Search

Introduction: Despite the increasing utilization of direct oral anticoagulant (DOAC) prescriptions, vitamin K antagonists (VKAs) remain the treatment of choice for treating and preventing thromboembolic events. The morbidity and mortality of VKAs are partly due to the difficulty of keeping the patient within the therapeutic range. For patients treated by VKA, time in therapeutic range (TTR) is a quality parameter of treatment, widely used in clinical trials but rarely by prescribers. It is well established that its use correlates with the risk of hemorrhage, thrombosis or mortality. We studied this parameter in a cohort of patients to evaluate the quality of their therapeutic follow-up and tried to identify risk factors for low TTR., Methods: The study was made in collaboration with LaboSud Oc Biologie for a duration of 4 months. It included 3387 patients representing 2,4029 INR. We calculated the patients' TTR. The laboratory transmitted to us the sex and age of each patient and the VKA molecule used, the therapeutic range and the specialty of the prescriber. We then analyzed the odds ratio associated with these different factors., Results: The mean TTR was 68%, close to the TTR recommended by scientific societies. Patient's sex was the only statistically correlated factor, with a worse equilibrium in females taking VKAs (OR=1.22, 95% CI: 1.06-1.39, P=0.00552). Many factors usually correlated with poor equilibrium under VKA have not been studied due to lack of information., Conclusion: Given the context of economic restriction and the TTR of our cohort close to the recommended 70%, there would be no benefit in terms of safety to prefer DOAC for the patients involved in this study. Regular monitoring of the individual patient's as well as the cohort's TTR should optimize the management of patients receiving VKAs., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Anti-phospholipid syndrome (APLS) is a condition characterized by the presence of raised plasma levels of anti-phospholipid antibodies associated with thrombo-embolic disease and/or poor obstetrical outcomes in women. The epidemiology of APLS is unknown in most sub-Saharan African countries due to limited access to diagnosis tools. We report the case of APLS in a 29-year-old obese woman that was preceded by pre-eclampsia and fetal death. The diagnosis of APLS was made during a thrombo-embolic episode 4 years after the poor obstetrical outcome. Her management was challenging, as she had three thrombo-embolic events within 18-months despite treatment with anti-coagulant (acenocoumarol)., Conclusion: This case highlights the need for screening for APLS after an episode of hypertensive disease in pregnancy or fetal death, and the challenges faced with the treatment, such as resistance to antivitamin K anti-coagulants and the desire for maternity.

Objectives: After elective aortic valve replacement, patients are at risk of developing valve thrombosis and systemic arterial thromboembolism. Current guidelines recommend antithrombotic therapy with aspirin or vitamin K antagonists (VKAs) during the first 3 months after the procedure, but have level 2 or 3 evidence. As a consequence, the most appropriate antithrombotic therapy is still a matter of debate. This retrospective study analysed all thromboembolic and bleeding complications in patients with either antiplatelet or anticoagulation therapy 1 year after bioprosthetic aortic valve replacement., Methods: A total of 402 patients undergoing bioprosthetic aortic valve implantation at the VU University Medical Centre and subsequently treated at three regional hospitals were included. The individual duration of either VKAs (acenocoumarol) or aspirin was determined and related to thrombotic and bleeding events. Patients were followed and censored at 1 year postoperatively for survival, cerebral ischaemia, myocardial infarction, peripheral arterial embolism, and minor and major haemorrhages., Results: A total of 24 thromboembolic complications and 31 bleeding episodes occurred. Multivariable analyses revealed that acenocoumarol caused more bleeding episodes (risk ratio [RR]: 8.41, 95% CI: 3.58-19.79) and a similar amount of thromboembolic events (RR: 1.2, 95% CI: 0.47-3.02) compared with aspirin. Prior use of acenocoumarol was found to be a risk factor for thromboembolic events (RR: 3.1, 95% CI: 1.31-7.19). Gender, dyslipidaemia, prior percutaneous coronary intervention, prior use of acenocoumarol and concomitant coronary artery bypass grafting were found to be predictors for bleeding events., Conclusions: In patients 1 year following bioprosthetic aortic valve replacement, acenocoumarol therapy was associated with a significant increased risk of bleeding events and no reduction in thromboembolic events compared with antiplatelet therapy. These findings support the recommendations of aspirin over VKAs as postoperative thromboprophylaxis., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: The anticoagulant therapy with acenocoumarol is generally associated with a high risk of bleeding and thromboembolic events., Purpose: We applied eight already existing acenocoumarol dosing algorithms to Bulgarian patients with low acenocoumarol dose requirements and investigated which of these algorithms would predict most precisely the dose anticoagulant., Materials and Methods: Two patients with Bulgarian origin were referred to the outpatient clinical laboratory of "St. Ekaterina" University Hospital for Cardiovascular Surgery and Cardiology, Sofia, Bulgaria. After obtaining written informed consent, both patients were genotyped for polymorphisms in genes for Cytochrome P450 2C9 (CYP2C9), Vitamin K epoxide reductase (VKORC1), Apolipoprotein E (APOE), and Cytochrome P450 4F2 (CYP4F2)., Results: All applied acenocoumarol dosing algorithms predicted relatively similar doses of coumarin anticoagulant in both patients. However, van Schie et al.'s algorithm allowed more accurate calculation of the optimal dose in our patients with extremely low acenocoumarol requirements. Genotyping of selected polymorphic variants in CYP2C9 and VKORC1 showed that both patients were compound heterozygotes for CYP2C9 (CYP2C9*2/*3) and homozygotes for both variants in VKORC1 (VKORC1 1173 T/T, and VKORC1-1639 A/A). This combination of genotypes suggested high sensitivity to acenocoumarol leading to the low anticoagulant dose requirements (0.25 and 1 mg/day, respectively) needed to reach the target International Normalized Ratio of 2.5-3.5., Conclusions: The genotyping of polymorphic variants in VKORC1 and CYP2C9, together with clinical and demographic parameters, can serve for more precise definition of the individual starting and maintenance doses of coumarin derivatives in each patient.

