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Background Frailty is associated with significant morbidity and mortality among elderly adults. Whether frailty predicts adverse outcomes in patients treated with oral anticoagulants for stroke prevention in atrial fibrillation remains uncertain. Purpose To examine the impact of frailty in clinical outcomes in elderly patients with non-valvular atrial fibrillation treated with edoxaban. Methods This is an observational prospective single centre cohort study enrolling consecutive naïve to anticoagulation patients of age ≥80 years starting oral anticoagulation with edoxaban for stroke prevention in non-valvular atrial fibrillation and followed up for 2 years. At baseline, all patients were evaluated for frailty, comorbidities, medications, and stroke and bleeding risk factors. Frailty was assessed using the Survey of Health Ageing and Retirement in Europe Frailty Index (SHARE-FI) tool, a validated frailty measure centred on health resource utilisation, with the cohort stratified into non-frail, pre-frail and frail. The clinical outcomes were the cumulative incidence of stroke/systemic embolism, major bleeding, and clinically relevant non-major bleeding (CRNMB), and individual components part of the composite outcome. Results Among 160 patients who received edoxaban for stroke prevention in atrial fibrillation, 34% were frail, 20% pre-frail, 46% non-frail. The mean age of the cohort was 85±4 years and 58% were female. The mean CHA2DS2VASc score was 4±1. Mean Cockroft-Gault creatinine clearance (CrCl) was 52±17 mL/min, and edoxaban 30mg was administered to 59% of patients as per indications (weight ≤60 kg and/or, CrCl 15–50 ml/min). The follow up extended for 681±289 days. Primary endpoint occurred in 46 patients (28.7%; annualised rate 15.4%patient-years): 19 events occurred in non-frail, 9 in pre-frail, and 18 in frail patients (p=0.6). Stroke/systemic embolism occurred in 2.2%, major bleeding in 5.0%, and CRNM bleeding in 10.0% of patients. Frailty was not a predictor of the events part of the composite outcome (non-frail 5.4% vs pre-frail 0% vs frail 1.9%, p=0.27; non-frail 5.4% vs pre-frail 9.4% vs frail 1.9%, p=0.29; and non-frail 13.5% vs pre-frail 3.1% vs frail 9.3%, p=0.25; for stroke/systemic embolism, major bleeding, and CRNMB, respectively). Cumulative rate of events (Figure) did not differ in frail versus the rest (non-frail and pre-frail) of patients (p=0.521). Conclusions Frailty status was not a predictor of events among the elderly with atrial fibrillation treated with edoxaban. Anticoagulation with edoxaban is feasible in octogenarians even if frail. Funding Acknowledgement Type of funding sources: None.

BackgroundData on fluctuation of antibodies directed against domain 1 (anti-D1) of β2-glycoprotein I (β2GPI) are scarce. Patients with antiphospholipid syndrome (APS) and all three criteria tests for antiphospholipid antibodies (aPL) display higher titers of anti-D1, which correlate with anti-β2GPI levels.ObjectivesThis project aims at evaluating predictors of the variation of anti-D1 titers over time in a large international cohort of persistently aPL positive patients.MethodsAntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking (APS ACTION) Registry was created to study the course of persistently aPL-positive patients with or without autoimmune disorders over at least 10 years. Inclusion criteria are positive aPL by Updated Sapporo Criteria tested within one year prior to enrolment. Patients are followed every 12±3 months with clinical data and blood collection. Patients with available blood samples from at least three time points were included in this analysis. Anti-β2GPI and anti-D1 IgG were tested by chemiluminescence (BioFlash, Werfen) at APS ACTION core laboratories. Positive results were defined as >20 CU, according to the manufacturer. Clinical data were retrieved from APS ACTION online database. Anti-D1 titers within the same subject were compared by Friedman’s test. A mixed linear model was built to identify predictors of the fluctuation of anti-D1 antibody titers over time.ResultsIn this longitudinal study, 230 patients with anti-D1 tested at 4 time points were included (Table 1). Patients with thrombotic APS had anti-D1 titers significantly higher than those without thrombosis (p=0.022). Among 135 patients with at least one anti-D1 positive result, anti-D1 titers varied significantly over time (Friedman statistics: 508.5, pTable 1.Demographic and Clinical Characteristics of 230 APS ACTION Registry Patients with anti-D1 tested ≥3 time points during the follow-upAnti-D1 pos samplesAnti-D1 neg samplesp-valueOverall sample(n=135)(n=95)(n=230)Age [years] mean (SD)42.3 (11.8)48.8 (13.0)0.000145.0 (12.7)%Female (n)71.9 (97)65.3 (62)0.35869.1 (159)Associated systemic autoimmune disease39.3 (53)44.2 (42)0.53941.3 (95)aPL without APS19.3 (26)34.7 (33)0.01025.7 (59)Thrombotic APS54.1 (73)53.7 (51)53.9 (124)Obstetric APS11.9 (16)5.3 (5)9.1 (21)Thrombotic/+obstetric APS14.8 (20)6.3 (6)11.3 (26)aCL IgG89.5 (119/133)25.5 (24/94)63.0 (143/227)aCL, IgM36.1 (48/133)27.7 (26/94)0.23432.6 (74/227)Anti-2GPI, IgG93.2 (124/133)39.4 (37/94)70.9 (161/227)Anti-2GPI, IgM34.6 (46/133)21.3 (20/94)0.04329.1 (66/227)LA82.8 (82/99)59.5 (44/74)0.00172.8 (126/173)ConclusionTreatment with HCQ and vascular events during follow-up were identified as significant predictors of the fluctuation of anti-D1 antibody titers over time.Disclosure of InterestsNone declared.

