Major bleeding in patients undergoing PCI and triple or dual antithrombotic therapy: a parallel-cohort study.

The combination of oral anticoagulants with dual antiplatelet therapy (DAT) in patients undergoing percutaneous coronary intervention with stent implantation (PCI-stenting) is subject to controversy due to the high risk of bleeding. In this multicenter retrospective parallel-group study, we compared the rate of adverse events in chronically anticoagulated patients who underwent PCI-stenting and were discharged on aspirin, clopidogrel and warfarin (triple antithrombotic therapy [TT] group) and were followed in Italian anticoagulation centers, with a parallel cohort of patients who underwent PCI-stenting and were discharged on DAT group. The primary endpoint was the incidence of major bleeding while the patients were in TT and DAT. A secondary endpoint was the occurrence of major ischemic adverse events (MACEs). The final cohort consisted of 229 TT patients and 231 DAT patients followed up for 6 and 7 months, respectively. There were 11 (4.8%; 9.1% patient/years) major bleeding events in the TT group (1 was fatal) as compared to 1 (0.4%; 0.7% patient/years) event in the DAT group (p = 0.003). Of the 28 (6.1%) MACE recorded during the follow-up, 12 (5.2%) occurred in the TT group and 16 (6.9%) in the DAT group. In conclusion, despite close monitoring of anticoagulated patients in dedicated centers, the major bleeding incidence remains high among unselected patients undergoing PCI-stenting and treated with TT. Any efforts to minimize these events should be pursued.

Standardized low-molecular-weight heparin bridging regimen in outpatients on oral anticoagulants undergoing invasive procedure or surgery: an inception cohort management study.

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.

Survey of lupus anticoagulant diagnosis by central evaluation of positive plasma samples.

OBJECTIVE: To determine whether the diagnosis of lupus anticoagulant (LAC) in a large cohort of positive patients was confirmed at a reference laboratory. METHODS: Over a 1-year period, each participating center collected samples from LAC-positive patients. Plasma was filtered and kept deep-frozen until it was sent on dry ice to the reference laboratory by express courier. Centers returned detailed laboratory information and clinical data from each patient. The reference laboratory screened plasma samples by diluted Russell viper venom time (dRVVT) and kaolin clotting time (KCT). When these were prolonged, 1:1 mixing studies were carried out, and confirmatory tests were performed as appropriate. Positive samples were further tested by thrombin time (TT). The presence of heparin was checked by measuring antifactor Xa activity when TT was prolonged. Negative samples were tested by activated partial thromboplastin time using hexagonal phospholipids. RESULTS: Plasma samples from 302 patients from 29 anticoagulation clinics were analyzed. LAC was excluded in 71 samples (24%), because dRVVT and KCT screening test results were normal (34) or reversed to normal by mixing studies (35). The remaining two samples were considered negative because they contained heparin. LAC-negative patients showed different characteristics from those in whom diagnosis was confirmed. They were significantly older (49.7 vs. 45.0 years, P < 0.03), were more often first diagnosed (66% vs. 41%, P < 0.001), and were more frequently judged as mild in LAC potency (60% vs. 25%, P < 0.0001). Moreover, anticardiolipin and anti-beta(2)-glycoprotein I antibody values were more often normal in LAC-negative (82%) than in LAC-positive (42%) samples (P < 0.0001). LAC-positive samples identified by both dRVVT and KCT (146/231, 63%) showed a LAC potency that was significantly stronger than that in samples in which LAC diagnosis was made by a single test. CONCLUSIONS: A false-positive LAC diagnosis is not uncommon across specialized centers. Patients' characteristics and a complete antiphospholipid antibody profile may help to identify these individuals.

Comparison between different D-Dimer cutoff values to assess the individual risk of recurrent venous thromboembolism: analysis of results obtained in the DULCIS study.