Recent studies suggest that sickle cell disease (SCD) is a hypercoagulable state contributing to vaso-occlusive events in the microcirculation, resulting in acute and chronic sickle cell-related organ damage. In this article, we review the existing evidence for contribution of hemostatic system perturbation to SCD pathophysiology. We also review the data showing increased risk of thromboembolic events, particularly newer information on the incidence of venous thromboembolism. Finally, the potential role of platelet inhibitors and anticoagulants in SCD is briefly reviewed., (Published by Elsevier Inc.)

Appropriate dosing of coumarins is difficult to establish, due to significant inter-individual variability in the dose required to obtain stable anticoagulation. Several genetic and other clinical factors have been associated with the coumarins dose, and some pharmacogenetic-guided dosing algorithms for warfarin and acenocoumarol have been developed for mixed populations. We recruited 147 patients with thromboembolic disease who were on stable doses and with an international normalized ratio (INR) between 2 and 3. We ascertained the influence of clinical and genetic variables on the stable acenocoumarol dose by multiple linear regression analysis in a derivation cohort (DC; n = 117) and developed an algorithm for dosing that included clinical factors (age, body mass index and concomitant drugs) and genetic variations of VKORC1, CYP2C9, CYP4F2 and APOE. For purposes of comparison, a model including only clinical data was created. The clinical factors explained 22% of the dose variability, which increased to 60.6% when pharmacogenetic information was included (p<0.001); CYP4F2 and APOE variants explained 4.9% of this variability. The mean absolute error of the predicted acenocoumarol dose (mg/week) obtained with the pharmacogenetic algorithm was 3.63 vs. 5.08 mg/week with the clinical algorithm (95% CI: 0.88 to 2.04). In the testing cohort (n = 30), clinical factors explained a mere 7% of the dose variability, compared to 39% explained by the pharmacogenetic algorithm. Considering a more clinically relevant parameter, the pharmacogenetic algorithm correctly predicted the real stable dose in 59.8% of the cases (DC) vs. only 37.6% predicted by the clinical algorithm (95% CI: 10 to 35). Therefore the number of patients needed to genotype to avoid one over- or under-dosing was estimated to be 5.