Introduction Recurrent thromboembolism is a major risk factor for chronic thromboembolic pulmonary hypertension (CTEPH). Antiphospholipid antibodies (aPL) are a recognized risk factor for recurrent thromboembolism, however, their contribution to the development of CTEPH is currently unknown. Purpose The aim of this study was to evaluate the prevalence of antiphospholipid autoantibodies in a large cohort of consecutive patients with CTEPH. Methods Starting May 2013 to December 2018, 297 CTEPHpatients were consecutively enrolled. Diagnosis was confirmed with standardized right heart catheterization, 2D or/and 3D pulmonary angiography in all patients.All patients were also screened for thrombophilia including lupus anticoagulant IgG/IgM anticardiolipin antibodies and IgG/IgM aβ2GPI antibodies. Clinical and demographic characteristics, laboratory profile and hemodynamic data were compared between patients with aPL positive and aPL negative laboratory profiles. Results Overall, 297 consecutive patients with CTEPH were assessed for aPLs. Of these, 23 patients (7.7%) resulted positive for laboratory tests exploring aPL. Among patients with positive aPL, profile 17 (74%) were positive for all three test exploring aPL (LA+, aCL+, aB2GPI+). When compared to CTEPH patients without aPL test positivity, those positive for aPL were significantly younger (30.0 vs 55.6 years, p Conclusions These findings suggest that young patients with pulmonary embolism should be assessed for aPLs to guide anticoagulation therapy and prevent recurrences. Additionally, younger age, more proximal lesions and less severe hemodynamic profiles make majority patients with APS good candidates for PEA surgery.

The antiphospholipid syndrome (APS) identifies a condition at increased risk of vascular occlusion and/or pregnancy complications. Patients are defined as having APS if they have at least one clinical (vascular occlusion and/or pregnancy complications) and one laboratory criterion at the same time. The laboratory criteria that define APS are repeated positivity (confirmed 12 weeks apart) for lupus anticoagulants and/or antibodies targeted against cardiolipin or β(2) -glycoprotein I immobilized on solid surfaces. Over the years, APS has attracted the interest of many medical specialties. The aim of this review is to provide an update on (i) the laboratory criteria that determine the presence of APS, (ii) how the antibodies increase the risk of vascular occlusion and foetal loss and (iii) the treatment of the related clinical events.

One of the conclusions of the subcommittee meeting on Lupus Anticoagulant/Phospholipid dependent antibodies, held in Geneva on 2007, was the need to update the guidelines on Lupus Anticoagulant (LA) detection. Particular emphasis was given to several aspects discussed in this official communication. A new paragraph is dedicated to the patient selection, and aims to minimize inappropriate requests for LA testing. Modalities for blood collection and processing are fully delineated and the choice of tests is limited to dRVVT and a sensitive aPTT. Calculation of cut-off values for each diagnostic step are clearly stated. A final paragraph reports the interpretation of the results in general and in particular situations.

