood pressure, plasma renin activity, insulin, and glucose. To ascertain the zygosity of twins, highly discriminating micro- and minisatellite systems with variable numbers of tandem repeats were analyzed by PCR amplification followed by polyacrylamide gel electrophoresis. Subjects were also genotyped for the 4G/5G polymorphism by PCR. Estimates of genetic variance and heritability were obtained for PAI-1:Ag, and for body mass index, mean blood pressure, plasma renin activity, glucose, and insulin by jointly examining data in a path analysis with TWINAN90. Results showed that 12 pairs of twins were MZ and 13 were DZ. All tests of genetic variance [within pair (WP): F=6.24, P=0.002; among component (AC): F=2.62, P=0.04; average absolute difference t test=3. 00, P=0.004] showed significant genetic variance of PAI-1:Ag, but not of the other variables. Three tests of heritability (WP=0.837, P=0.002; AC=1.791, P<0.05; intraclass correlation: 1.180, P=0.001) consistently showed significant PAI-1:Ag heritability. Additive genetic influences (A), dominance genetic effect (D), and random environmental influences (E) accounted for 0.714, 0.154, and 0.132 of PAI-1:Ag variance, respectively. No effect of different 4G/5G genotypes was found. Thus, these results show significant genetic variance and heritability of PAI-1:Ag and suggest that A is more important than both D and E in determining PAI-1:Ag variance.
The coinheritance of hypoplasminogenemia and heterozygous factor V deficiency in a relative with thrombotic disease and no hemorrhagic tendency is described. The proposita, a 28-year-old woman, suffered from neurologic disturbances due to two ischemic cerebral lesions confirmed by nuclear magnetic resonance scan. She was found to be affected with heterozygous plasminogen deficiency in a coagulation study for inherited thrombophilia. Moreover, she disclosed a prolongation of prothrombin time and activated partial thromboplastin time, which was compatible with heterozygous factor V deficiency. Her father, with a history of deep vein thrombosis, was also affected with plasminogen deficiency, as well as three brothers and one sister who were asymptomatic. The mother of the proposita showed borderline or slightly decreased factor V levels and normal plasminogen levels; she was therefore considered to be heterozygous for factor V deficiency. Heterozygous factor V deficiency was also found in one brother and one sister of the proposita, and they were both asymptomatic. Among the other available family members, one brother and one sister of the proposita, all asymptomatic for either thrombotic or bleeding events, showed a normal clotting and fibrinolytic profile. To our knowledge, this is the first case of combined heterozygous plasminogen and factor V deficiency in the same family. Two of six patients with hypoplasminogenemia showed thrombotic events, and in one of these symptomatic cases the coexistence of factor V deficiency did not prevent the occurrence of thrombosis. As expected, no hemorrhagic tendency was observed in patients with heterozygous factor V deficiency, who may be mildly symptomatic only in 10% of cases.
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A deletion/insertion polymorphism (4G or 5G) in the promoter of the plasminogen activator inhibitor type 1 gene has been suggested to be involved in regulation of the synthesis of the inhibitor, the 4G allele being associated with enhanced gene expression. A relationship between 4G/5G polymorphism and PAI-1 levels was found in patients with cardiovascular and metabolic diseases, but not in healthy subjects. In the present work we studied the distribution of PAI-1 4G/5G genotype and its relation to fibrinolytic capacity in 70 unrelated patients with deep vein thrombosis. Each patient was assayed before and after 20 min. Venous occlusion for euglobulin lysis time, t-PA antigen and activity, and PAI-1 antigen and activity. The prevalence of 5G homozygous carriers was significantly lower in patients than in controls (10% vs. 26%, p=0.009). The 5G allele frequency was reduced, even though not significantly, in DVT patients compared to healthy subjects (0.40 vs. 0.51, respectively). In the patient group, the mean PAI-1 antigen and activity levels were significantly higher than among controls and related to the 4G/5G polymorphism. In patients with 4G/5G and 4G/4G genotype a significant correlation was found between PAI-1 levels and the global fibrinolytic activity as evaluated by euglobulin lysis time. The prevalence of a reduced fibrinolytic potential due to PAI-1 excess was 45.7% among DVT patients. Moreover, the prevalence of PAI-1 induced hypofibrinolysis was strongly related to PAI-1 polymorphism, since it was significantly lower in 5G homozygous patients (28.6%) than in both 4G/5G carriers (55.3%, p <0.001) and 4G homozygous patients (57.9%, p <0.001). In conclusion, in patients with deep vein thrombosis the 4G polymorphism of PAI-1 gene promoter may influence the expression of PAI-1 and it should be taken into consideration as a facilitating condition for pathological fibrinolysis together with other environmental and genetic factors. Whether this has any significance in regard to the pathogenesis of venous thrombosis remains to be proven.