Vitamin K antagonists (VKA) are effective in primary and secondary prevention of thromboembolism, but the associated risk of bleeding is an important limitation. The majority of bleeds are clinically mild. In this study, we assessed whether these minor bleeds are associated with major bleeding, when controlling for other important risk indicators, including the achieved quality of anticoagulation. For this, 5898 patients attending a specialized anticoagulation clinic were retrospectively studied for 1 year after initiation of VKA therapy. The risk of major bleeding was estimated using a multivariate piecewise exponential model with time-varying exposure for occurring minor bleeds. In patients with a minor bleed (N=1015) subsequent major bleeding occurred more frequently than in patients without a minor bleed (N=4883), with an incidence rate of 2·3 [95% confidence interval (CI) 1·4-3·7] vs. 1·2 per 100 person-years (95% CI 0·9-1·7). The adjusted relative risk of subsequent major bleeding after a minor bleed was 2·9 (95% CI 1·1-7·2, P =0·024). The percentage of time that a patient had an International Normalized Ratio (INR) above 5 was also independently associated with major bleeding, with a 2·2-fold increased risk in patients with at least 9% of time above INR 5 (95% CI 1·3-4·0, P=0·006). Minor bleeds alert for subsequent major bleeding, independent of the quality of anticoagulation., (© 2011 Blackwell Publishing Ltd.)

The aim of the study is to present our own perioperative bridging therapy with low molecular weight heparin (LMWH) for surgical patients with thrombophilia on long-term acenokumarol therapy [oral anticoagulant (OAC)]. In some European countries, the drug used in secondary antithrombotic prophylaxis is acenokumarol. Forty-two patients with inherited thrombophilia and 21 with antiphospholipid syndrome underwent surgery. All patients were on long-term OAC. This OAC was interrupted 2 days before elective surgery and since that day half of the individual therapeutic dose of LMWH was administered. On day of surgery, the LMWH therapeutic dose was divided into two parts. Starting with day 2 after surgery, the patient was again given half of the individual dose of LMWH every 24 h. On day 4, OAC was additionally included. Both drugs were administered until stabilization of international normalized ratio (INR) values within the therapeutic target for 2 consecutive days. LMWH was then interrupted, whereas OAC continued. No symptoms or episodes of venous thromboembolism were observed. No intraoperative or postoperative hemorrhagic complications were reported. The results suggest that our perioperative bridging therapy is safe and effective for prevention of thromboembolic and hemorrhagic complications.

The study included 25 patients at high risk of thromboembolic complications. All of them were treated with acenocoumarol for 6 months under control of the frequency of hemorrhage and episodes of severe hypocoagulation (a more than 3-fold rise in INR). All the patients underwent CYP2C9 and VKORC1 genotyping. It was shown that the presence of CYP2C9*2 and CYP2C9*3 alleles in the CYP2C9 locus and the AA genotype of the polymorphous G-1639(3673)A marker of the VKORC1 gene was not associated with the development of severe hypocoagulation episodes (p = 0.261--for CYP2C9, p = 0.616 and 0.361 for VKORC1 in the total group and a subgroup of patients having the CYP2C9*1/*1 genotype respectively and treated with acenocoumarol. The search for other genetic markers of efficacy and safety of this drug should be continued.

Subtherapeutic anticoagulation levels increase both the risk and severity of thromboembolism. The aim of this study was to determine the cumulative incidence of subtherapeutic international normalised ratios (INRs) and to identify risk factors associated with a low INR. We performed a cohort study in 7,419 patients from a Dutch anticoagulation clinic. Patients who started a first treatment with oral anticoagulants between January 2000 and December 2005 and who were stably anticoagulated (4 consecutive INRs in the therapeutic range) were included. Within the cohort a nested case control study was performed to identify risk factors of subtherapeutic INRs and to determine how often a subtherapeutic INR is the result of medical interference in case of invasive procedures, hospital admissions, haemorrhage or overanticoagulation. In patients with a stable anticoagulation, the median time to a first low INR was 40 weeks. A subtherapeutic INR occurred twice as often in patients using acenocoumarol as in those using phenprocoumon (hazard ratio [HR] 2.1, 95% confidence interval [95%CI]:2.0 - 2.3) and was more common in patients with a high therapeutic range compared to a low therapeutic range (HR 1.8, 95%CI:1.5 - 2.2). Occurrence of a low INR also depended on indication for anticoagulant therapy, with the highest risk in patients who used anticoagulants as prophylaxis and the lowest risk in patients with mechanical heart valves. In 30% of cases the subtherapeutic INR was preceded by an event necessitating vitamin K or discontinuation of the anticoagulant drug.

