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The objective of the study is to assess the prevalence of target organ damage (TOD) at carotid, cardiac, renal and peripheral vascular levels in a population at intermediate cardiovascular risk, with adjunctive major risk factors (AMRF). From March 2007 to July 2009 we examined 979 subjects at intermediate cardiovascular risk, as indicated by the Italian algorithm "Progetto Cuore"; the patients were aged 40-69 years, sensitized by one or more AMRF such as family history for cardiovascular disease (CVD), being overweight or obese, and smoking habit (more than 10 cigarettes/day). We measured common carotid intima-media thickness (cc-IMT) and plaque at any level, left ventricular mass index (LVMI), urine albumin/creatinine ratio (UACR), and ankle-brachial index (ABI). The prevalence of at least one TOD was 63% (617 subjects), cc-IMT was high in 48.2% (472), UACR abnormal in 14.1% (138), LVMI high in 12.6% (117) and ABI pathological in 9.1% (89). In those with carotid damage 423 had a plaque, amounting to 43.2% of the total population. Of note, carotid damage was present in all subjects with 3 TODs, and in 92% of subjects with 2 TODs. A multivariate logistic regression model including conventional factors and AMRF indicated that age 50-69 years, systolic blood pressure, relevant smoking and CV risk score ≥15 were independently and significantly associated with at least one TOD, and at least, with carotid damage. Among the AMRF, peripheral arterial disease was associated with relevant smoking, with an odds ratio (OR) of 3 [confidence interval (CI) 1.80-4.97, p < 0.0001]; overweight and obesity both had selective associations with cardiac damage with OR 2.75 (CI 1.2-6.3, p < 0.01) and OR 3.89 (CI 1.61-9.73, p < 0.01). A substantial proportion of people at intermediate risk, with at least one AMRF have at least one TOD, a major predictor of cardiovascular outcomes.

Statins appear to have beneficial effects on fibrous cap stabilisation but their effects on plaque thrombogenicity have not been reported. To evaluate the thrombogenicity of human carotid plaques before and after atorvastatin treatment, 59 patients with bilateral carotid stenosis eligible for two-step carotid endoarterectomy (CEA) were randomly assigned to atorvastatin, 20 mg/day, or placebo. Histological and immunohistochemical analyses, Tissue Factor (TF), Tissue Factor Pathway Inhibitor (TFPI) antigens (Ag) and TF activity were determined in endoarterectomy specimens obtained at baseline and after treatment. Mean TFAg and TFPIAg levels from plaques removed at the first CEA were 55 +/- 56 and 32 +/- 26 pg/mg. After placebo, TFAg and TFPIAg content was higher in the second than the first CEA. Plaques removed at the second CEA from atorvastatin-treated patients had a lower macrophage content than plaques at the first CEA. TFAg and TFPIAg levels, and TF activity in plaques after atorvastatin treatment were lower (respectively 29, 18% and 56%) than after placebo. These findings indicate that atorvastatin reduce the inflammatory/thrombotic phenotype of carotid plaque, suggesting that these drugs may indeed have a beneficial effect on cerebrovascular events.

Better preoperative identification of those patients at high risk of developing a deep vein thrombosis (DVT) after hip surgery could reduce the incidence of this postoperative complication, which still occurs despite prophylaxis. One hundred fifty-nine patients undergoing elective total hip replacement and given anticoagulant prophylaxis, were investigated, looking for the presence of a hypercoagulable state, that represents one element of Virchow's triad predisposing to DVT. Plasma levels of three markers of coagulation activation, namely prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III complexes (TAT) and D-dimer were measured using ELISA procedures and were correlated with the results of the postoperative phlebography. A high correlation (p < 0.001) between the preoperative plasma levels of F1 + 2 and the risk of postoperative venous thromboembolism was detected. The performance of TAT and D-dimer levels in predicting DVT was lower. These findings support the hypothesis that preoperative measurement of coagulation activation markers might be useful in predicting DVT following a total hip replacement.

Elevated plasma levels of lipoprotein(a) [Lp(a)] have been associated with an increased risk of cardiovascular disease. The aim of the present study was to investigate whether Lp(a) plasma levels were associated with subsequent ischemic events and with fibrinolytic variables in patients with established atherosclerotic disease enrolled in the prospective PLAT study. Lp(a) levels and fibrinolytic variables in 37 atherosclerotic patients who subsequently developed an atherothrombotic event during the first year of follow-up (cases) were compared with those in paired controls, matched for age, sex, diagnosis at enrollment and lipid pattern, who remained free from vascular events during the same time frame. Median and mean Lp(a) levels were similar in cases (6.05 mg/dl; 13.8 +/- 19.4 mg/dl) and controls (6.05 mg/dl; 17.1 +/- 21.6 mg/dl). In the whole group plasma Lp(a) levels correlated significantly with the increase of t-PA antigen (r = 0.368; p = 0.002) and fibrinolytic activity (r = 0.410; p = 0.001) induced by venous stasis but not with baseline fibrinolytic variables. These findings indicate that in patients with established atherosclerotic disease Lp(a) may interfere in vivo with the fibrinolytic process but is not predictive of subsequent ischemic events.

