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V De Stefano

Publications and source records attributed to V De Stefano.

At least 37 records · Page 2Linked to original sources
PubMed2001

Hyperhomocysteinemia and prevalence of polymorphisms of homocysteine metabolism-related enzymes in patients with inflammatory bowel disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) have an increased risk of thrombotic complications. Moreover, a hypercoagulable state has been hypothesized as a contributing factor in the pathogenesis of IBD. Recently, a growing amount of interest has focused on mild-to-moderate hyperhomocysteinemia as a risk factor for thromboembolic disease. We aimed to evaluate the prevalence of hyperhomocysteinemia in patients with IBD and to investigate the contribution of genetic defects in the enzymes involved in homocysteine (Hcy) metabolism and vitamin status in determining increased levels of plasma total Hcy (tHcy). METHODS: The concentrations of tHcy, folate, and vitamin B12 as well as the prevalence of methylenetetrahydrofolate reductase (MTHFR) 677C to T mutation and the 68-bp insertion at exon 8 of cystathionine beta-synthase (CBS) were measured in patients with IBD and healthy controls. RESULTS: In all, 17 out of 64 IBD patients (26.5%) and four out of 121 (3.3%) controls had hyperhomocysteinemia with a statistically significant difference (p < 0.0001). No significant difference was found between IBD patients and controls with regard to the prevalence of homozygotes for the C677T variant (TT) of MTHFR or the prevalence of heterozygotes for the CBS-gene mutation (IN). Among the IBD patients the only independent factor significantly associated with hyperhomocysteinemia was folate deficiency (p = 0.0002), regardless of the MTHFR or the CBS genotype. CONCLUSIONS: IBD patients have a higher prevalence of hyperhomocysteinemia than do healthy controls. Folate deficiency is the only independent risk factor in developing hyperhomocysteinemia.

Adult↗
PubMed2001

Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia.

Homozygous carriers of factor V Leiden have an approximately 80-fold increased risk of venous thrombosis. Also double heterozygous carriers of both the factor V Leiden and the prothrombin gene mutations are at high thrombotic risk. The magnitude of the risk of venous thrombosis in pregnant women with the two severe thrombophilic conditions has not been estimated so far. We performed a multicenter retrospective family study in women with homozygous factor V Leiden, double heterozygous factor V Leiden and the prothrombin gene mutation, and women with normal coagulation. Only relatives of index patients with thrombosis formed the study cohort. Fifteen homozygous and 39 double heterozygous women were compared to 182 women with normal coagulation. Venous thrombosis occurred in 3 of 19, 2 of 50 and 1 of 221 pregnancies, respectively. One thrombotic episode occurred in the third trimester, the remaining 5 in the postpartum. The prevalence of venous thrombosis was 15.8% (95% CI 3.4-39.6) for homozygotes. 4.0% (95% CI 0.5-13.7) for double heterozygotes and 0.5% for women with normal coagulation. The relative risk of pregnancy-related venous thrombosis was 41.3 (95% CI 4.1-419.7) for homozygous and 9.2 (95% CI 0.8-103.2) for double heterozygous carriers. In conclusion, homozygous carriers of factor V Leiden and, to a lesser extent, double heterozygous carriers of factor V Leiden and of the prothrombin mutation have an increased risk of venous thrombosis during pregnancy, particularly high during the postpartum period. On the basis of these findings we recommend that these women receive anticoagulant prophylaxis at least in the postpartum, that should perhaps be extended to the whole pregnancy in homozygous carriers.

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PubMed2001

Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism.

Factor V Leiden and factor II G20210A mutations are two frequent genetic risk factors involved in venous thromboembolism (VTE). The goal of this pooled analysis of 8 case-control studies, comprising a total of 2310 cases and 3204 controls, was to precisely estimate the risk of VTE in patients bearing both mutations (double heterozygotes). Odds ratios for VTE were 4.9 (95% CI; 4.1-5.9) for the factor V Leiden and 3.8 (3.0-4.9) for the factor II G20210A mutation. Fifty-one cases (2.2%) and none of the controls were double heterozygotes. The odds ratio for venous thrombosis in double heterozygotes was 20.0 (11.1-36.1). Twelve percent of patients heterozygous for factor V Leiden were also heterozygous for factor II G20210A and conversely 23% of patients heterozygous for factor II G20210A were also heterozygous for factor V Leiden. Furthermore, in this large population we analyzed the effect of oral contraceptive (OC) in women carrying one of these mutations. Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-1 8.45). The odds ratio of the association of factor II mutation and OC use was 7.14 (3.39-15.04). Finally, we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69). Conversely, factor II G20210A mutation was equally balanced in both patient groups.

