Pasquale Parise

Enoxaparin for the Prevention of Venous Thromboembolism Associated With Central Vein Catheter: A Double-Blind, Placebo-Controlled, Randomized Study in Cancer Patients

PURPOSE The extent of venous thromboembolism (VTE) associated with central vein catheters (CVC) in cancer patients remains unclear. The aim of this study was to evaluate the efficacy and safety of the low molecular weight heparin, enoxaparin, in the prevention of VTE. PATIENTS AND METHODS In a multicenter, double-blind study, consecutive cancer patients scheduled for CVC insertion were randomly assigned to receive either subcutaneous enoxaparin 40 mg once a day or placebo. Treatment was started 2 hours before CVC insertion and continued for 6 weeks. The primary end points of the study were deep vein thrombosis (DVT), confirmed by venography of the CVC limb performed 6 weeks after randomization, or clinically overt pulmonary embolism, confirmed by objective testing during the study drug administration. Patients were assessed for bleeding complications. RESULTS Three hundred eighty-five patients were randomized, of which 321 (83.4%) underwent venography. A venography was adequate for adjudication in 155 patients in each treatment group. A DVT was observed in 22 patients (14.1%) treated with enoxaparin and in 28 patients (18.0%) treated with placebo, corresponding to a relative risk of 0.78 (95% CI, 0.47 to 1.31). No major bleeding occurred. Five patients (2.6%) in the enoxaparin group and two patients (1.0%) in the placebo group died during the treatment period. CONCLUSION In this study, no difference in the rate of CVC-related VTE was detected between patients receiving enoxaparin and patients receiving placebo. The dose of enoxaparin used in this study proved to be safe. Clinical trials evaluating higher enoxaparin doses could optimize the efficacy of this agent for this indication.

Effect of Peritoneal Dialysis, Haemodialysis and Kidney Transplantation on Blood Platelet Function

Quantitation of the thrombocytopathy of uraemics may be one useful way of evaluating forms of therapy. 24 patients treated by haemodialysis and peritoneal dialysis at two different times had platelet aggregation studies whose parameters were compared with those of 24 normal persons, 5 successful transplants or 13 untreated uraemics. Renal transplantation and peritoneal dialysis improved platelet function. The haemodialysis procedure itself impaired platelet function: this was not due to heparin.

Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in hypertriglyceridemic patients.

In order to assess the efficacy of gemfibrozil on lipid and haemostatic parameters in patients with plurimetabolic syndrome, a multicenter double-blind placebo controlled, parallel study was carried out in 56 patients with primary hypertriglyceridemia and glucose intolerance. These patients had elevated PAI activity and antigen and t-PA antigen levels at rest and after venous occlusion. Gemfibrozil reduced plasma triglyceride levels (P<0.001), whereas it increased free fatty acids (P<0.05) and high density lipoprotein cholesterol levels (P<0.05). In those patients reaching normalization of plasma triglyceride levels (triglyceride reduction > or =50%) (n=15), insulin levels (P<0.05) as well as the insulin resistance index were reduced by gemfibrozil treatment, suggesting an improvement of the insulin resistance index in this patient subgroup. Gemfibrozil treatment did not affect plasma fibrinolysis or fibrinogen levels, despite marked reduction of plasma triglycerides and improvement of the insulin sensitivity associated with triglyceride normalization.