Efficacy and safety of i.v. dermatan sulphate (DS) and heparin (H) in controlling laboratory alterations due to DIC were compared in 10 patients with acute leukaemia, in a prospective, randomised pilot study. The time courses of the coagulation and fibrinolysis markers for DIC were similar in the two treatment groups except for activated partial thromboplastin time and thrombin time, which were prolonged in the H but not in the DS group. Blood product support tended to be greater in the H than in the DS group. DS appears to be as effective as H in controlling thrombin production during leukaemic cytolysis and may represent a safer alternative to H in the management of DIC in acute leukaemia.

A case-control comparison within the framework of the prospective, multidisciplinary PLAT Study was performed to assess whether altered baseline fibrinolytic variables were associated with an elevated risk of ischemic thrombotic events in patients with documented coronary, cerebral, and/or peripheral atherosclerotic disease. Fibrinogen, D-dimer, tissue plasminogen activator (t-PA) antigen, and fibrinolytic activity before and after venous stasis (delta = difference between the two values), t-PA inhibitor, and lipid levels in 60 atherosclerotic patients with a thrombotic event during the first year of follow-up were compared with those in 94 atherosclerotic patients without such events, who were matched for age, sex, and diagnosis at enrollment. Events were associated with a higher release of delta t-PA antigen (P = .047), higher D-dimer (P = .024), and higher t-PA inhibitor (P = .001) levels. delta Fibrinolytic activity was correlated inversely with t-PA inhibitor (P < .01) and triglycerides (P < .05). D-Dimer was also correlated with systolic blood pressure (P < .01). Atherosclerotic patients at higher risk of thrombotic ischemic events are characterized by increased fibrin turnover and impaired fibrinolytic activity due to high t-PA inhibitor levels. This hemostatic disequilibrium may participate with conventional risk factors such as elevated triglyceride levels and systolic blood pressure in the multifactorial mechanism of ischemic sequelae in patients with preexisting vascular atherothrombotic disease.

The Progetto Lombardo Atero-Trombosi (PLAT) Study was a prospective, multicenter, multidisciplinary study of the association among hemostatic variables, conventional risk factors, and atherothrombotic events in four groups of patients with preexisting vascular ischemic disease (335 myocardial infarction survivors, 123 patients with stable angina pectoris, 160 with transient ischemic attacks, and 335 with peripheral vascular disease). In the myocardial infarction group, univariate analysis showed that atherothrombotic events were associated with high fibrinogen (p = 0.001), factor VIII:C (p less than 0.001), and von Willebrand factor antigen (vWF:Ag) (p = 0.004) levels and with low high density lipoprotein cholesterol (p = 0.043), factor VII (p = 0.019), and protein C (p = 0.044) levels; multivariate analysis produced associations with high fibrinogen and factor VIII:C levels and low protein C levels. By both univariate and multivariate analysis, events in the angina pectoris group were associated with high vWF:Ag (p = 0.026) and leukocyte (p = 0.033) levels and the presence of carotid arterial stenosis (p = 0.063); associations with high leukocyte (p = 0.037) and factor VIII:C (p = 0.186) levels, family history (p = 0.031), and diabetes (p = 0.061) were also found in the group with transient ischemic attacks. In those with peripheral vascular disease, events were associated with Fontaine stage greater than or equal to IIB (p = 0.024), high factor VIII:C levels (p = 0.073), and low protein C (p = 0.028), fibrinogen (p = 0.030), antithrombin III (p = 0.054), and factor VII (p = 0.057) levels by univariate analysis and with Fontaine stage and low fibrinogen levels by multivariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

We recently succeeded in eradicating a Fusarium infection by treatment with liposomal amphotericin B (L-AmB). The patient, a 22-year-old man with acute lymphoblastic leukaemia (ALL), developed fever and diffuse cutaneous maculopapular necrotising nodules during post-chemotherapy neutropenia. Fusarium verticilloides was isolated from the skin, and hyphae were observed on direct microscopy. Despite increased WBC and amphotericin B (AmB) treatment (0.7 mg/kg/day for 11 days), he remained febrile and a chest X-ray revealed pulmonary lesions. Fusarium infection was confirmed by bronchial aspirate. AmB was increased to 1 mg/kg/day, and continued for 16 days (total dose 1630 mg). A slight improvement was observed at tomography, but nephrotoxicity developed. Treatment was changed to L-AmB (3 mg/kg/day). The patient received this drug for 20 days (total dose of 3850 mg) with complete regression of the pulmonary lesions. No adverse event occurred, and nephrotoxicity resolved. The patient was discharged from hospital cured of the Fusarium infection and in clinical and haematological remission. No relapse of fusariosis occurred, despite additional courses of intensive chemotherapy. Ambisome could represent an important advance in antifungal treatment since it allows aggressive treatment and eradication of mycoses refractory to conventional therapy while avoiding renal toxicity.

