Determination of lupus anticoagulant (LA), anticardiolipin (aCL) and β2-Glycoprotein 1 (aβ2GP1) antibodies is mandatory to classify patients with antiphospholipid syndrome (APS) into risk categories.
...To measure relevant antibodies, considered to be those of the IgG isotype directed towards β2GP1 and particularly those directed to Domain 1 (Dm1) of the molecule.
In this cross-sectional study we measured IgG aβ2GP1-Dm1 by a chemiluminescent immunoassay in a group of individuals initially positive for IgG aβ2GP1 and classified as triple (LAC+, IgG aCL+, IgG aβ2GP1+, n = 32), double (LAC-, IgG aCL+, IgG aβ2GP1+, n = 23) or single positive (LA-, IgG aCL-, IgG aβ2GP1+, n = 10).
Geometric mean and standard deviation expressed as chemiluminescent units (CU) in triple, double and single positive groups were 273.0 ± 6.2, 18.2 ± 9.6 and 4.4 ± 2.2, respectively. The geometric mean obtained in 40 healthy subjects was 2.0 ± 2.0. Mean CU values were significantly different among groups and with respect to values found in 40 healthy subjects (P < 0.0001). Positive values of IgG aβ2GP1-Dm1 (above 14.2 CU) were found in 45 individuals while 20 individuals (20/65 = 30.8%) positive for IgG aβ2GP1 were negative for IgG aβ2GPI-Dm1. There was a significant association between positive IgG aβ2GP1-Dm1 and thromboembolic events (P = 0.001). Positive and negative values of IgG aβ2GP1-Dm1 were consistently confirmed after 12 weeks, with only three low positive values being negative after 12 weeks. In conclusion, IgG aβ2GP1-Dm1 seems a robust and reproducible test that in association with the classic tests may be useful in clinical practice in identifying individuals at high risk of developing thromboembolic events.
AIMSWe assessed the cumulative incidence of recurrent stroke, major bleeding and all-cause mortality associated with restarting antithrombotic treatment, in patients experiencing an ...anticoagulation-related event (stroke or major bleeding), occurred during anticoagulation therapy for AF.METHODS AND RESULTSWe performed a retrospective population-based analysis on linked claims data of patients resident in the Veneto Region, treated with DOACs for AF and discharged (2013-2020) from the hospital for stroke, intracranial haemorrhage (ICH), and major bleeding. To adjust for competing risk of death and reduce confounding, we started the follow up after a 120-days blanking period, counting events in patients resuming oral anticoagulation versus those that did not. Risks of all-cause mortality, ischemic stroke (IS)intracranial haemorrhage (ICH), and other major bleeding events (MB) were estimated with multivariable Cox proportional hazard models and propensity score to adjust for differences in baseline characteristics. Overall, 1029 patients (mean age 77 years) were included in the final cohort: 23% experienced an IS, 18% an ICH, and 59% MB. Of these, 77% resumed anticoagulation. The cumulative incidence of events was significantly lower in patients resuming therapy. In the multivariable analysis considering age, sex and propensity score as covariates, resumption of anticoagulation significantly reduced the risk of a cumulative event (HR 0.45, 95%CI 0.35-0.57, p < 0.01). Stratifying for the index event, among patients with IS (92% resumed therapy), we observed a risk reduction of 81%; in patients with ICH (64% resumed therapy), we observed a risk reduction of 64% and for patients with MB (76% resuming therapy), we observed a risk reduction of 49%.CONCLUSIONSIn patients with AF who experienced an anticoagulation-related event, resuming oral anticoagulation was associated with better outcomes for all-cause mortality and subsequent events as compared with patients who did not resume treatment.
Despite extensive research, the pathogenesis of antiphospholipid syndrome (APS) remains obscure in many aspects. However, it is widely accepted that thrombosis is the result of a hypercoagulable ...state caused by antibodies directed against β2-glycoprotein I (β2-GPI), a protein whose physiological role is unknown. Although underestimated, platelets may be involved in APS and its thrombotic manifestations, especially arterial, in several ways. Thrombocytopenia is the most relevant non-criteria manifestation of APS, possibly caused by direct binding of anti-β2-GPI antibodies or anti-β2-GPI-β2-GPI complexes. On the other hand, platelets may have a key role in APS-related thrombosis due to the presence of multiple receptors that can interact with anti-β2-GPI antibodies (especially apolipoprotein E receptor 2' (apoER2') and glycoprotein Ibα (GPIbα)) with consequent release of different procoagulant mediators such as thromboxane B2, platelet factor 4 (PF4), and platelet factor 4 variant (CXCL4L1). The aim of this review is to put together evidence on the possible role of platelets in APS and to stimulate further research on the issue.
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.
