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Background: Attention has recently been paid to the cell and biochemical disorders involved in chronic venous insufficiency (CVI) and to their possible relationship to the endothelium., Methods: In the present study, carried out in 14 patients with CVI, we evaluated the levels of the inhibitor of elastase (I-EL) generated by polymorphonucleate cells in the blood reflowing from affected superficial veins of legs both at rest and after prolonged venous stasis (1 hour in standing position)., Results: We evaluated the I-EL both as percentage of activity (baseline 82.3+/-24.5%; after stasis 100.7+/-37.8%) and as absolute values (0.67+/-0.26 U/ml; after stasis 0.79+/-0.39 U/ml). In blood samples taken after venous stasis we found a tendency toward a trapping of white blood cells and an increase of the haematocrit over baseline. The difference in the percentages of activity of I-EL was statistically significant, but only a trend was observed for the absolute values., Conclusions: We believe that the typical haemodynamic disorders of patient with CVI increased by prolonged venous stasis can modify the function of white blood cells, which are closely linked with venous hypertension, thus playing an important role in the pathogenesis of skin ulcers.

Background: We have studied 64 patients with congestive heart failure, half of them also with chronic nonvalvular atrial fibrillation (AF). Patients were also stratified according to a history of prior stroke., Methods: The generation of thrombin was investigated by means of the molecular markers prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin III complex (TAT), because AF patients may have a hypercoagulable state. There was only a trend toward higher values of TAT and F1 + 2 for AF patients, while subjects with previous stroke (irrespective of AF) had increased levels of the markers of thrombin generation (TAT stroke+ 18.95 +/- 5.15 vs TAT stroke- 8.34 +/- 2.41; F1 + 2 stroke+ 2.22 +/- 0.29 vs F1 + 2 stroke- 1.32 +/- 0.12). The presence of spontaneous echo contrast (SEC) within left atrium was also investigated in 32 AF patients by transesophageal echocardiography., Results: TAT were significantly higher in subjects (n = 11) with SEC (TAT sec+ 37.5 +/- 13.41 vs TAT sec- 8.7 +/- 2.51, p = 0.008)., Conclusions: Finally, when we grouped into 1) those with both AF and stroke, 2) AF alone, 3) stroke alone and 4) sinus rhythm without stroke, levels of F1 + 2 were higher (and marginally higher TAT) in patients with AF and stroke than in those without stroke, revealing that there is a true clotting activation state in these subjects.

The prothrombotic effects of nonionic contrast media (NICM) have been evaluated in both biological and clinical studies. The question of whether there is a higher risk of thromboembolism during angiography with NICM than with ionic contrast media (ICM) has not yet been answered, nor has the precise role of the angiographic procedure per se in such complications been determined. The present study was performed to compare in vivo the potential prothrombotic effects during cardiac angiography of an NICM with those of an ICM, to estimate the effects of the procedure per se, and to assess how long these effects might be maintained. We measured blood levels of three markers of activation of blood coagulation: thrombin-antithrombin III (TAT) complexes, prothrombin fragment 1 + 2 (F1 + 2), and the split product of fibrin, D-dimer, before and after coronary angiography in three groups of patients. In group 1, 14 patients underwent coronary angiography with the NICM iopamidol 370. In group 2, 10 patients underwent coronary angiography with the ICM ioxaglate. In group 3, 10 patients were evaluated immediately after cardiac catheterization, before the injection of contrast material, as controls. No statistically significant differences between the three groups were found in TAT, F1 + 2, or D-dimer levels at different times before and after coronary angiography. There was a trend toward a transient increase in TAT levels after coronary angiography with iopamidol, which at first suggested a possible brief activation of hemostasis with this NICM, but a similar trend was also seen in the control group. We hypothesize that not only the type of contrast material, but also the angiographic procedure per se and patient-related factors all play roles in determining a prothrombotic state during coronary angiography.

Defibrotide has been evaluated in patients with peripheral arterial disease (PAD) of the lower limbs, with coronary artery disease (CAD), and with Raynaud's phenomenon (RP). In PAD patients, defibrotide improved physical performance, restored deficient fibrinolysis, and affected rheology and blood flow. Further events-oriented trials are needed. For CAD patients, defibrotide could be applicable as an adjunct treatment following thrombolysis, instead of heparin. Defibrotide does not increase bleeding risk. There is a need to study other medications together with defibrotide for their synergistic effects. In patients with RP, defibrotide restored deficient fibrinolysis, but its true clinical potential needs to be assessed.