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PubMed2001

Blood cells diseases and thrombosis.

BACKGROUND AND OBJECTIVES: In recent years knowledge about thrombophilia and the mechanisms underlying the pathogenesis of thrombosis has increased greatly. Nevertheless the role of leukocytes and red cells in thrombogenesis is not well established and is probably underestimated. EVIDENCE AND INFORMATION SOURCES: The contribution of leukocytes and red cells to thrombogenesis has been reviewed. Moreover, the prevalence of thrombosis as a complication of hematologic diseases has been examined. The authors are involved in the investigation and management of acute and chronic hematologic diseases as well as in investigation of thrombophilia. Pub-Med was employed as a source of information. STATE OF THE ART: Thrombosis is a major problem in myeloproliferative disorders such as polycythemia vera and essential thrombocythemia. A clonal involvement of megakaryocytopoiesis resulting in elevated levels of platelet-specific proteins, increased thromboxane generation, and expression of activation-dependent epitopes on the platelet surface is regarded as the main origin of thromboembolism; nevertheless, activation of leukocytes and the consequent release of elastase and alkaline phosphatase could play an important role, determining endothelial damage. Thrombosis is a relevant problem in some hemolytic anemias such as paroxysmal nocturnal hemoglobinuria and drepanocytosis. Thrombotic events in hemolytic anemias with membrane defects have been attributed, at least in part, to hypercoagulability related to the exposure of phosphatidylserine of red cell membrane activating plasma prothrombinase and supplying a procoagulant phospholipid anionic surface. A moderate but well-established risk for thrombosis occurs in acute promyelocytic leukemia and acute lymphoblastic leukemia; this risk could be increased by antiblastic drugs affecting the procoagulant activity of cells and the production of coagulation inhibitors from the liver. PERSPECTIVES: Thrombotic complications during hematologic diseases other than thrombophilia due to plasma alteration could be decreased not only by anticoagulant and antiaggregating agents but also by drugs inhibiting activation of leukocytes and red cells and their interaction with platelets.

Animals↗
PubMed2000

Alpha(2)-macroglobulin levels are high in adult patients with congenital antithrombin deficiency.

Antithrombin is responsible for about 80% of the progressive inhibitory activity of thrombin in human plasma. The role of other protease inhibitors known to inhibit thrombin is not completely clarified. However, their contribution may become relevant when antithrombin is low. We elected to investigate adult patients with congenital antithrombin deficiency to assess the concentration of other naturally occurring thrombin inhibitors such as alpha(2)-macroglobulin, alpha(1)-antitrypsin, heparin cofactor II, and C(1)-inhibitor. The study included 59 patients with congenital antithrombin deficiency with and without a previous history of thrombosis, together with an equal number of control subjects matched for age and sex. Statistically significant differences (patients vs. controls) were observed only for alpha(2)-macroglobulin (i.e., 120 vs. 102%, p<0.01). Further analysis of antithrombin-deficient carriers with and without a past history of thrombosis showed that alpha(2)-macroglobulin levels were higher than the 90th percentile of control distribution more often in asymptomatic than symptomatic men (odds ratio=0.04; confidence interval=0.003-0.60), but not in women (odds ratio=2.14; confidence interval=0.35-13.1). In conclusion, results from this cross sectional study showed that alpha(2)-macroglobulin levels were high in patients with congenital antithrombin deficiency. Furthermore, the high levels were found more often in asymptomatic than symptomatic men. Whether this increase provides protection against thrombosis should be evaluated in a prospective study.

Adolescent↗
PubMed2000

The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both.