Background— Bridging therapy with low–molecular-weight heparin is usually recommended in patients who must stop oral anticoagulants before surgical or invasive procedures. To date, there is no universally accepted bridging regimen tailored to the patient’s thromboembolic risk. This prospective inception cohort management study was designed to assess the efficacy and safety of an individualized bridging protocol applied to outpatients. Methods and Results— Oral anticoagulants were stopped 5 days before the procedure. Low–molecular-weight heparin was started 3 to 4 days before surgery and continued for 6 days after surgery at 70 anti–factor Xa U/kg twice daily in high-thromboembolic-risk patients and prophylactic once-daily doses in moderate- to low-risk patients. Oral anticoagulation was resumed the day after the procedure with a boost dose of 50% for 2 days and maintenance doses afterward. The patients were followed up for 30 days. Of the 1262 patients included in the study (only 15% had mechanical valves), 295 (23.4%) were high-thromboembolic-risk patients and 967 (76.6%) were moderate- to low-risk patients. In the intention-to-treat analysis, there were 5 thromboembolic events (0.4%; 95% confidence interval, 0.1 to 0.9), all in high-thromboembolic-risk patients. There were 15 major (1.2%; 95% confidence interval, 0.7 to 2.0) and 53 minor (4.2%; 95% confidence interval, 3.2 to 5.5) bleeding episodes. Major bleeding was associated with twice-daily low–molecular-weight heparin administration (high-risk patients) but not with the bleeding risk of the procedure. Conclusions— This management bridging protocol, tailored to patients’ thromboembolic risk, appears to be feasible, effective, and safe for many patients, but safety in patients with mechanical prosthetic valves has not been conclusively established.

It has been observed that elderly patients with nonvalvular atrial fibrillation (NVAF) benefit from standard [an international normalised ratio (INR) goal of 2.0-3.0] oral anticoagulant treatment (OAT). The hypothesis that lower-intensity anticoagulation therapy can offset the higher bleeding risk in this population has never been tested in an 'ad hoc' clinical trial. Patients over 75 years of age with NVAF were randomised to receive warfarin to maintain the INR at 1.8 (range 1.5-2.0) or at a standard target of 2.5 (range 2.0-3.0). There were 135 patients in the low-intensity and 132 in the standard-intensity groups. During a mean follow-up lasting 5.1 years, 59 primary outcome events (thromboembolism and major haemorrhage) were recorded, 24 (3.5 per 100 patient-years) in the low-intensity group and 35 (5.0 per 100 patient-years) in the standard-intensity group (HR=0.7, 95% CI 0.4-1.1, p=0.1). The reduction in the primary endpoint was mainly due to a diminution in major bleedings (1.9 vs. 3.0 per 100 patient-years; HR=0.6, 95% CI 0.3-1.2, p=0.1). The median achieved INR value was 1.86 in the low-intensity and 2.24 in the standard-intensity group (p0.001). The frequency of INR testing was 26.1 +/- 13.5 vs. 24.3 +/- 11.6 days, p0.0001). In this exploratory study we observed a low rate of stroke and major bleeding in elderly patients (75) being managed in an anticoagulation clinic for primary stroke prevention with low-intensity anticoagulation (INR 1.5-2.0). However, further trials are needed to confirm the hypothesis generated by the present study.

Objective This study aims to assess the predictive value of residual venous obstruction (RVO) for recurrent venous thrombo-embolism (VTE) in a study using D-dimer to predict outcome. Design This is a multicentre randomised open-label study. Methods Patients with a first episode of idiopathic VTE were enrolled on the day of anticoagulation discontinuation when RVO was determined by compression ultrasonography in those with proximal deep vein thrombosis (DVT) of the lower limbs. D-dimer was measured after 1 month. Patients with normal D-dimer did not resume anticoagulation while patients with abnormal D-dimer were randomised to resume anticoagulation or not. The primary outcome measure was recurrent VTE over an 18-month follow-up. Results A total of 490 DVT patients were analysed (after excluding 19 for different reasons and 118 for isolated pulmonary embolism (PE)). Recurrent DVT occurred in 19% (19/99) of patients with abnormal D-dimer who did not resume anticoagulation and 10% (31/310) in subjects with normal D-dimer (adjusted hazard ratio: 2.1; p = 0.02). Recurrences were similar in subjects either with (11%, 17/151) or without RVO (13%, 32/246). Recurrent DVT rates were also similar for normal D-dimer, with or without RVO, and for abnormal D-dimer, with or without RVO. Conclusions Elevated D-dimer at 1 month after anticoagulation withdrawal is a risk factor for recurrence, while RVO at the time of anticoagulation withdrawal is not.