INTRODUCTION: D-dimer assay, generally evaluated according to cutoff points calibrated for VTE exclusion, is used to estimate the individual risk of recurrence after a first idiopathic event of venous thromboembolism (VTE). METHODS: Commercial D-dimer assays, evaluated according to predetermined cutoff levels for each assay, specific for age (lower in subjects <70 years) and gender (lower in males), were used in the recent DULCIS study. The present analysis compared the results obtained in the DULCIS with those that might have been had using the following different cutoff criteria: traditional cutoff for VTE exclusion, higher levels in subjects aged ≥60 years, or age multiplied by 10. RESULTS: In young subjects, the DULCIS low cutoff levels resulted in half the recurrent events that would have occurred using the other criteria. In elderly patients, the DULCIS results were similar to those calculated for the two age-adjusted criteria. The adoption of traditional VTE exclusion criteria would have led to positive results in the large majority of elderly subjects, without a significant reduction in the rate of recurrent event. CONCLUSION: The results confirm the usefulness of the cutoff levels used in DULCIS.

Thrombotic events during oral anticoagulant treatment: results of the inception-cohort, prospective, collaborative ISCOAT study: ISCOAT study group (Italian Study on Complications of Oral Anticoagulant Therapy).

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 - of < or =90 days vs. >90 = 20.6, C.I. 12.7-33.5; p <0.0001). The risk was higher in patients aged > or =70 y (1.62, C.I. 1.0-2.61; p <0.05), and when indication for anticoagulant treatment was peripheral/cerebral arterial disease (1.84, C.I. 1.01-3.36; p <0.05). The frequency of thrombotic events was 17.5% when international normalised ratio (INR) levels were < 1.5, decreasing to 2.3% for INRs within the 2-2.99 category (relative risk of INRs <2.0 vs. > or =2 = 1.88, C.I. 1.16-3.07; p <0.05). 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 are <2.0 INR, in patients > 70 years and in those with cerebrovascular/peripheral arterial disease.

An improved test to identify aPC-resistant factor V-Leiden.

A functional clotting assay was recently reported to detect the factor V-Leiden mutation (R506Q) in patients receiving oral anticoagulants and in patients with Lupus Anticoagulant inhibitor. The original assay (Dahlback) to detect resistance to activated protein C (aPC-resistance) frequently gave unreliable findings in these patients. The change in the method is the use of bovine thromboplastin in a PT-derived assay, with a 1:10 sample dilution. In these conditions a reference normal plasma gives a prolongation of more than 35 seconds, while samples with a heterozygous or homozygous mutation give a prolongation respectively of 10-18 seconds or less 2 seconds. The test is easily automated and quickly performed on ACL/3000, and the reproducibility is good.

Prevalence of HFE mutations in upper Northern Italy: study of 1132 unrelated blood donors.

BACKGROUND: In the Italian general population, prevalence of C282Y is lower than in Northern European countries. We hypothesised a higher prevalence of C282Y in Northern than in Central and Southern Italy. We previously identified a nonsense mutation (W169X) in haemochromatosis probands originating from a Northern Italian region (Brianza). AIM: To define the prevalence of HFE mutations in that region. Subjects and methods. A total of 1132 unrelated blood donors from the Blood Banks of Monza and Merate were investigated for C282Y, H63D, S65C and W169X mutations by PCR-restriction assays. A total of 300 were also tested for rare HFE and TFR2 mutations by reverse-hybridization test strips. RESULTS: Two C282Y homozygotes, eight C282Y/H63D compound heterozygotes, 27 H63D homozygotes and one W169X heterozygote were found. The allele frequencies of C282Y, H63D, S65C, and W169X were 3.2, 13.4, 1.3, and 0.04%, respectively. CONCLUSIONS: Our results confirm the existence of a decreasing frequency of C282Y allele from upper to lower Northern Italy. This difference is probably related to the larger Celtic component of upper Northern Italian populations in which screening studies for haemochromatosis may even be cost effective. W169X, due to its severity, should be looked for in all haemochromatosis patients of Northern ancestry with an incomplete HFE genotype.

Clinical course of high-risk patients diagnosed with antiphospholipid syndrome.