Factor V Leiden and the G20210A mutation in the prothrombin gene are the most frequent abnormalities associated with venous thromboembolism. It is unknown whether the risks due to the presence of either mutation are of the same magnitude. We compared the prevalence and incidence rate of venous thromboembolism in relatives with either mutation or both. The finding of different rates might influence the strategies for primary prevention of thrombosis in carriers of these mutations. The study population included 1076 relatives of probands with the prothrombin gene mutation, factor V Leiden or both who underwent screening for inherited thrombophilia and were found to be carriers of single mutations or double mutations or who were non-carriers. The prevalence of venous thromboembolism was 5.7% in relatives with the prothrombin gene mutation, 7.8% in those with factor V Leiden, 17.1% in those with both mutations and 2.5% in non-carriers. Annual incidences of thrombosis were 0.13% [95% confidence interval (CI) 0.06-0.24], 0.19% (0.13-0.25), 0.42% (0.15-0.83) and 0.066% (0.03-0.11), respectively, and the relative risk of thrombosis was two times higher in carriers of the prothrombin gene mutation, three times higher in those with factor V Leiden and six times higher in double carriers than in non-carriers. The incidence of venous thromboembolism in carriers of the prothrombin gene mutation is slightly lower than that observed in carriers of factor V Leiden, whereas in carriers of both mutations it is two or three times higher. These findings suggest that lifelong primary anticoagulant prophylaxis of venous thromboembolism is not needed in asymptomatic carriers of single or double mutations. Anticoagulant prophylaxis seems to be indicated only when transient risk factors for thrombosis coexist with mutations.

Adolescent↗
PubMed2000

Homocysteine, coagulation, platelet function, and thrombosis.

Over the last 30 years, a growing body of evidence has documented the role of hyperhomocysteinemia (HHcy) as an independent vascular risk factor. However, the mechanisms through which elevated circulating levels of homocysteine (Hcy) cause vascular injury and promote thrombosis remain elusive. Most findings have been achieved in in vitro studies employing exceedingly high concentrations of Hcy, whereas only a few studies have been carried out in vivo in humans. In homocystinuric patients, homozygotes for mutations of the gene coding for the cystathionine beta-synthase enzyme, abnormalities of coagulation variables reflecting a hypercoagulable state, have been reported. In vitro studies provide a biochemical background for such a state. In homocystinuric patients, an in vivo platelet activation has also been reported. The latter abnormality is not corrected by the bolus infusion of concentrations of hirudin, which determines a long-lasting impairment of the conversion of fibrinogen to fibrin by thrombin; in contrast, it appears at least in part lowered by the administration of the antioxidant drug probucol. During the autooxidation of Hcy in plasma, reactive oxygen species are generated. The latter initiate lipid peroxidation in cell membranes (potentially responsible for endothelial dysfunction) and in circulating lipoproteins. Oxidized low-density lipoproteins (LDL) may trigger platelet activation as well as some of the hemostatic abnormalities reported in such patients. Thus the oxidative stress induced by Hcy may be a key process in the pathogenesis of thrombosis in HHcy. Accumulation of adenosylhomocysteine in cells (a consequence of high circulating levels of homocysteine) inhibits methyltransferase enzymes, in turn preventing repair of aged or damaged cells. This mechanism has been recently documented in patients with renal failure and HHcy and provides an additional direction to be followed to understand the tendency to thrombosis in moderate HHcy.

Adolescent↗
PubMed2000

Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism.

Hyperhomocysteinemia is an established risk factor for deep vein thrombosis. Factor V Leiden has been reported to potentiate the thrombotic risk related with severe hyperhomocysteinemia, being more represented in thrombotic patients with homocystinuria as compared with patients without a history of thrombosis. The results concerning the interaction between moderate hyperhomocysteinemia and inherited thrombophilic factors such as Factor V Leiden or the prothrombin G20210A mutation are contradictory. The relative risk for venous thrombosis has been reported to be increased 10- to 50-fold in patients carrying both hyperhomocysteinemia and inherited thrombophilia in comparison with normal controls, suggesting a synergistic interaction, yet other studies failed to confirm such conclusion. The heterogeneity of these findings is in part due to the small number of individuals with double defects, leading to statistically unreliable results. Genotyping for mutations that are possible causes of moderate hyperhomocysteinemia, such as the thermolabile variant (C677T) of methylenetetrahydrofolate reductase (MTHFR), does not seem useful to identify individuals at higher risk for venous thromboembolism. In fact, in most of the studies the presence of the C677T MTHFR homozygous genotype does not increase the thrombotic risk associated with Factor V Leiden or the prothrombin mutation.

