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Background: 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., Methods: 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., Findings: 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, p < 0.001). 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, p < 0.01), and during the first 90 days of treatment compared with later (11.0 vs 6.3, 1.75, 1.27-2.44, p < 0.001). A fifth of the bleeding events occurred at low anticoagulation intensity (INR < 2, 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 INR > 4.5, 7.91, 5.44-11.5, p < 0.0001)., Interpretation: 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 levels > 300 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, p < 0.01). 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 BMI > 30, 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 (P < 0.001) and white blood cell (WBC) counts (P < 0.01) significantly dropped. Globulin levels decreased, while albumin levels increased leading to significantly (P < 0.001) 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.

In the natural history of patients with peripheral obliterative arterial disease (POAD) the prognosis of the complaint "intermittent claudication" is relatively good and the amputation rate is presently only about 3%. However, POAD patients carry a high risk of cardiovascular events and their cumultative mortality rate within 10 years is as high as 40-50%. Atherothrombotic events in the coronary and, less frequently, cerebral arteries are by far the first cause of death and disability in these patients. The rationale for antithrombotic drugs in the treatment of POAD lies in the pivotal role of platelet activation and thrombin formation in the evolution of the atherothrombotic lesions, but also in the effect of some of these drugs on the regulation of microcirculatory responses. In acute thrombotic arterial occlusion, Heparin is the "first application" drug, especially in support of interventional revascularisation procedures. Regional thrombolysis often coupled with angioplasty (PTA), or systemic thrombolysis, are effective in revascularisation of especially infrainguinal-supra popliteal occlusions. However, controlled clinical trials are needed. In chronic POAD, intermittent claudication can be improved with a rational walking exercise programme, but, besides pentoxyphilline, especially ticlopidine significantly adds to the benefits of exercise. Regarding districtual progression of atherothrombosis and especially cardiovascular events, both aspirin and ticlopidine have been shown effective in single studies or meta-analyses. In a recent observational study of pooled data the cumulative endpoint including myocardial infarction, stroke and vascular death was reduced by 25 +/- 10% in the generality of patients treated with antiplatelet drugs. Finally, in critical limbs ischemia (CLI), some prostanoid compounds as Iloprost and Prostaglandin E1 favourably influence rest pain and ulcer healing, but less evidence is available on their effects on hard events as amputation and death. In conclusion, following the general indication to "be conservative" in the treatment of these patients, it seems clear that antithrombotic drugs have become by far a key medication in all different phases of POAD.

The acute and chronic effects on blood coagulation and fibrinolysis of a new molecular weight dermatan sulphate (Desmin 370) have been investigated in a double blind, placebo-controlled cross over study in 12 healthy volunteers. The compound (100 and 200 mg) was injected IM and the expected heparin cofactor II potentiating effect, reflecting dermatan sulphate activity, peaked after 2 h and was still detectable after 9 h. Surprisingly for this type of compound, a substantial increase in anti-Xa activity also appeared and lasted up to 12 h in the absence of a significant change in aPTT. The bovine-thrombin time was not changed, while human-thrombin times were slightly, albeit non-significantly, prolonged. The activity of t-PA was increased 6h after the higher dose, but the overall pattern of fibrinolytic activities did not suggest any important change after drug treatment in comparison to placebo. No residual or cumulative effect on any of the investigated parameters was detectable 24 h after the injection on the 4th and 8th days during repeated daily administration. Parallel in vitro and in vivo investigations showed that the unexpected anti-Xa effect was not attributable to contamination by traces of low molecular weight heparin. Desmin 370, a low molecular weight dermatan sulphate that potentiates heparin cofactor II and also inhibits Factor Xa, deserves clinical evaluation as an antithrombotic agent.

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.

