Why Antiphospholipid Antibody Syndrome Should Be On Your Radar

In April 2007, Graham R.V. Hughes, MD, wrote an article in The Rheumatologist titled, “Put Hughes Syndrome on Your Radar,” about this fascinating, relatively new disease called antiphospholipid syndrome (APS) that he had described some three decades earlier with Aziz Gharavi, MD, and E. Nigel Harris, MPhil, MD, DM.¹ As clinical manifestations of APS increasingly are uncovered, every specialty in medicine must put this disease on its radar.

In the original description of APS, it was observed that, among patients suffering from systemic lupus erythematosus (SLE), there was an association between the presence of circulating antiphospholipid antibodies (aPLs) and thrombosis, pregnancy loss, and thrombocytopenia.² Several years later, it became clear that APS can occur in the absence of an underlying systemic autoimmune disease (primary APS).^3,4

Clinical Manifestations

A long list of clinical manifestations has been reported in APS affecting all organs, though some manifestations are less evident than others and require a high index of suspicion in order to make the diagnosis of APS.⁵

The manifestations of APS can be summarized by the presence of thrombotic events, pregnancy morbidity, and the detection of circulating aPLs. Both arterial and venous thrombosis can occur in APS. These can present with recurrent deep vein thrombosis; thrombosis of the internal organ vasculature such as the kidney, liver, lung, or brain; stroke or transient ischemic attacks; limb ischemia; or infarction of internal organs.⁶ The pregnancy morbidity is defined by either unexplainable death of a healthy fetus after 10 weeks’ gestation, premature birth of a healthy baby before 34 weeks’ gestation, or three or more consecutive unexplainable miscarriages before 10 weeks’ gestation.⁶

Some clinical manifestations are of particular interest, such as livedo reticularis. This is not only an important marker for APS, but is considered a risk factor for arterial thrombosis.⁷

Diffuse small-vessel thrombosis in multiple organ systems is a manifestation of catastrophic antiphospholipid syndrome, which is characterized by multi-organ failure and a mortality rate exceeding 50%.⁸

Classification Criteria

Several criteria for the classification of APS have been developed in parallel with a better understanding of its pathogenesis. The last revision of the APS criteria requires the patient to meet at least one clinical criterion and one laboratory criterion.

The clinical manifestations focused on vascular thrombosis and obstetric complications, while the lab criteria required the presence of either lupus anticoagulant (LAC), anticardiolipin (aCL), or anti–β2 glycoprotein–I antibodies (anti-β2GPI) on two occasions 12 weeks apart.⁹

Seronegative APS

Seronegative APS was first described in 2003. This group consisted of patients with typical clinical manifestations of APS, including arterial thrombosis, thrombocytopenia, heart valve lesions, and recurrent pregnancy loss, but with negative tests for LAC, aCL, and anti-β2GPI antibodies.^10,11 Ongoing research has revealed the existence of other lipid-binding antibodies, including those targeting phosphatidylethanolamine, phospholipid-binding plasma proteins, phospholipid-protein complexes, and anionic phospholipids other than cardiolipin, which may induce thrombosis.¹² The clinical relevance of these “non-criteria” is being debated. Their relevance will need confirmation by larger longitudinal studies.

Pathogenesis of APS

Multiple pathways are implicated in the pathogenesis and thrombus formation in APS, including cellular effects (on platelet membranes, endothelial cells, and monocytes), plasma coagulation regulatory proteins (clotting components such as prothrombin, protein C, and protein S), and fibrinolysis.¹³

A two-hit hypothesis may explain thrombosis in APS: aPLs (first hit) increase the risk of thrombotic events that occur in the presence of another thrombophilic condition (second hit). According to this model, the initiating “first hit” injury disrupts the endothelium and the “second hit” potentiates thrombus formation.¹⁴

Antiphospholipid Antibodies

Anti-β2GPI antibodies are considered the most clinically significant of the aPLs since several studies have shown that aPLs are strongly associated with thrombosis.¹⁵

