Maria Teresa Sartori

The fibrinolytic potential in patients with Cushing's disease: a clue to their hypercoagulable state

The aim of our study was to determine the fibrinolytic potential in a large group of patients with Cushings disease. These patients had a significant shortening of the activated partial thromboplastin time and increase in factor VIII/von Willebrand factor complex compared to normal controls. The mean levels of plasminogen, tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor (PAI) activity were significantly higher than in normal subjects, whereas the basal fibrinolytic activity was similar to that seen in the control group. In 17 out of 30 Cushing patients and in 17 normal subjects the fibrinolytic potential was determined with the venous occlusion test. In the Cushing group, the release of t-PA antigen after 20 min of venous occlusion was comparable to that observed in the control group. However, Cushing patients showed a lower fibrinolytic activity than normal subjects, since a lesser shortening of the euglobulin lysis time and a non-significant rise of plasminogen activator activity levels were found. Moreover, in these patients the PAI activity values remained unchanged and significantly increased after venous occlusion test also. In conclusion, the impaired fibrinolytic activation seen in Cushing patients after venous occlusion can be explained by the inhibitory effect of the high PAI levels on plasminogen activators. The defective fibrinolytic potential could further contribute to the hypercoagulable state in Cushings disease. High PAI Levels before surgery may represent an additional risk factor for post-surgical thromboembolic complications in Cushing patients.

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

Summary.  Background:  Little information is available on the long‐term clinical outcome of cerebral vein thrombosis (CVT).

Should we give thromboprophylaxis to patients with liver cirrhosis and coagulopathy

Patients with liver cirrhosis are characterized by decreased synthesis of both pro- and anticoagulant factors, and recently there has been evidence of normal generation of thrombin resulting in a near normal haemostatic balance. Although it is generally recognized that bleeding is the most common clinical manifestation as a result of decreased platelet function and number, diminished clotting factors and excessive fibrinolysis, hypercoagulability may play an under recognized but important role in many aspects of chronic liver disease. In fact, they can encounter thrombotic complications such as portal vein thrombosis, occlusion of small intrahepatic vein branches and deep vein thrombosis (DVT). In particular, patients with cirrhosis appear to have a higher incidence of unprovoked DVT and pulmonary embolism (PE) compared with the general population. In dedicated studies, the incidence of DVT/PE ranges from 0.5% to 1.9%, similar to patients without comorbidities, but lower than patients with other chronic diseases (i.e, renal or heart disease). Surprisingly, standard coagulation laboratory parameters are not associated with a risk of developing DVT/PE; however, with multivariate analysis, serum albumin level was independently associated with the occurrence of thrombosis. Moreover, patients with chronic liver disease share the same risk factors as the general population for DVT/PE, and specifically, liver resection can unbalance the haemostatic equilibrium towards a hypercoagulable state. Current guidelines on antithrombotic prophylaxis do not specifically comment on the cirrhotic population as a result of the perceived risk of bleeding complications but the cirrhotic patient should not be considered as an auto-anticoagulated patient. Therefore, thromboprophylaxis should be recommended in patients with liver cirrhosis at least when exposed to high-risk conditions for thrombotic complications. Low molecular weight heparins (LWMHs) seem to be relatively safe in this group of patients; however, when important risk factors for bleeding are present, graduated compression stockings or intermittent pneumatic compression should be considered.

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

Summary.  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.

Reduced fibrinolytic potential one year after kidney transplantation : relationship to long-term steroid treatment

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 Cushings 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 Cushings 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 PAI-I gene 4G/5G Polymorphism and Deep Vein Thrombosis in Patients with Inherited Thrombophilia