High levels of tissue plasminogen activator (t-PA) have been reported to be the main component of the high fibrinolytic activity measured in patients during orthotopic liver transplantation. However, a previous study of our group suggested that specific t-PA may not completely account for the massive fibrinolytic activities recorded. In the present study we investigated the fibrinolytic patterns in 10 consecutive liver cirrhosis patients undergoing OLT. Euglobulin fibrinolytic activity, measured either on physiologic (fibrin plates) or amidolytic substrates, increased as expected during anhepatic and reperfusion phases, but largely exceeded the specific activity of t-PA, as proved by quenching procedures using anti-t-PA antibodies. The presence of plasmin- and trypsin-like amidolytic activities was detected in native plasmas at the end of anhepatic and reperfusion phases, together with decreased levels of protease inhibitors, especially alpha 1 Antitrypsin. In conclusion, the hyperfibrinolytic pattern recorded in the central OLT phases is not only attributable to an increased t-PA concentration, and is better described as a complex "lytic" state also including the presence of free proteases (plasmin- and trypsin-like), with limited participation of u-PA. Although t-PA increase is probably the main mechanism of stimulation of the fibrinolytic system during OLT, actual and not just potential proteolytic activities can be found in this condition independent of the occurrence of major hemorrhagic complications.

A protein S gene polymorphism, detectable by restriction analysis of amplified exonic sequences, was investigated in a family with members affected by protein S deficiency, deep vein thrombosis and ictus. The clinical laboratory findings as well as RFLP analysis were consistent with the presence of a type WP III protein S deficiency clearly marked by a polymorphic allele, thus enabling us to determine the carrier status in several subjects. The RFLP analysis, extended to platelet mRNA after reverse transcription and amplification, demonstrated that the mRNA produced by the putative defective gene was present in a subject affected by thrombosis.

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.

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 laboratory assessment of the lupus anticoagulant, a factor frequently associated with venous and arterial thrombosis, recurrent miscarriages and abortions, is not straightforward, as indicated by the variety of tests proposed and the different results obtained. On account of the marked variability and heterogeneity of lupus anticoagulant among patients, no single test or reagent will identify all patients with lupus anticoagulant, and a panel of several tests has to be used. This is time consuming and increases the workload of the laboratory. The aim of this study was to assess the minimum number of tests necessary for the satisfactory identification of the patient with lupus anticoagulant. Our study confirms that lupus anticoagulant may be present in a significant number of patients with normal routine activated partial thromboplastin time, a test which therefore cannot be used as the sole criterion for identifying patients suspected of having lupus anticoagulant. In contrast all patients who had positive results in at least one test could be detected (100% sensitivity) with two combinations of tests: (1) dilute activated partial thromboplastin time and Kaolin clotting time and (2) dilute activated partial thromboplastin time and tissue thromboplastin inhibition test. Since the latter inhibition test has been reported to give a high number of false-positive or negative results, we suggest the combination of dilute activated partial thromboplastin time and Kaolin clotting time as the standard pair of tests for the screening of suspected lupus anticoagulant patients.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

The effects of oils with different amounts of n6 and n3 fatty acid precursors and derivatives were evaluated on phospholipid composition and PGE2 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 PGE2 synthesis, while arachidonate values did not show significant variations. A decrease of PGE2 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.

During the last decade interesting data have been collected on the epidemiological significance of some coagulation factors as risk indices for major cardiovascular events and, also, for the prognosis of atherothrombotic disease. The factors for which evidence is most convincing include: plasma fibrinogen, coagulation factor VII, and an inhibitor of fibrinolysis, namely the plasminogen activator inhibitor PAI-1. These data have been provided by studies of primary predictivity, in which the said parameters were measured in healthy subjects whose cardiovascular outcome was followed. Studies of secondary predictivity, or prevalence studies have also been extremely helpful. In these, the coagulation factors measured in patients already suffering from atherothrombotic disease were correlated with its severity, extension and outcome. From these data, the plasma fibrinogen level emerges as the coagulation parameter best correlated with cardiovascular events, that is, as both a primary and a secondary predictor. The predictive power of plasma fibrinogen level appears to be no less significant than that of blood cholesterol. Although a few methodological problems must still be overcome, hyperfibrinogenemia is gaining increasing consideration as a new, important risk factor for cardiovascular events. It is however premature to consider the said parameters not only as risk indices but also as causal factors of atherothrombotic disease. In fact, their pathogenic and causal role, although supported by high biological plausibility, has not yet been confirmed by interventional studies aimed at assessing whether or not therapeutic lowering of these values is associated with reduced cardiovascular risk.

