Gentian Denas

Clinical course of high‐risk patients diagnosed with antiphospholipid syndrome

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

Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study

Persistent antiphospholipid (aPL) antibodies are occasionally found in subjects without prior history of thromboembolic events (TEs), raising the dilemma of whether to initiate or not a primary thromboprophylaxis. A first TE is considered rare in aPL carriers, but previous studies did not consider the aPL profile nor was the test positivity confirmed in a reference laboratory. In this study, 104 subjects with high-risk aPL profile (positive lupus anticoagulant, anticardiolipin, and anti-β(2)-glycoprotein I antibodies, triple positivity) confirmed in a reference laboratory, were followed up for a mean of 4.5 years. There were 25 first TEs (5.3% per year): the cumulative incidence after 10 years was 37.1% (95% confidence interval [CI], 19.9%-54.3%). On multivariate analysis, male sex (hazard ratio = 4.4; 95% CI, 1.5-13.1, P = .007) and risk factors for venous thromboembolism (hazard ratio = 3.3; 95% CI, 1.3-8.5, P = .01) were independent predictors for TEs. Aspirin did not significantly affect the incidence of TE. In conclusion, the occurrence of a first TE in carriers of high-risk aPL profile is considerable; it is more frequent among male subjects and in the presence of additional risk factors for venous TE. These data can help in the decision to initiate primary thromboprophylaxis in these subjects.

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.

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.

Antiphospholipid syndrome and the heart: A case series and literature review

Antiphospholipid syndrome is a rare autoimmune disease characterized by a high tendency of developing thrombotic events. It is diagnosed in the presence of specific laboratory criteria (positivity for lupus anticoagulant, and the presence of anticardiolipin and aβ2GPI antibodies) and clinical criteria such as thrombosis in any district (arterial or venous) and pregnancy morbidity. Being a multisystem disease, the heart is commonly affected by direct (autoimmune mediated action) or indirect (thrombosis) pathological mechanisms. Heart valve lesions are the most frequent manifestations; however, the haemodynamic significance is quite uncommon but when it occurs it may require surgery that further complicates the picture due to the high risk of thrombosis. Coronary arteries and myocardium are also affected leading to ischaemic heart disease and left ventricular dysfunction. Other findings include chronic thromboembolic pulmonary hypertension and accelerated atherosclerosis. The consequences of heart involvement may be significant in overt disease. The treatment of cardiac complications is challenging and requires an in-depth knowledge of the disease.

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.

What have we learned about antiphospholipid syndrome from patients and antiphospholipid carrier cohorts

Venous or arterial thrombosis or pregnancy morbidity in the presence of circulating antiphospholipid antibodies (aPL) define the antiphospholipid syndrome (APS). In terms of accepted APS criteria, aPL are detected by one coagulation test (lupus anticoagulant; LAC) and two immunoassays (anticardiolipin antibodies and anti-β2-glycoptrotein I antibodies). In patients with APS, a single positive test carries a much lower risk of thrombosis recurrence or new pregnancy loss than does multiple (or triple) positivity. The same holds true for aPL carriers, namely subjects with laboratory tests but without clinical criteria for APS. Thus, very different risk categories exist among patients with APS as well as in carriers of aPL. Triple positivity apparently identifies the pathogenic autoantibody (antidomain I-II of β2-glycoptrotein I); it is in this category of patients that trials on new therapeutic strategies should focus.

Incidence of a first thromboembolic event in carriers of isolated lupus anticoagulant

Among the so called antiphospholipid (aPL) antibodies Lupus Anticoagulant (LAC) is considered the strongest risk factor for thromboembolic events. In individuals without a previous thromboembolic event (carriers), LAC is a risk factor when associated with the presence of anticardiolipin (aCL) and aβ2-Glycoprotein I (aβ2GPI) antibodies. On the other hand, data on carriers of isolated LAC positivity are sparse and inconclusive. The aim of this study was to prospectively determine the incidence of thrombosis in a cohort of carriers of isolated LAC positivity. One-hundred seventy-nine carriers of LAC confirmed twelve weeks apart and in a reference laboratory were studied. During a total follow up of 552 person-years, there were seven thromboembolic events (1.3% person-y). All the seven patients had at least one adjunctive major risk factor for thrombosis. The cumulative incidence of thromboembolic events was 3.1% (95% CI 0.6-5.6) after 2years, and 5.9% (95% CI 1.2-10.6) after 5 and 10years. On a multivariate regression analysis considering age, sex, autoimmune disease, risk factors for arterial and venous thrombosis, use of aspirin, only age was found to be an independent predictor of thromboembolic events (HR=1.1, 95% CI 1.0-1.2, p=0.02). These data might be relevant in clinical practice and underline the importance of differentiating LAC carriers in terms of isolated positivity or positivity associated with the presence of antibodies to aCL and β2-glycoprotein I.