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An international, multi-centre trial was carried out to test the haemorheological effects of ketanserin, a serotonin antagonist, after treatment of intermittent claudicants for 1 year. Ha ...

Intermittent claudication is the main clinical feature of chronic symptomatic atherothrombotic disease of the lower limbs (peripheral arterial disease [PAD]). The natural history of these patients includes a relatively limited risk for deterioration toward acute or chronic critical limb ischaemia and amputation. Patients with PAD have a high cardiovascular mortality rate, however, which is related to acute myocardial infarction and stroke (fourfold to sixfold increase in l0-year risk for these conditions). In fact, PAD is often associated with multifocal atherothrombotic arterial involvement. The presence of diffuse atherothrombotic lesions in PAD patients significantly increases their cardiovascular risk burden. Conversely, in the general population as well as in coronary patients the presence of PAD is an independent risk factor for increased mortality. Evidence of plaque instability may occur simultaneously at different locations. Finally, increased intima-media thickness at the common carotid and femoral arteries can be associated with overt disease at other arterial regions.

Arteries, veins and capillaries share the feature of hosting the "endothelial organ", an ubiquitous structure lining the surface of the entire circulatory tree. Endothelial cells and their supporting elements as the basement membrane, the intracellular matrix, and the surface covering glycocalyx, although displaying significant regional differences, maintain a common response to injury and to pharmacological stimuli. Sulodexide (SDX), a highly purified extractive glycosaminoglycan (GAG), shows many biological actions indicating effectiveness in arterial disorders and diseases. In fact, SDX besides inhibiting experimental arterial thrombogenesis displays, especially by the oral route, a number of vascular protective actions that are largely independent of those affecting blood coagulation. Among the activities relevant to arterial disorders, the agent provides restoration of damaged glycocalyx and of degraded intracellular matrix, as well as antiproliferative, antinflammatory, antioxidant, anti-proteolytic and anti-ischemic activities. Among the latter properties, the inhibiting effect on the enzyme family of matrix metalloproteinases (MMPs), and especially on the expression of MMP9 and its precursor, seems of crucial importance given the role of these matrix degrading enzymes in the pathogenesis and progression of atherothrombosis in coronary, carotid and peripheral arteries. These important biological data, many of them very recent, supply clues for the interpretation of a number of previous clinical trials in arterial diseases. Studies published in the years 1990-2005, showing significant reduction of cardiovascular events after a myocardial infarction, as well as a marked improvement in the walking ability in patients with peripheral arterial disease, deserve today an active re-appraisal likely conducive to new clinical research protocols in the field of primary and secondary prevention of cardiovascular disease of atherothrombotic nature.

Objectives to assess the effect of treatment with mesoglycan, a sulphated polysaccharide compound, on the healing of venous ulcers. Design randomised, placebo-controlled, double-blind, multicentre trial. Methods non-diabetic outpatients with chronic venous insufficiency confirmed by duplex ultrasound, normal ankle/arm pressure index and presence of a leg ulcer were eligible. Patients were randomised to mesoglycan, 30 mg/day intramuscularly for 3 weeks followed by 100 mg/day orally, or matching placebo, as an adjunct to compression therapy and topical wound care. Treatment and observation were continued until complete ulcer healing or for 24±1 weeks. Time to ulcer healing and healing rates were estimated with the Kaplan–Meier method. Results One hundred and eighty-three patients were randomised and included in the analysis (92 mesoglycan, 91 placebo). Median ulcer area upon inclusion was 3.6 cm2in the mesoglycan group and 3.9 cm2in the placebo group. The estimated time to heal 75% of the patients was 90 days on mesoglycan versus 136 days on placebo, while the cumulative rate of healing by the end of observation was 97% versus 82%, respectively. The difference in favour of mesoglycan was statistically significant (p

Screening for thrombophilia in women candidate to the pill is still a matter of debate. Oral contraceptives may trigger venous thromboembolic events in carriers of common inherited thrombophilic defects. General screening is not cost-effective from an epidemiological point of view if the objective is to prevent death due to venous thromboembolism during oral contraception (OC). However, clinicians deal with single patients and personal and/ or family history for venous thromboembolism have limited value for identifying those women at risk of VTE complications during OC. A pharmacogenetics approach in prescribing OC on the basis of each woman's genetic make-up could increase drug safety. A proper evaluation of the cost-effectiveness, the medical, psychosocial and legal consequences is needed before general screening with genetic testing for inherited thrombophilia can be recommended before OC. Copyright © 2002 S. Karger AG. Basel.