Domain I of β2GPI was shown to be an integral pathogenic component of this protein. The interaction of β2GPI with phospholipids induces major conformational change in this protein, which exposes hidden epitopes within domain I. Anti-β2GPI with specificity to domain I (anti–Dm1) increases susceptibility to thrombosis, and high titers are present in patients who have all three aPLs.¹⁶ Triple antibody positivity has been associated with a high risk of thrombosis and pregnancy morbidity.¹⁷

Otomo et al recently formulated the antiphospholipid score, to quantify the risk of thrombosis/obstetric events in a cohort of patients with various autoimmune diseases.¹⁸ Five clotting assays for LAC and six enzyme-linked immunosorbent assays (ELISA)—IgG/IgM aCL, IgG/IgM β2GPI, and IgG/IgM phosphatidylserine-dependent antiprothrombin (aPS/PT) antibodies—were included. The authors concluded that combining assays may compensate for the lack of standardization of single assays. High aPL scores (≥30) can provide a useful quantitative index for diagnosing APS and may serve as a predictive marker for thrombosis in autoimmune diseases.¹⁸

The Global APS Score (GAPSS) is another scoring system that provides substantial improvement in risk prediction of thrombosis and pregnancy loss. GAPSS is derived from the combination of independent risk for both thrombosis and loss of pregnancy. It combines the patient’s aPL profile, their conventional cardiovascular risk factors, their autoimmune antibody profile, and their use of thromboprophylactic drugs.¹⁷

Mechanisms of Pregnancy Loss

The mechanism of pregnancy loss associated with aPL remains uncertain. Thrombosis of the microvasculature of the placenta and subsequent infarction resulting in placental insufficiency, fetal growth restriction, and ultimately, fetal loss, represents a possible mechanism. Other potential mechanisms include complement activation leading to a defective placentation mediated directly by aPL and the disruption of the annexin A5 (AnxA5), which is a potent vascular and placental anticoagulant protein.¹³ A decrease in AnxA5 has been shown in aPL-treated endothelial cells.^13,19

In a prospective study known as “Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus (PROMISSE),” researchers have examined 250 pregnant patients with SLE and/or aPL and found that LAC is the primary predictor of adverse pregnancy outcome after 12 weeks’ gestation in aPL-associated pregnancies. If the LAC was not present, aCL and anti-β2GPI alone did not predict adverse pregnancy outcome.^20,21

In a recent multicenter, population-based case–control study of 582 stillbirths and 1,547 live births, Silver et al found that elevated levels of aCL and anti-β2GPI antibodies were associated with an approximate threefold to fivefold increased odds of stillbirth. The authors suggested consideration of testing for aPLs in cases of otherwise unexplained stillbirth.²²

APS ACTION

Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) is the first international research network created specifically to design and conduct large-scale, multi-center clinical trials in persistently aPL-positive patients. The network has launched two important collaborative international projects. The first is a randomized controlled trial of hydroxychloroquine in the primary thrombosis prevention of persistently aPL-positive, thrombosis-free patients without systemic autoimmune diseases. The second is a web-based registry of aPL-positive patients with or without systemic autoimmune diseases, which will also include annual blood collection for aPL testing and future basic science studies.²³

Treatment

It is not surprising that management of aPL-positive patients focuses on anticoagulation and antithrombotic therapies. However, due to the low prevalence of the disease, randomized controlled trials have faced limitations in recruiting sufficient participants to represent the wide spectrum of the disease and thus empower the study design. As a consequence, much of the evidence-based practice in the management of APS has relied on the methodologically weaker observational studies. This has led to controversy and debate regarding what the best practices should be. Recent consensus recommendations have been published for the prevention and long-term management of thrombosis in aPL-positive patients.^6,17

Anticoagulation with warfarin forms the cornerstone of conventional therapy in aPL-induced thrombosis. It is agreed that therapy should be indefinite, with a target internationalized normal ratio (INR) of 2.0–3.0.²⁴ Patients with arterial thrombosis should be managed with either combined anticoagulant antiaggregant therapy, such as aspirin (INR 2.0–3.0), or treatment with warfarin alone (INR > 3.0). The patient’s bleeding risk should be evaluated carefully before commencing anticoagulant therapy.¹⁷

