Hemostatic changes in vasculitides.

The systemic vasculitides are an heterogeneous group of rare diseases characterized by inflammation and fibrinoid necrosis of blood vessel walls. Today it is well known that the inflammatory process characterizing vasculitides activates coagulation factors, inhibits anticoagulant factors, inhibits fibrinolytic processes, increases platelet activity and production and determines endothelial dysfunction. So far the mortality in vasculitides, even if falling, remains substantially high. Patients with vasculitic syndrome are at increased risk of developing atherosclerosis and in these patients prevalence of cardiovascular disease and cardiovascular events is higher than in the general population. Vasculitides can be associated with antiphospholipid syndrome. It is important to establish a strategy of antithrombotic therapy management in vasculitic patients, but this has not yet been clearly achieved.

Haemostatic effects of phytoestrogen genistein in postmenopausal women.

INTRODUCTION: Genistein is an isoflavone phytoestrogen derived from the soybean which acts as natural selective estrogen receptor modulator. Various studies have pointed out its cardioprotective role. The aim of the study was to evaluate the haemostatic effects of genistein in postmenopausal women. MATERIAL AND METHODS: In this double-blind placebo-controlled trial we enrolled 104 healthy postmenopausal women with osteopenia. 53 patients (mean age 54.9+/-4.2 yr; BMI 23.4+/-3.2 Kg/m(2)) received genistein (54 mg/day) and 51 patients (mean age 55.4+/-4.3 yr; BMI 23.6+/-3.6 Kg/m(2)) received an identical placebo-tablet. Both groups received a calcium and vitamin D supplement. Plasma levels of D-dimer (DD), plasminogen activator inhibitor-1 (PAI-1) and prothrombin fragment 1+2 (F1+2) were measured at baseline and after 6 and 12 months of treatment. RESULTS: Baseline characteristics of the two groups were similar. Compared with placebo, genistein decreased significantly DD (p<0.001), but did not affect PAI-1 and F 1+2 plasma levels. CONCLUSION: The results of our study do not confirm effects of genistein on activation of the haemostatic system, but on the contrary the significant decrease of DD could indicate a possible cardioprotective role of genistein in postmenopausal women.

Long-term hemostatic effects of cholesterol-lowering therapy with atorvastatin.

This study assessed hemostatic effects of an HMC-CoA reductase inhibitor, atorvastatin, on different parameters in 32 hypercholesterolemic patients of both sexes. In the patients and in 25 control subjects, plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor (PAI-1), D-dimer, prothrombin fragment 1 + 2 (F1 + 2), total cholesterol, triglycerides and fibrinogen had been measured. All these parameters were evaluated in patients after 6 and 12 months of treatment with atorvastatin at a dosage of 20 mg/day. This treatment significantly lowered the total cholesterol level in all patients. Moreover, after 6 months of atorvastatin treatment, PAI-1 and F1 + 2, which were both increased at baseline, were significantly reduced. This reduction continued after 12 months. The present results show that a reduction of hemostatic abnormalities, which exist in hypercholesterolemia, may be another important effect of the atorvastatin therapy.

Hemostasis and fibrinolysis factors in first-degree relatives of patients with Type 2 diabetes without hypertension.

First-degree relatives of type 2 diabetic patients with or without a family history of hypertension are at increased risk for cardiovascular diseases. The aim of this study was to verify some possible hemostatic alterations in first-degree relatives of type 2 diabetic, normotensive and hypertensive patients. In 78 non-diabetic, normotensive first-degree relatives of type 2 diabetic patients (47 without a family history of hypertension and 31 with a family history of hypertension) and in 36 normoglycemic, normotensive subjects with no family history of hypertension, we evaluated plasma levels of fasting glucose and insulin, tissue-type plasminogen activator (t-PA), plasminogen activator-inhibitor (PAI-1), D-dimer (DD) and prothrombin fragment 1 + 2 (F1+2). Insulin resistance, calculated by the HOMA model, and plasma levels of t-PA and PAI-1 were significantly higher in relatives of diabetics compared to controls. As far as the thrombin activation indexes are concerned, we detected a significant increase in DD and F1+2 in relatives of diabetics with hypertension compared to other study subjects. In conclusion, our data indicate that familial predisposition may influence the hemostatic system in first-degree relatives of diabetic and/or hypertensive patients.

Increased indexes of thrombin activation in advanced stages of hypertension.