Acute intravenous administration in man of defibrotide (CAS 83712-60-1), a polynucleotide derivative, induces increase of 6-keto-PGF1 alpha and PGE2 production from appropriately stimulated whole blood. In the present study including acute and chronic experiments, defibrotide (Prociclide) orally administered during two weeks to healthy volunteers significantly increased the amounts of 6-keto-PGF1 alpha generated after appropriate stimulation in whole blood and in a neutrophilic leukocytes-platelet suspension. Similar effects were observed for PGE2, while TXB2 production was unchanged. Furthermore, platelet aggregation induced by calcium ionophore A23817 and production of leukotriene B4 from whole blood and isolated polymorphonuclear neutrophils were inhibited. The observed results suggest that defibrotide is biochemically active also by the oral route although the pharmacological and clinical value of the observed changes needs to be assessed.

Thirty-seven patients affected by polycythaemia rubra vera (PRV) and with at least one additional thrombotic risk factor (overt vascular disease, diabetes mellitus, treated hypertension, smoking habit, plasma hyperviscosity, hyperfibrinogenemia) were enrolled in a double-blind randomized placebo-controlled study, and 18 were given ticlopidine 250 mg, b.i.d., for 60 days. All the patients had previously been submitted to cytoreduction, and PRV was under control in all cases at the start of the study. During the study, the haematological parameters were controlled every 15 days, and venesection was performed if haematocrit was greater than 46%. Whole blood viscosity, at low and high shear rates, plasma viscosity, and fibrinogen were measured on days 0 and 60. In the ticlopidine group, we recorded a significant 13.14% reduction of the mean fibrinogen level after treatment (390 +/- 63 vs. 449 +/- 97 mg/dl, p less than 0.01). All the other haemorheological parameters were not significantly modified by ticlopidine treatment, nor were there significant modifications recorded in the placebo group. Our study shows that ticlopidine may reduce a probable thrombotic risk factor (hyperfibrinogenemia) in PRV patients.

In this study we report the data obtained from extensive haemostatic testing of 25 patients undergoing orthotopic liver transplantation and the results of an open randomized pilot trial of antithrombin III concentrate administration during surgery. Marked differences in transfusional needs and in pre- and intraoperative blood coagulation and fibrinolytic changes were observed between recipients with liver cirrhosis and those with primary biliary cirrhosis. In the former, the increases in tissue-type plasminogen activator activity, total euglobulin fibrinolytic activity, and fibrin-derived degradation products occurred earlier and were more marked, as were the signs of increased thrombin formation. Supplementation of antithrombin III concentrate during surgery failed to induce significant changes in the main parameters studied and in the transfusional needs.

Heparin fractions and fragments are useful tools in the elucidation of the mechanism of action of heparin and similar substances. The identification of portions with low or high affinity for antithrombin III and of a 'core' pentasaccharide responsible for anti-factor Xa activity has been possible thanks to heparin fractionation and fragmentation procedures. The development of low molecular weight heparins led to the production of substances with a molecular weight around 5,000, considerably variable in chemical structure, anti-factor Xa and anti-factor IIa activities, and experimental antithrombotic effects. The original rationale according to which fragments with high anti-factor Xa activity and anti-factor Xa/anti-factor IIa ratio would retain optimal antithrombotic activity with greatly reduced prohemorrhagic actions, turned out to be an oversimplification of the problem. In fact, neither is the anti-factor Xa activity the only determinant of the antithrombotic effect, nor is the anti-factor IIa activity a good predictor of hemorrhage. Despite disaggregation of the original rationale, low molecular weight heparins have already proved to be at least as effective and safe, and more conveniently and practically administered, as unfractionated heparin in the prophylaxis of deep-vein thrombosis.