In the medical literature reports are accumulating a number of case reports suggesting the potential efficacy and safety of the combination of low-dose aspirin and warfarin to improve the efficacy of antithrombotic therapy in several clinical conditions, ranging from unstable angina to myocardial infarction. The advantages deriving from such a combination have to be considered together with its hemorrhagic risk. Thus the efficacy of such a treatment has to be proved by large clinical trials before the use of this potentially dangerous therapy can be transferred into common clinical practice.

The aim of this study was to assess the effects of fluvastatin and pravastatin on lipid profiles and urinary thromboxane (TX) A2 metabolites (11-dehydro TXB2 and 2,3-dinor TXB2) in patients with type IIa hypercholesterolemia. A total of 20 patients (13 men, 7 women; mean age 53 +/- 9 years) with primary type IIa hypercholesterolemia (Fredrickson's classification) in a 4-week, double-blind, parallel-group study were randomized to fluvastatin or pravastatin, both at 40 mg once daily (at bedtime), after a single-blind, 4-week, placebo run-in period. Total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides were measured after placebo (baseline) and after 4 weeks of double-blind treatment. Thromboxane metabolites were measured at the same time points, using an enzyme immunoassay kit, in 12 hr urine samples. At baseline, the mean +/- SD levels of total cholesterol, LDL-C, triglycerides, and HDL-C were: 292 +/- 23, 213 +/- 47, 186 +/- 119 and 41 +/- 17 mg/dL with fluvastatin; and 301 +/- 40, 212 +/- 40, 150 +/- 124 and 43 +/- 10 mg/dL with pravastatin, respectively. Baseline thromboxane-metabolite levels were positively and significantly (p < 0.04) correlated with levels of total cholesterol, but not LDL-C. Compared with baseline, total cholesterol and LDL-C were significantly (p < 0.01) decreased by 27% and 30% with fluvastatin, and by 23% and 31% with pravastatin, respectively. HDL-C increased from 41 +/- 17 to 59 +/- 25 mg/dL with fluvastatin, and from 43 +/- 10 to 46 +/- 12 mg/dL with pravastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor necrosis factor alpha (TNF-alpha) is a cytokine that affects endothelial cells' function by changing their antithrombotic potential to a net procoagulant effect. Only a few data have so far been reported for the pathophysiologic role of TNF in vascular diseases in the involvement of microvessels and/or macrovessels and a prothrombotic state. In the present study the authors evaluated plasma TNF (and interleukin-1) levels in 20 patients with chronic arterial obstructive disease (CAOD) with intermittent claudication and 10 CAOD patients with more severe disease (pain at rest/skin ulcers). In addition, they studied 10 patients with Raynaud's phenomenon (RP), suspected to be secondary to a collagen disease. The control group consisted of 20 subjects matched for sex and age with the three groups of patients. TNF levels were assayed by enzyme-linked immunosorbent assay. The antigen levels of von Willebrand factor (vWF), tissue plasminogen activator (t-PA), and its inhibitor (PAI) were also determined as markers of release from the endothelium, while the fragment 1 + 2 of prothrombin (F1 + 2) and thrombin-antithrombin III (TAT) complexes were assessed as indexes of systemic thrombin generation. TNF levels were significantly higher in both groups of CAOD patients than in controls or RP patients, and the same was true for vWF. t-PA was significantly higher only in the CAOD subjects with more severe disease. No differences among groups were seen in PAI antigen/activity or thrombin generation. When data were corrected for age, TNF no longer differentiated CAOD patients from controls and RP subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

The activity of trapidil, an antiaggregating agent with PDGF antagonist properties, was investigated in order to verify its possible modulating effect in the endothelial and platelet activation. PDGF, t-PA, PAI-1 and ET-1 plasma levels were measured before and after a 2 month treatment period with trapidil 200 mg tablets bid or placebo in 30 patients affected by POA in Fontaine stage II. PDGF and PAI-1 significantly (p < 0.05) increased in the placebo group, and PDGF also in the comparison between treatments (p < 0.05). Aggregation data demonstrate an absence of Ca++ antagonist action of trapidil. The results of this study suggest that trapidil can interfere with the combined vascular and platelet response in atherogenesis.