Background
New oral anticoagulants may simplify long-term therapy in conditions requiring anticoagulation. Rivaroxaban is a direct factor Xa inhibitor that has been extensively studied and is now ...approved for the prevention and therapy of a number of thromboembolic conditions.
Objective and methods
This is a multicentre, randomized, open-label, study that will evaluate if Rivaroxaban 20 mg od (or 15 mg od in patients with moderate renal insufficiency) is non-inferior to warfarin (INR target 2.5), for the prevention of thromboembolic events, major bleeding and death in high risk (triple positive) patients with antiphospholipid syndrome. Secondary endpoints will assess the incidence of any individual component of the composite end point. An external adjudication committee will evaluate all suspected outcome events. This will be a unique trial, as it will enrol the biggest homogenous cohort of high risk APS individuals.
Conclusion
The methods and the study design should be appropriate to achieve study results that are both scientifically valid and relevant to clinical practice.
Whether antibodies directed to β2-Glycoprotein I (aβ2GPI) are responsible for LA activity is not well defined. However, in the absence of such antibodies the molecule responsible for LA phenomenon is ...unknown.
The aim of this study was the biochemical identification of the target antigen epitope of aPL responsible of LA activity in the absence of aβ2GPI antibodies together with the biological and clinical characteristics of these patients in comparison with classical triple positive patients.
A comparison of patients with LA without (LA+/aβ2GPI−) and those with (LA+/aβ2GPI+) associated aβ2GPI antibodies was performed. Size exclusion chromatography and analytical chromatography were used to identify the molecule with LA activity in patients LA+/aβ2GPI-.
Analytical size-exclusion chromatography revealed a peak of 996Kd with LA activity perfectly overlapping that of IgM anti phosphatidylserine/prothrombin (aPS/PT) antibodies. Similarly, all the 25 LA+/aβ2GPI− patients were positive for aPS/PT antibodies. LA+/aβ2GPI− compared to 33 LA+/aβ2GPI+ patients turned out to be significantly older, with a lower rate of previous thromboembolic events and a weaker LA activity. Search for aPS/PT and aβ2GPI antibodies in patients with LA is useful to identify two subgroups of LA at different risk of thromboembolic events.
•Isolated LA (LA+,aβ2GPI-) shows a peculiar pattern of antiphospholipid antibodies (aPS/PT usually of IgM isotype).•Isolated LA are older, at lower thrombotic risk, and have a weaker LA potency with respect to LA+/aβ2GPI+.•The distinction is useful in clinical practice when deciding the appropriate treatment.
Essentials The prevalence of thrombocytopenia in patients with antiphospholipid syndrome is not well defined. We studied triple positive patients with antiphospholipid syndrome and its catastrophic ...variant. Prevalence of thrombocytopenia was 6% and 100% in patients who developed the catastrophic form. In triple positive patients thrombocytopenia is low and platelets drop during the catastrophic form.
Background Thrombocytopenia is the most common non-criteria hematological feature in patients with antiphospholipid syndrome (APS). This condition is more common in patients with catastrophic APS (CAPS). Objectives To evaluate the prevalence of thrombocytopenia in a large series of high-risk patients with APS, and to assess the behavior of the platelet count during CAPS. Methods/Patients This was a cross-sectional study in which we analyzed the platelet counts of a homogeneous group of high-risk APS patients (triple-positive). Six of these patients developed a catastrophic phase of the disease, and the platelet count was recorded before the acute phase, during the acute phase, and at recovery. Results The mean platelet count in 119 high-risk triple-positive patients was 210 × 10
L
. With a cut-off value for thrombocytopenia of 100 × 10
L
, the prevalence of thrombocytopenia was 6% (seven patients). No difference between primary APS and secondary APS was found. In patients who suffered from CAPS, a significant decrease from the basal count (212 ± 51 × 10
L
) to that at the time of diagnosis (60 ± 33 × 10
L
) was observed. The platelet count became normal again at the time of complete remission (220 ± 57 × 10
L
). A decrease in platelet count always preceded the full clinical picture. Conclusions This study shows that, in high-risk APS patients, the prevalence of thrombocytopenia is low. A decrease in platelet count was observed in all of the patients who developed the catastrophic form of the disease. A decrease in platelet count in high-risk APS patients should be considered a warning signal for disease progression to CAPS.
