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Thrombolytic Therapy for Thromboembolism of Vertebrobasilar Artery

Thrombolytic therapy was carried out on four patients with brain stem stroke due to thromboembolism of the vertebrobasilar system. Diagnosis was confirmed by angiography. Clinical and instrumental findings indicated a very poor prognosis. Two of these patients were treated with urokinase and the other two with streptokinase for periods ranging from 16 to 44 hours. The interval between onset of symptoms and start of therapy was less than 10 hours for three of these patients. All made a gradual and almost complete recovery after only a few hours of treatment, and only one presented minimal residual neurological disability. The conditionof the fourth patient, who started therapy four days after the first episode, remained unchanged until he died 16 hours later. Our observations suggest that thrombolytic therapy may be useful in treat ing recent acute life-threatening brain stem stroke.

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.

“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.

In vitro and ex vivo effects of indobufen on red blood cell deformability

SummaryWe have studied the effect of indobufen, a cyclo-oxygenase blocking agent which has proved useful in patients with obstructive vascular disease, on red blood cell (RBC) filterability in vitro and in a pilot study ex vivo.The addition of indobufen in vitro to blood samples from 10 healthy volunteers did not significantly modify RBC deformability.We evaluated the ex vivo effect of indobufen (200 mg bd) in 14 patients with obstructive vascular disease. A significant improvement in RBC deformability was noted on the 5th, 14th, and 28th days of treatment, 2 h after the morning dose. Acetylsalicylic acid given to 6 similar patients had no effect suggesting that the positive haemorheological effect of indobufen is probably not linked to its cyclooxygenase blocking effect.

Effect of DDAVP on plasma level of factor XII

Summary. The effect of DDAVP on blood coagulation factors was investigated after its intravenous infusion into normal subjects. A marked increase in factor XII was observed in addition to the expected rise of factor VIII coagulant activity (VIII:C), factor VIII related antigen (VIII:Ag) and plasminogen activator. DDAVP also produced a concomitant but less pronounced rise of factor VII, but there was no change in factors V, IX, X and XI.

Safety and efficacy of ximelagatran: meta-analysis of the controlled randomized trials for the prophylaxis or treatment of venous thromboembolism.

BACKGROUND Ximelagatran has been approved in Europe for VTE prophylaxis in orthopedic surgery at fixed doses and without laboratory monitoring. Aim of the study was to evaluate safety and efficacy of ximelagatran in a meta-analysis of prophylaxis and/or treatment randomized controlled trials. METHODS Absolute risk of events for ximelagatran and OR for its comparison with LMWH and coumarins were calculated. Subgroup analysis was performed for ximelagatran regimen, comparator agent, type of surgery, starting time of prophylaxis. RESULTS Twelve studies and 16,992 patients were meta-analysed. Ximelagatran showed an absolute risk of major VTE of 4.04% and 1.69% and of major bleedings of 1.68% and 1.03% in prophylaxis and treatment trials, respectively. In prophylaxis trials, a significant excess mortality (OR: 2.5; 95% CI: 1.02 - 6.13) and an excess in major bleedings (OR: 1.41; 95% CI: 0.93 - 2.14) was found in the whole ximelagatran group. No evidence of treatment effect for major VTE was seen in the comparison with LMWH (OR: 1.01; 95% CI: 0.52 - 1.97). The cohort of patients treated with 24 mg b.i.d. showed similar results. An increase in the absolute risk of bleeding (from 1.04% to 3.03%) was found between post and preoperative administration of ximelagatran. Major VTE risk was increased when ximelagatran was compared to b.i.d. LMWH. CONCLUSIONS Ximelagatran can be considered for its potential advantages for prevention and treatment of VTE. Future efforts are needed by researchers to prospectively investigate the best postoperatively starting time and by clinicians to monitor overall mortality in prophylactic use.