Background: Blastic crisis (BC) is the terminal event in the natural history of most chronic myelogenous leukemia (CML) patients. Depletion of the normal stem cell compartment, as well as the proliferative advantage and frequent pharmacoresistance of the blastic clone, contribute to the poor prognosis of CML patients in this phase. Recent clinical trials have shown that idarubicin (IDR) in combination with cytosine arabinoside (ARA-C) is more active than daunorubicin at comparable doses in acute myelogenous leukemia (AML). Furthermore, IDR alone also exhibits antitumoral activity in the BC of CML., Methods: Twelve Ph+ CML patients in BC (male 8, female 4; median age 45 yrs., range 19-55 yrs.) were treated with IDR 12 mg/m2/die for 3 consecutive days in sequential combination with Ara-C (1 hour i.v. infusion) 120 mg/m2/12 hrs. for 7 consecutive days. BC exhibited a myeloid phenotype in 9 and a lymphoid phenotype in 3 cases. Median duration of the previous chronic phase had been 36 months (range 6-180)., Results: Clearing of peripheral and bone marrow blasts was achieved in all but one patient. Three other patients were classified as resistant because of blastic regrowth, and 3 died of infection during postchemotherapeutic aplasia. Two patients achieved complete remission (CR) and 3 partial remission (PR). The median duration of response was 11 months (range 6-32)., Conclusions: In BC of CML the IDR/Ara-C combination led to an encouraging rate of either partial or complete responses. The relatively long duration of unmaintained response was even more interesting, with the duration of PR approaching that of CR. These data suggest that IDR should be considered as one of the first-line drugs in the treatment of BC of CML.

Forty consecutive neutropenic patients with acute leukemia receiving oral ciprofloxacin (500 mg twice daily) and ketoconazole (200 mg daily) for selective intestinal decontamination were compared retrospectively with 33 comparable patients treated with polymyxin E (1,500,000 U x 3/day) and nystatin (1,000,000 U x 3/day). The incidence of febrile episodes was slightly lower in ciprofloxacin treated patients (87.5% vs 100%). No gram-negative sepsis was observed in this group compared with seven cases in patients receiving polymyxin E (p less than 0.01). Furthermore, eight patients in ciprofloxacin group (20%) had gram-positive sepsis, compared with five (15.5%) in the polymyxin E group. The incidence of documented fungal infections was similar in the two groups. Ciprofloxacin appears to be an effective agent for the prevention of gram-negative infections in granulocytopenic patients with acute leukemia, but may contribute to a shift in the type of infections in these patients towards those caused by gram-positive microorganisms, intrinsically fairly sensitive or with acquired drug resistance.

Congenital heterozygous dysfibrinogenemia was diagnosed in a young woman with bleeding tendency. 3 other asymptomatic members of her family (mother and the 2 sisters) had abnormal fibrinogen. The proposita's plasma exhibited prolonged thrombin and reptilase times. Plasma fibrinogen concentration determined by functional assay was 0.3 g/l, whereas immunologic assay revealed normal fibrinogen levels. Turbidity curves, representing the rate of thrombin-induced fibrin formation, were markedly delayed both in the presence and absence of Ca2+. Isoelectric focusing and SDS electrophoresis of reduced fibrinogen showed normal charge and size of the subunit chains. Release of fibrinopeptide B by thrombin was normal, whereas HPLC elution diagrams of fibrinopeptide A showed an abnormal peak A* with a slightly shorter retention time than the normal fibrinopeptide A. The amino acid analysis showed that the arginine in peak A* is replaced by histidine (A alpha 16 Arg----His).

The effect of treatment with 1,25-dihydroxyvitamin D3 administered at the dose of 1.50-3.00 ug/day for at least 12 months was evaluated in three patients with idiopathic myelofibrosis and in five patients with idiopathic thrombocythemia. This treatment did not cause any significant change in the hematological values or the clinical course of the myeloproliferative diseases in any of the patients. Based on these data, treatment with 1,25-dihydroxyvitamin D3 in non toxic doses seems to be of doubtful benefit in patients with these disorders.