Summary. Background: The role of risk stratification in normotensive patients with acute pulmonary embolism (PE) is still unclear. Objectives: We evaluated, in these patients, the usefulness of six prognostic markers for predicting in-hospital adverse events related to PE and 3-month mortality. Patients/Methods: Two hundred and one consecutive patients with confirmed acute PE and normal blood pressure, who were administered conventional anticoagulation, were recruited in a multicentre prospective cohort study with 3 months of follow-up. At baseline, they received a comprehensive risk-evaluation including echocardiographic assessment of right ventricular dysfunction, determination of troponin I, brain natriuretic peptide and D-dimer, arterial blood gas analysis and a clinical score. Primary outcome of the study was PE-related in-hospital death or clinical deterioration. Secondary outcomes were in-hospital and 3-month all-cause mortality. Results: The primary outcome occurred in one patient (0.5%), who died from PE during hospitalization. The in-hospital and 3-month all-cause mortality were 2% and 9%, respectively. None of the prognostic markers was predictive of the primary outcome. Clinical score, troponin I and hypoxemia predicted in-hospital all-cause mortality (P = 0.02, 0.01 and

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

Background The optimal duration of oral anticoagulation in patients with idiopathic venous thromboembolism is uncertain. Testing of d-dimer levels may play a role in the assessment of the need for prolonged anticoagulation. Methods We performed d-dimer testing 1 month after the discontinuation of anticoagulation in patients with a first unprovoked proximal deep-vein thrombosis or pulmonary embolism who had received a vitamin K antagonist for at least 3 months. Patients with a normal d-dimer level did not resume anticoagulation, whereas those with an abnormal d-dimer level were randomly assigned either to resume or to discontinue treatment. The study outcome was the composite of recurrent venous thromboembolism and major bleeding during an average follow-up of 1.4 years. Results: The d-dimer assay was abnormal in 223 of 608 patients (36.7%). A total of 18 events occurred among the 120 patients who stopped anticoagulation (15.0%), as compared with 3 events among the 103 patients who resumed anticoagulation (2.9%), for an adjusted hazard ratio of 4.26 (95% confidence interval [CI], 1.23 to 14.6; P = 0.02). Thromboembolism recurred in 24 of 385 patients with a normal d-dimer level (6.2%). Among patients who stopped anticoagulation, the adjusted hazard ratio for recurrent thromboembolism among those with an abnormal d-dimer level, as compared with those with a normal d-dimer level, was 2.27 (95% CI, 1.15 to 4.46; P = 0.02). Conclusions Patients with an abnormal d-dimer level 1 month after the discontinuation of anticoagulation have a significant incidence of recurrent venous thromboembolism, which is reduced by the resumption of anticoagulation. The optimal course of anticoagulation in patients with a normal d-dimer level has not been clearly established. (ClinicalTrials.gov number, NCT00264277.)

Lupus anticoagulants (LA) are immunoglobulins which inhibit phospholipid (PL)-dependent coagulation tests. LA are not specific, as they may reflect the presence of antibodies to human prothrombin, human beta(2)-Glycoprotein I (beta(2)GPI), an association of previous antibodies or other antibodies. Antibodies to human beta(2)GPI act as in vitro anticoagulants by enhancing the binding of beta(2)GPI to PL, and this binding may be influenced by calcium ion concentration. A reduction in final calcium concentration, from 10 mm to 5 mm, increased coagulation times in both dilute Russell Viper Venom Time (dRVVT) and dilute Prothrombin Time (dPT) when plasmas of patients with antibeta(2)GPI antibodies were used. Ten LA patients showed increased dRVVT and dPT ratios from means of 1.5 to 1.7 (P0.001) and 2.4 to 4.3 (P = 0.002), respectively. Instead, all LA-positive antibeta(2)GPI antibody-negative patients showed decreased coagulation times from mean ratios of 1.5 to 1.3 (P = 0.004) in dRVVT and from 2.0 to 1.5 (P = 0.01) in dPT. These results are confirmed by running dRVVT of normal plasma spiked with affinity purified IgG antibeta(2)GPI antibodies. Therefore, when a PL-dependent coagulation test is run twice, at different final calcium concentrations, antibeta(2)GPI LA can be identified.