Introduction: Thromboembolic accidents and haemorrhage are the main complications observed during long-term follow-up of mechanical heart valve patients. Several suggestions for improving anticoagulation quality have been made, including international normalised ratio (INR) self-monitoring., Objectives: We report the preliminary results of a single-centre, open, randomised study (scheduled population of 200 patients), which compares monthly laboratory monitoring (group A) versus weekly self-monitoring of INR (group B). The primary aim is INR stability improvement within the target range, and the secondary aim is adverse events reduction., Patients and Methods: Between May 2004 and June 2005, 67 patients with an average age of 56.6 years (+/-9.6), were enrolled in the study (group A: 34 patients, group B: 33 patients). The mean follow-up was 47 weeks (+/-11.5). The two groups differed only in the sex ratio (44.1 and 21.2% of women in groups A and B respectively, p=0.0459). Mechanical heart valves were aortic in 73% of patients, mitral in 13.5%, and multiple in 13.5%. Sixty-five patients (97%) were treated with fluindione, the others with acenocoumarol. The intraclass correlation coefficient between the self- and laboratory-monitored INR was 0.75., Results: The time spent in the INR target range (group A: 53+/-19%, group B: 57+/--19%, p=0.45) and the time spent in the INR therapeutic range, between 2 and 4.5, (group A: 86+/-14%, group B: 91+/-7%, p=0.07) are longer in group B, but not significantly so. For patients outside the range, the absolute mean deviation of INR from the target or therapeutic range (range standardized between 0 and 100) is lower for the self-monitoring group (41.1+/-39.3 and 11.27+/-11.2) than for the control group (62.4+/-72.6 and 39.2+/-52.8). This difference is significant (p=0.0004 and p=0.0005). Eighteen adverse events were reported: 17 haemorrhages, 13 in group A (9 mild, 4 serious) and four in group B (all mild), and one sudden death in group B, two days after the patient's discharge. No thromboembolic events were reported. Six patients (8.8 %), 3 in each group, dropped out of the study., Conclusion: This first study evaluating INR self-monitoring in France shows that this method leads to better stability of the INR within the target range. On the basis of these preliminary data, this appears to be related to a decrease in serious haemorrhages (11.8% serious haemorrhage cases in group A versus 0% in group B, p=0.06, NS).

Background: Vitamin K antagonists, the current standard treatment for prophylaxis against stroke and systemic embolism in patients with atrial fibrillation, require regular monitoring and dose adjustment; an unmonitored, fixed-dose anticoagulant regimen would be preferable. The aim of this randomised, open-label non-inferiority trial was to compare the efficacy and safety of idraparinux with vitamin K antagonists., Methods: Patients with atrial fibrillation at risk for thromboembolism were randomly assigned to receive either subcutaneous idraparinux (2.5 mg weekly) or adjusted-dose vitamin K antagonists (target of an international normalised ratio of 2-3). Assessment of outcome was done blinded to treatment. The primary efficacy outcome was the cumulative incidence of all stroke and systemic embolism. The principal safety outcome was clinically relevant bleeding. Analyses were done by intention to treat; the non-inferiority hazard ratio was set at 1.5. This trial is registered with ClinicalTrials.gov, number NCT00070655., Findings: The trial was stopped after randomisation of 4576 patients (2283 to receive idraparinux, 2293 to receive vitamin K antagonists) and a mean follow-up period of 10.7 (SD 5.4) months because of excess clinically relevant bleeding with idraparinux (346 cases vs 226 cases; 19.7 vs 11.3 per 100 patient-years; p<0.0001). There were 21 instances of intracranial bleeding with idraparinux and nine with vitamin K antagonists (1.1 vs 0.4 per 100 patient-years; p=0.014); elderly patients and those with renal impairment were at greater risk of such complications. There were 18 cases of thromboembolism with idraparinux and 27 cases with vitamin K antagonists (0.9 vs 1.3 per 100 patient-years; hazard ratio 0.71, 95% CI 0.39-1.30; p=0.007), satisfying the non-inferiority criterion. There were 62 deaths with idraparinux and 61 with vitamin K anatagonists (3.2 vs 2.9 per 100 patient-years; p=0.49)., Interpretation: In patients with atrial fibrillation at risk for thromboembolism, long-term treatment with idraparinux was no worse than vitamin K antagonists in terms of efficacy, but caused significantly more bleeding.