Vitamin B6 is involved in the metabolism of long chain polyunsaturated fatty acids and phospholipids. We have studied the interaction between pyridoxine deficiency and low amounts of dietary essential fatty acids (EFA) in the rat. The fatty acid composition of kidney phospholipids of pyridoxine deficient animals shows a decrease of 20:3 n9 and an increase of 20:4 n6 in comparison with control and pair fed animals. This variation of fatty acid composition could be due to the simultaneous effect of vitamin B6 deficiency, which reduces the oxidation of linolenate, and of a low intake of EFAs which stimulates delta-6-desaturase. The dietary treatment also influences kidney Prostaglandin E 2 (PGE 2 ) levels which are higher in vitamin B6 deficient animals. This effect could be correlated with a higher response to sympathic stimulation caused by the simultaneous presence of vitamin B6 deficiency and low EFA availability. Also the higher level of arachidonate could be involved in promoting PGE 2 synthesis.

BACKGROUND: Terutroban is a selective prostaglandin endoperoxide (TP) receptor antagonist with antithrombotic, antivasoconstrictive and antiatherosclerotic properties and is currently in development for long-term cardiovascular secondary prevention. OBJECTIVES: TAIPAD is an international, double-blind, randomized controlled study comparing the effects of five dosages of oral terutroban vs. aspirin and placebo on platelet aggregation in peripheral arterial disease (PAD) patients. PATIENTS/METHODS: After 10 day's placebo run-in, included patients (n = 435; ankle-brachial pressure index, 0.7 ± 0.1) were randomly allocated to aspirin 75 mg day(-1), terutroban 1, 2.5, 5, 10 or 30 mg day(-1) or placebo. On day 5, the placebo group was reallocated to one of the terutroban groups for the rest of the study (day 83). Ex vivo platelet aggregation induced by the thromboxane analog U46619 (7 μm) was measured 24 h after dosing, as well as platelet aggregation induced by arachidonic acid (AA), collagen and ADP. RESULTS: Terutroban dose-dependently inhibited U46619-induced platelet aggregation at days 5 and 83. At day 5, the inhibition was significant vs. placebo for all terutroban dosages (P < 0.001). Terutroban (5, 10 and 30 mg day(-1)) was at least as effective as aspirin in inhibiting platelet aggregation induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP). Terutroban was well tolerated, with a safety profile similar to aspirin. CONCLUSIONS: In PAD patients, terutroban dose-dependently inhibited platelet aggregation 24 h after dosing, and was at least as effective as aspirin at 5, 10 and 30 mg day(-1). Terutroban was well tolerated.

Thirty-two patients with acute, proximal-vein thrombosis were treated with heparin and alteplase (0.25 versus 0.5 mg/kg/24 h during 3-7 days) in a randomized, double-blind, multicenter, European (ETTT) trial. The treatment resulted in a decrease of the venographic Marder's score from 18 (6-25) to 13 (2-24) units (median, range) in Group I (0.25 mg/kg/24 h, n = 15, median decrease 3.0, p = 0.32) and from 17.5 (3-33) to 15.5 (0-27) in Group II (0.5 mg/kg/24 h, n = 16, median decrease 4.0, p = 0.23). Comparison of the sequential venograms could be performed in 14 cases of Group I and in 15 cases in Group II. A minority of patients showed substantial partial recanalization of the initially obstructed veins on the control venogram (one in each treatment group) and most of the control venograms showed either thrombus size reductions (5 in Group I, 7 in Group II) or no change or even deterioration (8 in Group I, 7 in Group II). Major bleedings were observed in 7 patients (7/32, 22%), 5 of them occurring in Group II (5/17, 29%). Thus, the results of the ETTT trial show that the used low dosages of alteplase administered intravenously over 3-7 days in heparinized patients cannot be recommended as a treatment for patients with deep venous thrombosis of lower limbs and/or pelvis. Further studies are needed to define a more suitable dosage regimen of alteplase in this indication.