Platelet activation and platelet-derived growth factor (PDGF) play a pivotal role in the pathogenesis of atherosclerosis. Evidence has been accumulating that in the evolution of chronic arterial obstructive disease (CAOD) platelets are also crucially important. The aim of the present study was, therefore, to assess plasma levels of PDGF in patients with different degrees of CAOD according to Fontaine. Twenty patients (17 men, 3 women, mean age sixty-eight +/- seven years) with intermittent claudication (Fontaine stage II) entered the study and their PDGF levels were assessed by radioimmunoassay. Ten additional patients (7 men, 3 women, mean age seventy-three +/- seven years) with more severe CAOD (leg pain at rest/skin ulcers) were also studied. Ten healthy subjects (6 men, 4 women, mean age fifty-four +/- six years) comprised the control group. Patients in stage II were reinvestigated after sixty days of a "training" procedure. Patients with both intermittent claudication and more severe disease had higher levels of PDGF than controls (controls 165.9 +/- 119.1 pg/mL; Fontaine stage II 403.5 +/- 218.4; Fontaine stage III/IV 578.1 +/- 637.2: ANOVA P = 0.04) with no difference between the two groups of patients. After the training period, PDGF levels were significantly higher than at baseline (863.7 +/- 819.6 pg/mL vs 403.5 +/- 218.4) but without significant improvement of physical performance. The elevation of PDGF levels in blood from CAOD patients could be the result of marked platelet activation due to interaction with a widely damaged peripheral vasculature. The same was not true for coronary heart disease, in which normal values of PDGF in venous blood were found.(ABSTRACT TRUNCATED AT 250 WORDS)

The differential diagnosis of Raynaud's Phenomenon (RP) is still problematic because of the wide variety of underlying etiological possibilities. Therefore, the diagnostic screening of patients requires easily reproducible, rapid and reliable tests to find those cases of RP secondary to a connective tissue disorder. The present study of 106 consecutive RP patients was carried out by using a combination of clinical examination, biomicroscopy of fingernail folds and bulbar conjunctiva (with scoring of vascular damage), plus the assessment of antinuclear antibodies on HEP2 cells. On the basis of the reported findings, it can be concluded that patients with RP secondary to collagen disease or so suspected also show abnormalities of the conjunctival microcirculatory bed. Patients with both primary and suspected secondary RP are significantly younger at the time of first diagnosis than patients with collagen disease-associated RP.

Antiplatelet agents have been studied in a number of clinical trials to evaluate their efficacy in the prevention of ischemic cardiovascular events related to platelet-rich thrombi. Acetylsalicylic acid (ASA) is definitely effective in the hospital phase of acute myocardial infarction; it also prevents cardiovascular events but not anginal attacks in patients with unstable angina and reduces the rate of occlusion of coronary artery bypass grafts. ASA is often used in the post-infarction period, even though anticoagulant therapy is probably more effective; it is also effective in patients with transient ischemic attacks in the brain. Ticlopidine is the treatment of choice in patients with major stroke and in those with peripheral vascular ischemia; it can also be considered a valid alternative to ASA in the management of transient ischemic attacks and unstable angina. There is at the moment little role for antiplatelet agents in the primary prevention of cardiovascular disease.

Platelet aggregation and fibrinogen binding were studied in 15 individuals before and 7 days after the oral administration of ticlopidine (250 mg b.i.d.). Ticlopidine significantly inhibited platelet aggregation induced by adenosine diphosphate (ADP), the endoperoxide analogue U46619, collagen or low concentrations of thrombin, but did not inhibit platelet aggregation induced by epinephrine or high concentrations of thrombin. Ticlopidine inhibited 125I-fibrinogen binding induced by ADP, U46619 or thrombin (1 U/ml). The ADP scavengers apyrase or CP/CPK, added in vitro to platelet suspensions obtained before ticlopidine, caused the same pattern of aggregation and 125I-fibrinogen binding inhibition as did ticlopidine. Ticlopidine did not inhibit further platelet aggregation and 125I-fibrinogen binding induced in the presence of ADP scavengers. After ticlopidine administration, thrombin or U46619, but not ADP, increased the binding rate of the anti-GPII b/III a monoclonal antibody 7E3 to platelets. Ticlopidine inhibited clot retraction induced by reptilase plus ADP, but not that induced by thrombin or by reptilase plus epinephrine, and prevented the inhibitory effect of ADP, but not that of epinephrine, on the PGE1-induced increase in platelet cyclic AMP. The number of high- and low-affinity binding sites for 3H-ADP on formalin-fixed platelets and their Kd were not modified by ticlopidine. These findings indicate that ticlopidine selectively inhibits platelet responses to ADP.