Prevention of Pregnancy Loss

With proper management, including preconceptional counseling and pharmacological treatment, more than 75% of pregnant women with aPLs will deliver a viable, healthy infant. However, pregnancy should be carefully planned. Women with either severe pulmonary hypertension or those who have suffered a recent thrombotic event, particularly stroke, should be discouraged from conceiving.²⁵

Recurrent early (pre-embryonic or embryonic) miscarriage: Despite the general recommendation of combined therapy with aspirin and heparin for all women with obstetric APS, data from observational studies in this subgroup of women have reported 79% to 100% pregnancy success rates with low-dose aspirin.²⁵ Therefore, the option of monotherapy with aspirin may be a valid option in selected cases within the subgroup of women with recurrent early miscarriages.

Fetal death (>10 weeks’ gestation) or prior early delivery (<34 weeks’ gestation) due to severe pre-eclampsia or placental insufficiency: Combination therapy with aspirin and heparin in this category of patients is recommended. Aspirin is best started before conception, and then unfractionated heparin or low–molecular weight heparin (LMWH) can be given once pregnancy has been confirmed.²⁵

Antiphospholipid syndrome with thrombosis: In patients with APS who have suffered a previous thrombosis, low-dose aspirin and therapeutic dose heparin or LMWH at anticoagulant doses are recommended.²⁵ The change from warfarin to heparin should be achieved prior to six weeks’ gestation to avoid exposing the mother to the potential teratogenic effects of vitamin K-antagonists.

Postpartum period: Heparin should be continued intrapartum and postpartum until the patient is ready to start therapy with vitamin K-antagonists. Both warfarin and subcutaneous heparin are compatible with breastfeeding. Antithrombotic coverage of the postpartum period is also recommended in women with aPLs who have not had a previous thrombosis. Prophylactic-dose heparin or LMWH is recommended. The duration is variable, ranging from one to six weeks, and should be tailored according to the presence of additional risk factors.

Novel Oral Anticoagulants

The novel oral anticoagulants, dabigatran etexilate and rivaroxaban, are rapidly absorbed and have been shown to be effective in the management of venous thromboembolism. They may be considered as potential new therapies for the management of thrombosis in APS without the need for laboratory monitoring.^26,27 A clinical trial with rivaroxaban is currently underway to elucidate its safety and efficacy in the prevention of thrombosis in APS.²⁸

Statins

The recent consensus guidelines advocate the use of statins as adjuvant therapy. This rationale is based on their pleiotropic effects; in addition to lowering lipid levels, they also have antiinflammatory and antithrombotic effects.^17,29 For example, a recent study by Lopez-Pedrera et al revealed that fluvastatin modulates a chain of events involving the downregulation of tissue factors, adhesion molecules, and downstream signaling and transcription factors in monocytes.³⁰ This may attenuate the procoagulant state seen in APS.

Hydroxychloroquine

Hydroxychloroquine (HCQ) is an antimalarial drug commonly used in the management of SLE due to its antiinflammatory and antithrombogenic properties. The consensus guidelines recommend the use of HCQ as an alternative treatment modality in patients with recurrent APS.¹⁷

Rituximab

Rituximab is a CD-20 monoclonal antibody commonly used in the treatment of rheumatoid arthritis. In a recent uncontrolled and nonrandomized pilot study to evaluate the safety of rituximab in aPL-positive patients with non-criteria manifestations of APS, Erkan et al suggested that the safety of rituximab in aPL-positive patients is consistent with the general safety profile of this drug.³¹ Despite the lack of observing any substantial change in aPL profiles, rituximab may be effective in controlling some, but not all, non-criteria manifestations of APS.

Conclusion

Since its first description three decades ago, APS is now recognized as a common autoimmune disorder, linking immunology with thrombovascular disease. Ongoing research into the pathogenesis, diagnosis, and management of APS has significantly contributed to the understanding of this syndrome, and introduced the concept that some individuals with connective tissue diseases require anticoagulation, rather than steroids or antiinflammatory treatments.

Dr. Uthman is head of the division of rheumatology, faculty of medicine at American University of Beirut in Lebanon, and Dr. Khamashta is director of the Graham Hughes Lupus Research Laboratory in the division of women’s health at King’s College of London’s Rayne Institute in London.

References

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