We checked the feasibility of self-screening for atrial fibrillation (AF) by instructed patients pts and prompt home self-administration of an initial dose of low-molecular weight heparin (LMWH) prior to seeking medical attention., Investigated Group and Methods: Pts with persistent AF and low risk of systemic embolisation qualified to elective cardioversion (CV) were the subjects of our interest. All pts were trained to identify AF by palpation of the radial pulse and to self-inject LMWH in case of arrhythmia recurrence. 232 pts (mean age 59.8 +/- 8.6 years) who maintained sinus rhythm (SR) during 4 weeks following successful cardioversion (CV) and correctly recognized AF recurrence and those without episodes of AF were equipped with nadroparine after acenocoumarol discontinuation. Thromboembolic prophylaxis was continued with antiplatelets agents or those no additional risk factors of systemic embolisation were left without medical therapy., Results: 191 pts had AF recurrence during the mean 2.6 +/- 1.7 years observation period, 172 of them correctly identified AF episode, including 162 who performed LMWH injections at home. 7 pts, who had performed LMWH injections, presented with SR on arrival to hospital, 6 pts had AF1.2 out of 21 pts who failed to identify their AF episodes and 1 pt of those who correctly detected the AF recurrence but failed to perform LMWH self-injection suffered from ischemic stroke (sensitivity 96.1%, specificity 60.4%). No side effects of domiciliary LMWH self-injection were found., Conclusion: When properly trained, the majority of pts can accurately diagnose AF recurrence and self-inject initial dose of LMWH, what is feasible and may represent an attractive anti-thromboembolic strategy.

Objective: Antiplatelet agents are used for prevention of thromboembolism in surgical patients and in patients with chronic atrial fibrillation. Up to date, however, results of randomized studies comparing antiplatelet agents and oral anticoagulation have not been reported. The aim of this study was to compare the efficacy and safety of triflusal (an antiplatelet agent) versus acenocoumarol for primary prevention of thromboembolism in the early postoperative period after implantation of a bioprosthesis., Methods: In this prospective, multicentric, randomized, open pilot trial, patients were assigned to treatment with triflusal (600mg/d) or acenocoumarol (target INR 2.0-3.0). Study medication was started 24-48h after valve replacement with a bioprosthesis, and continued for 3 months. Four follow-up visits were scheduled: baseline, and at 1, 3 and 6 months thereafter. The primary end-point was a composite of the rate of thromboembolism, severe hemorrhage and valve-related mortality., Results: A total of 193 patients were included (97 received triflusal and 96 acenocoumarol), with a mean age of 72.5 years. Half were men. Aortic valve replacement was performed in 181 patients (93.8%), mitral valve replacement in 10 patients (5.2%) and double valve replacement in 2 (1.0%). Hospital mortality was 11 (5.7%). Primary outcome was recorded in 9 patients with triflusal (9.4%) and in 10 patients with acenocoumarol (11%). There were nine episodes (4.7%) of thromboembolism, six in the triflusal group and three in the acenocoumarol group, and three episodes of permanent neurological deficits, one in the triflusal group and two in the acenocoumarol group. Severe hemorrhage: nine episodes, six in the acenocoumarol group and three in the triflusal group. None of the observed differences in efficacy were statistically significant. Regarding safety, three patients in triflusal group reported at least one hemorrhage, compared to 10 in acenocoumarol group (P=0.048)., Conclusions: There were no significant differences in efficacy between both groups, however, triflusal showed a significantly lower incidence of bleeding episodes.

Objectives: To evaluate the incidence of thromboembolic and haemorrhagic events in a cohort of patients with mechanical heart valves who had to withhold acenocumarol and were treated with enoxaparin., Design: Observational prospective study., Setting: In hospital; after discharge, and follow up by telephone call., Patients and Methods: All consecutive patients with mechanical heart valves admitted to the authors' hospital between May 1999 and January 2002 who had to interrupt treatment with acenocumarol and were treated with enoxaparin as an alternative to other methods were enrolled. In each patient, the following characteristics were prospectively determined: the reason for interrupting acenocumarol, demographic data, estimated global risk for thromboembolic events, international normalised ratio before starting enoxaparin treatment, number of days taking enoxaparin, and mean level of anti-Xa activity during treatment. All patients were followed up through clinical history during the hospitalisation and by telephone after discharge to detect thromboembolic events., Main Outcome Measure: Presence of thromboembolic or haemorrhagic events., Results: 82 patients were identified and followed up for a mean of 2.8 months (range 1.5-3.5 months) after discharge. 61 of them (74%) had one or more associated thromboembolic risk factors. Acenocumarol was interrupted (to perform an invasive procedure in 74 patients and because of haemorrhagic complication in 8) an average of 11.2 days (range 3-40 days). Most patients received the standard enoxaparin dose (1 mg/kg at 12 hour intervals). Mean (SD) anti-Xa activity was 0.58 (0.3) IU/ml (median 0.51). There were 8 minor and 1 major bleeding events during enoxaparin treatment. No thromboembolic complications were clinically detected during hospitalisation or during follow up (95% confidence interval 0% to 3.6%)., Conclusions: Enoxaparin may be an effective and relatively safe substitute anticoagulant for patients with mechanical heart valves who must withhold acenocumarol.

