By Vojtech Novotny, MD, PhD
Bergen Stroke Research Group, Department of Neurology, Bergen, Norway
The first description of antiphospholipid syndrome (APS) is dated to 1983 following the discovery of lupus anticoagulant immunoglobulin and its relation to autoimmune disorders.1 APS represents an autoimmune condition characterized by a wide range of clinical manifestations. Besides various multi-organ and pregnancy complications, the APS also known as Hughes or sticky blood syndrome often leads to systemic thromboembolism, mainly deep venous thrombosis, and stroke.2
APS is accompanied by the presence of antiphospholipid antibodies (aPL), primarily lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-beta(2)-glycoprotein I (aB2GPI). The circulating antibodies induce endothelial dysfunction and interfere with the coagulation pathways by competing with coagulation factors. This leads to a procoagulant state, clot formation, and recurrent thromboembolic events. The pathophysiology is probably based on a “two-hit hypothesis” where the first hit represents the asymptomatic presence of aPL antibodies occurring in approx. 1-5% of the population. The second hit represents a stress condition (pregnancy, infection, etc.) triggering the pathologic state itself.2, 3
APS has up to five times higher prevalence among women. Symptom onset is usually between 30-40 years of age. APS-related stroke represents up to 20% of stroke events in patients under 45 years of age. In older patients, APS is less common, however, it is more prevalent in males, and stroke as a complication is more common.4, 5 APS-related nonbacterial thrombotic endocarditis (NBTE) may explain the embolic stroke mechanism. Platelet activation and endothelial dysfunction may lead to a hypercoagulable state in the affected vessel, thus local thrombosis.6
Clinical hints include female sex, age under 50 years, recurrent stroke, lack of traditional risk factors, presence of autoimmune connective tissue disorders, and family history of early-onset stroke. Besides brain and vessel imaging and more extensive laboratory testing, transesophageal echocardiography should be preferred over transthoracic echocardiography as it is more sensitive to unveil small valvular vegetations typical for nonbacterial thrombotic endocarditis (NBTE) occurring in approx. 80% of APS patients suffering stroke or TIA.7
As the APS varies in its phenotype and severity, an individual treatment approach is necessary. Primary prevention with antiplatelets therapy should be started only in patients with additional risk factors, including cardiovascular comorbidities, eventually high-risk APS profile.8 However, in stroke patients with positive aPL antibodies – not fulfilling diagnostic criteria for APS – a similar approach as in stroke patients with negative aPL is recommended. For patients who meet the criteria for APS, moderate-intensity anticoagulation (INR 2-3) is reasonable.9 High-intensity anticoagulation (INR >3.1) or heparinoids are often used in clinical practice if patients suffer a recurrent thromboembolic event despite moderate-intensity anticoagulation.8 Another approach may be moderate-intensity anticoagulation combined with antiplatelet which may, however, lead to higher bleeding risk.10 There are scarce data on the usage of direct oral anticoagulants (DOAC) in APS-related stroke. Embolization to multiple organs within a short time, so-called catastrophic APS, may rarely occur. Here, a high-dose steroid treatment, i.v. immunoglobulins or plasma exchange alongside intensive anticoagulation treatment is often indicated.11 Further monitoring of treatment response may be achieved by microemboli detection.12
In conclusion, a considerable part of young stroke cases is due to APS. This fact makes the APS an important etiology to consider in the diagnostic work-up, mainly in patients under 45 years of age. With increasing stroke prevalence worldwide, further research is therefore necessary to reduce permanent disability in the young stroke population.
- Hughes GRV. Thrombosis, Abortion, Cerebral Disease, and the Lupus Anticoagulant. Brit Med J 1983;287:1088-1089.
- Lim W. Antiphospholipid syndrome. Hematol-Am Soc Hemat 2013:675-680.
- Misita CP, Moll S. Antiphospholipid antibodies. Circulation 2005;112:E39-E44.
- Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome – Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum-Us 2002;46:1019-1027.
- Hughes GRV. Migraine, memory loss, and “multiple sclerosis”. Neurological features of the antiphospholipid (Hughes’) syndrome. Postgrad Med J 2003;79:81-83.
- Dokuni K, Matsumoto K, Tanaka H, Okita Y, Hirata K. A case of non-infective endocarditis accompanied by multiple cerebral infarctions and severe mitral regurgitation as initial presentation of primary antiphospholipid syndrome. Eur Heart J-Card Img 2015;16:572-572.
- 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;36:592-596.
- 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;20:206-218.
- Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke 2011;42:227-276.
- Panichpisal K, Rozner E, Levine SR. The Management of Stroke in Antiphospholipid Syndrome. Curr Rheumatol Rep 2012;14:99-106.
- Kazzaz NM, McCune WJ, Knight JS. Treatment of catastrophic antiphospholipid syndrome. Curr Opin Rheumatol 2016;28:218-227.
- Kargiotis O, Psychogios K, Safouris A, et al. The Role of Transcranial Doppler Monitoring in Patients with Multi-Territory Acute Embolic Strokes: A Review. J Neuroimaging 2019;29:309-322.
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