Mauro Berrettini

Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT)

BACKGROUNDnBleeding 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.nnnMETHODSnIn 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.nnnFINDINGSn43% 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).nnnINTERPRETATIONnWe 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.

A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS).

Summary.u2002 Background:u2002The optimal intensity of oral anticoagulation for the prevention of recurrent thrombosis in patients with antiphospholipid antibody syndrome is uncertain. Retrospective studies show that only high‐intensity oral anticoagulation [target international normalized ratio (INR) >3.0] is effective but a recent randomized clinical trial comparing high (INR range 3.0–4.0) vs. moderate (INR 2.0–3.0) intensities of anticoagulation failed to confirm this assumption. Methods:u2002We conducted a randomized trial in which 109 patients with antiphospholipid syndrome (APS) and previous thrombosis were given either high‐intensity warfarin (INR range 3.0–4.5, 54 patients) or standard antithrombotic therapy (warfarin, INR range 2.0–3.0 in 52 patients or aspirin alone, 100u2003mgu2003day−1 in three patients) to determine whether intensive anticoagulation is superior to standard treatment in preventing symptomatic thromboembolism without increasing the bleeding risk. Results:u2002The 109 patients enrolled in the trial were followed up for a median time of 3.6u2003years. Mean INR during follow‐up was 3.2 (SD 0.6) in the high‐intensity warfarin group and 2.5 (SD 0.3) (Pu2003<u20030.0001) in the conventional treatment patients given warfarin. Recurrent thrombosis was observed in six of 54 patients (11.1%) assigned to receive high‐intensity warfarin and in three of 55 patients (5.5%) assigned to receive conventional treatment [hazard ratio for the high intensity group, 1.97; 95% confidence interval (CI) 0.49–7.89]. Major and minor bleeding occurred in 15 patients (two major) (27.8%) assigned to receive high‐intensity warfarin and eight (three major) (14.6%) assigned to receive conventional treatment (hazard ratio 2.18; 95% CI 0.92–5.15). Conclusions:u2002High‐intensity warfarin was not superior to standard treatment in preventing recurrent thrombosis in patients with APS and was associated with an increased rate of minor hemorrhagic complications.

Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: A four-year prospective study from the italian registry

PURPOSEnTo assess the natural history and risk factors for thrombosis in a large cohort of unselected patients with antiphospholipid antibodies.nnnPATIENTS AND METHODSnThree hundred sixty consecutive patients (118 males, 242 females, median age 39 years [range 2 to 78]) fulfilling the currently accepted criteria for diagnosis of lupus anticoagulant (LAC) (n = 326) and/or raised immunoglobulin G anticardiolipin antibodies (IgG ACA) (n = 185) were collected from 16 Italian institutions and prospectively observed for a median of 3.9 years (range 0.5 to 5). Main endpoints were the occurrence of arterial or venous thrombosis, the outcome of pregnancies, and any severe complications leading to hospitalization or death.nnnRESULTSnThirty-four patients developed a thrombotic complication, with a total incidence of 2.5% patient-years. Multivariate logistic regression analysis identified two independent risk factors for thrombotic events: a previous thrombosis (RR 4.9; 95% CI, 1.76 to 13.7; P < 0.005) and IgG ACA titer above 40 units (RR 3.66; 95% CI, 1.24 to 10.8; P < 0.01). A total of 28 pregnancies were observed in 25 women and 11 (39%) were abortive. Adverse pregnancy outcomes were significantly more frequent in women with a history of miscarriage or vascular occlusion (9/16, 56%) than in asymptomatic women (2/12, 17%) (P = 0.035). Four patients developed non-Hodgkins lymphoma during the follow-up. Eighteen patients died. Vascular events and hematological malignancies represented the most frequent causes of death (n = 5 for each).nnnCONCLUSIONSnThe present study shows that: (a) previous thrombosis and ACA titer > 40 U are independent predictors of thrombosis; (b) history of miscarriage or vascular disease is significantly associated with adverse pregnancy outcome; (c) hematological malignancies can develop during follow-up in patients with antiphospholipid antibodies.

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.

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.

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.

Tissue Factor Pathway Inhibitor Levels in Patients with Homocystinuria

Thrombotic events are a well-recognized complication of homocystinuria. However, the mechanisms involved in the atherogenic and thrombotic effects of homocyst(e)ine remain incompletely understood. The objective of this study was to determine the role of endothelial cell activation/damage as indicated by levels of thrombomodulin, tissue factor and tissue factor pathway inhibitor, and factor VII activity in patients with homocystinuria. Six patients with homocystinuria, nonresponsive to pyridoxine, treated only with trimethylglycine (betaine) were injected with a bolus of 20 IU/kg body weight of unfractionated commercial heparin to induce the release of tissue factor pathway inhibitor from the vascular endothelium. Tissue factor, thrombomodulin, and factor VII activity were measured by enzyme-linked immunosorbent assay and clotting assay before heparin administration. Tissue factor pathway inhibitor antigen and activity were measured before and 5 minutes after the bolus of heparin. Levels of homocyst(e)ine were elevated (patients: 144.2+/-19.2 micromol/L; controls: 10.2+/-0.9 micromol/L); however, levels of thrombomodulin, tissue factor, and tissue factor pathway inhibitor antigen were not statistically different from the control group. In contrast, tissue factor pathway inhibitor activity showed a significantly increased level (patients: 2.09+/-0.34 U/L; controls: 1.14+/-0.20 U/L; p<0.05) that was correlated with homocyst(e)ine. Factor VII activity was significantly decreased (patients: 64.7+/-5.1%; controls: 91.4+/-4.7%; p<0.05) and inversely correlated with homocyst(e)ine. After heparin the patients released higher amounts of tissue factor pathway inhibitor antigen and activity compared with the control group; however, the difference was not statistically significant. Although not treated with antithrombotic drugs, none of the patients had any thromboembolic complications after starting betaine. In addition to betaine treatment, the enhanced factor pathway inhibitor antigen activity observed in this small series of patients suggests that factor pathway inhibitor antigen may play an additional, as yet unexplained, role in this genetic disorder.

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.

Failure to Demonstrate Beneficial Effect of Prostacyclin (PGI2) Infusion on Red Blood Cell Deformability in Patients with Peripheral Vascular Disease: A Possible Role of the Leukocytes:

The effect of prostacyclin (PGI2) on red blood cell deformability is still con troversial. The authors have evaluated some hemorrheologic parameters during PGI2 infusion to patients with severe obstructive peripheral arterial disease not suitable for surgery and not responsive to other medical treatments. PGI2 infu sion resulted in a positive clinical effect in 12 of 16 patients, who experienced a significant improvement of their rest pain lasting from two days to more than seven months. Hematocrit, platelet count, and fibrinogen were not modified during PGI2 infusion whereas leukocyte count rose significantly. The evaluation of red blood cell filterability (VRBC) (volume of RBC filtered in one minute) by a whole blood filtration technique showed no significant changes during PGI 2 treatment. However, since whole blood filterability is nega tively correlated to leukocyte count, a specific regression line was elaborated to remove the potential negative influence of the increased leukocyte counts. VRBC values adjusted to a standard leukocyte number significantly increased during PGI2 treatment.