Mitral stenosis (MS) in association with atrial fibrillation (AF) is a clinical condition at high risk for systemic thromboembolism. Although oral anticoagulants greatly reduce the incidence of thromboembolism in these patients, the optimal intensity of treatment has never been tested in specific clinical trials, and current recommendations are derived from studies of nonrheumatic AF. In this study we tested the effectiveness of two different intensities. The study design was carried out as an open randomized prospective study in an anticoagulation clinic. We randomized 103 patients with MS and AF to a low (target INR = 2) or moderate (target INR = 3) anticoagulation regimen. The primary end points were systemic thromboembolism, major bleeding and vascular death. During a mean follow-up of 4.5 years, 1 systemic embolism occurred in the low intensity group (0.41 per 100 pt/yrs, CI 0.01-2.3), and 1 minor stroke occurred in the moderate intensity group (0.40 per 100 pt/yrs, CI 0.01-2.3; p = ns). Major bleeding occurred in 8 patients, with 3 in the low intensity (1.25 per 100 pt/yrs) and 5 in the moderate intensity group (2.0 per 100 pt/yrs, Incidence Rate Ratio 0.6, CI 0.1-3.1; p = ns). Total events (systemic embolism, major bleeding and vascular death) occurred in 7 low intensity patients and 8 moderate intensity patients. As expected, minor bleeding was more frequent in the moderate intensity group of patients, who actually had more intense treatment and required closer monitoring of oral anticoagulant treatment. These data suggest that low intensity anticoagulation, as performed in an anticoagulation clinic, is effective and safe in high risk patients with MS and AF.

The goal of investigation was to determine whether long-term anticoagulant therapy influences the mortality rate in CHF. The method consisted in the calculation of the annual death rate of the patients with CHF class III-IV NYHA: group A (controls)--who did not receive anticoagulant or antiplatelet therapy; group B--treated with Acenocumarol or Aspirin. The results show in group A, which included 150 patients, during the 5-year interval under study 30 deaths, representing an annual death rate of 4%. In group B, which included 325 patients of which 75 treated with Acenocumarol and 250 patients with aspirin, 20 deaths were recorded during the same 5-year interval, representing an annual death rate of 1.2%. Thus, the mortality risk proved to be 70% lower in group B than in the control group. It came out that the main mechanism of death in CHF is thrombembolism and in this circumstance anticoagulant or antiplatelet therapy would be essential.

Background: It is yet unclear whether vitamin K antagonist treatment should be stopped abruptly or gradually after an episode of venous thromboembolism. The mode of withdrawal might influence a potential development of a hypercoagulable state, which could influence the risk for recurrent disease., Methods: We prospectively studied 37 consecutive patients in whom acenocoumarol was discontinued either abrupt (18) or gradually (19) (2/3 and 1/3 of the initial dose for one week). Blood sampling was performed at various time points up to 18 days after complete withdrawal and was analysed for INR, prothrombin fragment F1 + 2 and D-dimer. All patients were clinically followed-up for the assessment of the association between hypercoagulability and occurrence of disease such as recurrent venous thromboembolism or malignancy., Results: An approximately fourfold increase was observed (median increase from 0.3 to 1.3 nmol/l) in the F1 + 2 levels after both abrupt and gradual withdrawal and in the D-dimer concentrations in the abrupt withdrawal group (0.10 to 0.44 mg/l), while those in whom acenocoumarol was discontinued gradually showed a less pronounced increase of the D-dimer levels (0.11 to 0.29 mg/L) (not significant). During follow-up one recurrent venous thromboembolic event occurred in each group, and a diagnosis of cancer was made four times. All these patients had the highest D-dimer concentrations measured in the entire study group., Conclusions: This study indicates the potential for a hypercoagulable state after acenocoumarol discontinuation, which was not prevented by tapering the acenocoumarol dose. D-dimer, measured 2 to 3 weeks after acenocoumarol withdrawal, might be an important tool to identify patients at risk for recurrent venous thromboembolism and/or for the presence of an underlying malignancy.

