By Kateriine Orav, Department of Neurology, North Estonia Medical Centre, Tallinn, Estonia
Thrombophilias are hereditary or acquired conditions that predispose patients to thrombosis. Thrombophilia testing is commonly performed in patients with a cryptogenic ischemic stroke, especially in younger patients. Yet the association between ischemic stroke and many of these conditions, especially inherited disorders is uncertain and we have little knowledge about whether these conditions should affect management. Recently, Salehi Omran et al. have published a comprehensive review on thrombophilia testing after ischemic stroke which highlights current knowledge on this topic.1
While hereditary thrombophilias have mainly been associated with venous thrombosis, antiphospholipid syndrome (APS) is an acquired immune-mediated thrombophilia that is an established risk factor for arterial thrombosis including ischemic stroke.1 The revised Sapporo criteria define APS by thrombosis, pregnancy complications or both in patients with persistent antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies or anti-β2GPI antibodies) on two or more occasions at least 12 weeks apart.2 Infectious agents are the main triggers for the formation of antiphospholipid antibodies. Molecular mimicry and misfolding of glycoproteins have been described as possible mechanisms. However, a genetic predisposition or secondary triggers are necessary for these antibodies to become pathogenetic and cause thrombosis.3
The estimated annual incidence of APS is 2 new cases per 100,000 individuals and prevalence 50 cases per 100,000.4 Antiphospholipid antibodies also occur in 1-5% of the general population but usually in low titers.3 The prevalence of antiphospholipid antibodies among young stroke patients is about 17%.5 The main clinical manifestations of APS are thrombosis and obstetric complications including recurrent miscarriages (especially after the 10th gestation week), fetal deaths, preeclampsia and intrauterine growth restriction.5 Venous thrombosis is the most common manifestation of APS, but arterial thrombosis is also prevalent. Approximately 20% of individuals with APS may develop a stroke.6 The mechanism of stroke in APS can be thrombotic or cardioembolic.7 Mitral valve pathology is the most common cause of cardioembolic stroke in APS, mainly due to valvular lesions consisting of immune complex deposits (Libman-Sacks endocarditis).8 Some clinical clues that a patient with thrombosis may have antiphospholipid syndrome are livedo reticularis, signs of another systematic autoimmune disease, unexplained prolongation of aPTT and mild thrombocytopenia.5
Catastrophic APS is a rare and life threatening form of the disease. It is classified as definite if thrombosis affects three or more organs and develops within 7 days in a patient with persistently positive antiphospholipid antibodies.5 More than 50% of patients with catastrophic APS develop clots in brain vessels.3
The management of arterial thrombosis due to APS consists of indefinite anticoagulation therapy with vitamin K antagonists (VKA) or combined antiaggregant-anticoagulation therapy.9 Dual antithrombotic therapy is mainly reserved for patients with significant cardiovascular risk factors or recurrent thrombotic events.5 A recent meta-analysis concluded that direct oral anticoagulants compared with VKAs may be associated with an increased risk of stroke in patients with APS and high-dose VKA compared to standard-dose VKA did not seem to alter the thromboembolic risk but may increase the risk for bleeding.10 The ASTRO-APS and RISAPS studies are ongoing to evaluate apixaban and rivaroxaban for stroke prevention in APS patients. Management can also be guided by the risk profile of the patients’ antiphospholipid antibodies with positive lupus anticoagulants conferring the highest risk.5 Traditional cardiovascular risk factors add to the thrombotic risk associated with antiphospholipid antibodies, therefore these should also be addressed.5 Catastrophic APS is managed with anticoagulation, corticosteroids, plasma exchange and intravenous immunoglobulins.3
Acquired coagulopathies have gained some limelight during the COVID-19 pandemic. Coagulopathy has emerged as an important feature of the disease and there are overlaps with other acquired coagulopathies including catastrophic antiphospholipid syndrome. However, COVID-19 has specific clinical and laboratory features that do not meet the criteria of any other known coagulopathy.11 COVID-19 patients with prolonged aPTT have been found to have high rates of lupus anticoagulant present compared to historical controls with elevated aPTT.12 However, as with ischaemic stroke, testing of antiphospholipid antibodies can be unreliable in the setting of infection, thrombotic events and anticoagulation, therefore these results must be interpreted with caution.1 COVID-19 will surely increase our knowledge of acquired coagulopathies and it will be interesting to see if APS could be one of the possible mechanisms implicated in the hyperthrombotic state in COVID-19.13
- Salehi Omran S, Hartman A, Zakai NA, Navi BB. Thrombophilia Testing After Ischemic Stroke: Why, When, and What? Stroke. 2021;52(5):1874-1884.
- Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306.
- Schreiber K, Sciascia S, de Groot PG, et al. Antiphospholipid syndrome. Nat Rev Dis Primers. 2018;11;4:17103.
- Duarte-García A, Pham MM, Crowson CS, et al. The Epidemiology of Antiphospholipid Syndrome: A Population-Based Study. Arthritis Rheumatol. 2019;71(9):1545-1552.
- Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med. 2018;24;378(21):2010-2021.
- Cervera R, Boffa MC, Khamashta MA, Hughes GR. The Euro-Phospholipid project: epidemiology of the antiphospholipid syndrome in Europe. Lupus. 2009;18(10):889-93.
- Ricarte IF, Dutra LA, Abrantes FF, et al. Neurologic manifestations of antiphospholipid syndrome. Lupus. 2018;27(9):1404-1414.
- Erdogan D, Goren MT, Diz-Kucukkaya R, Inanc M. Assessment of cardiac structure and left atrial appendage functions in primary antiphospholipid syndrome: a transesophageal echocardiographic study. Stroke. 2005;36(3):592-6..
- Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus. 2011;20(2):206-18.
- Bala MM, Celinska-Lowenhoff M, Szot W, et al. Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome. Cochrane Database Syst Rev. 2017;10(10):CD012169.
- Merrill JT, Erkan D, Winakur J, James JA. Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications. Nat Rev Rheumatol. 2020;16(10):581-589.
- Bowles L, Platton S, Yartey N, et al. Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19. N Engl J Med. 2020;16;383(3):288-290.
- Hanff TC, Mohareb AM, Giri J, et al. Thrombosis in COVID-19. Am J Hematol. 2020;95(12):1578-1589.