The effects of oils with different amounts of n6 and n3 fatty acid precursors and derivatives were evaluated on phospholipid composition and PGE 2 synthesis of rat kidneys. Dietary lipids were: olive oil, an olive-blackcurrant-fish oil mixture and a blackcurrant-fish oil mixture. We observed in the kidneys of rats fed the blackcurrant-fish oil mixture a significant decrease in PGE 2 synthesis, while arachidonate values did not show significant variations. A decrease of PGE 2 synthesis could be due to competitive and inhibitory effects of fatty acids other than arachidonate, observed in the kidney phospholipid composition in our dietary conditions.

Goal of this study was to investigate whether appropriately applied spa therapy in several indications could be associated with a subsequent fall in the need for costly health services and missed working days due to sick-leave. The Naiade project was a multicenter observational, longi- tudinal, questionnaire-based study comparing an "entry" inquiry addressed to patients before an entry thermal cycle, and a "return" inquiry after 1 year. Routine statistical methods were used for comparisons. The study was carried out in 297 of the 340 certified Italian spa centers. Inquiries were managed by the spa doctor(s), with the collaboration of family doctors, and when necessary, hospitals, other health services, labour offices and employers. After exclusion of regular customers and of patients with acute disease phases or severe health conditions, 39,943 patients divided into eight diseases subgroups (rheumatic, respiratory, dermato- logic, gynaecologic, otorhynologic, urinary, vascular and gastroenteric) underwent entry inquiry and appropriate spa treatment. Patients who returned for treatment after 1 year ("index year") were 23,680 (59.2%) and received return inquiry. Outcomes considered were: frequency and duration of hospitalisation periods; missed working days; regular use of disease-specific drugs; and resort to "non-spa" rehabilita- tion therapies. The data collected at return inquiry were compared with those of entry inquiry. All the considered outcomes appeared to be significantly reduced in the index year in seven of the eight disease subgroups in comparison with the previous year. In conclusion, disease-appropriate spa treatments were followed by a reduction in the need of subsequent health interventions in most disease subgroups. The health promoting value of spa treatments should therefore undergo more rigorous assessment with rando- mised controlled studies.

TheG20210A prothrombin mutation, associated with elevated prothrombin levels, is a risk factor for venous thromboembolism (VTE) and displays a strong interaction with oral contraceptives (OC). Nodata are available onVTE risk ofOCuse in women with high prothrombin levels, either associated or not with themutation. The aim of this study was to evaluate the risk of VTE in OC users with high prothrombin levels, either including or excluding carriers of the prothrombin mutation. Prothrombin levels were measured by a chromogenic assay in 152 women who suffered from VTE in reproductive age and in 296 healthy women. Subjects carrying thrombophilic alterations other than the G20210A prothrombin mutation were excluded. Prothrombin levels were stratified into quartiles. The OR of subjects in the upper quartile were 3.10[95%confidence interval (CI)1.73-5.55] and2.07(95%CI1.11-3.85)in all women and in those not carrying the prothrombin mutation, respectively. Among the 152 patients, 88 had experienced VTE during OC; in the control group we considered as OC users the women who had used OC for at least 6 months in the 2 years before presentation but had stopped the treatment at least 3 months before the time of blood sampling (n=127).For the interaction betweenOCand prothrombin levels only the two extreme strata of prothrombin were considered. Women with the lowest prothrombin levels and who did not use OC were used as reference category. The VTE risk of using OC in subjects with prothrombin levels in the upper quartile was increased5.4-fold (95%CI2.38-12.3) and3.5-fold (95%CI1.48-8.22) in all women and in those not carrying the prothrombin mutation, respectively. We conclude that elevated prothrombin levels, even in women without the G20210A prothrombin mutation, are associated with an increased risk for venous thromboembolism and that oral contraceptive use potentiates such association. © 2003 International Society on Thrombosis and Haemostasis.

Chronic venous disorders carry lifelong medical and social burdens. Within conservative approaches, spa hydrotherapy is popular among patients with venous disorders in Europe, but whether the practice is associated with health or social benefits remains controversial.The present work is a substudy of the nation-wide Italian Naiade Project, a large multicenter observational exercise on spa treatments in different disease groups. The "Chronic Phlebopathies" substudy included 2504 patients with primary or secondary varicosis or non-varicose venous insufficiency. After a first visit and administration of a detailed questionnaire, patients underwent a "thermal cycle" of 15-20 days consisting of underwater active and passive physical therapy with mineral waters. The same procedures were repeated after 1 year on the 1352 patients (54%) who spontaneously returned to the same spa. Primary endpoints of the study were some indicators of the use of health resources related to the year after the first thermal cycle, compared with the same indicators recorded at first visit using appropriate statistical methods.The occurrence of acute venous episodes, working days missed, number and duration of hospital admissions, consumption of drugs and physical therapies were all significantly reduced in the year after thermal therapy, thus indicating lesser use of health resources.The study suggests that thermal hydrotherapy in patients with chronic venous disorders is associated with health and social benefits.