Genetic and acquired factors may influence phenotypic expression of inherited thrombophilia. Hypofibrinolysis due to excess PAI-I can be found in patients with deep vein thrombosis (DVT) and 4G/5G polymorphism of the PAI-1 gene may modulate the inhibitors synthesis. In 149 patients with inherited thrombophilia, the possible thrombotic contribution of both 4G/5G polymorphism and PAI-1 plasma levels was evaluated. Sixty-seven patients with idiopathic DVT and 98 normal subjects were also studied. By comparison with controls, a significantly higher prevalence of 4G/4G genotype was seen in idiopathic DVT and in thrombophilia patients, although in this latter group the difference only remained significant in cases symptomatic for thrombosis (p=0.01). The 4G/4G genotype was associated with a greater risk of thrombosis both in symptomatic thrombophilia patients (OR 2.85, 95% CI 1.26-6.46) and in idiopathic DVT patients (OR 3.1, 95% CI 1.26-7.59). The greater frequency of 4G allele in symptomatic thrombophilia patients with respect to controls was statistically significant (p=0.04). Compared to healthy subjects, PAI-i:Ag levels were higher in symptomatic thrombophilia patients and related to the 4G/5G polymorphism, with significantly higher values in the 4G/4G carriers. In conclusion, PAI-1 4G/5G polymorphism may influence PAI-i expression and thrombotic risk in patients with inherited thrombophilia.

Anticoagulation for portal vein thrombosis in cirrhotic patients should be always considered

We read with interest the review by Fimognari et al. [1] on portal vein thrombosis (PVT) in hepatic cirrhosis and the commentary by Ageno et al. [2] in Internal and Emergency Medicine. We agree with the authors that there is still scanty evidence about the influence of PVT on the prognosis of patients with hepatic cirrhosis, although we should consider that a clinically significant variceal bleeding leads to a higher mortality in cirrhotic compared with non-cirrhotic patients. Moreover in our published series of 28 patients with PVT considered for radiological treatment, mortality was 10% in the group in which radiological treatment failed [3]. In the absence of cirrhosis, liver function is usually well preserved, but significant portal hypertension may result in serious life-threatening complications, including variceal bleeding, intestinal venous congestion and ischemia [4], as well as the production of ascites in elderly patients according to our clinical experience. In addition, portal hypertension increases the risk of any abdominal surgery. An established algorithm for indication and modality of treatment of PVT is not present at the moment. Wider series have been published about the use of anticoagulation in noncirrhotic patients with PVT, reporting reperfusion in about 40% of cases without increased bleeding complications in the anticoagulated group [4]. Moreover, anticoagulation should be considered in all non-cirrhotic patients with PVT because at least 30% of cases are characterized by prothrombotic coagulation defects [5]. Anticoagulation has been advocated by some to treat PVT in patients with underlying liver disease. However it is clear that the cirrhotic patient is more complex, and is at a greater risk of major complications when anticoagulated, especially if severe portal hypertension is present. Therefore, additional considerations are necessary. In the largest series reported on the use of anticoagulation in patients with PVT and liver cirrhosis, Francoz et al. describe 19 patients on a waiting list for liver transplantation who underwent anticoagulation therapy, obtaining recanalization in 42% without additional bleeding complications [6]. However, only 4 patients had advanced liver disease (Child C), and the severity of the portal hypertension was not well described by the authors. Moreover we should consider that patients on the waiting list for liver transplantation represent a particular subgroup in which the follow-up may be closer and the appearance of PVT might be promptly recognized and possibly treated. We believe that clinical scenario of typical cirrhotic patients with PVT referred to a tertiary referral center could be very different. Most patients are referred when the thrombus is old and sometimes extended into other splanchnic vessels. Indication to anticoagulation is still an issue. Although it may appear clear that cost-benefit in the attempt to treat a recent PVT could be in favor of the treatment, indications for anticoagulation in patients with established PVT is still under debate, unless underlying prothrombotic defects are present. However, if we consider that all patients with advanced liver disease should be considered for liver transplantation, unless contraindicated, there are further clinical issues to be discussed. While PVT per se is not a contraindication to liver transplantation, extension of thrombus into the remaining splanchnic vessels can severely reduce M. Senzolo (&) C. Ferronato P. Burra Gastroenterology Section, Department of Surgical and Gastroenterological Sciences, University Hospital of Padua, Via Giustiniani 2, 35136 Padua, Italy e-mail: marcosenzolo@hotmail.com

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.

Endothelial dysfunction in haemophilia patients

Summary.  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.

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

Summary.  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.