BACKGROUND: The hemostatic system plays an important role in thrombotic lesions, which can complicate the clinical course of hypertensive patients. The aim of this study was to verify a possible activation of the blood clotting processes, the evaluation of two markers of thrombin activation in 62 hypertensive patients, with and without vascular complications, compared with a control group. METHODS AND RESULTS: In 22 patients with newly diagnosed uncomplicated essential hypertension, in 40 hypertensive patients with clinically evident vascular complications (20 patients with controlled blood pressure and 20 with uncontrolled and high blood pressure) and in 20 normotensive sex- and age-matched subjects, two indexes of thrombin generation and action, namely prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA) were evaluated. The observed values show an increase of the F1 + 2 levels in patients with overt vascular complications; those with higher blood pressure, moreover, showed FPA levels higher than those with controlled blood pressure. CONCLUSIONS: These results seem to indicate that plasma F1 + 2 levels are significantly elevated, as a marker of a thrombosis-prone status, in patients with organic damage. Successively, with progress of hypertension and increasing blood pressure, the evidence of elevated FPA levels seems to indicate a clear prethrombotic situation which could turn into a thrombotic state.

Correlation between family history of hypertension and haemostatic disorders.

BACKGROUND: The aim of this study was to evaluate whether a family history of hypertension is associated with haemostatic disorders. METHODS: In 38 normotensive subjects with a family history of hypertension (relatives) and in 46 sex, age and body mass index matched controls with no family history of hypertension, tissue-type plasminogen activator (t-PA), plasminogen activator-inhibitor (PAI-1), D-dimer (DD) and prothrombin fragment 1+2 (F1+2) were evaluated. RESULTS: The t-PA and PAI-1 observed values were significantly higher than the values detected in the controls. CONCLUSIONS: These data seem to suggest a correlation between family history of hypertension and haemostatic disorders.

Evaluation of haemostatic parameters and circadian variations of the haemostatic system in patients with systemic sclerosis and Raynaud's phenomenon.

BACKGROUND: Systemic sclerosis (SSc) is a multisystemic disease characterized by proliferation and swelling of endothelial cells and other disorders. Raynaud's phenomenon (RP) is a disturbance, with unknown pathogenesis, that may be a precursor to SSc. The aim of this study was to investigate possible alterations in the haemostatic system and to examine whether there is a circadian variation in haemostatic variables at the initial stage of SSc. METHODS: In 20 patients with RP (in all patients secondary to SSc) and in 10 controls the levels of thrombomodulin (TM), beta-thromboglobulin (beta-TG), D-dimer (DD), tissue-type plasminogen activator (t-PA) and plasminogen activator-inhibitor (PAI-1) were measured in venous plasma samples taken at 9.00 and 14.00. RESULTS: Only TM levels were found to be higher in patients than in controls. Moreover the PAI-I levels, in the patient group, showed a significant circadian rhythm (with peak values at 9.00). No significant circadian variations for the other parameters were detected. CONCLUSIONS: These data seem to indicate that in patients with RP there is an endothelial damage reflected by a significant elevation of the TM plasma level and a circadian variation in plasma PAI-1, which was higher in the morning. This observation may be an area worth exploring for its importance potential in the knowledge of Raynaud's phenomenon.

Efficacy evaluation of prostaglandin E1 against placebo in patients with progressive systemic sclerosis and significant Raynaud's phenomenon.

BACKGROUND: Raynaud's phenomenon, due to connective tissue diseases, is difficult to treat successfully. Symptomatic improvement has been reported using nifedipine or iloprost, but adverse side effects may limit their use. The purpose of this study was to examine the effects of PGE1 (Alprostadil) in patients with scleroderma and severe Raynaud's disease. METHODS: Twelve females, aged 50-67 years, were included in the study with six of them receiving a 3-hour infusion of alprostadil at the standard dosage of 60 micrograms in 250 cc of physiological infusion for six consecutive days and the remaining six receiving placebo (250 cc of physiological infusion administered in the same manner). RESULTS: After infusion, blood flow, digitally measured by telethermography was increased only in patients treated with alprostadil. The number, frequency and severity of attacks recorded were reduced only in patients treated with alprostadil. No side effects were recorded during and after the infusion. CONCLUSION: In conclusion, alprostadil is effective in the management of Raynaud's phenomenon, due to scleroderma.

Study of thrombinic activation indexes, in patients with lower limb critic ischaemia, before and after prostaglandin E1 therapy.