Hyperhomocysteinemia is a common finding in heart transplant recipients and may represent a risk factor for graft failure. However, the time-course, determinants and effects of medical therapy on total homocysteine plasma levels after heart transplantation remain undetermined. The aim of this study was to prospectively analyze 1) the time-course of total homocysteine in heart transplant recipients; 2) the effects of folate supplements and cyclosporine A on total homocysteine; 3) the relation among renal function, serum vitamin levels, and total homocysteine.Fifty-two heart transplant recipients consecutively evaluated for routine follow-up during 1998 were included in the study (mean age 54 +/- 12 years; 28% female). Among the 52 patients, 10 patients were treated with folate for the entire period of the study (Group F), while 26 patients never received folate (Group NF). The remaining 16 patients who did not take folate on a regular basis were excluded from subgroup analysis. Total homocysteine and creatinine plasma levels were assayed at entry into the study (time 0) and at the end of the study, 12 months later (time 12).Homocysteinemia increased significantly from time 0 to time 12 (p0.001), regardless of creatinine plasma levels (p = 0.03) and folate intake (p0.01). However, total homocysteine levels were lower in Group F compared to Group NF at time 0 and time 12 (p0.02). On multivariate analysis, time of follow-up, serum creatinine and lack of folate intake were positive independent predictors of total homocysteine.Homocysteinemia increased over time in heart transplant recipients, regardless of renal function and folate administration. Lower total homocysteine levels were associated with folate intake, suggesting that folate supplements may play a role in the prevention of vascular allograft disease.

Patients undergoing surgery for cancer are at high risk for venous thromboembolism (VTE). Agents that selectively inhibit thrombin, such as dermatan sulphate, have potential for a favourable benefit-risk ratio in the prevention of this complication.Patients scheduled for elective abdominal, thoracic, gynecologic or urologic surgery for cancer resection, were randomised to dermatan sulphate (600 mg intramuscularly on the second day before surgery, then 300 mg once daily), or calcium heparin (5,000 IU subcutaneously t.i.d., starting 2 hours before operation). Both treatments were continued until postoperative day 7 or until adequate mobilisation was achieved. Bilateral venography was scheduled at the end of treatment. Venograms were centrally assessed in blind conditions. The study outcomes were VTE (venographically proven deep vein thrombosis IDVT] or symptomatic, objectively confirmed pulmonary embolism) and bleeding complications.At 27 centres, 842 patients were randomised and underwent surgery (418 dermatan sulphate, 424 heparin). Efficacy was assessed in 521 patients with adequate venography and/or confirmed pulmonary embolism. DVT was observed in a total of 96 patients; symptomatic non-fatal pulmonary embolism developed in 2 patients (one per group), who also had DVT at venography. Postoperative VTE occurred in 40 of 267 patients on dermatan sulphate, 15.0%, versus 56 of 254 patients on heparin. 22.0% (p = 0.033). Relative risk reduction was 32.7% (95% confidence interval, 3.1 to 53.2%). The rate of bleeding complications in all operated patients was 6.9% with dermatan sulphate and 7.5% with heparin (confidence interval for the absolute risk difference, -4.1 to 2.9%). The inhospital mortality rate was 1.2% and 1.4%, respectively.In oncologic surgery, dermatan sulphate prevents VTE more effectively than heparin without increasing bleeding complications.

