Antiphospholipid syndrome
Across the Table on Antiphospholipid Syndrome
The antiphospholipid syndrome (APS) is a common disorder affecting patients with and without autoimmune disease. Despite wider recognition of APS among physicians as well as the expanding research collaborations, many clinical questions are still encountered in clinical practice, which require further evidence-based studies.
In this “Across the Table” edition, Jack Cush, MD, and Doruk Erkan, MD, MPH,discuss some of these APS-related questions, and Erkan offers his approach to diagnosis and management.
Cush: What are the pitfalls in testing for antiphospholipid syndrome?
Erkan: The major pitfall in testing antiphospholipid antibody (aPL) is the interpretation of the results. As you know, the most commonly used tests to detect aPL are the lupus anticoagulant [LA] coagulation assay, anticardiolipin antibody (aCL) enzyme-linked immunosorbent assay [ELISA], and anti-β2-glycoprotein-I antibody (aβ2GPI) ELISA. Given that not every positive aPL test is clinically significant, it is critical to determine whether patients have ‘clinically significant’ (rather than positive or negative) aPL profiles. The following points may help:
- Transient aPL positivity is common during infections. Thus documentation of persistent (at least 12 weeks apart) autoimmune aPL test is important.
- A positive LA test is a better predictor of aPL-related clinical events compared with other aPL tests. However, it is important to note that false-negative/positive results may occur in warfarin-, heparin-, or direct oral anticoagulant (DOAC) – receiving patients. Thus, the test should not be ordered in anticoagulated patients.
- Moderate to high titer aCL/aβ2GPI (≥40 U) correlates better with clinical events than do lower titers; IgG isotypes are more predictive than IgM isotype; and triple clinically significant aPL positivity (LA, aCL, and aβ2GPI) is more meaningful than single or double aPL.
- Clinical judgment is required when interpreting the significance of aPL tests if aCL or aβ2GPI IgG/IgM titers are in the lower range (20-40 U); only one aPL determination is available; and/or aCL or aβ2GPI IgA is the only positive ELISA test.
Cush: How extensive should antiphospholipid antibody (aPL) testing be? Should we order all possible aPL tests?
Erkan: We should order all the tests discussed above; moderate-to-high titer isolated IgA aCL or aβ2GPI positive patients with a negative LA test is extremely rare but possible. Recently, several additional aPL tests have been developed; their prognostic and clinical significance are still to be determined with additional clinical studies, and most of them are not commercially available. Among them, based on the conclusions of the 14th International Congress on aPL Laboratory Diagnostics Task Force, antiphosphatidylserine/prothrombin (aPS/PT) antibodies are the most promising, which may contribute to APS diagnosis and to risk stratification in aPL-positive patients. Thus, when APS is highly suspected in LA, aCL, and aβ2GPI negative patients, aPS/PT can be considered if available.
Cush: Of those diagnosed (clinically and serologically) with the antiphospholipid syndrome – who needs to be on lifelong anticoagulation?
Erkan: Antiphospholipid Syndrome patients with vascular events generally receive life-long anticoagulation, despite the lack of high-quality data on the risk of recurrence and optimal duration of anticoagulation. Given that at least 50% of thrombotic events in aPL-positive patients have recognizable triggers, the possibility of discontinuing anticoagulation in highly selected patients exists, especially when the triggers are eliminated. However, discontinuation of anticoagulation is a critical decision that requires careful assessment of comorbidities, triggers, and residual thrombosis as well as patient education. The 13th International Congress on aPL Treatment Task Force recommended that “in cases of first venous event, low-risk aPL profile, and a known transient precipitating factor, anticoagulation could be limited to 3–6 months.” Given the importance of this question, i.e., anticoagulation withdrawal in APS, the development of a multicenter clinical trial protocol to determine whether indefinite anticoagulation is appropriate for all APS patients, is in progress.
Cush: Is there a role of rivaroxaban or similar drugs in antiphospholipid syndrome?
Erkan: No, until further evidence is available, direct oral anticoagulants (DOACs), i.e., rivaroxaban, apixaban, edoxaban, or dabigatran are not recommended in APS patients requiring long-term anticoagulation. Firstly DOACs are not indicated in general population patients with arterial thrombosis and/or recurrent thrombosis on therapeutic anticoagulation. Secondly, a recent randomized controlled trial of warfarin versus rivaroxaban (RAPS Trial) demonstrated that rivaroxaban was inferior to warfarin (in this study, the primary outcome measure was percentage change in endogenous thrombin potential, not a clinical thrombotic event). The APS Treatment Trends Task Force of the 15th International Congress on aPL concluded that “insufficient evidence exists to make recommendations at this time regarding DOAC use in APS; the RAPS trial suggests that rivaroxaban might be useful in selected APS patients with single venous thromboembolism requiring standard-intensity anticoagulation; however, this needs to be confirmed with additional studies using clinical outcome measures”. Randomized controlled trials designed to determine the role of DOACs in the management of thrombotic APS patients are in progress.
Cush: Should hydroxychloroquine be used in all antiphospholipid antibody-positive patients?
Erkan: No, hydcroxychloroquine (HCQ) should not be used in all aPL-positive patients. Antithrombotic properties of HCQ have been established in experimental models; there are studies both in the general population and in aPL-positive/negative systemic lupus erythematosus patients suggesting that HCQ decreases the risk of thrombosis. However, well-designed controlled studies assessing the prophylactic role of HCQ against thrombosis in persistently aPL-positive patients without other systemic autoimmune diseases are still lacking. Thus, HCQ should be considered only in aPL-positive patients with lupus or lupus-like disease (primarily for non-aPL purposes), and in those with aPL-manifestations not responsive to the standard treatment.