Twenty-one thyroprival patients, previously submitted to total thyroidectomy for tumours, were investigated during stabilized L-thyroxine supplementation and at the end of a 20-25 day "no-therapy" period, necessary for a 131I total body scintigraphy. During supplementation therapy a lower than normal mean beta-thromboglobulin (beta-TG) release level was found, the other blood clotting and platelet function tests being normal. After substitution therapy withdrawal, platelet function tests showed reduced adrenalin aggregation, increased collagen threshold aggregating concentrations, decreased beta-TG release values and reduced aggregation to ristocetin, whereas blood clotting tests showed prolonged aPTT values and reduced levels of factor VIII:C and vWf:Ag. We conclude that in acquired hypothyroidism the lowering of factor VIII:C and vWf:Ag (acquired von Willebrand disease) is associated with impaired platelet reactivity not only to ristocetin but also to collagen and especially adrenalin. In the patients investigated these changes were almost completely corrected by substitutive therapy with L-thyroxine at clinically effective doses.

Few studies have dealt with blood-clotting changes in patients affected by homocystinuria. The aim of this contribution is to briefly review studies published so far on the topic and report the results of our investigation performed in 3 patients. At baseline we found reduced antithrombin III and factor VII levels in all the patients, in line with the results of other authors, and other slight and less constant changes such as lowered factor X activity and protein C antigen, and increased beta-thromboglobulin levels. During pyridoxine and folate treatment, antithrombin III activity rapidly returned to normal; factor VII increased and beta-thromboglobulin decreased. These blood-clotting abnormalities may play a role in the thrombotic tendency associated with homocystinuria. Their nature is still uncertain, but the improvement observed during active metabolic treatment suggests that the defect in amino acid transsulfuration of homocystinuria may directly affect synthesis or activity of some clotting factors.

The effects of ticlopidine treatment (250 mg b.i.d. for 21 months) on fibrinogen and other rheological variables, as compared to placebo, were studied in 44 patients with intermittent claudication due to peripheral arterial occlusive disease. Blood samples were collected every 3 months during this double-blind, randomised placebo-controlled trial which lasted 21 months. Consistently lower values of fibrinogen, haematocrit and whole blood viscosity at high and low shear rate levels were found in the ticlopidine group; the intergroup differences were statistically significant at most but not all follow-up examinations. A significant time-related variance was observed in the ticlopidine group for the measured variables, also after correction for the variability found in the placebo group. Thus, the observed changes in the ticlopidine group are mainly treatment related. These effects on fibrinogen and haemorheology may contribute, besides the known antiplatelet activity of the drug, to the clinical improvement reported in a larger group of claudicants to which the present subset of patients belong.

Hemorheologic parameters were measured in cerebrovascular patients with a history of stroke or recurrent ischemic attacks in a quiescent phase of the disease. All patients were submitted to aortic arch angiography and then classified according to the presence or absence of detectable arterial lesions. In comparison with a group of control subjects, cerebrovascular patients had significantly elevated levels of blood and plasma viscosity, fibrinogen, factors VIII:C and VIIIR:Ag and lowered values of erythrocyte filtration. Blood viscosity was increased and erythrocyte filtration reduced only in male patients. Elderly patients had higher blood viscosity and fibrinogen levels, and those with a history of stroke also showed the highest hematocrit and plasma viscosity values. Patients with a stroke history compared with those affected by remittent ischemic attacks, and patients with positive in comparison with those with negative angiograms were characterized only by higher fibrinogen (and sometimes factor VIII) levels, but not by other differences in hemorheologic values. It is concluded that changes in hemorheologic values consistent with hyperviscosity are a feature of cerebrovascular patients also in the quiescent phase of the disease and not only as a result of acute ischemic attacks. These changes are however most frequent in males and in elderly subjects, while they seem to be almost evenly distributed in patients with or without evidence of arterial disease.