Thrombotic complications constitute an important risk in transplant recipients, in whom a hypercoagulable state and hypofibrinolysis have been associated with immunosuppressive treatment, especially with cyclosporine. In no case have clotting and fibrinolytic abnormalities been correlated with steroid immunosuppression, even though steroids were always administered. Previous studies found a relationship between hypercorticism and hypofibrinolysis both in Cushing's disease and after renal transplantation. The aim of this investigation was to compare fibrinolytic potential using the venous occlusion test in two similar groups of heart transplant patients treated with or without steroids. Euglobulin lysis time, tissue-type plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) activities, and antigens were determined before and after the venous occlusion test. A reduced fibrinolytic potential (significant prolongation of lysis time) due to a significant increase in PAI-1 activity and antigen levels was found in heart transplant patients treated with steroids, as compared with patients without steroid treatment and control subjects. The prevalence of reduced fibrinolytic potential was 69.2% (18 cases) in the steroid-treated group and 34.8% (8 cases) in the non-steroid-treated group. In every case, the impaired fibrinolytic potential was due to high basal PAI-1 levels. Our results are compatible with the presence of a hypofibrinolytic state secondary to long-term steroid treatment. In heart transplant recipients, steroid-induced hypofibrinolysis may constitute a further risk factor for thrombotic disease.
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Thromboembolic complications constitute an important risk in renal transplant patients, in whom a hypercoagulable state is associated with immunosuppressive treatment, and the presence of hypercoagulability and hypofibrinolysis specifically with cyclosporine. Hypercorticism secondary to steroid treatment has been associated with a thrombophilic state and the presence of a reduced fibrinolytic potential in particular. The aims of this study were to first evaluate the fibrinolytic potential by the venous occlusion (VO) test in 19 renal transplant (RT) patients, and then compare these findings with those obtained in similar groups of normal subjects and patients with Cushing's disease. The following tests were carried out before and after the VO test: euglobulin lysis time and t-PA and PAI-1 activities and antigen. Compared with normal controls, RT and Cushing's patients both showed a similar significant increase in PAI-1 activity and concentration. The VO test revealed a similar impairment in fibrinolytic potential in both the RT and Cushing groups. High and pathological PAI-1 levels before and after the VO test were consistent with a defective fibrinolytic potential due to the inhibitory effect of PAI-1 on plasminogen activation. A hypofibrinolytic state was found in 68.4% of RT patients. Our results suggest that an imbalance in the fibrinolytic system is a typical feature of RT patients one year after transplantation. Steroids appear to be the immunosuppressive drug mainly involved in determining thromboembolic risk after renal transplantation.
The acute simultaneous release of tissue plasminogen activator (t-PA) and von Willebrand factor (vWF) from endothelial cells in response to a variety of agonists including thrombin, DDAVP, histamine and adrenalin has been described. In the present study we investigated the effect of venous occlusion on the circulating levels of t-PA and vWF, as well as the molecular organization of vWF in 20 normal subjects. After occlusion a significant increase in plasma t-PA levels was observed even after the values were corrected for haemoconcentration. Venous occlusion also enhanced plasma vWF values, but the increase was abolished when the correction for haemoconcentration was introduced. Following venous occlusion, no circulating abnormally large vWF multimers were detected in the subjects studied. These forms are normally not present in the circulation and are released from endothelial cells through the regulated vWF pathway; their absence therefore seems to demonstrate that this pathway is not activated after venous occlusion. Since occlusion does not enhance vWF synthesis, the increase in vWF observed in the subjects investigated may be fully attributed to haemoconcentration.
The association between heterozygous factor VII deficiency and severe hemophilia A in the same family is described. The 18-year-old proposita had a negative personal history for bleeding events and underwent clotting evaluation after a fortuitous finding of a prolonged PT. Decreased levels of both factor VII activity and antigen to about 50% of normal, compatible with heterozygous deficiency, were found in her and in three other asymptomatic siblings. Two uncles on the paternal side had severe hemophilia A and also showed low factor VII levels. However, in these two patients factor VII deficiency was secondary to chronic liver disease due to hepatitis B and C virus infections. Combined clotting defects in the same kindred may be due to an independent segregation of two separate defects or to common gene(s) malfunction. Factor VII deficiency is frequent and probably underestimated in the general population. For these reasons factor VII deficiency can easily segregate with other clotting defects.
Patients with antiphospholipid antibodies may suffer from thrombotic events and recurrent spontaneous abortions. A defective fibrinolytic potential has been described in women with recurrent fetal losses. We investigated the prevalence of anticardiolipin antibodies and of various fibrinolytic abnormalities in 64 females with a history of at least two abortions of unknown origin. Anticardiolipin antibodies were present in the serum of 31 patients (48.4%). The overall prevalence of fibrinolytic disorders was 67.2% (43 cases) and resulted significantly higher than that of aCL positivity (P = 0.03). In most of cases the impaired fibrinolytic potential after venous occlusion test was due to increased PAI-1 levels; only in a few instances a defective fibrinolytic response was due to reduced t-PA release, a combined defect or an intrinsic fibrinolytic deficiency. After division of patients in two groups on the basis of the aCL presence, the distribution of different fibrinolytic defects was similar in aCL positive and negative women, suggesting the lack of correlation between hypofibrinolysis and aCL antibodies. Plasminogen abnormalities resulted compatible with congenital hypoplasminogenemia in two aCL negative women, whereas in four aCL positive patients they were suggestive for acquired dysplasminogenemia. Our results indicate that patients with recurrent spontaneous abortions may present fibrinolytic disorders, which occur independently and more often than aCL positivity. An accurate investigation of the fibrinolytic potential, and, namely, of PAI-1 levels, should be included in the study of females suffering from repeated fetal losses.