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PubMed2000

Prevalence of factor V Leiden and the G20210A prothrombin-gene mutation in inflammatory bowel disease.

A hypercoagulable state has been hypothesized as a contributing factor in the pathogenesis of inflammatory bowel disease (IBD); moreover, such patients have an increased risk of thrombotic complications. The aim of the present paper was to study the prevalence of the two most important causes of inherited thrombophilia: factor V Leiden and the G20210A prothrombin-gene mutation in patients with Crohn's disease (CD) and ulcerative colitis (UC). Fifty-two patients affected by IBD (33 UC and 19 CD, 16 female and 36 male; mean age, 42 years) and 156 healthy controls (48 female and 108 male; mean age, 37 years) were studied. Seven out of 52 patients (13%) had previous thrombotic events. High molecular weight DNA was analysed for the presence of factor V Leiden and the G20210A prothrombin-gene mutation. One out of 52 IBD patients (1.9%) and three out of 156 control subjects (1.9%) were heterozygous for factor V Leiden. One IBD patient (1.9%) and four healthy controls (2.6%) were heterozygous for the prothrombin-gene mutation. The prevalence of the two mutations was similar in patients and controls. In the subgroup of IBD patients with previous thrombotic events, only one patient was heterozygous for the prothrombin-gene mutation. Factor V Leiden and the G20210A prothrombin-gene mutation do not seem to play a major role in the pathogenesis of IBD or be associated with an increased incidence of thrombotic complications, but with limited data.

Adult↗
PubMed2000

Dose-intensive melphalan with stem cell support (CM regimen) is effective and well tolerated in elderly myeloma patients.

BACKGROUND AND OBJECTIVE: Multiple myeloma (MM) typically afflicts elderly patients. High-dose therapy has recently been shown to lead to a better outcome than standard treatment, mainly in younger patients. The extent to which older subjects can benefit from intensified approaches without excessive toxicity is examined in this study. DESIGN AND METHODS: Between December 1994 and May 1997, 12 Italian Multiple Myeloma Study Group institutions entered 68 patients at diagnosis (median age 65) into an intensified chemotherapy regimen: cyclophosphamide (CY) 3 g/m(2) plus melphalan 60 mg/m(2) followed by peripheral blood progenitor cells (PBPC) and G-CSF (CM regimen). CY (day 0) and G-CSF were used to mobilize PBPC harvested by a single leukapheresis on day 10. Melphalan was infused on day 11. PBPC were kept unprocessed at 4 degrees C for 48 hours and reinfused on day 12. Three CM regimens were delivered at 6-month intervals. RESULTS: Sufficient PBPC to support the first CM cycle were available (median CD34(+) harvest: 4.9x10(6)/kg), but dropped significantly after the second (median CD34(+) harvest: 2x10(6)/kg) and the third (median CD34(+) harvest: 0.9x10(6)/kg). The median durations of severe neutropenia (absolute neutrophil count < 500 microL) were 3, 4, and 3 days, and those of severe thrombocytopenia (platelets < 25,000/microL) were 2.5, 2, and 1 days, after the first, second and third courses, respectively. The frequency of extramedullary toxicities was low. Treatment-related mortality (TRM) was 3% after the first CM, only. Complete remission (CR) was 14% after the first, 16% after the second and 27% after the third CM. After a median follow-up of 34 months (range 19-49 months), median event-free survival was 35.6 months. INTERPRETATION AND CONCLUSIONS: These results indicate that dose-intensity of melphalan can be increased by reinfusing PBPC with acceptable low toxicity. The combination of CY and melphalan followed by PBPC is an effective chemotherapy for elderly myeloma patients. Repeated melphalan infusion hampered subsequent CD34(+) harvests.

Aged↗