Effects of Desmopressin on Hemostasis in Patients with Liver Cirrhosis

The aim of this double-blind, placebo-controlled crossover study was to investigate the effect of 1-deamino-8-D-arginine vasopressin (dDAVP) on hemostasis in patients with chronic liver disease. Nine consecutive patients with biopsy-proven liver cirrhosis and related coagulation abnormalities received in a random order dDAVP, 0.5 microgram/kg, or saline intravenously. Blood samples were taken before dDAVP infusion and 30, 60 and 180 min after its end. dDAVP infusion induced a statistically significant shortening of the bleeding time from 9 min (range 6.5-15.5) to 6 min (range 4.5-9.5) at 1 h after the infusion. The activated partial thromboplastin time was significantly shortened at 30 and 60 min after dDAVP infusion. Plasma levels of factor VIII, XI and XII coagulant activities were significantly increased at all sampling times after dDAVP infusion. The maximum increase over basal values in plasma levels of factor VIII, XI and XII was 63, 22 and 40%, respectively. dDAVP did not induce any significant changes of prothrombin time, thrombin clotting time, fibrinogen, plasma levels of factor II, V, VII, IX, X, factor XII antigen, protein C (activity and antigen), antithrombin III, plasminogen and alpha 2-antiplasmin. Placebo infusion did not produce any significant changes in the evaluated parameters. We conclude that dDAVP can positively influence the hemostatic system in patients with liver cirrhosis. The clinical relevance of this hemostatic improvement deserves further evaluation.

Cephalosporin-induced hypoprothrombinemia: is the N-methylthiotetrazole side chain the culprit?

The reported high incidence of vitamin-K-reversible hypoprothrombinemia associated with the new beta-lactamase-stable cephalosporins prompted us to evaluate the effect on hemostasis of three cephalosporins (cefamandole, ceftriaxone, and ceftazidime) in 30 patients with serious infections. Cefamandole and ceftriaxone, both containing a sulfhydryl group, induced a significant and similar prolongation of prothrombin time and decrease in factor VII activity. Ceftazidime, in contrast, had no effect on these two parameters.

Effects of low molecular weight heparins on fibrin polymerization and clot sensitivity to t-PA-induced lysis.

We have previously demonstrated that therapeutic concentrations of unfractionated heparin (UFH) impair fibrin polymerization leading to the formation of clots which are more sensitive to lysis induced by tissue plasminogen activator (t-PA). The aim of this study was to compare the effect of UFH with that of three different low molecular weight heparins (LMWHs) on clot sensitivity to t-PA-induced lysis. Labelled fibrin clots, prepared from plasma containing UFH, Fraxiparine, Reviparine, Enoxaparine or saline, were incubated in phosphate buffer containing t-PA (0.1 and 0.5 microgram/ml) and plasminogen (20 micrograms/ml). The extent of clot lysis was quantified by counting the residual radioactivity of the clots and by measuring D-dimer levels released into the medium. Fibrin polymerization and clot structure were evaluated by means of a turbidimetric assay and by electron microscopic scanning. Pre-incubation of plasma with 0.5 or 1.0 U/ml UFH resulted in a marked dose-dependent acceleration of lysis induced by 0.1 or 0.5 microgram/ml t-PA. In contrast, lysis rates induced by 0.5 microgram/ml t-PA were not modified by pre-incubation of plasma with LMWHs. When exposed to 0.1 microgram/ml t-PA clots formed from plasma containing 0.5-2 IU/ml of Fraxiparine, Reviparine and Enoxaparine showed only a minor increase in lysis rates compared to control clots. There was not a clear dose-response curve with LMWHs. Furthermore, lysis rates obtained with UFH-treated clots were always significantly higher than those seen with LMWHs-treated clots.(ABSTRACT TRUNCATED AT 250 WORDS)

“In vitro” and “ex vivo” effects of picotamide, a combined thromboxane A2-synthase inhibitor and -receptor antagonist, on human platelets

SummaryPicotamide (G 137), a new non prostanoid inhibitor of in vitro arachidonic acid induced platelet aggregation, has been further characterized in in vitro and ex vivo studies.When whole blood was activated with collagen in the presence of picotamide 5×10−4 M, thromboxane B2 production was decreased, and 6-keto-PGF1α generation was significantly increased, suggesting a reorientation of platelet endoperoxide metabolism following blockade of thromboxane synthetase. Picotamide also inhibited platelet aggregation and clot retraction induced by the endoperoxide analogue U46619 in human platelets, indicating thromboxane A2-receptor antagonism, possibly of competitive nature.A single oral dose of picotamide 1 g in 24 healthy volunteers produced a significant inhibition of collagen, arachidonic acid and U46619-induced platelet aggregation. Serum levels of thromboxane B2 were also reduced.Chronic administration of picotamide 1.2 g/d to patients with vascular disease resulted in a prompt and persistent fall in their increased plasma levels of β-thromboglobulin.The results indicate that picotamide is a combined thromboxane B2-synthetase inhibitor and thromboxane A2-receptor antagonist in human platelets, and that it may prove useful as an antithrombotic agent.