The paper reports on rate and type of thrombotic events occurring during the observational, prospective, inception-cohort, multicenter ISCOAT study. 2,745 unselected, daily practice patients, consecutively referring to 34 Italian anticoagulation clinics to monitor the oral anticoagulant treatment, were included in the study from beginning of their first anticoagulant course. During a total follow-up of 2,011 patient-years of treatment 70 thrombotic events (3.5 per 100 patient years) were recorded in 67 patients: 20 fatal (1%), 39 major (1.9%) and 11 minor (0.6%). 34/70 events occurred within the first 90 days of treatment (relative risk - at multivariate analysis - ofor =90 days vs.90 = 20.6, C.I. 12.7-33.5; p0.0001). The risk was higher in patients agedor =70 y (1.62, C.I. 1.0-2.61; p0.05), and when indication for anticoagulant treatment was peripheral/cerebral arterial disease (1.84, C.I. 1.01-3.36; p0.05). The frequency of thrombotic events was 17.5% when international normalised ratio (INR) levels were1.5, decreasing to 2.3% for INRs within the 2-2.99 category (relative risk of INRs2.0 vs.or =2 = 1.88, C.I. 1.16-3.07; p0.05). The recorded rate of thrombotic events was lower than that reported in the few available studies. A greater risk should be expected during the first 90 days of treatment, when anticoagulation levels are2.0 INR, in patients70 years and in those with cerebrovascular/peripheral arterial disease.

Mental capacity was assessed in 311 apparently self-sufficient patients (or = 60 years of age, 170 men) under stabilised oral anticoagulant treatment (OAT) by administering the Hodkinson's Abbreviated Mental Test (AMT). The international normalized ratios (INR) recorded during the 3 months before and the 3 after the data of test administration were examined by the INR-Day software program. The percentage of time spent within, below or above the intended therapeutic range was calculated in patients who scored abnormally at AMT, and compared with matched controls with normal AMT results. Forty patients [12.9%; 28 women (19.8%) and 12 men (7.1%), P0.0011] had abnormal AMT results; the rate seemed to increase with age. Most of these patients (35, 75%) had only elementary education. Patients with abnormal AMT results spent more time outside the intended therapeutic ranges than 40 matched controls (20.9% of the observed time vs 13.7%, P0.0001; odds ratio 1.68, CI 1.53-1.84). Unsuspected reduction of mental ability or attention levels was found in a number of elderly patients receiving OAT; these patients presented longer periods of either under- or over-anticoagulation and were, therefore, exposed to a higher risk of thrombotic or bleeding complications. Anticoagulation clinics would be advised to assess mental abilities in elderly patients before starting OAT.

Clinical diagnosis of deep venous thrombosis (DVT) of the leg is unreliable. An accurate diagnosis is important for therapeutic decision since anticoagulant treatment, though potentially dangerous, is useless in case of a false positive diagnosis, whereas a false negative diagnosis may lead to withdrawal of an extremely necessary anticoagulation. Contrast venography is still recognized as the gold standard method for the diagnosis of DVT, but in recent years a variety of accurate non-invasive methods has been developed. The ultrasound compression sonography (CUS) is considered a simple non invasive test highly sensitive and specific for proximal DVT in symptomatic outpatients, though non adequately sensitive and specific for isolated calf DVT. Plasma D-dimer levels (DD, fibrin degradation products) have a high negative predictive value for DVT. The aim of this study, performed in outpatients with suspected leg DVT, was to validate, versus venography, a non-invasive, easy to perform and fast diagnostic procedure based on a combination of CUS and D-dimer test. End points of the procedure were: confirmation or exclusion of proximal DVT; suspicion of isolated calf DVT in which case the test would be repeated in a few days to detect any possible proximalization of thrombosis.Sixty-eight consecutive outpatients, 37 male, with clinically suspected first episode of leg DVT were eligible and examined with CUS, DD test and venography.The results showed that the diagnostic procedure under examination has a high sensibility and specificity for DVT.It can thus be recommended as routine diagnostic procedure in symptomatic outpatients with suspected DVT reserving venography special cases only.

Dietary precursor and derivative polyunsaturated fatty acids influence metabolic parameters, such as eicosanoid synthesis. We have studied the effect of dietary intakes of lipids containing different amounts of precursor and derivative fatty acids (olive oil, olive-blackcurrant-fish oil mixture, blackcurrant-fish oil mixture, MCT (medium chain triglycerides)-soyabean oil mixture) on serum thromboxane B2 (TXB2) in four groups of rats. Plasma fatty acid composition showed differences related to dietary intakes. TXB2 levels were similar in all conditions except in the group receiving the mixture of olive-blackcurrant-fish oils which showed lower values.