Thrombotic Complications Still a Problem in APS
Events and related deaths persist in patients with antiphospholipid syndrome.
Morbidity and mortality are improving but remain high among patients with the systemic autoimmune condition known as antiphospholipid syndrome (APS), a large, prospective European study found.
Among 1,000 patients enrolled in the Europhospholipid project, 17% of patients developed thrombotic events during the years 1999 to 2004, as did 15% of patients during the years 2004 to 2009, according to Ricard Cervera, MD, PhD, of the University of Barcelona in Spain, and colleagues.
In addition, the standardized mortality ratio during the 10-year study was 1.8 (95% CI 1.5-2.1) compared with the general population, and the mean age at death was 59, the researchers reported in the June Annals of the Rheumatic Diseases.
“Therefore, it is imperative to increase the effort in determining the optimal prognostic markers and therapeutic measures to prevent these important complications of the APS,” they stated.
Among the clinical features of APS are stroke, transient ischemic attacks (TIA), deep vein thrombosis (DVT), and pulmonary embolism (PE), as well as obstetric complications including preeclampsia and early pregnancy loss. The condition also is associated with high titers of antiphospholipid antibodies and multiple other non-thrombotic manifestations such as seizures.
The syndrome can be primary or associated with another disease, usually systemic lupus erythematosus (SLE).
Little is known about how treatment has influenced the long-term outcomes of APS, with previous studies being small and of short duration.
Cervera and colleagues instituted the Euro-Phospholipid project in 1999 to chronicle the “real world” disease course of European patients with APS. Twenty participating centers each enrolled 50 consecutive patients who fulfilled the criteria for “definite APS.”
A total of 82% of the cohort was female, and almost all were white. Mean age at the time of enrollment was 42.
The syndrome was primary in 53%, associated with SLE in 36%, and associated with other conditions such as lupus-like syndrome in the remainder.
During the 10 years of follow-up, which were divided into two 5-year periods, 42% of patients were lost to follow-up.
Among the thrombotic events that occurred, strokes were seen in 5% of patients, TIA in 5%, DVT in 4%, and PE in 4%.
In contrast, during a median of 6 years’ follow-up before the study period, stroke had occurred in 20%, TIA in 11%, DVT in 39%, and PE in 14%.
A total of 16% of women became pregnant during the decade-long study, and 73% of the pregnancies were successful. That represented a significant improvement over baseline, when the rate of live births was only 48%.
The most frequent obstetric complication was fetal loss before 10 weeks in 17% of the pregnancies. Intrauterine growth restriction was seen in 26% and premature birth in 48%.
In comparing primary APS patients with SLE-related APS, the researchers found that the SLE subgroup more often had arthritis (21% versus 3%), hemolytic anemia (16% versus 2%), livedo reticularis (21% versus 7%), and myocardial infarction (4% versus 1%).
Most patients received antithrombotic treatment with aspirin or other antiplatelet agents. During the first 5 years of the study, 35% of patients were on low-dose anti-aggregant medications, as were 28% in the next 5 years.
Oral anticoagulants were being taken by 40% of patients during the first 5 years and by 37% during the second 5 years. In 62% of anticoagulant users, the target international normalized ratio (INR) was 2 to 3, and in 38% the target was 3 to 4.
In the second 5-year period, 25% of patients on antithrombotic therapy and 5% of those not on the treatment developed thrombosis, while 8% and 2%, respectively, developed an obstetric complication.
There were 61 major bleeding events during the 10-year follow-up among patients on antithrombotic medications, with 25% being cerebral, 16% being gastrointestinal, and 8% being intra-abdominal. Ten were fatal.
The most common causes of death were serious thrombotic events, with myocardial infarction, strokes, and PE accounting for 37%. Infection, primarily bacterial, was the cause in 27% and hemorrhage in 11%.
The probability of survival at 5 years was 94%, decreasing to 91% at 10 years.
The observation that arterial events continue to occur despite current treatment strategies suggests that “this particular group of patients may need a higher anticoagulation target (INR 3-4) as well as strict control of comorbidities and prothrombotic factors,” the investigators wrote.
“This long-term study provides updated information on APS morbidity and mortality characteristics. Patients with APS still develop significant morbidity and mortality despite current treatment (mainly oral anticoagulants and/or anti-aggregant agents),” Cervera and colleagues concluded.
Antiphospholipid syndrome
The antiphospholipid syndrome causes venous, arterial, and small-vessel thrombosis; pregnancy loss; and preterm delivery for patients with severe pre-eclampsia or placental insufficiency. Other clinical manifestations are cardiac valvular disease, renal thrombotic microangiopathy, thrombocytopenia, haemolytic anaemia, and cognitive impairment. Antiphospholipid antibodies promote activation of endothelial cells, monocytes, and platelets; and overproduction of tissue factor and thromboxane A2. Complement activation might have a central pathogenetic role. Of the different antiphospholipid antibodies, lupus anticoagulant is the strongest predictor of features related to antiphospholipid syndrome. Therapy of thrombosis is based on long-term oral anticoagulation and patients with arterial events should be treated aggressively. Primary thromboprophylaxis is recommended in patients with systemic lupus erythematosus and probably in purely obstetric antiphospholipid syndrome. Obstetric care is based on combined medical-obstetric high-risk management and treatment with aspirin and heparin. Hydroxychloroquine is a potential additional treatment for this syndrome. Possible future therapies for non-pregnant patients with antiphospholipid syndrome are statins, rituximab, and new anticoagulant drugs.
ARYAN'S BLOG 