Randomized clinical trials have demonstrated the efficacy and safety of oral anticoagulants in the prevention of systemic thromboembolism in nonrheumatic atrial fibrillation. The benefit of this treatment is particularly evident in patients in whom atrial fibrillation is associated with a major risk factor for systemic thromboembolism (patients75 years of age, history of hypertension, previous left ventricular failure or previous systemic thromboembolism) or those in whom two minor risk factors are present (patients between 65 and 75 years of age, diabetes, ischemic heart disease). According to these recommendations, all the patients75 years of age with chronic or paroxysmal atrial fibrillation should receive oral anticoagulant treatment to maintain an INR between 2.0 and 3.0. However, as the risk of bleeding during oral anticoagulant treatment increases with age, the benefit/risk ratio should always be evaluated in elderly patients. Although high risk patients do not benefit from aspirin treatment, aspirin or other antiplatelet agents might be indicated in medium risk patients or in those in whom the risk of bleeding with oral anticoagulants is considered too high. New antithrombotic regimens will be tested in the near future.

We carried out a prospective, randomized trial to test whether a computer-based decision support system to initiate and maintain oral anticoagulant (OA) treatment can improve the laboratory quality of therapy.Two separate sets of patients on oral anticoagulants, in five Italian anticoagulant clinics, were studied: 335 patients in the first three months of treatment (stabilization phase), 916 patients (775 patient-years) beyond the third month of treatment (maintenance phase). Patients were randomized to a computerized system, which included algorithms able to suggest OA dosing and to schedule appointments (computer-aided dosing) or to an arm in which OA were prescribed by the same teams of expert physicians without such algorithms (control group). Primary outcomes were: A) the percentage of patients reaching a stable state of anticoagulation during each of the first three months of treatment; B) the percentage of time individuals spent within the aimed therapeutic range (maintenance phase).Patients in the computer-aided dosing group achieved a stable state significantly faster (p0.01) and they spent more time within the therapeutic range during maintenance (p0.001) than controls. The favorable effect of computer-aided dosing was mainly due to a reduction of the time spent below the therapeutic range and was associated with an increase of mean INR value, of anticoagulant drug dosage, and with a reduction of the number of appointments per patient (all changes significant: p0.001).The computer decision-aided support improves the laboratory quality of anticoagulant treatment, both during long-term maintenance and in the early, highly unstable phase of treatment, and it also significantly reduces the number of scheduled laboratory controls.

Self-testing and self-monitoring with portable prothrombin time (PT) monitors has been shown to be feasible and safe. However the ability of patients on chronic oral anticoagulant therapy (OAT) to self-adjust their dose without specific training has never been properly evaluated. The aims of this study were to evaluate: 1) the ability of patients on chronic OAT to self-adjust their dose without specific training; 2) the integration of a portable PT monitor (Coagucheck, Roche Diagnostics, Germany) for home use into routine patient care in anticoagulation clinics.A nested case-control study was conducted in four centers of the Italian Federation of Anticoagulation Clinics (FCSA). Patients (n=78) on stable OAT for at least 6 months (cases: 47 men, 31 women, age range: 18-75 years) were enrolled on a volunteer basis after passing an Abbreviated Mental Test and providing informed consent. After three instruction sessions on the use of Coaguchek, subjects performed the PT test at home, communicated the INR results to the Center and suggested the dose adjustment and date for next control as they thought appropriate. However, they were requested to follow the prescription made by the Center. Controls (78 subjects) matched by age (+/- 5 years), sex and therapeutic range with the cases, were selected from among those who attended the anticoagulation clinics and managed by usual care.When compared with the dose prescribed by the Clinic, the dose suggested by warfarin and acenocoumarol users was equal to or within +/- 6% of the mean weekly dose in 80% and 82% of suggestions, respectively. Time spent in the therapeutic range during the study was the same (80%) for cases and controls.Selected patients on chronic anticoagulant therapy can acquire a satisfactory ability for self-adjustment of OAT dose without specific training.