Bleeding is the most serious complication of the use of oral anticoagulation in the prevention and treatment of thromoboembolic complications. We studied the frequency of bleeding complications in outpatients treated routinely in anticoagulation clinics.In a prospective cohort from thirty-four Italian anticoagulation clinics, 2745 consecutive patients were studied from the start of their oral anticoagulation (warfarin in 64%, acenocourmarol in the rest). The target anticoagulation-intensity was low (international normalised ratio [INR]or = 2.8) in 71% of the patients and high (2.8) in the remainder. We recorded demographic details and the main indication for treatment and, every 3-4 months, INR and outcome events. Such events included all complications (bleeding, thrombosis, other), although only bleeding events are reported here, and deaths. We divided bleeding into major and minor categories.43% of the patients were women. Nearly three-fifths of the patients were aged 60-79; 8% were over 80. The main indication for treatment was venous thrombolism (33%), followed by non-ischaemic heart disease (17%). Mean follow-up was 267 days. Over 2011 patient-years of follow-up, 153 bleeding complications occurred (7.6 per 100 patient-years). 5 were fatal (all cerebral haemorrhages, 0.25 per 100 patient-years), 23 were major (1.1), and 125 were minor (6.2). The rate of events was similar between sexes, coumarin type, size of enrolling centre, and target INR. The rate was higher in older patients: 10.5 per 100 patient-years in those aged 70 or over, 6.0 in those aged under 70 (relative risk 1.75, 95% Cl 1.29-2.39, p0.001). The rate was also higher when the indication was peripheral and/or cerebrovascular disease than venous thromboembolism plus other indications (12.5 vs 6.0 per 100 patient-years) (1.80, 1.2-2.7, p0.01), and during the first 90 days of treatment compared with later (11.0 vs 6.3, 1.75, 1.27-2.44, p0.001). A fifth of the bleeding events occurred at low anticoagulation intensity (INR2, rate 7.7 per 100 patient-years of follow-up). The rates were 4.8, 9.5, 40.5, and 200 at INRs 2.0-2.9, 3-4.4, 4.5-6.9, and over 7, respectively (relative risks for INR4.5, 7.91, 5.44-11.5, p0.0001).We saw fewer bleeding events than those recorded in other observational and experimental studies. Oral anticoagulation has become safer in recent years, especially if monitored in anticoagulation clinics. Caution is required in elderly patients and anticoagulation intensity should be closely monitored to reduce periods of overdosing.

Indobufen ((+/-)-2-[p-(1-oxo-2-insoindolinyl)-phenyl]-butyric acid, indo) is a drug inhibiting platelet function by a reversible block of the arachidonic acid metabolism at the level of cyclooxygenase. Since tolerability profile of such drugs is mostly linked to extra-platelet cyclooxygenase inhibition, we prospectively evaluated the extent of platelet and extra-platelet cyclooxygenase inhibition by in vivo administration of indo in comparison with ASA. We assessed the effects of the two drugs on the ex vivo generation of TXB2 and 6-keto-PGF1 alpha in whole blood, as indices of the production of TXA2 and PGI2 (prostacyclin), respectively, either after spontaneous clotting at 37 degrees C for 1 h (Study 1) or after the addition of 2 micrograms/ml collagen (Study 2). Generation of 6-keto-PGF1 alpha in whole blood is a mixed index of platelet and extra-platelet cyclooxygenase activity, deriving from both platelet and white blood cell arachidonic acid metabolization. Fifteen patients with ischemic heart disease and baseline serum TXB2 levels300 ng/ml were allocated to receiving one single administration of either indobufen 200 mg (n = 6) or aspirin 500 mg (n = 9). Whole blood prostanoid generation was assessed at 0, 1, 2, 4, 6, 8, 12 and 24 h after drug administration (Study I). Ten healthy male volunteers were allocated to a double-blind, randomized crossover comparison of indo 200 mg b.i.d. vs. ASA 300 mg/d for 7 days (Study 2). Prostanoid generation and whole blood platelet aggregation were performed before and at the end of each study period (Day 0 and Day 7). At each time-point after single dose administration (Study 1), indobufen caused less % inhibition of whole blood 6-keto-PGF1 alpha than of TXB2. At 2 h, TXB2 was reduced to a similar extent after ASA (98 +/- 4%) and indo (97 +/- 6%) (p = N.S.), while inhibition of 6-keto-PGF1 alpha was clearly different (98% after ASA, 81 +/- 2.5% after indo, p0.01). After one week of ASA or indo (Study 2) the maximum extent of whole blood platelet aggregation was similarly inhibited (from 17.2 +/- 1.4 ohms to 3.6 +/- 1.3 ohms with ASA; from 18.3 +/- 1.0 ohms to 1.6 +/- 0.7 ohms with indo (p ASA vs. indo = N.S.). Despite equal inhibition of whole blood TX production after collagen (from 49.0 +/- 4.3 ng/ml to 1.1 +/- 0.6 ng/ml with ASA, from 49.8 +/- 1.3 ng/ml to 1.4 +/- 0.6 ng/ml with indo), again, however, 6-keto-PGF1 alpha production was less affected by indo than by ASA (from 409 +/- 30 pg/ml to 37 +/- 13 pg/ml with ASA, inhibition = 91%; from 396 +/- 35 to 318 +/- 40 with indo, inhibition = 20%). These differential effects of indo and ASA might lead to a better platelet selectivity, tolerability and benefit/risk profile of indo vs. ASA, which are worthy of further assessment.