The aim of this study was to investigate the blood coagulation changes in three patients with homocystinuria, in baseline condition and during therapy. At baseline, antithrombin III activity and factor VII levels were reduced in all three patients; antithrombin III protein and protein C antigen were also slightly lowered in one patient, and factor X in another. beta-Thromboglobulin, a measure of platelet activation, was increased in one case. During pyridoxine treatment, antithrombin III activity was rapidly restored to normal; factor VII increased and beta-thromboglobulin decreased. These data suggest that, in addition to platelet activation, abnormalities of blood clotting, and particularly reduction of antithrombin III, may play a role in the thrombotic tendency associated with homocystinuria. The nature of these clotting alterations is still uncertain, but their improvement during active metabolic treatment suggests that the defect in amino acid transsulfuration of homocystinuria may directly affect synthesis or activity of some liver-dependent clotting factors.

Defibrotide is a polynucleotide extracted from mammalian lung, which shows antithrombotic and anti-ischaemic activity in animals, probably related to stimulation of fibrinolysis and/or enhancement of prostacyclin production. The effect of a single infusion of defibrotide on fibrinolysis and the levels of certain prostanoids in man has been investigated in a cross-over double-blind placebo-controlled study. Evaluation of changes in fibrinolysis was difficult because of the spontaneous activation observed after placebo. However, the fast-acting plasminogen activator inhibitor was decreased only at end of the defibrotide infusion, suggesting a moderate profibrinolytic effect superimposed on the spontaneous activation. There was a marked and prolonged elevation of the plasma level of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin. In collagen stimulated whole blood, both 6-keto-PGF1 alpha and prostaglandin E2 production were also greatly increased, with no consistent indication of inhibition of thromboxane B2. It is suggested that defibrotide stimulates prostacyclin and prostaglandin E2 production by leucocytes or via platelet/leukocyte interactions. The effects observed here should be useful in guiding subsequent clinical trials.

Plasma fibrinopeptide A (FPA) was measured in 50 patients with liver cirrhosis divided into 'moderate' or 'severe' cirrhotics according to standard clinical and laboratory criteria. FPA was significantly higher than in normal controls although no relation to the severity of disease was found. After a single intravenous administration of heparin there was a significant decrease in FPA levels in the patients. High molecular weight fibrinogen (HMWF) was also determined for some of the patients and was significantly greater than in the normal controls. However, there was no correlation between FPA and HMWF. The greater values of FPA and their responses to heparin indicate that there is increased thrombin formation in a number of patients with liver cirrhosis, with no apparent relation to the severity of the disease.

The rationale of the hemorheologic approach to the pathophysiological knowledge and to the treatment of obstructive arterial diseases of the limbs is discussed in this paper. Indeed, the hemodynamic concepts are the natural frame in which the hemorheologic phenomena have to be considered. Proceeding from this background, it seems evident that the viscosity of blood and its major determinants have a limited role in the regulation of blood flow and pressure gradient through a stenotic artery. On the contrary, viscosity factors are of outstanding significance in the regulation of blood flow in the microcirculation, especially in presence of a reduced perfusion pressure and of exhausted arteriolar vasodilation capacity. Consequently, therapeutic measures capable of modifying one or more viscosity determinants may improve blood flow in the microcirculation of territories related to a stenotic artery. Baseline alterations of viscosity or viscosity determinants may be found in patients with obstructive arterial disease, being classified as primary, associated or secondary to arterial obstruction and ischemic damage. However, the presence of such baseline changes is not relevant to the indication of hemorheologic treatments.

