Type Vicenza variant of von Willebrand disease (VWD) is characterized by a low plasma von Willebrand factor (VWF) level and supranormal VWF multimers. Two candidate mutations, G2470A and G3864A at exons 17 and 27, respectively, of the VWF gene were recently reported to be present in this disorder. Four additional families, originating from northeast Italy, with both mutations of type Vicenza VWD are now described. Like the original type Vicenza subjects, they showed a mild bleeding tendency and a significant decrease in plasma VWF antigen level and ristocetin cofactor activity but normal platelet VWF content. Unlike the original patients, ristocetin-induced platelet aggregation was found to be normal. Larger than normal VWF multimers were also demonstrated in the plasma. Desmopressin (DDAVP) administration increased factor VIII (FVIII) and VWF plasma levels, with the appearance of even larger multimers. However, these forms, and all VWF oligomers, disappeared rapidly from the circulation. The half-life of VWF antigen release and of elimination was significantly shorter than that in healthy counterparts, so that at 4 hours after DDAVP administration, VWF antigen levels were close to baseline. Similar behavior was demonstrated by VWF ristocetin cofactor activity and FVIII. According to these findings, it is presumed that the low plasma VWF levels of type Vicenza VWD are mainly attributed to reduced survival of the VWF molecule, which, on the other hand, is normally synthesized. In addition, because normal VWF-platelet GPIb interaction was observed before or after DDAVP administration, it is proposed that type Vicenza VWD not be considered a 2M subtype. (Blood. 2002;99:180-184)

Summary. 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 patientyears (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.

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. 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 patient

SummaryA 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 geno-type 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 homo-zygous 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.

A hypercoagulable state and an increased incidence of thromboembolic complications are reported in Cushing's syndrome. The hypercoagulable state is related to an increase in plasma clotting factors, especially Factor VIII and von Willebrand factor complex, and to an impairment of fibrinolytic capacity. Retrospective analysis of postoperative thromboembolic events in a large group of patients with Cushing's syndrome, including 75 patients (group 1) evaluated in the period from 1972-1981 not receiving anticoagulants, and 232 patients (group 2), evaluated in the period from 1982-2000. Patients of group 1 underwent routine hemostatic function, i.e. prothrombin time and activated partial thromboplastine time. Patients of group 2 underwent a thorough investigation as to hemostatic parameters and received prophylactic treatment with heparin and/or warfarin. Patients with Cushing's syndrome showed various abnormalities of hemostatic parameters. A significant correlation between activated partial thromboplastine time and urinary free cortisol was observed. During follow-up, 15 patients (20%; mean follow-up, 9.4 +/- 6.4 yr) of group 1 and 14 (6.0%; mean follow-up, 6.6 +/- 4.2 yr) of group 2 showed thromboembolic complications. Of these patients, eight of group 1 and one of group 2 died. Survival analysis demonstrated a significantly higher morbidity and mortality due to thromboembolic events in group 1, not receiving anticoagulant prevention, than in group 2, treated with anticoagulants in the perioperative period until cure of the disease and normalization of clotting parameters. Cushing's syndrome is associated with a hypercoagulable state. An adequate anticoagulant prophylaxis can reverse this prothrombotic state and avoid postoperative thromboembolic events.

The relationship between venous thromboembolism (VTE) and cancer is supported by several pathogenetic factors, including circulating microparticles (MP) originating from different cells and often bearing tissue factor. Since VTE often complicates the clinical course of patients with glioblastoma multiforme (GBM; WHO grade IV astrocytoma) and the role of MPs in these patients population is still not clear, this prospective study was conducted to evaluate the procoagulant activity of circulating MP (MP activity) in GBM patients. We enrolled 61 GBM patients undergoing gross-total or subtotal surgical resection followed by combined radio-chemotherapy; 20 healthy volunteers were tested as controls. Blood samples for MP activity and hemostatic profiles were obtained before and then 1 week and 1, 4, and 7 months after surgery. GBM patients had significantly higher mean MP activity levels than healthy controls before and 7 days after surgery. During the follow-up, MP activity levels became significantly lower 1 and 4 months after surgery (P = 0.007 and P = 0.018, respectively) than prior to surgery, but this decrease was only seen in the subgroup achieving complete tumor resection. MP activity levels increased in 7 (63.6%) of 11 patients who developed VTE. The different incidence of the increase in MP activity levels between patients with and without VTE was statistically significant (χ (2) = 4.93, P = 0.026; relative risk 1.38, 95% CI 1.03-1.86). GBM patients may have an increase in MP-associated procoagulant activity that could contribute to any prothrombotic states and increases the likelihood of VTE complications; this procoagulant activity drops during control of disease.

Early diagnosis and early treatment are key factors for the successful management of PVT in cirrhosis, so that screening of PVT and prompt start of anticoagulant treatment should be mandatory.

IntroductionLittle is known about the long-term outcome of cirrhotic patients with splanchnic vein thrombosis (SVT). This prospective cohort study aimed to describe the clinical presentation, bleeding incidence, thrombotic events, and mortality in patients with SVT associated with cirrhosis.MethodsAmong 604 consecutive patients with SVT enrolled over 2 years, 149 had cirrhosis. Major bleeding, thrombotic events, and all-cause mortality were recorded during a 2-year follow-up. In a subgroup, the degree of recanalization with or without anticoagulation therapy, and the correlation between clinical events and liver disease severity were also investigated.ResultsThe most common thrombosis sites were the portal (88%) and mesenteric veins (34%). At presentation, 50% of patients were asymptomatic. Anticoagulation was administered to 92/149 patients for a median of 6.5 months. Vessel recanalization was documented in 47/98 patients with a radiological follow-up. Anticoagulation was associated with a 3.33-fold higher of recanalization rate, and a lower recurrent thrombosis rate, while patients with and without anticoagulation experienced a similar rate of major bleeding episodes. Mortality rates were 6.8 per 100 patient-years for patients with thrombosis completely or partially resolving during the follow-up, and 15.4 per 100 patient-years for those with stable or progressing thrombosis. An impact of SVT on survival was only apparent in patients with more advanced liver disease (Child–Pugh B-C).ConclusionsPatients with SVT and cirrhosis have a substantial long-term risk of recurrent thrombotic events, which is reduced by anticoagulation therapy without any increase in bleeding risk. Anticoagulation can improve the likelihood of vessel recanalization, and is associated with a lower risk of death for decompensated patients.