Not So Benign
Antiphospholipid Antibody Syndrome: Clots, Complement, and Catastrophe!

Antiphospholipid syndrome (APS) is a thromboinflammatory disorder characterized by thrombosis and/or recurrent fetal loss accompanied by persistently positive tests for antiphospholipid antibodies (aPL). APS is not uncommon, accounting for 10 to 15% of recurrent pregnancy losses,¹  and is the leading cause of stroke in patients under 45 years of age, accounting for 20% of strokes in this age group.²  In catastrophic APS (CAPS), rapidly developing, widespread thrombosis leads to ischemic organ failure, which has high morbidity and mortality.³ 

The estimated prevalence of APS is 40 to 50 cases in 100,000.⁴  Women are affected 3 to 5 times more frequently than men,⁵  and most patients are diagnosed before the age of 50 years.⁶  APS is common in people with systemic autoimmune disorders (secondary APS) and complicates over one-third of systemic lupus erythematosus cases.

Stroke and lower extremity deep vein thrombosis are the most common arterial and venous thrombotic events, respectively. However, thrombosis at unusual sites, such as the cerebral venous sinuses or splanchnic vasculature, should prompt testing for APS. Recurrent thrombosis can occur despite anticoagulation therapy.⁷  CAPS is the most severe form of thrombotic APS, in which macro- and micro-vascular thromboses develop in multiple (≥3) organs within a short time (<1 week) and small vessel thrombosis is seen on tissue biopsy. CAPS is frequently associated with a “trigger” such as infection, surgery, pregnancy, or changes in anticoagulation.

Recurrent pregnancy loss or premature birth due to severe preeclampsia or placental insufficiency are hallmarks of obstetric APS. Live birth rates are only around 70%, and rates of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) are also increased in those with obstetric APS.⁸ 

Some patients exhibit predominantly microvascular involvement, such as livedoid vasculopathy, diffuse alveolar hemorrhage, or antiphospholipid nephropathy. Other “non-criteria” manifestations include thrombocytopenia, livedo reticularis, skin ulcers, valvular disease, migraines, etc.^7,9 

The majority of aPL are directed not against phospholipids but against a variety of phospholipid binding proteins expressed on or bound to cellular membranes.¹⁰  These antibodies, particularly those directed against β2-glycoprotein-I (β2GPI), drive the pathogenesis of thrombosis and obstetric complications.¹¹  Multiple pathogenic downstream effects of aPL have been described, including the inhibition of natural anticoagulants and fibrinolysis and the potentiation of procoagulant mechanisms. Increasingly recognized as a thromboinflammatory disease, APS is characterized by activation of leukocytes (particularly monocytes and neutrophils), endothelium, and platelets that leads to prothrombotic and proinflammatory changes.¹²  Complement activation plays a critical role in aPL-associated pregnancy loss and thrombosis and can be observed in 90% of patients with CAPS. Further, 50% of patients with CAPS have mutations in complement genes, a frequency similar to that observed for atypical hemolytic uremic syndrome.¹³  The multiple-hit hypothesis argues that aPL lead to a generalized prothrombotic state and that an environmental second-hit may be required to trigger thrombosis or CAPS.¹⁴ 

Updated in 2006, the Sapporo classification criteria for APS require both objectively confirmed thrombosis or pregnancy morbidity (Table 1) and persistently positive results for lupus anticoagulant (LA), anti-β2GPI, and/or anti-cardiolipin IgM or IgG antibodies.¹⁵  The clinical significance of IgA aPL or “non-criteria” aPL directed against phospholipid binding proteins such as prothrombin, phosphatidylserine, and phosphatidylethanolamine remains controversial, and these assays are not routinely performed in clinical practice.

Clinical severity in APS varies widely, ranging from asymptomatic carrier status to single/recurrent thrombosis to CAPS. Persistent LA is the strongest isolated predictor of thrombotic and obstetric complications.¹⁶  IgG anti-β2GPI and anti-cardiolipin antibodies are more strongly associated with thrombosis than IgM antibodies.¹¹  Triple positivity (positivity for LA, anticardiolipin, and anti-β2GPI antibodies) is associated with the highest risk for first or recurrent thrombosis.¹⁷  However, the aPL profile does not identify patients who are at risk of developing CAPS or anticoagulant-refractory thrombosis or, conversely, patients who have minimal ongoing thrombosis risk and may safely discontinue anticoagulation. Further, not all patients with aPL develop thrombosis; even triple-positive patients experience initial thrombosis at a rate of only 5.3% per year.¹⁷ 

Indefinite anticoagulation with a vitamin K antagonist (warfarin) with a target international normalized ratio (INR) of 2 to 3 remains the standard of care for thrombotic APS.¹⁸  For arterial thrombosis, antiplatelet therapy (aspirin) is commonly added to warfarin.¹⁹  Direct oral anticoagulants (DOACs) are not recommended for thrombotic APS: Recent trials in both high-risk (triple positive APS) and unselected thrombotic APS populations have demonstrated increased rates of recurrent thrombosis (particularly arterial thrombosis) among patients taking rivaroxaban or apixaban when compared with those observed among patients taking warfarin.^20,21  However, these trials were not enriched for patients with lower-risk APS (e.g., single-positive APS). DOACs may still be considered for some patients with lower-risk APS without arterial thrombosis or recurrent events, those who are either unwilling or unable to undergo appropriate INR monitoring, and those who are already on stable anticoagulation with a DOAC.²²  Recurrent thrombosis on therapeutic warfarin may be treated by adding antiplatelet therapy, escalating the intensity of warfarin (INR >3), or switching to low-molecular-weight heparin (LMWH). During pregnancy, patients with APS are treated with prophylactic doses of LMWH in combination with low-dose aspirin; therapeutic doses of LMWH are substituted in those with a history of thrombosis.²³ 

For CAPS, firstline “triple therapy” that includes a combination of anticoagulation, high-dose corticosteroids, and plasmapheresis or intravenous immunoglobulin is the standard of care.²⁴  In a series of 471 patients, triple therapy was associated with a lower rate of mortality (28.6%) than other combination therapies (41.1%).²⁵  Rituximab is sometimes used as adjuvant treatment, especially when cases are refractory to firstline therapy.²⁶  Recent mechanistic insights support a role of complement inhibition in CAPS and anticoagulant-refractory thrombotic APS. Real-world evidence suggests that terminal complement inhibition with eculizumab is effective in a subset of CAPS cases and may be most appropriate for patients with thrombocytopenia and features of thrombotic microangiopathy.^27,28  Additional research is needed to identify patients who will benefit from these targeted therapies.

APS is a thromboinflammatory disorder with pleomorphic disease manifestations, ranging from asymptomatic carrier status to rapidly progressive multiorgan thrombosis with high mortality. The majority of patients do well on vitamin K antagonists, but there is a pressing need to improve risk stratification tools to guide personalized therapy and for clinical trials designed to investigate novel targeted approaches, such as complement inhibition for the more severe forms of APS.

Dr. Chaturvedi has received honoraria for participation on advisory boards or received consulting fees from Alexion, Sanofi, UCB, Sobi, and Takeda, and has received honoraria/royalties from UpToDate.com and Dynamed.com. Dr. Gerber has served on advisory boards for Apellis Pharmaceuticals and Alexion Pharmaceuticals and contributed to the Merck Manual, for which she received an honorarium. Dr. Gerber's spouse is an employee of Pfizer and holds stock.