BACKGROUND: The characteristics and the clinical course of antiphospholipid syndrome (APS) in high-risk patients that are positive for all three recommended tests that detect the presence of antiphospholipid (aPL) antibodies have not been described. METHODS: This retrospective analysis of prospectively collected data examined patients referred to Italian Thrombosis Centers that were diagnosed with definite APS and tested positive for aPL [lupus anticoagulant (LA), anti-cardiolipin (aCL), and anti-beta2-glycoprotein I (beta2GPI) antibodies]. Laboratory data were confirmed in a central reference laboratory. RESULTS: One hundred and sixty patients were enrolled in this cohort study. The qualifying events at diagnosis were venous thromboembolism (76 cases; 47.5%), arterial thromboembolism (69 cases; 43.1%) and pregnancy morbidity (11 cases; 9.7%). The remaining four patients (2.5%) suffered from catastrophic APS. The cumulative incidence of thromboembolic events in the follow-up period was 12.2% (95% CI, 9.6-14.8) after 1 year, 26.1% (95% CI, 22.3-29.9) after 5 years and 44.2% (95% CI, 38.6-49.8) after 10 years. This was significantly higher in those patients not taking oral anticoagulants as compared with those on treatment (HR=2.4 95% CI 1.3-4.1; P<0.003). Major bleeding associated with oral anticoagulant therapy was low (0.8% patient/years). Ten patients died (seven were cardiovascular deaths). CONCLUSIONS: Patients with APS and triple positivity for aPL are at high risk of developing future thromboembolic events. Recurrence remains frequent despite the use of oral anticoagulants, which significantly reduces the risk of thromboembolism.

Prevalence and significance of anti-prothrombin (aPT) antibodies in patients with Lupus Anticoagulant (LA).

OBJECTIVE: Anti-prothrombin (aPT) antibodies have been found in Lupus Anticoagulant (LA) positive patients. Their prevalence and relative contribution to thromboembolic risk in LA-positive patients is not well defined. The aim of this study was to determine their presence and association with thromboembolic events in a large series of patients with confirmed LA. METHODS: Plasma from LA-positive patients was collected at Thrombosis Centers and sent to a reference central laboratory for confirmation. Positive plasma was tested using home-made ELISA for the presence of aPT and anti-beta(2)GPI antibodies. RESULTS: LA was confirmed in 231 patients. Sixty-one of 231 (26%, 95%CI 22-33) LA positive subjects were positive for IgG aPT and 62 (27%, 95% CI 21-33) were positive for IgM aPT antibodies. Clinical features of Antiphospholipid Syndrome (APS) were not associated with the presence of IgG aPT [43 APS in 61 (70%) positive and 109 APS in 170 (64%) negative IgG aPT subjects, p=ns] or IgM aPT. Rate of positivity of IgG and IgM a beta(2)GPI was significantly higher than that of IgG and IgM aPT. Clinical events accounting for APS occurred in 97 of 130 (75%) IgG a beta(2)GPI positive and in 55 of 101 (54%) IgG a beta(2)GPI negative patients (OR 2.4, 95% CI 1.4 to 4.3, p=0.002). No significant association with clinical events in patients positive for both IgG aPT and IgG a beta(2)GPI as compared to those positive for one or another test was found. When patients negative for both IgG aPT and IgG a beta(2)GPI (LA positive only) were compared with remaining patients, a significantly lower association with clinical events was found (OR=0.4, 95% CI: 0.2 to 0.7, p=0.004). CONCLUSIONS: As compared to IgG a beta(2)GPI, the prevalence of IgG aPT in patients with LA is significantly lower and not associated with the clinical features of APS.

Coagulation abnormalities in migraine and ischaemic cerebrovascular disease: a link between migraine and ischaemic stroke?

Migraine, particularly migraine with aura, is a risk factor for ischaemic stroke. The mechanisms underlying this association are obscure. One hypothesis is that shared risk factors may be the cause of this association. Over the last decade, studies have suggested an association between migraine and genetic abnormalities in coagulation factors which play an important role in stroke pathogenesis. Although the results of studies on various prothrombotic conditions are conflicting, findings suggest a higher frequency of some genetic abnormalities in migraine with aura patients. Thus, persistent hypercoagulability may explain the tendency for these patients to develop thromboembolic cerebrovascular events, especially when they are exposed to additional procoagulant stresses. Further studies on larger samples are required to test this hypothesis.

