Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by production of antibodies – antiphospholipid antibodies (aPL) – that “attack” the person’s own body, resulting in blood clots and/or pregnancy complications. Antiphospholipid-antibody-positive patients also may develop other clinical problems. These may include:
Collectively, such symptoms are known as “non-criteria’’ manifestations of APS (that is, they are not part of the current APS Classification Criteria).
The management of aPL-positive patients should be individualized based on the patient’s aPL-related clinical manifestations and additional medical conditions, if any. Asymptomatic aPL-positive individuals (no history of blood clots, miscarriages or other problems listed above) do not require specific treatment; sometimes low-dose aspirin can be considered for patients with a high risk of cardiovascular disease (for instance, in aPL-positive patients with hypertension and diabetes). For the secondary prevention of thrombosis (blood clot), current guidelines suggest patients take an oral anticoagulation (blood thinner) with a target International Normalized Ratio (INR) of 2 to 3; some centers prefer adding low-dose aspirin or increasing the target INR to 3 to 4 in patients with arterial thrombosis.
The management of the aPL-positive patients with or without APS is currently insufficient due to the fact that non-criteria manifestations of APS – for instance kidney disease – do not respond to blood thinners, and a small percentage of APS patients continue to develop blood clots despite optimal anticoagulation. Moreover, many foods and medications can cause the INR level to increase or decrease in warfarin-receiving patients; and high (above the treatment range) INR levels increase the risk of bleeding.
Recent studies based on newly understood mechanisms suggest new treatments that target different areas of coagulation system (that is, medications that interfere with clotting factors) or inflammation pathway (that is, medications that interact with one’s immune system with the goal of decreasing or eliminating the production and effects of the aPL). Thus, it is likely that a potentially safer immunomodulatory approach will play a bigger role in the management of aPL-positive patients in the near future as our understanding of the molecular mechanisms of aPL-mediated blood clots grows.
The antimalarial drug hydroxychloroquine (Plaquenil®), statins (cholesterol-lowering agents), B cell (a type of white blood cell) inhibition, and complement inhibition have recently been studied systematically in aPL-positive patients. In addition, recent findings suggest that mechanistic target of rapamycin (mTOR) pathway activation plays a role in the blood vessel inner layer thickening in aPL-positive patients, which leads to blood clot formation in small blood vessels. (Sirolimus, also known as rapamycin, is a medication that blocks mTOR pathway activation, which is approved for other diseases.)
Hydroxychloroquine (Plaquenil) is an antimalarial medication, which is used to treat systemic lupus erythematosus (SLE, also known as lupus). Hydroxychloroquine has anti-inflammatory effects and also inhibits platelet clumping, which is a key step in blood clot formation. There is evidence to suggest this drug may help reduce the blood clotting effects of aPL in mice and also decrease the risk of blood clots in SLE patients. In order to understand the protective role of hydroxychloroquine in aPL-positive patients without other systemic autoimmune diseases (for instance, lupus) controlled studies are planned or undergoing. For the time being, hydroxychloroquine may be used as an adjunctive therapy (supportive treatment used together with the primary treatment) in APS patients with difficult-to-control aPL-related clinical problems.
Statins are typically used to lower cholesterol levels. There is emerging evidence that these medications have anti-inflammatory effects on various cells. Some studies in mice suggest that statins have antithrombotic effects due to decreasing clot size through interactions with the clotting cascade. Also, two completed studies on human subjects concluded that statins decrease blood-clotting-related biomarkers in aPL-positive patients. Currently, there is no definitive evidence that statins prevent clots in APS patients but they can be considered in difficult-to-treat APS patients. This class of medications should be avoided in pregnant patients as they can cause birth defects.
Rituximab (Rituxan) is an infusion medication that targets and inhibits B cells, which are responsible for making antibodies. Rituximab is approved for other autoimmune conditions (including rheumatoid arthritis and vasculitis); it has been used to treat immune-mediated anemia and thrombocytopenia in APS patients with anecdotal success. Preliminary small scale studies show that rituximab may have a role in difficult-to treat APS patients, possibly in those with hematologic and small vessel involvement. However, well-designed, controlled clinical trials are needed before recommending the routine use of this agent.
Complement proteins are a number of small proteins that work together to as part of the body’s innate immune system. Studies in mice have shown that activation of certain complement proteins seem to be implicated in pregnancy complications. Furthermore, mice genetically engineered to lack certain complement proteins were less likely to develop aPL-related complications. These findings have led to the hypothesis that medications that inhibit or block certain of these complement proteins may be therapeutic in APS. Clinical reports of complement inhibitor treatments described positive outcomes in severely ill aPL-positive patients, but ongoing and future clinical trials will determine the role of complement inhibition in APS patients.
The direct oral anticoagulants (DOAC) include:
Unlike warfarin, all of these agents:
Pending the results of the large-scale controlled clinical studies in APS patients, the role of DOACs in the management of APS patients is unknown; thus they are currently not recommended. The 15th International Congress on Antiphospholipid Antibodies Task Force on Treatment Trends recently concluded that “insufficient evidence exists to make recommendations at this time regarding DOAC use in APS.” The recent rivaroxoban in antiphospholipid syndrome (RAPS) study suggested that rivaroxaban might be useful in selected APS patients with single venous blood clots requiring standard-intensity anticoagulation; however, given that the main outcome measure of this study was a blood test to predict blood clot risk (but not the blood clot itself) the task force also concluded that “RAPS findings need to be confirmed with additional studies using clinical outcome measures.”
Nazanin Ahmadzadeh, MD
Academic Visitor, Hospital for Special Surgery
Yasaman Ahmadzadeh, MD
Academic Visitor, Hospital for Special Surgery