Defibrotide is a polydeoxyribonucleotide extracted from mammalian organs (porcine) and prepared by controlled depolymerization, resulting in a single-stranded deoxyribonucleotide with a mean molecular weight of 15 to 30 kDa. Early studies of experimental pharmacology in different animal species (1981-1986) were focused on an antithrombotic effect in arteries, veins, and the microcirculation, attributed to a dose-dependent activation of fibrinolysis. More recently, a number of new data have raised interest in an "anti-ischemic" action of the substance, as suggested by its evident protective effect in different models of tissue and organ ischemia. Protection from myocardial ischemia was demonstrated in different experimental models, and several ischemic features, such as heart muscle contracture, loss of high-energy substrates, decline in beta-adrenergic receptor sensitivity, and drop in infarct-related blood flow, were successfully prevented. Similar protective effects were observed during liver and kidney ischemia and in different types of experimental shock. The mechanisms involved in the anti-ischemic properties of defibrotide have been investigated in studies of experimental and human pharmacology. The substance has been shown to modulate arachidonic acid metabolism by enhancing the production and release of prostacyclin and prostaglandin E2 from tissues and whole blood, and inhibiting leukotriene B4 generation in leukocytes. Furthermore, an effect of defibrotide on activation of polymorphonuclear leukocytes and their incorporation into thrombi was described. Favorable effects on blood rheology were also reported. In summary, defibrotide deserves attention for therapeutic trials in clinical conditions characterized by organ or tissue ischemia.

Deep vein thrombosis (DVT), if not properly treated, may be complicated by pulmonary embolism in about 50% of the cases within 3 months. Therefore, effective prevention of pulmonary embolism relies on three cornerstones: correct prophylaxis, early diagnosis, and correct treatment of DVT. In prophylaxis of DVT, low-dose heparin is effective in preventing postoperatory DVT and pulmonary embolism in medium risk operations, and also in "medical" DVT. In high risk operations and patients, personalized low-dose heparin, oral anticoagulants and especially low-molecular weight heparins have been used. The available controlled trials demonstrate that the low-molecular weight heparins are especially efficacious and also cost-effective in high risk situations as elective hip surgery. Validated techniques for early diagnosis of DVT are phlebography and, in symptomatic proximal DVT, also venous echotomography. Therapy of overt DVT is usually performed with infusional or subcutaneous heparin at therapeutic doses, followed by moderate range oral anticoagulants. In the initial treatment, low-molecular weight heparins at single subcutaneous daily dosing can substitute for standard heparin. Indication to thrombolytic therapy should be restricted to selected cases; thrombectomy has limited application. Caval filters may be useful in strictly selected indications, especially in presence of contraindications or resistance to anticoagulant treatments.

Epidemiological studies have shown that obesity, as well as haemorheological changes are risk factors for cardiovascular disease. The aim of this study performed in grossly obese subjects was to investigate: (a) the effects on haemorheological parameters of a 3 month period of very low calorie diet (VLCD, 514 and 470 Kcal/day in women and men respectively), and (b) the relationship between haemorheological test results at baseline and the different types of body fat distribution. Fifty-two obese healthy subjects (31 women), with BMI30, were examined at baseline; 34 of these (19 women), compliant with the diet, were also examined after 3 months VLCD. At baseline, the results of haemorheological variables were not significantly different for patients in the highest waist-to-hip ratio (WHR) tertile vs those in the other two tertiles. After VLCD, body weight and BMI decreased markedly. The values of Ht, plasma viscosity (PV), erythrocyte aggregation index (EAI) values (P0.001) and white blood cell (WBC) counts (P0.01) significantly dropped. Globulin levels decreased, while albumin levels increased leading to significantly (P0.001) higher A/G ratios. No significant changes in fibrinogen (Fgn) levels were recorded after diet. In conclusion, the present study demonstrates that prolonged VLCD associated with slimming in grossly obese subjects is effective in improving related haemorheological disorders, mainly of plasmatic type, except Fgn. Second, we found that, at least in these grossly obese subjects, there is no clear evidence of a relationship between the degree of haemorheological changes and WHR values.