The aims of this study were to investigate on the general adhesion of the patients to oral anticoagulant therapy, and particularly on the quality of life of our patients, the doctor-patient relationship and the Centre-patient relationship. For this purpose we administered a questionnaire containing 17 main questions each with a maximum of 4 secondary questions. The questionnaire was administered to two groups of 127 and 137 oral anticoagulated patients (127 males and 137 females, mean age 55 +/- 19 years), followed at two Anticoagulation Clinics, in two Italian cities, Cagliari (Sardinia) and Padua (North East Italy). The cities differed in the number of patients monitored and the management modalities of anticoagulation. The results show that oral anticoagulant therapy does not limit the life-style of the patients. Only 11% of the patients complain of limitations to their daily life. Fifty-two percent believe their health has improved, and 87% are not afraid of negative consequences. The doctor-patient relationship is considered very important by 96% of patients. Seventy-eight percent refer to the Anticoagulation Clinic also for other health problems, 93% consider it important to be assessed by the doctor at the Anticoagulation Clinic, while 83% believe the doctor should always hand out the results personally. We conclude that in general oral anticoagulant therapy is accepted by the majority of patients, in spite of the need for periodic monitoring. The doctor-patient relationship should be taken into account, even in the case of a monitored, computer-assisted method of dose-adjustment.

Prothrombin time (PT) is routinely used to monitor oral anticoagulant treatment in patients with the antiphospholipid antibody syndrome (APS). The fact that PT is a phospholipid (PL)-dependent coagulation test raises the possibility that lupus anticoagulant (LA) might interfere with this test, thus complicating the control of anticoagulant treatment. The effect of 6 affinity-purified preparations of anti- (a)beta2-glycoprotein I (GPI) antibodies with LA activity on the PT was tested. Instead of prolonging PT as expected, the abeta2-GPI antibodies reduced the PT of both normal plasma and anticoagulated plasma by a mean of 2.4 seconds and 5.6 seconds, respectively. This effect was also observed using other 5 commercially available preparations of thromboplastin. The abeta2-GPI-mediated reduction in PT was dose-dependent and was lost upon removal of beta2-GPI. The failure of abeta2-GPI antibodies to express LA activity in PT was found to depend on the fact that calcium ions were added together with PL at the beginning of the assay. In fact, modification of the standard diluted Russell viper venom time (dRVVT) test by adding calcium ions together with PL resulted in a loss of abeta2-GPI anticoagulant activity. The procoagulant effect was not as evident in an assay that used stimulated monocytes as a source of thromboplastin. These results show that abeta2-GPI antibodies exhibit an 'in vitro' procoagulant effect in PT and an anticoagulant effect in dRVVT only when the interaction with their antigen and PL occurs in the absence of calcium ions.

Anti-beta2-glycoprotein I (beta2-GPI) antibodies behave as classical Lupus Anticoagulants (LA), as they inhibit phospholipid-dependent coagulation reactions and their activity disappears in the presence of excess exogenous phospholipids (PLs). We have recently shown that a certain amount of PLs in the dilute Russell Viper Venom Time (dRVVT) test system is required to express LA activity of anti beta2-GPI antibodies. We have now extended this observation to two other tests, i.e., Kaolin Clotting Time (KCT) in which PLs are not added, and Tissue Thromboplastin Inhibition test (TTI) in which PLs are extremely diluted. In fact, affinity-purified antibody preparations from 5 patients with antiphospholipid syndrome did not express or only weakly expressed anticoagulant activity in both tests; the mean ratios of coagulation times obtained with purified antibodies and that of control buffer were 1.11 and 1.0 for KCT and TTI, respectively. On the contrary, the mean ratios in dRVVT were 1.31 and 1.49 at a PLs dilution of 1:8 and 1:64, respectively. Therefore, the presence of LA activity due to autoantibodies to beta2-GPI is characterized by a positive dRVVT and negative or only weakly positive KCT and TTI.

Adjusted-dose warfarin is effective for stroke prevention in patients with nonrheumatic atrial fibrillation (AF), but the risk of bleeding is high, especially among the elderly. Fixed minidose warfarin is effective in preventing venous thromboembolism with low risk of bleeding and no need for frequent clinical monitoring. Patients60 years with nonrheumatic AF were randomized in an open-labeled trial to receive fixed minidose warfarin (1.25 mg/day) or standard adjusted-dose warfarin (International Normalized Ratio [INR] between 2.0 and 3.0). Primary outcome events were ischemic stroke, peripheral or visceral embolism, cerebral or fatal bleeding, and vascular death. Secondary end points were major bleeding, myocardial infarction, and death. This study was discontinued before completion in light of publication of the Stroke Prevention in Atrial Fibrillation III trial, which indicated that low-intensity fixed-dose warfarin treatment (i.e., INR1.5) was insufficient for stroke prevention in high-risk patients with nonrheumatic AF. From a total of 1,209 considered patients, 303 were randomized to be studied (150 in the minidose group and 153 in the adjusted-dose group). Mean follow-up was 14.5 months. The rate of cumulative primary events was 11.1% (95% confidence intervals [CI] 4.0 to 18.2) in the fixed minidose group and 6.1% (95% CI 1.1 to 11.1) in the adjusted-dose group (p = 0.29). The rate of ischemic stroke was significantly higher in the minidose group (3.7% vs 0% per year, p = 0.025). Major bleedings were more frequent in standard treatment group (2.6% vs 1% per year, p = 0.19). Most thromboembolic complications occurred at INRs1.2, whereas the majority of hemorrhages occurred at INRs3.0. No significant difference in primary outcome events was observed in the abbreviated study. However, the significantly increased occurrence of ischemic stroke in the fixed minidose warfarin group suggests that this regimen does not protect patients with nonrheumatic AF.