Abstract Some previous observations suggest that a low platelet count is associated with an increased risk of adverse outcomes in patients with acute coronary syndromes (ACS). However, most of the ...data come from post-hoc analyses of randomized controlled trials and from studies including thrombocytopenia developed during hospital stay. Our aim was to assess the impact of low platelet count at admission on cardiovascular outcomes and treatment approach in patients hospitalized for ACS in a current real-life setting in Italy. Patients admitted to Italian coronary care units for ACS were enrolled in the START-ANTIPLATELET registry. Baseline clinical characteristics and treatment at discharge were recorded. Patients were followed-up at 6 months, 1 year and yearly thereafter. Low platelet count was defined as a count at admission < 150 > 100 k/µl or < 100 k/µL. Among 1894 enrolled patients, 157 (8.3%) had a platelet count < 150 > 100 k/µl and 30 (1.6%) < 100 k/µl. The median follow-up was 12.3 months (0.4–50.1). patients with low platelets were older (72 ± 10.4 vs 66 ± 12.4 years, p = 0.006), more frequently males (82.9 vs 72.1%, p = 0.001), hypertensive (90.0% vs 70.4%, p = 0.03), with non-valvular atrial fibrillation (NVAF) (17.1 vs 8.6%, p = 0.02), and peripheral arterial disease (11.5 vs 6.2% p = 0.01) and/or had a previous myocardial infarction (40 vs 18.7%, p = 0.008) and/or a PCI (14.6 vs 7.8%, p = 0.001) than patients with normal platelets. A slightly, but significantly, lower percentage of thrombocytopenic patients were treated with primary PCI (78.1 vs 84.4%, p = 0.04) and they were more frequently discharged on aspirin plus clopidogrel rather than aspirin plus newer P2Y 12 antagonists (51.9 vs 65.4%, p = 0.01). MACE-free survival was significantly shorter in thrombocytopenic patients compared to patients with normal platelets (< 150 > 100 k/µl: 37.6 vs 41.8 months, p = 0.002; HR = 2.7, 95% CIs 1.4–5.2; < 100 k/µl: 31.7 vs 41.8 months, p = 0.01; HR = 6.5, 95% CIs 1.5–29.1). At multivariate analysis, low platelet count, age at enrollment, low glomerular filtration rate, low ejection fraction, a previous ischemic stroke and NVAF were independent predictors of MACE. A low platelet count at admission identifies a subgroup of ACS patients with a significantly increased risk of MACE and these patients should be managed with special care to prevent excess adverse outcomes.
The revised classification criteria for the antiphospholipid syndrome state that antiphospholipid (aPL) antibodies (lupus anticoagulant LAC and/or anticardiolipin aCL and/or anti-β2 -glycoprotein I ...aβ2 GPI antibodies) should be detected on two or more occasions at least 12 weeks apart. Consequently, classification of patient risk and adequacy of treatment may be deferred by 3 months.
In order to early classify patient risk, we evaluated whether aPL positivity confirmation is related to aPL antibody profiles.
Consecutive patients referred to our center who were initially positive in one or more tests exploring the presence of aPL were tested after 3 months. During a 4-year period, 225 patients were initially positive in one or more tests, and 161 were available for confirmation after 3 months. Patients were classified as triple-positive (n = 54: LAC(+) , aCL(+) , aβ2 GPI(+) , same isotype), double-positive (n = 50: LAC(-) , aCL(+) , aβ2 GPI(+) , same isotype) and single-positive (n = 53: LAC or aCL or aβ2 GPI antibodies as the sole positive test).
Among subjects with triple positivity at initial testing, 98% (53 of 54) had their aPL profile confirmed after 12 weeks. The double-positive and single-positive groups had data confirmed in 42 of 50 (84%) and 23 of 57 (40%) subjects, respectively.
Our results show that high-risk subjects with triple-positive aPL profiles are identified early, at the time of the initial screening tests.
Platelet activation and decrease in platelet count characterize the development of the most feared form of antiphospholipid syndrome (APS), i.e. catastrophic APS (CAPS). We aimed to assess if ...immuno-affinity purified anti-β2-glycoprotein I (aβ2GPI) antibodies enhance platelet activation inducing a significant flow obstruction in a platelet function analyzer (PFA). Affinity purified aβ2GPI antibodies were obtained from 13 triple positive patients with a strong lupus anticoagulant (LA) and high titers of IgG anticardiolipin antibodies (aCL) and IgG aβ2GPI. Platelet activation stimulated by adenosine diphosphate (ADP) in the presence or absence of aβ2GPI was measured by the expression of P-selectin on platelet surface using flow cytometry. P-selectin expression remained close to baseline when normal whole blood was incubated with aβ2GPI alone. When stimulated using aβ2GPI combined with ADP, P-selectin expression (28.42 ± 5.15% vs. 20.98 ± 3.94%, p = 0.0076) was significantly higher than ADP alone. Closure time of normal whole blood passed through the PFA was significantly shorter using affinity purified aβ2GPI than control IgG both in Col/ADP (160.1 ± 62.1 s vs. 218.6 ± 43.8 s; p = 0.021) and Col/EPI cartridges (149.5 ± 26.7 s vs. 186.9 ± 45.5 s; p = 0.030). Thus, platelet activation is enhanced by aβ2GPI antibodies with a consequent premature closure in a PFA, possibly resembling that in microcirculation in patients with CAPS.
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