The clinical benefit of aspirin in the acute phase of myocardial infarction is dramatically suggested by the results of the ISIS-2 trial. However, the time course of pathophysiological events that lead to such a determining involvement of platelets still appears uncertain and further study is needed to single out exactly how early and how long antiplatelet drugs should be given, since there is a risk of bleeding complications due to the combination of the different antithrombotic therapies. Thrombolytic agents and heparin are in fact widely used for patients with acute myocardial infarction, even if the optimal schedule of treatment, including anti-aggregating therapy, is not yet firmly established. To avoid rethrombosis and to enhance the efficacy of coronary thrombolysis, thus reducing early mortality, several newer antiplatelet agents other than aspirin, such as antibodies against the platelet receptor of adhesive proteins, the glycoprotein IIb/IIIa and the RGD peptides, are currently under investigation.

Tissue plasminogen activator (t-PA) and its inhibitor (PAI) were assessed in venous blood drawn before and after venous occlusion (bvo, avo) for 33 patients with Raynaud's phenomenon (RP), 14 with primary RP (PRP), 9 with suspected secondary RP (SSRP), and 10 with definite collagen disease and secondary RP (SRP). There were significant differences in PAI values avo between PRP (and controls), SSRP, and SRP. PAI activity decreased significantly avo only in controls and in PRP, and there was significant t-PA antigen elevation avo in the same groups. In addition, since PAI is neutralized by activated protein C (PC), both PC antigen and PC activity were assessed avo and bvo. PC Ag remained unchanged in all groups, with PC activity significantly lower than controls in SRP and SSRP. Finally the authors looked for interference of anticardiolipin antibodies (ACA) and lupus-like anticoagulant (LAC) with the PC system in collagen disease-associated RP. Specific IgG ACA were found in only 1 patient with SRP. In conclusion, there is an endothelial derangement, involving t-PA release and PAI, in SSRP and SRP patients. The reduced PC activity in these latter groups appears to be due to increased PAI influence rather than to ACA/LAC.

Twenty outpatients presenting with Raynaud's phenomenon secondary to clinical or preclinical inflammation of connective tissue were treated orally with defibrotide 400 mg three times daily or a matching placebo in a randomized double-blind study. The test product defibrotide (a polydeoxyribonucleic acid compound of animal origin with demonstrated profibrinolytic activity when administered parenterally) was administered orally for 3 weeks in order to explore its effects on the parameters of extrinsic fibrinolysis before and after venous stasis. The antigen of t-PA and its inhibitor PAI, free and total, and the biologic activity of PAI were assayed in basal conditions and after treatment. Although a marked increase of t-PA was seen with the active treatment, PAI activity was significantly reduced by defibrotide. Immunoreactive PAI was not significantly modified by treatment, even though it dropped considerably after venous stasis in the defibrotide group. Thus, the disturbance of endothelial function that seems to occur in vasculitis and in Raynaud's phenomenon secondary to inflammation of connective tissue (or so suspected to be) would constitute the basis of a disturbance of fibrinolysis, which oral defibrotide seems able to correct. Further studies are warranted to define the clinical effectiveness of this treatment in patients with Raynaud's phenomenon.

Peripheral blood lymphocyte subpopulations and IgA production in vitro have been studied in 30 elderly subjects. Fifteen patients were treated with Bacillus subtilis (Enterogermina, Midy) and 15 with a placebo preparation. At the end of the treatment, a significant increase was noticed in lymphocytes bearing membrane IgA and Ia+ cells in the group treated with Bacillus subtilis, but not in the controls. Similarly, a significantly enhanced spontaneous production of IgA in vitro was seen in the treated subjects. The relevance of these findings to the understanding of the mode of action of Bacillus subtilis and its usefulness in different immunodeficiency states is discussed.

Inhibition of monocyte function is known to have important clinical consequences and to be present in a variety of diseases: Accordingly we evaluated the effect of Ticlopidine, a powerful and widely employed inhibitor of platelet aggregation, on the capacity of peripheral blood monocytes to ingest IgG-coated erythrocytes. Our results show that in vivo administration of this drug has no effect on monocyte phagocytosis, when tested with an in vitro assay. This finding suggests that Ticlopidine can be safely used in patients with depressed monocyte function and in those in whom an impairment of monocyte phagocytosis could lead to a deterioration of the clinical picture.