Fibrinogen degradation products generation is the major determinant of platelet inhibition induced by plasminogen activators in platelet-rich plasma

Abstract The platelet function defect induced by thrombolytic agents has been referred either to the degradation of platelet surface receptors or to the anti-aggregatory effect of fibrinogen degradation products (FgDPs). In the present study we have evaluated platelet aggregation induced by ADP, collagen and ristocetin after incubation of washed platelets or platelet-rich plasma (PRP) with plasmin (1.1–3.4IU/ml), plasminogen activators (PAs) (streptokinase 250–1000 IU/ml; urokinase, 10–1000 IU/ml; t-PA 0.5–10 μg/ml) or FgDPs (0.062–2 mg/ml). In parallel the surface levels of platelet GP lb and IIb/IIIa complex were determined by fluorescence flow cytometry using specific monoclonal antibody. Washed platelets treated with plasmin (1.1IU/ml) for 10 to 90 min showed a progressive reduction of ristocetin-induced platelet agglutination and a progressive reduction of surface GP Ib. Surface expression of GP IIb/IIIa complex was significantly increased after plasmin exposure. The addition of PAs to PRP resulted in a marked reduction of ADP-induced platelet aggregation. Collagen-induced platelet aggregation was only slightly affected. Similar changes were observed when PRP was preincubated with high concentrations of FgDPs. In PRP treated with PAs platelet surface levels of GP Ib and GP IIb/IIIa complex did not show any significant changes. In conclusion our results show that in plasma no proteolysis of platelet adhesive receptors occurs after plasminogen activation. The platelet inhibition observed after incubation of PRP with PAs is likely to be caused by FgDPs generation.

Exhausted platelets in chronic obstructive pulmonary disease.

Experimental and clinical evidence has suggested that vasoconstrictor substances released from activated platelets could play a role in mediating the pulmonary hypertension of hypoxemic patients with chronic obstructive pulmonary disease. In order to extend previous knowledge on platelet function in such patients, platelet production of malondialdehyde and plasma levels of beta-thromboglobulin were assayed in 12 patients before and after a short-term treatment with the platelet-inhibiting drug, dipyridamole. The impairment of platelet malondialdehyde generation concomitant with the increase of plasma levels of beta-thromboglobulin suggests that in patients with chronic obstructive pulmonary disease, blood platelets undergo chronic overstimulation and become exhausted. Dipyridamole can antagonize this platelet activation and thus may prove useful in reducing the pulmonary hypertension of these patients.

Generation of Arachidonic Acid Metabolites from Stimulated Whole Blood in Patients with Chronic Myeloproliferative Disorders

We have evaluated the arachidonic acid (AA) metabolism in patients with myeloproliferative disorders (MPD). In essential thrombocythemia (ET), the generation of thromboxane B2 was found significantly reduced and inversely correlated with platelet count. Polycythemia vera (PV) patients showed an increased formation of this metabolite of AA. Prostaglandin E2 and 6-keto-PGF1 alpha generation were markedly reduced in patients with chronic myelogenous leukemia. Our study confirms that the arachidonate metabolism is frequently deranged in patients with MPD. The opposite changes in thromboxane formation in ET and PV could be one of the factors responsible for the different incidences of thrombotic and hemorrhagic complications in these diseases.

Human pharmacokinetics and pharmacodynamics of MF 701 dermatan sulphate administered by continuous intravenous infusion

The pharmacokinetics and haemostatic effects of MF 701 dermatan sulfate (DS) administered by i.v. infusion were studied in 11 healthy volunteers. Each subject received 0.6 mg kg-1 h-1 MF 701 for 10 h. DS plasma concentrations were measured by a chromogenic assay based on the catalysis of thrombin inhibition by HCII. DS plasma levels followed a single compartment pharmacokinetic model, with a half-life of 1.28 +/- 0.46 h, a plasma clearance of 2.75 +/- 0.46 l/h and a volume of distribution of 4.92 +/- 1.36 1 (means +/- SD). Steady-state was reached 3 to 6 h after infusion started. The maximal DS plasma concentration was 16.4 +/- 5.7 micrograms/ml. Maximal APTT prolongation over pre-infusion values was 42 +/- 7%; TCT performed with bovine and human thrombin was prolonged by 16 +/- 7% and 83 +/- 35% respectively. No anti-IIa or anti-Xa activities were detected by chromogenic tests. The treatment was well tolerated. The pharmacokinetics of MF 701 infusion are consistent with those previously described after i.v. bolus administration. The infusion of MF 701 allows fast achievement and steady maintenance of elevated DS plasma concentrations.