Fibrin clots obtained from plasma containing heparin show a higher sensitivity to t-PA-induced lysis.

Although heparin is currently used in concomitance with thrombolytic agents to improve their efficacy, its effect on fibrinolysis is controversial. We have evaluated the sensitivity to t-PA-induced lysis of clots prepared from plasma preincubated in vitro with thera-peutic concentrations of heparin. The extent of t-PA-induced lysis was significantly increased by preincubation of plasma with 0.5 and 1.0 U/ml heparin. The concentration of t-PA required to give similar lysis rates were reduced by up to five times after adding 1.0 U/ml heparin to plasma prior to clot formation. Heparin added to the t-PA-containing medium after clot formation did not exert any signifi-cant effect. The effect of heparin was not mediated by the inhibition of thrombin as preincubation of plasma with hirudin did not modify clot sensitivity to t-PA. We also found that heparin significantly modified fibrin assembly and clot structure as assessed by a turbidimetric assay. Pre-incubation of fibrinogen with heparin caused an increase in the speed of fibrin fibre polymerization and in the turbidity of the final fibrin gel; changes known to be associated with the formation of thicker fibrin fibres. Thus the effect of heparin on clot sensitivity to lysis appears to be due to an increased permeability of these clots to fibrinolytic components. This may contribute to the antithrombotic activity and to the haemorrhagic risk of heparin. These findings could be particularly important for clinical thrombolysis. Our data suggest that the concomitant administration of heparin with thrombolytic agents, as well as inhibiting the accretion of new fibrin on the lysing thrombi, could also enhance the lysability of the fibrin eventually accreted on the thrombi.

Effects of Dipyridamole on the Hypoxemic Pulmonary Hypertension of Patients with Chronic Obstructive Pulmonary Disease

Based on the hypothesis that blood platelets contribute to the pathogenesis of hypoxemic pulmonary hypertension in patients with chronic obstructive pulmonary disease (COPD), the effect of a prolonged treatment with dipyridamole, a platelet-inhibiting drug, on hypoxemic pulmonary hypertension was evaluated in a double-blind cross-over study. Eight patients with COPD, pulmonary hypertension [mean systolic pressure 52.2 +/- (SD) 9.7 mm Hg; mean diastolic pressure 25.8 +/- (SD) 6.8 mm Hg] and shortened platelet regeneration time [mean 5.2 +/- (SD) 1.2 days] received, in a cross-over random sequence, the following two 3-month treatments: (a) dipyridamole 100 mg and acetylcysteine 100 mg every 6 h; (b) acetylcysteine, 100 mg every 6 h. Dipyridamole significantly prolonged the platelet regeneration time [mean 6.5 +/- (SD) 1.0 days; p less than 0.05]. There was no significant effect on diastolic pulmonary pressure. However, systolic pressure was significantly (p less than 0.05) lower after dipyridamole [46.8 +/- (SD) 16 mm Hg] than after placebo [56.1 +/- (SD) 14 mm Hg]. These results suggest that dipyridamole can slow the progression of hypoxemic pulmonary hypertension in patients with COPD.

Polyacrilonytrile versus cuprophan membranes for hemodialysis: evaluation of efficacy and biocompatibility by platelet aggregation studies.

The short- and long-term effect of hemodialysis with two different membranes — cuprophan and polyacrilonytrile — on platelet aggregation has been investigated in 12 uremic patients undergoing extracorporeal dialysis, passing from one treatment to the other. Cuprophan membranes failed to correct the defective platelet aggregation of uremia, and their thrombogenicity was documented by a fall in platelet count and further impairment of platelet aggregation during dialysis. On the contrary, polyacrilonitryle membranes showed the capacity to correct completely but transiently the platelet aggregation, without changes in platelet count. The results indicate that polyacrilonytrile membranes show a better biocompatibility toward platelets than cuprophan membranes.