The paper reports on rate and type of thrombotic events occurring during the observational, prospective, inception-cohort, multicenter ISCOAT study. 2,745 unselected, daily practice patients, consecutively referring to 34 Italian anticoagulation clinics to monitor the oral anticoagulant treatment, were included in the study from beginning of their first anticoagulant course. During a total follow-up of 2,011 patient-years of treatment 70 thrombotic events (3.5 per 100 patient years) were recorded in 67 patients: 20 fatal (1%), 39 major (1.9%) and 11 minor (0.6%). 34/70 events occurred within the first 90 days of treatment (relative risk - at multivariate analysis - ofor =90 days vs.90 = 20.6, C.I. 12.7-33.5; p0.0001). The risk was higher in patients agedor =70 y (1.62, C.I. 1.0-2.61; p0.05), and when indication for anticoagulant treatment was peripheral/cerebral arterial disease (1.84, C.I. 1.01-3.36; p0.05). The frequency of thrombotic events was 17.5% when international normalised ratio (INR) levels were1.5, decreasing to 2.3% for INRs within the 2-2.99 category (relative risk of INRs2.0 vs.or =2 = 1.88, C.I. 1.16-3.07; p0.05). The recorded rate of thrombotic events was lower than that reported in the few available studies. A greater risk should be expected during the first 90 days of treatment, when anticoagulation levels are2.0 INR, in patients70 years and in those with cerebrovascular/peripheral arterial disease.

Lupus anticoagulant (LA) is a general term to define immunoglobulins interfering with phospholipid-dependent coagulation tests. It is now clear that the phospholipid-dependence of some LA is related to the presence of the phospholipid-binding plasma protein beta 2-glycoprotein I (beta 2-GPI) and that autoantibodies to beta 2-GPI might represent a specific category of LA. To verify this hypothesis we have purified IgG autoantibodies to beta 2-GPI from plasma of 6 patients with antiphospholipid antibody syndrome, by means of agarose-immobilized human beta 2-GPI. All 6 preparations tested positive in anti-beta 2-GPI IgG antibody ELISA and showed a marked LA activity by prolonging dilute Russell Viper Venom Time (dRVVT) from a minimum of 5.3 s in patient # 1 to a maximum of 41.1 s in patient # 3. These IgG preparations behaved as typical LA, with this activity tending to disappear in the presence of increasing phospholipid (PL) concentrations. Moreover, the LA activity of the IgG preparations was not detectable in the absence of PL, in which case the ratio between dRVVT obtained in the presence and absence of IgG autoantibodies to beta 2-GPI was close to 1. This pattern was confirmed by using plasma from patients with antiphospholipid antibody syndrome testing positive for anti-beta 2-GPI IgG antibodies. These findings suggest that dRVVT performed both in the presence and absence of PL might constitute a sensitive screening test to detect specific antibodies with LA activity.

Bleeding 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.In 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.43% 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, p0.001). 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, p0.01), and during the first 90 days of treatment compared with later (11.0 vs 6.3, 1.75, 1.27-2.44, p0.001). A fifth of the bleeding events occurred at low anticoagulation intensity (INR2, 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 INR4.5, 7.91, 5.44-11.5, p0.0001).We 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.

