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.
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.
Diagnosis of the antiphospholipid syndrome (APS) is difficult as a result of limited specificity of existing assays for detecting clinically relevant antiphospholipid antibodies. ...Anti-beta2-glycoprotein I (beta 2GPI) antibodies play a central role in the disease process of APS.
We have investigated the relation between antiphospholipid antibodies with specificity for domain I of beta 2GPI and thrombosis/pregnancy morbidity in an international multicenter study.
Four hundred and seventy-seven patients derived from nine different centres met the inclusion criterion of having anti-beta 2GPI antibodies in their plasma/serum. Clinical data and results of tests for lupus anticoagulant, anti-cardiolipin antibodies and anti-beta 2GPI antibodies were established at the different centres of inclusion. After being re-tested for the presence of IgG and/or IgM anti-beta 2GPI antibodies, the samples were tested for the presence of IgG-directed against domain I of beta 2GPI and results were correlated with the thrombotic and obstetric history.
Re-testing for the presence of anti-beta 2GPI antibodies resulted in inclusion of 442/477 patients. IgG class anti-domain I antibodies were present in plasma of 243/442 patients (55%). 201/243 (83%) had a history of thrombosis. This resulted in an odds ratio of 3.5 (2.3-5.4, 95% confidence interval) for thrombosis. Anti-domain I IgG antibodies were also significantly correlated with obstetric complications odds ratio: 2.4 (1.4-4.3, 95% confidence interval).
In this multicenter study, the detection of IgG antibodies that are directed against domain I of beta 2GPI proved to be more strongly associated with thrombosis and obstetric complications than those detected using the standard anti-beta 2GPI antibody assay.
Essentials
The risk of bleeding influences the duration of anticoagulation (AC) after venous thromboembolism.
We assessed the ACCP bleeding risk score in an inception‐cohort of patients receiving AC.
...53% were categorized at high‐risk, but their bleeding rate was low during long‐term AC.
ACCP score had low predictive value for bleeding.
Summary
Background
The American College of Chest Physicians (ACCP) guideline proposes a score to decide on extended anticoagulation after an unprovoked venous thromboembolism (VTE).
Methods
We investigated the ACCP score to predict bleeding risk in an inception cohort of 2263 patients on long‐term anticoagulation (1522 treated with vitamin K antagonists VKAs and the remaining with direct oral anticoagulants DOACs) belonging to the Italian START2 Register.
Results
More than half the patients were categorized as high risk; nevertheless, a higher proportion received anticoagulation for > 1 year compared with those in the low‐risk category. For 3130 years (median 12 interquartile range 6, 24 months), 48 bleeding outcomes occurred (1.53%/year) in the cohort (1.7%/year and 0.95%/year in high‐ and low‐risk categories, respectively). The c‐statistic of the ACCP score was 0.55 (0.48–0.63), 0.50 (0.42–0.58) and 0.56 (0.48–0.64) in low‐, moderate‐ and high‐risk categories, respectively. The bleeding incidence was higher during the first 90 days of treatment (3.0%/year) than afterwards (1.2%/year; relative risk (RR), 2.5 1.3–4.7), and similar among the three categories. The bleeding rate was not different during the initial 3 months of treatment in patients receiving VKAs or DOACs; it was, however, lower in the latter patients in the subsequent period (0.5%/year vs. 1.4%/year, respectively).
Conclusion
The bleeding rate during extended treatment was rather low in our patients. ACCP score had insufficiently predictive value for bleeding and cannot be used to guide decisions on extended treatment. New prediction tools for bleeding risk during anticoagulant treatments (including DOACs) are required.
Essentials Prothrombin and partial thromboplastin time (PT/PTT) measure direct oral anticoagulants (DOACs). PT, PTT and specific tests for DOACs were performed on patients treated for atrial ...fibrillation. Normal PT/PTT don't exclude DOAC activity and their prolongation doesn't confirm DOAC action. The use of PT or PTT to evaluate DOAC activity could cause dangerous misinterpretations.
Background Prothrombin time (PT) and activated partial thromboplastin time (APTT) have been proposed to measure the effect of oral anti-activated factor X (FXa) or anti-activated FII drugs, respectively. Aims To evaluate the relationships and responsiveness of PT and APTT versus direct oral anticoagulant (DOAC) concentrations measured with specific coagulation tests performed with different platforms in four Italian anticoagulation clinics. Methods Six hundred and thirty-five patients with atrial fibrillation participated in the study: 240 were receiving dabigatran, 264 were receiving rivaroxaban, and 131 were receiving apixaban. Blood was taken at trough and peak within the first month (15-25 days) of treatment. PT, APTT, diluted thrombin time (dTT) calibrated for dabigatran and anti-FXa calibrated for rivaroxaban or apixaban were determined. Results For dabigatran, the correlation between APTT and dTT ranged from r = 0.80 to r = 0.62. For rivaroxaban, the correlation between the anti-FXa assay and PT ranged from r = 0.91 to r = 0.73. For apixaban, the correlation between the anti-FXa assay and PT was lower than for the two other drugs (r = 0.81 to r = 0.54). Despite the above significant correlations, the responsiveness of PT or APTT was relatively poor. A discrepancy between global testing and DOAC plasma concentrations was shown in a considerable proportion of patients, depending on the platform and drug, with values ranging from 6% to 62%. Conclusions Overall, poor responsiveness of the screening tests to DOAC concentrations was observed. PT and APTT normal values cannot exclude DOAC anticoagulant activity, and PT or APTT prolongation is not always associated with DOAC anticoagulant effect as determined with specific tests.
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.
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