Coagulation Education: Treatment Options for Antiphospholipid Syndrome

EULAR 2024 (VIENNA)—Antiphospholipid syndrome (APS) has long been recognized as a cause of thrombosis and obstetric complications, but only recently have the microvascular and non-thrombotic manifestations of the disease received greater attention. In a sweeping session at EULAR 2024 titled, How to Treat: Antiphospholipid Syndrome, Maria Tektonidou, MD, PhD, professor of rheumatology, head of the Rheumatology Unit, National and Kapodistrian University of Athens, Greece, provided current insight into patient risk profiles, co-morbidities of and future treatment directions for APS.

Complications

Dr. Tektonidou began by noting that APS is notoriously complex and hard to treat. It’s a rare condition, with a paucity of randomized clinical trials. It also has multiple subtypes, including obstetric and thrombotic types.

Obstetric APS

Women with obstetric APS may experience significant morbidity during pregnancy. Specifically, they risk eclampsia, thrombosis, miscarriage and intrauterine growth restriction. Methods of monitoring these complications include screening for hypertension and proteinuria in the mother and Doppler ultrasonography of the umbilical/uterine artery for the fetus. And recent guidelines recommend more proactive measures.

According to the 2019 EULAR Recommendations for the Management of APS in Adults, women with a history of obstetric APS should be treated on the basis of their clinical history. Low-dose aspirin plus prophylactic-dose heparin (i.e., 5,000 units given subcutaneously every 8–12 hours) is recommended for patients who have experienced three or more spontaneous abortions before the 10th week of gestation or a fetal loss at 10 weeks or more. Patients with a delivery before 34 weeks of gestation due to eclampsia, severe pre-eclampsia or placental insufficiency, low-dose aspirin alone or with prophylactic-dose heparin is recommended based on the individual’s risk profile. For patients with an indication for prophylactic-dose heparin during pregnancy, clinicians should consider continuing heparin treatment for six weeks after delivery to reduce the risk of maternal thrombosis.¹

 Dr. Tektonidou explained that in patients with recurrent pregnancy complications despite these interventions, therapeutic-dose heparin, hydroxychloroquine and low-dose prednisone (the latter in the first trimester) can be considered. It should be noted that the ACR also has published a guideline for clinician decisions in these situations. For example, a conditional recommendation in the ACR guideline is to treat pregnant patients with daily, low-dose aspirin beginning in the first trimester to prevent or delay the onset of gestational hypertensive disease.²

Thrombotic APS

In patients with thrombotic APS, secondary thromboprophylaxis strategies depend a great deal on if the prior clot was provoked (i.e., incited by surgery, trauma, etc.) or unprokoved (i.e., with no clear inciting event) and if it was venous or arterial.

In patients with a history of venous thrombosis and APS, vitamin K antagonist therapy with an international normalized ratio (INR) goal of 2–3 is recommended. If the clot was unprovoked, then long-term therapy is indicated. In a patient with arterial thrombosis and APS, vitamin K antagonist therapy with an INR goal of 2–3 or 3–4 is recommended depending on thrombosis and bleeding risk of the patient. Alternatively, vitamin K antagonist therapy with an INR goal of 2–3 plus low-dose aspirin can be considered for these patients.¹

Dr. Tektonidou noted the advent of direct oral anticoagulants has resulted in a desire to see if these agents can be used in patients with APS instead of vitamin K antagonist therapy. Therapy with vitamin K antagonist is challenging, requiring frequent blood tests and significant food restrictions. The therapy also has the potential for significant drug interactions. Despite the intellectual appeal of using direct oral anticoagulants for the treatment of thrombotic APS, evidence indicates it is inappropriate for most patients.

The Trial on Rivaroxaban in Antiphospholipid Syndrome (TRAPS) study was conducted in patients with high-risk APS, defined on the basis of the patients’ clinical history and triple positivity of lupus anticoagulant, anti-cardiolipin antibodies and anti-beta-2 glycoprotein antibodies. The study’s 120 patients were randomized to receive rivaroxaban or warfarin. Researchers followed these patients over time and evaluated prevention of thrombosis, major bleeding or vascular mortality as the study’s primary end point. Before the study concluded, the trial was stopped prematurely by the adjudication and safety committee due to an excess of events in the rivaroxaban group.³

In 2019, the European Medicines Agency advised direct oral anticoagulants not be used for patients with a history of thrombosis and APS, particularly for those with triple-positive disease.⁴

Dr. Tektonidou indicated that additional studies, such as ASTRO-APS, have shown that direct oral anticoagulants should be avoided even in patients at low risk of APS, such as those with one or two positive antiphospholipid antibodies and a lower risk clinical history.⁵

Clinical Pearls

When a patient experiences recurrent thrombotic events despite appropriate anticoagulation, said Dr. Tektonidou, consider the possibility of medication non-compliance before making medication adjustments. If necessary, such adjustments may include increasing the INR goal, adding low-dose aspirin or switching from a vitamin K antagonist to low molecular weight heparin.

Clinicians should be aware that patients with APS have an increased prevalence of traditional cardiovascular risk factors, metabolic syndrome and subclinical atherosclerosis than the general population. Research by Dr. Tektonidou et al. has shown that we are doing worse at achieving traditional cardiovascular risk factor targets in patients with APS—especially those with high/very high risk disease—than in patients with rheumatoid arthritis and diabetes mellitus.⁶ Hypertension, obesity and hyperlipidemia are all co-morbidities that clinicians must pay attention to in patients with APS, especially in individuals with concomitant systemic lupus erythematosus for whom atherosclerosis progression is already greater than that of the general population.

Conclusion

In the concluding section of his talk, Dr. Tektonidou noted that the new ACR/EULAR APS Classification Criteria address systemic manifestations of APS, including cardiac (e.g., valvular thickening and vegetations), hematologic (e.g., thrombocytopenia) and microvascular (e.g., livedoid vasculopathy, aPL nephropathy, pulmonary hemorrhage and myocardial disease) complications.⁷ With the recognition of these APS manifestations and the immunopathology that seems to underlie them, interest in the use of such treatments as rituximab, belimumab, daratumumab, eculizumab and sirolimus has been sparked.

Finally, Dr. Tektonidou highlighted a 2019 case report showing that chimeric antigen receptor T cell therapy may prove efficacious for the treatment of APS, and more exciting work is being done in this field in the U.S.^8,9

Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.

References

1. Tektonidou MG, Andreoli L, Limper M, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019 Oct;78(10):1296–1304.
2. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology Guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. 2020 Apr;72(4):529–556.
3. Pengo V, Hoxha A, Andreoli L, et al. Trial of rivaroxaban in antiphospholipid syndrome (TRAPS): Two-year outcomes after the study closure. J Thromb Haemost. 2021 Feb;19(2):531–535.
4. PRAC recommendations on signals. European Medicines Agency. 2019 May 6.
5. Woller SC, Stevens SM, Kaplan D, et al. Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: A randomized trial. Blood Adv. 2022 Mar 22;6(6):1661–1670.
6. Bolla E, Tentolouris N, Sfikakis PP, et al. Cardiovascular risk management in antiphospholipid syndrome: Trends over time and comparison with rheumatoid arthritis and diabetes mellitus. Lupus Sci Med. 2021 Dec;8(1):e000579.
7. Barbhaiya M, Zuily S, Naden R, et al. 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Arthritis Rheumatol. 2023 Oct;75(10):1687–1702.