Absence of interaction between rivaroxaban, tacrolimus and everolimus in renal transplant recipients with deep vein thrombosis or atrial fibrillation.

No data are available on rivaroxaban use in renal transplant recipients and on its surmised interaction with immunosuppressants. The aim was to investigate potential interactions between rivaroxaban and immunosuppressants in this setting. Renal transplant recipients with a stable renal function treated with rivaroxaban and tacrolimus with or without everolimus were investigated. All drugs and creatinine concentrations were determined daily for 2 weeks after the start of anticoagulation. Blood samples were drawn at 8.00 am and 3-4 h later for trough and peak concentrations, respectively. Bleeding and thrombotic events were recorded during a minimum follow-up of 6 months. In 8 renal transplant patients, rivaroxaban levels showed a predictable pharmacokinetic trend, both at Ctrough (30-61 µg/L) and at Cpeak (143-449 µg/L), with limited variability in the 25th-75th percentile range. Tacrolimus (Ctrough 3-13 µg/L; Cpeak 3-16 µg/L), everolimus (Ctrough 3-11 µg/L; Cpeak 5-17 µg/L) and creatinine concentrations were stable as well. Immunosuppressors variability before and after rivaroxaban were 30% and 30% for tacrolimus, 27% and 29% for everolimus, respectively, as well as 14% and 3% for creatinine. For rivaroxaban monitoring, the reference change value better performed in identifying significant variations of its concentration. No patient had bleeding or thrombotic events, worsening of renal graft function, and signs of immunosuppressants toxicity during a mean follow-up of 23 (9-28) months. In conclusion, rivaroxaban does not seem to interact with tacrolimus and everolimus in renal transplant recipients. Both anticoagulant and immunosuppressive effects seem warranted, without major bleeding complications and effect on the graft function.

Thrombosis of abdominal aorta in congenital afibrinogenemia: case report and review of literature.

Thrombotic events in congenital hypo-afibrinogenemia have been rarely reported, either in association or not with replacement therapy or thrombotic risk factors. We describe clinical findings and management of thrombosis of abdominal aorta with peripheral embolism in a patient with congenital afibrinogenemia. A review of arterial thrombosis in inherited hypo-afibrinogenemia was also performed. The patient with a severe bleeding history requiring prophylaxis with fibrinogen concentrates (FC) was admitted for ischaemia of the 4th right toe. An angio-CT of abdominal aorta showed a thrombosis from the origin of renal arteries to the carrefour with a distal floating part. No thrombotic risk factors were found; a previous traumatic lesion of aortic wall might have triggered the thrombus formation, whereas the role of FC prophylaxis remains uncertain. The patient was successfully treated with FC, enoxaparin followed by fondaparinux, and low-dose aspirin without bleeding or thrombosis recurrence. After 2 years, aortic thrombus was almost completely recovered. Sixteen hypo/afibrinogenemia patients with arterial thrombosis were found in Literature, showing that thrombosis often occurs at a young age, involves large vessels, its recurrence is not unusual, and therapeutic strategy is not defined yet. Our therapeutic approach was effective and also safe, but further studies are needed to improve the knowledge of pathogenesis and the anti-thrombotic management in this peculiar setting.

Venous thromboembolism in patients with Cushing's syndrome: need of a careful investigation of the prothrombotic risk profile.

A high incidence of venous thromboembolic (VTE) complications has been reported in Cushing's syndrome (CS), mostly post-operatively and attributable to hypercoagulability. The prevalence of symptomatic VTE was investigated retrospectively in 58 consecutive CS patients in relation to acquired and genetic thrombotic risk factors. Eight CS patients (14 %) developed VTE (group A), 3 of them related and 5 unrelated to surgery. These patients had higher urinary free cortisol (p = 0.01) and VWF levels (p = 0.02) than the 50 patients without VTE (group B), as well an increase in the hemostatically more efficient, high-molecular-weight VWF multimers (p = 0.002). Factor V Leiden and the prothrombin gene 20210A variants (the most common inherited thrombophilic defects) were more represented in group A than in group B, as was the genotype GCAG/GCAG of the VWF gene promoter, known to hyperinduce VWF upregulation under cortisol excess. All but one of the patients with VTE unrelated to surgery had at least four acquired and at least one inherited risk factor. Severe hypercortisolism and VWF levels with increased haemostatic activity are strongly associated with VTE in CS. VTE episodes unrelated to surgery are attributable to the synergistic action of acquired and inherited thrombotic risk factors. Based on these observations, we believe that severely affected CS patients should be screened for coagulation disorders and receive antithrombotic prophylaxis whenever they have concomitant prothrombotic risk factors.

Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced cirrhosis.