BACKGROUND: In this study the action of a prostaglandin, PGE1, was studied in a group of patients with peripheral arterial occlusive disease (PAOD). METHODS: In 16 patients (14 men and 2 women, aged 47-70 years, mean 57 +/- 7) with PAOD, Fontaine stage IIb and III in critical ischemia, the effects on two indexes of thrombin generation and action of the endovenous administration (2 hours) of 60 micrograms of Alprostadil-PGE1 for four weeks were evaluated. In all artheriopathic patients, before and after pharmacological treatment, the following haemostatic parameters were evaluated: the prothrombin fragment 1 + 2 (F1 + 2) and the fibrinopeptide A(FPA). RESULTS: The patients showed plasma levels of FPA significantly decreased at the end of the treatment. On the other hand, no significant difference in plasma F1 + 2 levels was observed after treatment. CONCLUSIONS: These results seem to indicate that plasma F1 + 2 levels are significantly elevated, as a marker of thrombosis status, in patients with PAOD before and after treatment with PGE1.

Clinical and haemostatic effects of intravenous prostaglandin E1 therapy in patients with peripheral arterial occlusive disease.

BACKGROUND: In this study the action of an antiaggregatory prostaglandin, PGE1, was studied in a group of patients with peripheral arterial occlusive disease (PAOD). METHODS: In 16 patients with PAOD Fontaine stage IIb and III the clinical and haemostatic effects of the endovenous administration of 60 micrograms/die of alprostadil-PGE1 for four weeks, were evaluated. Before and after pharmacological treatment, were evaluated the clinical symptoms (claudicatio intermittens and rest pain) and the following haemostatic parameters: plasma thrombomodulin (TM), beta-thromboglobulin (beta-TG), D-dimer (DD), tissue-type plasminogen activator (t-PA) and plasminogen activator-inhibitor (PAI-1). RESULTS: No significant difference in plasma TM, t-PA and PAI-1 levels was observed after the treatment. On the other hand the patients showed plasma levels of beta-TG and DD significantly decreased at the end of the treatment. From the clinical point of view both claudicatio intermittens and rest pain satisfactorily improved in all patients. CONCLUSIONS: This data confirmed the therapeutic efficacy of PGE1 in the treatment of PAOD patients.

Haemostatic effects of iloprost in patients with lower limb ischemia.

The aim of this study was to investigate the haemostatic effects of iloprost, a stable analogue of prostacyclin, in patients with peripheral arterial disease. In a group of 13 patients with obliterative arteriopathies of the lower limbs the plasma levels of thrombomodulin (TM), betathromboglobulin (beta-TG), D-dimer (DD) and plasminogen activator-inhibitor (pAI-1) were measured, and compared to the values obtained from 10 healthy volunteers. All the parameters were found to be significantly higher in vasculopathic patients. These haemostatic evaluations were carried out after 4 weeks of treatment with iloprost up to 2 ng/kg/min, 6 hours infusion per day. During and at the end of treatment a clinical improvement was recorded. The patients also showed a significant decrease in plasma beta-TG and DD at the end of treatment. These data suggest that iloprost exerts clinical improvement, in who may have a part the decrease of platelet activation and of fibrin turnover.

Haemostatic parameters in patients with primitive venous hypertension.

In twenty patients with primitive venous hypertension and in ten healthy subjects we have determined the plasmatic levels of: Thrombomodulin (TM), beta-Thromboglobulin (beta-TG), D-Dimer (DD), the tissue activator of the plasminogen (t-PA) and the inhibitor of the activator of the plasminogen (PAI-1). The levels of the parameter we studied have shown in the patients a significant difference of beta-TG (p < 0.01) and PAI-1 (p < 0.01) compared to the controls, whereas there was no significant difference in the other parameters we studied. Our data underline, in patients with primitive venous hypertension, the importance that the activation of the platelets and the reduction of the potential fibrinolytic can assume, together with the stasis, regarding the onset of thrombotic complications.

Haemostatic changes in patients with deep vein thrombosis.

Thrombomodulin (TM), beta-thromboglobulin (beta-TG), D-dimer (DD), tissue-type plasminogen-activator (t-PA), plasminogen activator-inhibitor (PAI-1) and quantitative determination of functional protein S (PS) were measured using ELISA procedures in the plasma of 16 untreated patients with newly-diagnosed deep vein thrombosis in the leg and in 10 healthy volunteers. No significant difference in plasma TM, t-PA and PS levels was observed among the controls and patients with deep vein thrombosis. These patients, on the other hand, showed plasma DD, beta-TG and PAI-1 levels significantly higher than the control subjects. These data show that in patients with deep vein thrombosis a hypercoagulable state is a common occurrence.