A double-blind randomized trial was conducted to research a hypercoagulable state rebound after abrupt versus gradual withdrawal of acenocoumarol, 20 patients were included: 10 in the abrupt withdrawal group (AW) and 10 in the gradual withdrawal group (GW). Between days 1 and 15,F1 + 2 was higher in group AW (P < 0.002). A significant increase of D-dimer with time was found (P < 0.001) without difference between the two groups, tPA and PAI-1 levels remained stable throughout without difference between the two groups. No rebound phenomenon was observed. Four thrombotic recurrences were observed: group AW: 1, group GW: 3 (P = 0.29). There is neither clinical nor biological support for a gradual anticoagulation withdrawal.

Objective: Identification of risk factors for bleeding and prospective evaluation of two bleeding risk scores in the treatment of acute venous thromboembolism., Design: Secondary analysis of a prospective, randomized, assessorblind, multicenter clinical trial., Setting: One university and 2 regional teaching hospitals., Patients: 188 patients treated with heparin or danaparoid for acute venous thromboembolism., Measurements: The presenting clinical features, the doses of the drugs, and the anticoagulant responses were analyzed using univariate and multivariate logistic regression analysis in order to evaluate prognostic factors for bleeding. In addition, the recently developed Utrecht bleeding risk score and Landefeld bleeding risk index were evaluated prospectively., Results: Major bleeding occurred in 4 patients (2.1%) and minor bleeding in 101 patients (53.7%). For all (major and minor combined) bleeding, body surface area < or = 2 m2 (odds ratio 2.3, 95% CI 1.2-4.4; p = 0.01), and malignancy (odds ratio 2.4, 95% CI 1.1-4.9; p = 0.02) were confirmed to be independent risk factors. An increased treatment-related risk of bleeding was observed in patients treated with high doses of heparin, independent of the concomitant activated partial thromboplastin time ratios. Both bleeding risk scores had low diagnostic value for bleeding in this sample of mainly minor bleeders., Conclusions: A small body surface area and malignancy were associated with a higher frequency of bleeding. The bleeding risk scores merely offer the clinician a general estimation of the risk of bleeding. In patients with a small body surface area or in patients with malignancy, it may be of interest to study whether limited dose reduction of the anticoagulant drug may cause less bleeding without affecting efficacy.

After cardiac valve replacement patients were blindly randomized into two groups, both receiving aspirin (330 mg) and dipyridamole (75 mg) twice daily and the oral anticoagulant acenocoumarol (Sintrom). An international normalized ratio of 2.0 to 2.99 was assigned to group A and 3.0 to 4.5 to group B; both groups were subsequently analyzed for thromboembolic and hemorrhagic complications. Final evaluation included 51 and 48 patients, respectively. The follow-up was 626 months for group A (12.3 months/patient) and 486 months for group B (10.1 months/patient). The frequency of thromboembolism was equal in both groups: one transient ischemic attack in group A (a rate of 1.92/100 patient-years) and two transient ischemic attacks in group B (a rate of 4.94/100 patient-years). There was, however, a statistical difference in bleeding complications between the two groups (p less than 0.02). Two patients bled in group A, a rate of 3.9% (3.8/100 patient-years), which represents an incidence of one episode each 25.6 years of treatment; 10 patients bled in group B, a rate of 20.8% (24.7/100 patient-years) representing an incidence of one episode each 4 years of treatment. We conclude that an international normalized ratio of 2 to 3 is safer than a ratio of 3 to 4.5 and confers good protection from thromboembolism when oral anticoagulant therapy is used conjointly with platelet function-inhibiting drugs in patients with mechanical substitute heart valves.

Anticoagulation therapy with acenocoumarin or with anticoagulants plus aspirin was given to 65 and 57 patients, respectively, with cardiac valve replacement. The follow-up was 1,462 months (22.5 months per patient) for the first group and 1,411 months (24.7 months per patient) for the second group. The frequency of embolic accidents was significantly lower in the group taking aspirin: Thirteen thromboembolic accidents were detected in patients receiving the anticoagulant and 3 in the group receiving the anticoagulant plus aspirin. These figures represent a 20.3 per cent incidence (one each 9.3 years of treatment) for the anticoagulant group and a 5.2 per cent incidence (one accident each 39.1 years of treatment) for the other group. The statistical significance between groups is p less than 0.005. There was no difference in the hemorrhagic risk between the two groups. We conclude that the use of an anticoagulant plus aspirin is a good and safe therapy for the prevention of thromboembolism in these patients.