INTRODUCTION: Cirrhotic patients may present thrombotic complications that warrant anticoagulant therapy. However, the efficacy of low-molecular-weight heparin (LMWH) in this clinical setting is still unclear. AIMS/METHODS: To evaluate the in vitro effect of LMWH on thrombin generation (TG) in cirrhotic patients at different stages of liver disease. Thirty cirrhotics (10 Child Pugh A, 10 Child Pugh B and 10 Child Pugh C), 10 subjects with inherited type 1 antithrombin (AT) defect and 10 healthy controls were studied. TG was determined at baseline and with anti-Xa levels after the addition of enoxaparin at 0.35 and 0.7 U anti-Xa mL. The endogenous thrombin potential (ETP) ratio at 0.35 and 0.7 U anti-Xa mL was obtained by dividing ETP with LMWH by ETP at baseline. RESULTS: Mean AT levels in all cirrhotic subgroups and in patients with AT deficiency were significantly lower than in controls. The 0.35 ETP ratio was significantly lower in cirrhotic patients than in controls (0.26 ± 0.1 vs. 0.48 ± 0.1, P < 0.001) and the reduction paralleled the severity of liver disease, in spite of the concomitant decrease in AT and anti-Xa activity. AT-deficient subjects showed a significantly increased 0.35 ETP ratio compared with both cirrhotic patients and controls (0.69 ± 1 vs. 0.26 ± 0.1, P < 0.001, and vs. 0.48 ± 0.1, P = 0.04 respectively). LMWH at 0.7 U anti-Xa mL completely inhibited TG in 9/30 cirrhosis patients with more advanced liver disease (Child Pugh B and C), whereas complete TG abolition was seen in only 1/10 controls. CONCLUSIONS: Cirrhotic patients show an increased response to LMWH, which correlates with the severity of liver disease, in spite of reduced AT and anti-Xa activity levels. Thrombin generation may be a useful tool to monitor the response to LMWH in cirrhotic patients.

Long-term outcomes of patients with cerebral vein thrombosis: a multicenter study.

BACKGROUND: Little information is available on the long-term clinical outcome of cerebral vein thrombosis (CVT). OBJECTIVES AND METHODS: In an international, retrospective cohort study, we assessed the long-term rates of mortality, residual disability and recurrent venous thromboembolism (VTE) in a cohort of patients with a first CVT episode. RESULTS: Seven hundred and six patients (73.7% females) with CVT were included. Patients were followed for a total of 3171 patient-years. Median follow-up was 40 months (range 6, 297 months). At the end of follow-up, 20 patients had died (2.8%). The outcome was generally good: 89.1% of patients had a complete recovery (modified Rankin Score [mRS] 0-1) and 3.8% had a partial recovery and were independent (mRS 2). Eighty-four per cent of patients were treated with oral anticoagulants and the mean treatment duration was 12 months. CVT recurred in 31 patients (4.4%), and 46 patients (6.5%) had a VTE in a different site, for an overall incidence of recurrence of 23.6 events per 1000 patient-years (95% confidence Interval [CI] 17.8, 28.7) and of 35.1 events/1000 patient-years (95% CI, 27.7, 44.4) after anticoagulant therapy withdrawal. A previous VTE was the only significant predictor of recurrence at multivariate analysis (hazard ratio [HR] 2.70; 95% CI 1.25, 5.83). CONCLUSIONS: The long-term risk of mortality and recurrent VTE appears to be low in patients who survived the acute phase of CVT. A previous VTE history independently predicts recurrent events.

Endothelial dysfunction in haemophilia patients.

Haemophilia patients may develop cardiovascular diseases, suggesting that their clotting defect does not protect them completely from atherosclerosis and its complications. We aimed to evaluate cardiovascular risk factors and, for the first time, the presence of endothelial dysfunction in middle-aged haemophilia patients. We studied 40 patients with haemophilia A and B (24 with moderate-severe disease and 16 with mild disease), and 40 healthy controls. Flow-mediated dilation (FMD), carotid ultrasound (US) intima media thickness (IMT), arterial blood pressure, body mass index (BMI), cholesterol, triglycerides, glucose, insulin, lipoprotein(a) and homocysteine levels were measured, and PAI-1 and t-PA levels before and after venous occlusion (VO), and antibodies to HIV, HBV and HCV were assayed. At least one cardiovascular risk factor was detected in 87.5% of patients, and 2 or more in 47.5% of cases. At US exam, none of the patients had significant carotid stenosis or significant differences in IMT compared to controls. In contrast, all the patients had a significant FMD impairment, associated with a reduced t-PA release after VO in 70% of cases. PAI-1 levels significantly correlated with BMI, triglycerides and insulin values. Fifteen haemophilia patients with chronic viral hepatitis and/or HIV infection showed a significantly lower FMD than patients without active infection. We found an endothelial dysfunction with impaired FMD and t-PA release in our haemophilia patients, usually associated with cardiovascular risk factors. Other pathogenic mechanisms, such as chronic viral infections, are likely to be involved in this endothelial damage, however.

Variations in fibrinolytic parameters and inhibin-A in pregnancy: related hypertensive disorders.