Effects of medium-term antihypertensive therapy on haemostatic parameters in patients with essential hypertension.

This study assessed the effects of the angiotensin-converting enzyme (ACE) inhibitor cilazapril on the main haemostatic variables in 22 patients, of either sex, with newly diagnosed uncomplicated essential hypertension. In the patients and in 10 control subjects, plasma levels of thrombomodulin, beta-thromboglobulin, D-dimer, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) had previously been measured. Only the levels of t-PA and PAI-1 were found to be higher than in controls. All these haemostatic evaluations were carried out after 6 and 12 months of treatment with an ACE inhibitor, cilazapril, 5 mg/day. This treatment significantly lowered the mean arterial pressure in the whole group from 133 to 106 mm Hg (after 6 months) and to 105 mm Hg (after 12 months), p < 0.05. No significant difference in any haemostatic parameters was observed after 6 and 12 months of treatment. The present study confirmed that treatment with cilazapril for 12 months lowers daytime ambulatory mean arterial pressure in patients with essential hypertension, without any significant increase in the tendency of blood to clot.

Protein S in normal subjects and patients with peripheral arterial disease.

The aim of the present study was to investigate if alterations in protein S levels occur in peripheral arterial disease. In a group of 33 patients with peripheral arterial disease and in a group of 10 healthy volunteers we have the quantitative determination of functional protein S. The observer values show non significant difference in protein S levels among vasculopathic patients and controls (only five out of 33 patients showed low protein S levels). These data seem to suggest that low protein S levels do not play an important role in the development of peripheral arterial disease.

Hemostatic disorders associated with arterial hypertension and peripheral arterial disease.

To study a possible hypercoagulability in vascular disease, in 22 patients with essential hypertension and in 13 patients with obliterative arteriopathies of the lower limbs we measured the levels of plasma thrombomodulin (TM), plasma and urine beta-thromboglobulin (beta-TG), plasma D-dimer (DD) and plasminogen activator-inhibitor (PAI-1) and compared to the values obtained from 10 healthy volunteers. The values observed in hypertensive patients show only PAI-1 levels significantly higher. All the parameters were found to be significantly increased in vasculopathic patients. These data confirm that in vasculopathic patients endothelium damage, platelet activation, impaired fibrinolytic potential and increase of fibrin turnover, occur. On the other hand, in the hypertensive patients, at first stages of the disease, we have found only an increase of PAI-1 plasma levels documenting impaired fibrinolytic potential.

[Platelet aggregation in normal and hypertensive subjects during cold pressor test]. / Studio dinamico dell'aggregazione piastrinica in normali ed ipertesi mediante cold-pressor-test.

The Authors have studied, in 5 normal subjects and in 10 with essential arterial hypertension, the behaviour of platelet aggregation before, during and after cold pressor test. It has been possible to evidence, in hypertensive subjects, a greater responsiveness of platelets to adrenaline induced aggregation. The Authors think that such effects may be due to hyperexcitability of sympathetic nervous system, which can regulate the functional behaviour of platelets in response to cold pressor test.

[Hypertriglyceridemia, IRI and platelet aggregation]. / Ipertrigliceridemia, IRI ed aggregazione piastrinica.

The Authors have studied in 13 patients with type IV hyperlipoproteinemie the behaviour of platelet aggregation and the response of IRI and blood nefa to an oral glucose load. Only two, in whom it has been possible to evidence a basal hypernefemia and a net hyperinsulinism in response to glucose oral load, showed platelet hyperaggregation to all inducers. These findings suggest that type IV hyperlipoproteinemia does not significantly influence platelet aggregation, in which IRI may have a possible role.

[Adrenal cortex production of aldosterone "in vitro" caused by angiotensin II: effects of indomethacin]. / Corticosteroidogenesi aldosteronica "in vitro" da angiotensina II: effetti dell'indometacina.

Angiotensin II increases aldosterone production of isolated and superfused bovine adrenal glands. Indomethacin shows a bi-phasic effect on the production of the above-mentioned hormone, inhibitory at low doses (0,2 microgram/ml), stimulatory at high doses (5.0 microgram/ml). Preincubation with this drug impedes the increase of aldosterone production induced by angiotensin II. It is likely that the steroidogenetic effect of angiotnesin II is carried out through the PGs.