It is reported on the occurrence of haemorrhagic complications at old age in patients treated with coumarin. Altogether 352 patients were examined, 96 of them were older than 70 years. A small part of the patients, above all men with obliterating vascular occlusions of the lower extremity were additionally given also thrombocyte aggregation inhibitors. The effective prothrombin level was nearly the same in the two, groups, i.e. in the patients younger and older than 70 years. There was no difference in frequency and severity of the haemorrhages with the exception of macrohaematuria which, however, appeared above all in the younger age group and in women older than 70 years. Under observation of the indications and with a regular control a long-term treatment with coumarin preparations can performed without any particular risk also at old age.

This report documents our experience with long term antithrombotic therapy (acenocoumarol plus aspirin) in 31 children and adolescents, from 5 months to 16 years of age. The valves replaced were mitral in 20 patients, aortic in 4, mitral-aortic in 4 and tricuspid in 3; the overall follow-up time was of 1336 months. Anticoagulant requirement in each children was not in correlation with age, but a significant increase (p less than 0.01) was found in association with sexual development. Our total incidence of embolic episodes was 1.49/1000 patient-months. The embolic incidence on adequate anticoagulated patients was 0.74/1000 patient-months and 93.7% of all patients were free of thrombo-embolic accidents up to 96 months of follow-up. Minor haemorrhage in relation to an excess of anticoagulant was 1.49/1000 patient-months. There has been only one major bleeding episode associated with severe sepsis, with an incidence of 0.74/1000 patient-months. No major difficulties were found in the management of anticoagulant treatment and its association with antiplatelet drugs in children.

The ADP- and collagen-induced thrombocyte aggregation has been investigated and statistically evaluated in 25 women. These patients had undergone vaginal hysterectomy and colporrhaphy due to descensus vaginae et uteri and received 500 ml Macrodex 6% during the operation and Sintrom from the 1st post-operative day as prophylactic treatment for early and late thromboembolism. After administration of dextran 60, the ability of the thrombocytes to aggregate was reduced by half, 2 hours post-operatively, independent of the concentration and type of agent added in the aggregation test, and remained at this level during the 1st post-operative day. The original values were once again attained on the 4th post-operative day. The speed and force of deaggregation showed reverse behaviour. There was no influence apparent due to age of the patient or phase of the cycle (proliferation, secretion and post-menopausal). By carrying out this combined prophylactic treatment for thromboembolism, satisfactory protection is provided in the dangerous phases during the operation and post-operatively.

202 patients undergoing surgery involving the lower limbs were given antithrombotic treatment for at least 21 days, or until they had regained full mobility. Following subcutaneous prophylaxis with a combination of heparin and dihydroergotamine, two oral regimens were compared in a controlled and randomized prospective study. The first treatment consisted of a combination of acetylsalicylic acid (ASA) and dihydroergotamine (DHE), and the second of acenocoumarol. The radiofibrinogen uptake test was carried out in high-risk patients (i.e. those undergoing hip surgery) to detect deep-vein thrombosis. No statistically significant difference was found between the two groups. However, the ASA/DHE combination enjoyed better patient acceptance and was much easier to use.

A comparison of the incidence of thromboembolic (TE) episodes was made in three groups of patient who underwent aortic valve replacement with the cloth-covered Starr-Edwards prostheses. Group 1 consisted of patients who received anticoagulants for either the entire period of follow-up or for a period of variable duration, after which these agents were no longer administered. When anticoagulants were stopped, 22 patients were categorized as Group 3 for study. Group 2 comprised patients who never received anticoagulants. Of the 147 patients followed in Group 1, 14 suffered one episode of TE. Six patients experienced major emboli; 3 of them died. Twenty of the 82 patients followed in Group 2 (no anticoagulants) suffered TE complications. There were 10 episodes of major emboli. Five of the 22 patients in Group 3 suffered an episode (all major) of TE. It is concluded from this study that anticoagulants should be given permanently to all patients with cloth-covered Starr-Edwards prostheses. Indeed, there is no period after operation when the incidence of TE is so low that anticoagulation may be safely discontinued.