The authors define pro-thrombotic states as conditions associated with a high frequency of thrombosis; this association is based on pathogenetic or simply clinical and epidemiological relationships. Thrombophilic states have well-defined, specific causes: antithrombin III, protein C and S and similar deficiencies for inherited thrombophilias, and lupus anticoagulant, antiphospholipid antibodies for the acquired forms. Another identifiable group is made up of several conditions predisposing to thrombosis (CPT) characterized by less specific and multiple mechanisms (e.g. malignancy, inflammatory bowel disease, nephrotic syndrome, diabetes, obesity, etc.). These conditions may induce thrombosis by themselves or contribute to its clinical onset in patients with true thrombophilic states. This is especially the case for patients who are taking contraceptive drugs, are pregnant, have undergone surgery or trauma. The term hypercoagulability states is by no means equivalent to either thrombophilia or CPT. In fact, hypercoagulability may be defined as "activation of blood coagulation" in the presence of specific markers such as fibrinopeptide A and prothrombin fragment F1 + 2. Hypercoagulability is therefore a laboratory rather than a clinical condition and can be a transient feature appearing during certain phases of thrombophilia or CPT. Lastly, conditions involving the presence of hemostatic risk factors for atherothrombosis are simply terms used to describe a statistical-epidemiological relationship between certain hemostatic variables (fibrinogen, factor VII, PAI, etc.) involving the risk of cardiovascular morbidity and mortality but not necessarily indicating a hypercoagulability state.

The acute and chronic effects of a preparation of dried garlic powder (Sapec) in a total daily dose of 900 mg on fibrinolysis and platelet aggregation have been evaluated in a randomized, double-blind, placebo controlled cross-over study of 12 healthy subjects. Total euglobulin fibrinolytic activity and t-PA (tissue plasminogen activator) activity were significantly higher 4 and 6 h after garlic and placebo ingestion, and no differences were recorded between treatments. After 14 days of treatment, t-PA activity was significantly higher after garlic, with inter-treatment significance. No significant changes in PAI (Plasminogen Activator Inhibitor) activity and fibrinogen levels were recorded. Platelet aggregation induced by adenosine diphosphate and collagen, and especially beta-thromboglobulin (beta-TG) release after collagen stimulation were significantly inhibited 2 and 4 h after garlic ingestion; platelet aggregation values were also significantly lower after 7 and 14 days of garlic treatment. No significant changes were found in adenosine triphosphate release and serum TXB2 levels after acute garlic administration.

Defibrotide (Def), a new antithrombotic drug, has been proposed as a prophylactic agent in postoperative DVT. Most of the studies to date, however, have either not been controlled or have used unverifiable systems for asymptomatic DVT diagnosis. This randomized pilot study compared Def versus standard low-dose calcium heparin (CH) prophylaxis after gynaecological surgery, using objective criteria for DVT diagnosis.Forty-one pts received 400 mg Def intramuscularly twice a day starting the day before surgery; 40 pts received 5000 IU CH s.c. twice daily beginning 2h before surgery. The two groups were well matched for all relevant risk factors. DVT was diagnosed by means of the 125I fibrinogen uptake test (FUT) and venography. Blood coagulation and fibrinolysis tests were also carried out perioperatively.Isotopic DVT (FUT-positive for two consecutive days) was recorded in 6 (14.6%) of the Def and 5 (12.5%) of the CH groups. In cases where FUT was positive for at least three consecutive days (4 in Def and 1 in CH), venography confirmed DVT in 3 cases (all in the Def group). No side-effects were recorded in either group and the amounts of transfused blood were not different. No significant differences in blood coagulation or fibrinolysis tests were recorded, except for higher fibrinogen levels on the 8th post-operative day in the Def group.These results do not indicate any trend suggesting that Def, as a prophylactic agent in gynaecological surgery, offers any clinical or practical advantages over standard low-dose heparin prophylaxis.