After a 3-month, single-blind, run-in period, 151 patients with intermittent claudication were randomly allocated to receive the antiplatelet agent ticlopidine (250 mg twice per day) or an identical placebo. One hundred and twenty patients completed the double-blind phase of the trial, which lasted 21 months. The primary analysis was performed according to the "intention-to-treat principle" in all 151 enrolled patients. There was, continuing on from the third month after randomization, a progressive and sustained improvement of the pain-free and maximum walking distances in the two treatment groups that was significantly greater in the ticlopidine group. The ankle-arm systolic blood pressure ratio at rest and after exercise increased in a significant manner in the ticlopidine group only. In a secondary analysis, with exclusion of 25 patients because of protocol violations at selection, consistently significant differences in favor of the ticlopidine group were still observed for maximum walking distance and systolic ankle-arm blood pressure ratio, both at rest and after exercise. No major side effects were reported in the treated group. It is concluded that long-term treatment with ticlopidine improves walking ability and ankle systolic blood pressure in patients with claudication.

The effect of a chemically stable prostacyclin analogue (Iloprost) on platelet function was investigated in a controlled study in patients with angiographically confirmed stable angina pectoris after ischaemic exercise. In placebo experiments, ADP platelet aggregation was increased after exercise only when measured in whole blood and not in PRP. While plasma thromboxane B2 levels were unchanged, those of 6-keto PGF1 alpha were significantly although transiently increased after exercise. Iloprost displayed a potent antiaggregating activity in PRP and also reversed platelet hyperaggregation occurring in whole blood determinations after exercise. Plasma thromboxane B2 levels were significantly reduced but occasionally a rebound increase occurred 30 min. after end of the infusion. In contrast plasma level of 6-keto PGF1 alpha did not change after Iloprost and its recorded post-exercise increase was counteracted, thus suggesting a negative feed-back mechanism between Iloprost and natural prostacyclin. The data also suggest that degradation of the analogue is probably accomplished through pathways different from those of PGI2.

The changes in blood rheologic properties induced by exposure to high altitude plus heavy and prolonged physical strain were investigated in 14 climbers of an Italian expedition to Himalaya (maximum altitude reached m 7350). In blood samples collected immediately after return, alterations of some haemorheologic parameters were observed in comparison with baseline values, and namely an increase in relative blood viscosity, fibrinogen and erythrocyte filtration time along with a fall in platelet count. Treatment with a drug acting on the red cell deformability (Pentoxifylline) appeared to prevent the changes in blood viscosity and erythrocyte filterability. In the 9 climbers whom we were able to re-examine after three months, all altered parameters were found to be restored to baseline values. These results contribute to the knowledge of the pathogenesis of high altitude disease and stress the significance of altered haemorheology as one of the mechanisms possibly involved in the vascular events observed in this condition.

In this study, formation of arachidonic acid-derived prostanoids was investigated in saphenous veins of varicosed and nonvaricosed patients, all undergoing saphenectomy respectively for varicosis or in preparation for coronary bypass operation. Venous production of prostacyclin (PGI2), thromboxane A2 (TXA2) and prostaglandin E2 (PGE2) was assessed by bioassay and/or radioimmunologic assays as appropriate. Fragments of saphenous veins from varicosed patients produced significantly less PGI2 and more TXA2 and PGE2 than those from the control patients. Addition of arachidonic acid to incubation mixtures dose dependently increased release of these prostanoids, but the levels of PGI2 produced were consistently lower in veins from varicosed patients. No differences were found in varicosed patients between various segments of the same vein, no matter whether macroscopically affected or unaffected. These results demonstrate that the cyclooxygenase pathway in the venous wall of subjects with varicosis is shifted toward lesser formation of PGI2 and higher production of proaggregatory and proinflammatory prostanoids such as PGE2 and TXA2. These biochemical changes may be relevant to inflammation and thrombogenesis in varicosis.