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.
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.
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).
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.
Summary
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.
To determine whether the diagnosis of lupus anticoagulant (LAC) in a large cohort of positive patients was confirmed at a reference laboratory.
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.
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.
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.
Abstract 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-β2 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 aβ2 GPI was significantly higher than that of IgG and IgM aPT. Clinical events accounting for APS occurred in 97 of 130 (75%) IgG aβ2 GPI positive and in 55 of 101 (54%) IgG aβ2 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 aβ2 GPI as compared to those positive for one or another test was found. When patients negative for both IgG aPT and IgG aβ2 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 aβ2 GPI, the prevalence of IgG aPT in patients with LA is significantly lower and not associated with the clinical features of APS.
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.
Abstract
Mechanical heart valve (MHV) replacement in patients with rheumatic valve disease is common in Africa. MHV requires long–life anticoagulation (OAT) and managing this can be difficult. ...Prosthetic valve thrombosis (VT) is a pathological entity characterized by thrombus formation on the prosthetic structures, with subsequent prosthesis dysfunction. Salam Centre for Cardiac Surgery was built in Khartoum Sudan by Emergency NGO. Since April 2007 high–quality and free–of–charge medical and cardio–surgical treatment has been offered to patients. More than 10000 cardiac surgery, 80% of which for MHV replacement, were performed. The aim of the work is to analyze the characteristics of patients with VT, the risk factors and clinical follow–up. From Aug 1, 2018 to Nov 30, 2022, 287 VT involving 237 patients were collected.The incidence is 1.36% p/y. The most relevant risk factor was the interruption of anticoagulant therapy and irregular INR control (N. 142; 49,5%). In 101 cases (35,2%) a clinical factor (infection, pregnancy, eosinophilia, heart failure) was the main cause of VT. The diagnosis, suspected with the Transthoracic Echo and confirmed with fluoroscopy, was done at the OPD visit (32,4%) in asymptomatic or at triage for symptomatic patients (67,6%). 236 patients were admitted to Salam Centre.The treatments of choice were thrombolysis, performed with 2 different protocols, fast and low dose–slow infusion (Alteplase 25 mg./6 hrs), followed by Triple Therapy (TT) (Warfarin, LMWH and Aspirin) (N.189–65,8%), TT alone (N.44– 15,3%) or Warfarin and Aspirin (N.54–18,8%). 210 events (73,2%) ended with unblocked valve,24 events ended with the death of the patient (8,3%); low dose/slow infusion regimen had less deaths. Thrombolysis was more effective (unblockage 79,9%). Warfarin and Aspirin and not admission to Salam Centre were linked to less unblokage and high mortality rate.
Conclusions
The incorrect conduct of OAT represents the most relevant risk factor for VT.Many are the underlying causes, from economic and social factors to insufficient patient awareness. MOH intervention to offer free of charge INR check, but also patient education must be improved. VT is caused also by intercurrent clinical events such as pregnancy, infection. Eosinophilia represents a chapter that deserves a detailed study.Patients with history of VT must be followed by a dedicated clinic that aims to increase patient loyalty in order to intercept risk factors as early as possible.
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.
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 ≤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% CI 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, 12–2·7, 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).
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.
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.
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.
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