Genetic abnormalities of the protein C system: shared risk factors in young adults with migraine with aura and with ischemic stroke?

Migraine, particularly migraine with aura (MA), may be a risk factor for ischemic stroke (IS). The reasons for this association are unknown. We investigated the presence of genetic abnormalities of the protein C system in 83 MA patients, 31 IS patients, and 124 healthy controls, all aged under 45 years. We found an increased frequency of activated protein C resistance due to Arg506Gln factor V mutation, and of protein S deficiency in both disorders, with figures higher than those reported in the general population and significantly different from those found in controls. These prothrombotic genetic abnormalities may be shared risk factors in IS and MA, and may play a role in increasing the risk of cerebrovascular disease in migraineurs.

[Hemorrhagic complications of oral anticoagulant therapy: results of a prospective multicenter study ISCOAT (Italian Study on Complications of Oral Anticoagulant Therapy)]. / Complicanze emorragiche della terapia anticoagulante orale: risultati dello studio prospettico multicentrico ISCOAT (Italian Study on Complications of Oral Anticoagulant Therapy).

BACKGROUND: To assess the incidence of bleeding complications during oral anticoagulant therapy (OAT) in a population of patients representative of daily practice in Italian anticoagulation clinics. DESIGN: prospective, inception-cohort, multicentre. SETTING: Thirty-four anticoagulation clinics federated in the Italian Federation of Anticoagulation Clinics. PATIENTS: 2745 consecutive patients, included from beginning of their first OAT course. Most patients were aged between 60 and 79 y (57.8%), with 8% being > or = 80 y. Venous thromboembolism was the most frequent indication for OAT (one third of all the patients), followed by non ischemic heart disease which mainly included atrial fibrillation (16.8% of patients). Warfarin (in 63.8% of patients) and acenocoumarol were the only anticoagulant drugs used. The targeted anticoagulation intensity was low (INR < or = 2.8) in 71% of patients and high (INR > 2.8) in the remainder. OUTCOMES: Fatal, major and minor bleeding events. Thrombotic events were also recorded, though not analyzed in the present report. FINDINGS: During the 2011 patient-years (pt-y) of follow-up, 153 bleeding complications (7.6% pt-y) were recorded--5 fatal (all cerebral haemorrhages, 0.25% pt-y), 23 major (1.1% pt-y) and 125 minor (6.2% pt-y). The rate of events did not vary according to sex, coumarin type, size of enrolling centre or targeted therapeutic range; it was higher in older patients (10.5% pt-y in those aged > or = 70 y, relative risk--RR--1.75, p < 0.001), in cases where indication for anti-coagulant treatment was peripheral and/or cerebrovascular disease (12.5% pt-y; RR 1.80, p < 0.01) and during the first 90 days of treatment (11% pt-y, RR 1.75, p < 0.001). One fifth of bleeding events occurred at a very low anticoagulation intensity (INR < 2; the category rate being 7.7% pt-y); the rate was 4.8% pt-y in the 2.0-2.9 INR category, reaching 9.5% pt-y, 40.5% pt-y and 200% pt-y in the 3-4.4, 4.5-6.9 and > or = 7 INR categories respectively (RR for INR levels > 4.5 = 7.91, p < 0.0001). CONCLUSIONS: The overall rate of bleeding events recorded in the present study was much lower than that recorded in other (including recent) observational and experimental studies. The risk of bleeding increased in the following cases: age > 70 y; arterial vascular disease as indication for OAT; first 3 months of treatment; INR values > or = 4.5. OAT has become safer in recent years, particularly if monitored in special anticoagulation clinics. Caution should be exercised when prescribing OAT in elderly patients and the intensity anticoagulation levels should be closely monitored to minimize incidental periods of overanticoagulation.

Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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, 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). INTERPRETATION: 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.