S. Padayattil Jose

Clinical course of high‐risk patients diagnosed with antiphospholipid syndrome

See also Galli M. The antiphospholipid triangle. This issue, pp 234–6.

Antiphospholipid syndrome: antibodies to Domain 1 of β2-glycoprotein 1 correctly classify patients at risk

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.

Correct laboratory approach to APS diagnosis and monitoring

Triple positivity (positive Lupus Anticoagulant, anticardiolipin and anti β2-glycoptrotein I antibodies) identifies the pathogenic autoantibody (anti Domain I of β2-glycoptroteinI) that is present in patients with definite Antiphospholipid Syndrome (APS). This is supported by the fact that aβ2GPI antibodies obtained by affinity purification in these patients possess LA activity. Moreover, patients and carriers of this profile carry a much higher risk of thrombosis and pregnancy loss than APS patients with positivity for only one of the tests. Thus, very different risk categories exist among patients with APS as well as among carriers of aPL. Clinical studies and interventional trials should first take these high risk subjects into consideration.

Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: Rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial:

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.

Confirmation of initial antiphospholipid antibody positivity depends on the antiphospholipid antibody profile

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 [aβ2GPI] 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.

Antibodies to Domain 4/5 (Dm4/5) of β2-Glycoprotein 1 (β2GP1) in different antiphospholipid (aPL) antibody profiles

BACKGROUND Determination of the three recommended tests for the diagnosis of antiphospholipid syndrome [Lupus Anticoagulant (LA), anticardiolipin (aCL) and anti β2-Glycoprotein 1 (aβ2GP1) antibodies] allow physicians to allocate patients into classification (risk) categories. OBJECTIVES To measure antibodies of IgG isotype directed towards Domain 4/5 (Dm4/5) of β2GP1. PATIENTS/METHODS In this cross-sectional study we measured IgG aβ2GP1-Dm4/5 in a group of individuals 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). RESULTS Geometric mean and standard deviation of IgG aβ2GP1 values expressed as Chemiluminescent Units (CU) in triple, double, single positive groups and in 40 healthy individuals were 1795±783, 321±181, 29±8 and 5.0±1.0, respectively (ANOVA p<0.0001). Geometric mean and standard deviation of IgG aβ2GP1-Dm4/5 expressed as Optical Density (OD) in triple, double and single positive groups and in 40 healthy individuals were 0.16±0.13, 0.16±0.15 and 0.26±0.15, 0.13±0,11, respectively (ANOVA p<0.002). Individuals in the single positive group, expressed significantly higher values with respect to triple (p=0.04) and double (p=0.03) positive groups. Approximate OD cut-off value (99° percentile) calculated in 40 normal control subjects is 0.404. Positivity to IgG aβ2GP1-Dm4/5 according to this cutoff was found in only 5 individuals, 3 in triple positive and 2 in single positive groups and was not associated with thromboembolism. CONCLUSION Mean level of IgG aβ2GP1-Dm4/5 is higher in single positive group. There is no association between positivity to IgG aβ2GP1-Dm4/5 and thromboembolic events.

Antiphospholipid syndrome: critical analysis of the diagnostic path.

Antiphospholipid syndrome (APS) is diagnosed in the presence of vascular thrombosis or pregnancy morbidity occurring in patients with circulating antiphospholipid antibodies (lupus anticoagulant [LA] and/or IgG/IgM anticardiolipin [aCL] and/or IgG/IgM anti-β2glycoprotein I [aβ2GPI] antibodies). Each test may identify different autoantibodies; a single test makes the diagnosis possible when positive on two or more occasions at least 12 weeks apart. However, single test positivity may be unrelated to pathogenic antibodies, which are now considered to be a subclass of aβ2GPI antibodies directed against the domain I of this protein. Conversely, all three positive tests identify a single class of aβ2GPI antibodies, thus identifying high-risk patients with APS.

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.

APS - Diagnostics and challenges for the future.

Diagnosis of antiphospholipid syndrome (APS) is essentially based on the detection of circulating antiphospholipid (aPL) antibodies. Progress have been made on the standardization of tests exploring the presence of aPL as guidelines on coagulation and immunological tests were recently published in the literature. Clinical relevance of aPL profile has come from prospective cohort studies in populations with a homogeneous antibody profile supporting the view that triple positivity is a high risk pattern in patients and carriers. In addition to the classic ones, several other tests have been proposed for the diagnosis of APS. The detection of antibodies directed to domain 1 and 4/5 of β2-Glycoprotein I (β2GP1) were found to be particularly sound. Several issues remain to be addressed. We do not yet know what is the physiological function of β2GP1 and the pathophysiology of thrombosis and pregnancy loss in these patients. Moreover, treatment is poorly defined especially in the case of feared catastrophic APS.

Laboratory testing for antiphospholipid syndrome

This is a practical report on laboratory tests for the diagnosis of antiphospholipid syndrome (APS). After a general definition of APS, this study deals with appropriateness and timing in requesting the determination of antiphospholipid (aPL) antibodies. Lupus anticoagulant (LAC), anticardiolipin (aCL), and anti β2‐glycoprotein I (aβGPI) are the mandatory tests to be performed, while other tests are not yet validated for clinical use. Interpretation of results is an important discussed issue that implies a close liaison between clinical pathologists and clinicians. Finally, a personal definition of APS according to aPL antibody profile closes the manuscript.