We evaluated the in vitro anticoagulant action of dermatan sulfate (DS) (aPTT, antiXa, anti-thrombin) and its effect on human platelet aggregation and beta TG/PF4 release induced by threshold doses of aggregating agents, compared with standard heparin (SH). In pooled plasma, DS prolonged aPTT much less than SH, had no measurable antiXa activity, showed an anti-thrombin activity similar to that shown by SH at a tenfold higher dilution. DS had no direct effect on human platelet aggregation and beta TG/PF4 release. Moreover it did not significantly affect platelet aggregation and release by ADP and collagen, whereas it completely inhibited platelet aggregation and beta TG/PF4 release by thrombin. These data in vitro confirm that thrombin inhibition induced by DS is accompanied by a far lesser aPTT prolongation compared to heparin, without any appreciable interference with platelet function.

Recombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent characterized by elevated but not absolute fibrin specificity. However, its therapeutic dose is high and associated with a variable degree of systemic activation of the fibrinolytic system. Thrombolytic drugs are widely used in acute myocardial infarction and have now begun to be considered for deep vein thrombosis (DVT), pulmonary embolism (PE), and peripheral artery thrombosis (PAT) as well. Although anticoagulant therapy is effective in reducing the immediate complications of venous thromboembolism, thrombolytic therapy has various advantages over anticoagulant therapy, including lysis of thrombi with recanalization of venous circulation, reduction of venous valve damage and prevention of post-phlebitic syndrome. The different dosage regimens of rt-PA recently evaluated (0.71 to 1.76 mg/kg/24 h for 2-4 days) in DVT have caused consistent thrombolysis but also excessive bleeding. The optimal therapeutic range for rt-PA in DVT remains to be determined. Thrombolytic therapy is superior to heparin treatment only in hemodynamically compromised patients with massive PE. The minor systemic fibrinolytic effect and the faster action on thrombi of rt-PA compared with the first generation thrombolytic agents, streptokinase (SK) and urokinase (UK), are very interesting and explain the positive results recently obtained in PE with this drug (50 mg over 2 h, followed, if necessary, by 40-50 mg over 4-5 h) by Goldhaber and Verstraete.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple (100 mg twice daily for 21 days) but not single (100 mg) oral doses of metoprolol significantly reduced the number (Bmax) and the KD of beta-adrenoceptors on intact lymphocytes from nine healthy volunteers. Sulphinpyrazone (400 mg twice daily for 21 days) did not change lymphocyte beta-adrenoceptors and did not modify their reaction to chronic metoprolol. In vitro sulphinpyrazone (10-4M) increased [3H]-DHA specific binding on intact lymphocytes. This effect was not modified by metoprolol, sulphinpyrazone or the two combined. Metoprolol and sulphinpyrazone did not interact in the experimental model of beta-adrenoceptors on intact lymphocytes in conditions mimicking long-term treatment.

After some preliminary remarks of a biochemical and pharmacological nature, the authors have started a clinical study to test the antiinflammatory activity of the S-adenosyl-methionine (SAMe). An open trial, carried out on 90 patients with severe degenerative arthropathies has shown that 30 mg SAMe intravenously twice a day for 14 days have a marked anti-inflammatory effect a rather term and no side-effects. In a "double-crossover" investigation, SAMe was next compared to indomethacin by i.m. administrations to 15 arthropathic patients. The therapeutic responses of the two drugs proved exactly alike, whereas the side-effects following indomethacin administration were not present after SAMe. In 9 patients affected with rheumatoid arthritis administrations of SAMe have proved less effective, although some clinical parameters showed improvements.

Platelet production time (PPT), circulating platelet aggregates (CPA ratio) and plasma beta-thromboglobulin (beta TG) were determined in patients with essential mixed cryoglobulinemia (EMC) before and after two months' treatment with sulfinpyrazone. Sulfinpyrazone determined a clinical improvement in 8 of the 16 patients. Basal PPT and CPA ratio were reduced compared with normal values but not significantly; after sulfinpyrazone treatment both PPT and CPA ratio increased to normal levels. High plasma beta TG levels were found before and after treatment. These data suggest that in some cases of EMC there is a picture of in vivo platelet activation, but with the small number of patients it was not possible to evaluate a possible correlation between platelet hyperactivity and the clinical picture.

In the Anturane Reinfarction Italian Study the trend of some specific and quantitative haemostatic parameters is being investigated in different series of patients balanced for sulfinpyrazone and placebo. In a series of young male patients who had had myocardial infarction 6 months previously, it has been shown that the placebo treatment subsample presented shortened platelet production time (PPT), increased levels of plasma beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4), and increased factor VIII related antigen (VIII:RAg) compared with a matched control group. A close correlation between plasma concentration of VIII:RAg and PPT was evidenced in the same treatment subsample. The sulfinpyrazone treatment subsample presented normalized PPT accompanied by reduction of VIII:RAg but not of beta-TG or PF4 levels.