The antiphospholipid antibodies (aPL) present in autoimmune disorders are associated with thromboembolic episodes, and their binding to phospholipids (PL) is mediated by a plasma cofactor, beta 2-glycoprotein I (beta 2GPI). Both PL and beta 2GPI seem necessary for binding, thus indicating that the two components comprise the epitope against which aPL are directed. Using an anti-beta 2GPI antibody ELISA with the antigen adsorbed onto polyvinylchloride (PVC) plates, we detected high antibody titres in 12 out of 12 plasma from patients with the antiphospholipid syndrome. No or very low positivity was obtained when the same ELISA was carried out in polystyrene (PST) plates, while an increasing positivity was found when processed (i.e. more hydrophilic) or COOH-surface PST plates were used. When beta 2GPI dependent IgG-aPL were purified using agarose-immobilized cardiolipin, 4 out of 4 preparations were highly positive in anti-beta 2GPI antibody ELISA using PVC plates, while beta 2GPI was not fully recognized by aPL-IgG when adsorbed onto PST plates. These findings demonstrate that aPL are, in fact, anti-beta 2GPI antibodies directed against a cryptic epitope which is expressed when beta 2GPI is bound to anionic phospholipid, or another suitable surface.

Although observations have implied that lupus anticoagulants have immunologic specificity toward anionic phospholipids, this assumption has been directly demonstrated in only one patient with a monoclonal IgM paraprotein. We tested the generality of this hypothesis directly by isolating five IgG lupus anticoagulants from patients with lupuslike syndromes and/or thrombosis. IgG lupus anticoagulant fractions were isolated free of other plasma proteins and free of contaminating phospholipid by adsorption to and elution from cardiolipin-cholesterol- dicetyl phosphate liposomes, followed by chromatography on protein A- Sepharose. Cardiolipin liposomes, but not phosphatidylcholine liposomes, were capable of removing all, or nearly all, lupus anticoagulant activity from patient plasma. The affinity-purified IgG preparations reacted with cardiolipin, phosphatidylserine, phosphatidylinositol, and phosphatidic acid, but not with phosphatidylcholine or phosphatidylethanolamine, and inhibited calcium- dependent binding of prothrombin and of factor X to phosphatidylserine- coated and to cardiolipin-coated surfaces. F(ab')2 fragments retained lupus anticoagulant activity and bound to cardiolipin in an enzyme- linked immunosorbent assay (ELISA). Anticardiolipin and lupus anticoagulant activity were both present in acidic fractions on isoelectric focusing. These data strongly suggest that most, if not all, lupus anticoagulants are antibodies that have immunologic specificity towards anionic phospholipids, thereby blocking the calcium- mediated binding of vitamin K-dependent coagulation factors to coagulation-active phospholipid surfaces.

Eight patients with massive pulmonary thromboembolism documented by angiography were treated with Urokinase (UK) 4.400 IU/Kg/hr for 12 hours. UK i.v. infusion was started immediately after angiographic evaluation (Miller index) and was followed by anticoagulant therapy with heparin and sodium warfarin. All patients survived even though 4 pts. were in shock before treatment. Significant reduction of pulmonary obstruction (reduction of Miller index) was obtained in 7 patients with 48 hours from withdrawal of the drug. Mild superficial bleedings which did not influence the clinical course were the only complication recorded. Neither bleedings nor angiographic improvement showed a correlation with thrombin time prolongation. Indications for thrombolytic therapy of pulmonary embolism and particularly prevention of the major haemorrhagic complications are briefly discussed. It is concluded that the high doses of UK suggested by Food and Drug Administration may be used safely in patients affected by massive pulmonary thromboembolism with or without shock, if patients are adequately selected and prevention of major haemorrhagic complications is continued throughout treatment.

The fibrin/fibrinogen degradation products were measured in 24 synovial fluids sampled from patients with knee joint effusion. It has been observed that they are increased in synovial fluid involved in inflammatory processes. Their presence and concentration seem to be related to the control of local inflammation.

It was our aim to assess whether factor V Leiden (FVL) and G20210A prothrombin (FII) mutation are associated with the presence of residual vein obstruction (RVO) after a standard course of anticoagulation for a first episode of idiopathic proximal deep-vein thrombosis (DVT) of the lower limbs, with or without symptomatic pulmonary embolism (PE). Patients were enrolled in two prospective multicentre studies: PROLONG and PROLONG II. RVO was detected by compression ultrasonography according to the method of Prandoni on the day of anticoagulation withdrawal. Patients were also screened for FVL and FII mutation. The presence of FVL and/or FII mutation was determined in 872/963 (90.5%) patients, in 753 of whom RVO was assessed. FVL was significantly less frequent among subjects with isolated PE (7/176:4%) than among patients with either DVT and PE (15/133:11.3%; p=0.0018) or isolated DVT (89/563:15.8%; p