BACKGROUND: The mechanisms leading to pregnancy-related hypertensive disorders, and pregnancy-induced hypertension (PIH) and pre-eclampsia (PE) in particular, are still not clear. Diagnostic criteria are clinical because specific markers of the condition are lacking. A role of the fibrinolytic system has been suggested. OBJECTIVES: We aimed to evaluate the behavior of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1), PAI-2, and the placental hormone inhibin-A in women with a normal pregnancy vs. women with pregnancies complicated by PIH or PE. METHODS: Blood samples were drawn between the 25th and 30th gestational week (GW) and between the 31st and 36th GW in order to assay t-PA, PAI-1, PAI-2 and inhibin-A; routine biochemical exams, ultrasonography umbilical artery pulsatility index (PI), placental weight and newborn weight were measured. RESULTS: In pregnancies complicated by hypertensive disorders, PAI-1 levels were higher than in controls and increased significantly after the 25th GW, especially in PE, as did inhibin-A. PAI-2 levels were significantly lower after the 30th GW in patients with PIH and PE. The PAI-1/PAI-2 ratio was significantly higher in PE patients than in controls as of the 25th GW, but only after the 30th GW in patients with PIH. Inhibin-A was significantly correlated with fibrinolytic parameters, and inversely with newborn weight. Receiver-operator characteristic curves for PAI-1 and inhibin-A showed a high sensitivity and specificity for PE. PAI-2 correlated with newborn and placental weight, and inversely with PI of the umbilical artery. CONCLUSIONS: Fibrinolytic tests (especially PAI-1) and inhibin-A monitoring during pregnancy may help in the early diagnosis of pregnancy-related hypertensive disorders.

Psychological aspects and coping styles of parents with Haemophilic child undergoing a programme of counselling and psychological support.

Parents of children affected by haemophilia must face, often without prior knowledge, the difficult challenge imposed by such a pathology. To satisfy the need of information, guideline and psychological support for a better quality of life, 30 parents with haemophiliac children have participated in a programme of counselling and psychological support. Such a programme has the aim of guiding the group trough a process of discovery, comparison and personal growth and stimulating adaptive processes of problem-solving and decision-making. The aim of this paper was to verify how the programme influenced coping strategies and other psychological constructs such as depression and anxiety. Subjects of this study were administered the following psychological tests: COPE (coping, orientation to problems experienced), BDI (beck depression inventory), STAI-Y form (state-trait anxiety inventory) at the beginning and at the end of the programme. The results show that by the end of the programme subjects are characterized by a greater use of problem-focused coping strategies, typical of individuals who think that the situation is susceptible to change, and a minor use of emotion-focused coping strategies, related to individuals who regard the situation as immutable. The use of avoidance -focused coping strategies seems to remain at the same level even if it was low. Also the other psychological aspects investigated, namely depression and anxiety, did receive a positive influence. The results show how significant such programme has been for parents.

[Femoral and humeral head osteonecrosis in a patient with hypofibrinolysis and hyperhomocysteinemia. A case report and a review of the literature]. / Osteonecrosi delle teste femorali ed omerali in un paziente con ipofibrinolisi e iperomocisteinemia. Descrizione del caso e revisione della letteratura.

Osteonecrosis is a disease characterized by the death of marrow and bone tissues. All bones may be affected, most commonly those of the hip, knee, shoulder, ankle as well as the small bones of the hands and feet. When the disease involves a weight-bearing joint there is a significant risk that subarticular fracture may develop leading to disabling arthrosis and requiring, therefore, arthroplasty surgery. Osteonecrosis typically affects patients in their third, fourth and fifth decades of life and is associated with many factors including other diseases and co-morbidities. Multifocal osteonecrosis is defined according to the involvement of at least three separated anatomic sites. We describe the case of a young man with osteonecrosis of the shoulder and hip joints which required total arthroplasty. Among biochemical investigations, an increase in the plasminogen activator inhibitor type 1 (PAI-1) levels associated with mild hyperhomocysteinemia was present. Another finding was the HLA B27, without signs of spondyloarthropathies. In patients with osteonecrosis, especially if multifocal, a careful medical history, a complete physical examination and some biochemical investigations, particularly those related to thrombophilia and hypofibrinolysis, should be performed.

Fibrinolytic variables in patients with recurrent venous thrombosis: a prospective cohort study.

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.

Role of the 4G/5G polymorphism of PaI-1 gene promoter on PaI-1 levels in obese patients: influence of fat distribution and insulin-resistance.

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.

Are fasting plasma homocyst(e)ine levels heritable? A study of normotensive twins.

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.

Improved fibrinolytic capacity after withdrawal of steroid immunosuppression in renal transplant recipients.

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 heterozygous plasminogen deficiency and factor V Leiden defect in the same kindred.

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.

Determinants of plasma levels of plasminogen activator inhibitor-1 : A study of normotensive twins.

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.

Familial association of hypoplasminogenemia and heterozygous factor V deficiency.

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.

4G/5G polymorphism of PAI-1 gene promoter and fibrinolytic capacity in patients with deep vein thrombosis.

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.