Current concepts in the diagnosis and management of antiphospholipid syndrome and ocular manifestations
Journal of Ophthalmic Inflammation and Infection volume 11, Article number: 11 (2021)
Antiphospholipid syndrome (APS) is an autoimmune disorder associated with obstetrical complications, thrombotic complications involving both arteries and veins, and non-thrombotic manifestations affecting multiple other systems presenting in various clinical forms. Diagnosis requires the presence of antiphospholipid antibodies. The exact pathogenesis of APS is not fully known. However, it has recently been shown that activation of different types of cells by antiphospholipid antibodies plays an important role in thrombosis formation. Ocular involvement is one of the important clinical manifestations of APS and can vary in presentations. Therefore, as an ophthalmologist, it is crucial to be familiar with the ocular findings of APS to prevent further complications that can develop. Furthermore, the ongoing identification of new and specific factors contributing to the pathogenesis of APS may provide new therapeutic options in the management of the disease in the future.
Antiphospholipid syndrome (APS) is a systemic autoimmune condition characterized by vascular thrombosis involving both arteries and veins, fetal losses, and thrombocytopenia in the presence of antiphospholipid antibodies (aPL) including lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL), and anti-β2 glycoprotein-I (anti-β2GPI) [1, 2].
Antiphospholipid syndrome can be divided into two forms: primary and secondary. Patients with no clinical or laboratory evidence of any other associated systemic disease are defined as having primary APS. Secondary APS is defined as the patient having other comorbid conditions, most commonly systemic lupus erythematosus (SLE). Association with other autoimmune diseases, drug reactions, infections, and malignancies are also under the classification of secondary APS [1, 3].
Clinical manifestations of APS fall under a wide spectrum including asymptomatic carrier patients with aPL positivity, classical APS with vascular thrombosis and/or fetal losses, aPL positivity without thrombotic APS findings (i.e., thrombocytopenia, hemolytic anemia, livedo reticularis, and seizures), or catastrophic APS characterized by multi-organ failure due to multiple microthrombosis [1, 4, 5].
Antiphospholipid syndrome typically affects young to middle-aged adults, most commonly between the ages of 15 and 50. Both primary and secondary APS are more common in women than men in about a 1:3.5 male-to-female ratio for primary APS and 1:7 for secondary APS associated with SLE . The estimated incidence of APS is around 5 new cases per 100,000 persons per year, with a prevalence of around 40–50 cases per 100,000 persons . APL positivity was reported as 13.5% for stroke, 11% for myocardial infarction, 9.5% with deep venous thrombosis, and 6% in pregnancy mortality .
Ocular findings are seen in 15–88% of patients with primary APS . Taking into account the higher frequency of ocular findings of APS, regular consult with an ophthalmologist may be able to detect early signs leading to a diagnosis of APS and may prevent life-threatening conditions associated with systemic thrombosis.
A diagnosis of APS is based on the revised Sapporo criteria and requires the presence of at least one clinical criteria (vascular thrombosis and/or pregnancy morbidity) and one laboratory criteria (persistence of at least 12 weeks of lupus anticoagulant and/or medium-high titers of IgG or IgM autoantibodies against β2GPI or cardiolipin)  (Table 1).
Pathogenesis of Antiphospholipid syndrome
Though the exact pathogenesis is not known, two possible mechanisms have been described to explain the pathophysiology of APS: antiphospholipid antibodies may alter hemostatic reaction by cross-linking cell surface-bound antigens or aPL may directly trigger cell activation resulting in alterations in expression or production of various molecules [3, 4].
Anti-β2GPI antibodies are known to be one of the major responsible causes of thrombotic events in APS [4, 9, 10]. It has been demonstrated that anti-β2GPI antibodies potentiate thrombosis by binding to β2GPI on cell surfaces activating endothelial cells, monocytes, platelets, neutrophils, fibroblasts, and trophoblasts. Such action induces various pathways, depending on cell type [10, 11].
Recent studies suggest that APS is more related to endothelial cell activation (Fig. 1) rather than antibody-mediated coagulation . Endothelial cell activation through Toll-like receptor (TLR) family as a result of anti-β2GPI antibodies and endothelial cell interaction was first described in 2003 . Allen et al. showed the effect of TLR4 in endothelial cell activation in response to anti-β2GPI antibodies. They also demonstrated that TLR4 signaling consisted of a complex of protein including annexin A2, TLR4, calreticulin, and nucleolin . A recently discovered pathway shows that anti-β2GPI antibodies may cause endothelial cell activation by releasing endothelial cell-derived extracellular vesicles through TLR7 and that these endothelial vesicles may contribute to the activation of unstimulated neighboring endothelial cells by paracrine signaling .
Another arterial vascular endothelial related pathology described in APS is intimal hyperplasia. Arterial vasculopathy in APS is a contributor of large artery occlusion rather than thrombosis . It has been recently demonstrated that aPLs activate AKT/ mammalian target of rapamycin (mTOR) pathway in the endothelial cells and cause proliferation of endothelial and vascular smooth muscle actin cells. A correlation between anticardiolipin and anti-β2GPI antibodies titers and mTOR pathway activation degree has also been shown .
Platelet activation also has an important effect on thrombus formation in ALP. Anti-β2GPI antibodies bind to β2GPI receptors on platelets and can cause both arterial and venous thrombosis, resulting in increased production of glycoprotein 2b-3a and thromboxane A2 [5, 17].
Other studies demonstrate that neutrophils may also contribute to pathologic clotting, especially venous thrombosis in APS [18, 19]. Neutrophils release neutrophil extracellular traps (NETs), which consist of nucleus originated DNA and histones, as well as cytoplasm derived granule proteins, such as neutrophil elastase and myeloperoxidase. Intrinsic coagulation cascade can be activated by the DNA part of NETs. Proteases in NETs play a role in inactivation of particular anticoagulation factors [18, 20, 21]. Furthermore, histones induce platelets [18, 22]. In addition, APS neutrophils show proinflammatory signature expression related to interferon (IFN)-mediated signaling pathway, cellular defense and intercellular adhesion. Neutrophil adhesion also has an important role in thrombus formation. It has been shown that P-selectin glycoprotein ligand-1 (PSGL-1), which interacts with endothelial selectins in neutrophil rolling, is upregulated in APS. In that same study, PSGL-1 deficiency was demonstrated to prevent antiphospholipid antibody-mediated thrombosis by affecting neutrophil and NETs mediated pathway .
In pregnancy, β2GPI is noted to be present on placental trophoblast cells and maternal decidual cells. In vitro studies have shown that aPLs engaging with trophoblast cells can cause proinflammatory cytokine secretion, inhibition of trophoblast migration, increased secretion of trophoblast anti-angiogenic sEng and disruption of trophoblast-endothelial interaction in spiral artery transformation .
The classic clinical presentation of APS is characterized by venous and arterial thrombosis, fetal losses, and thrombocytopenia. Deep venous thrombosis of the lower limbs is the most common clinical subtype of venous thrombosis followed by pulmonary embolism. Although arterial thromboembolic events are less common, it has a higher mortality and morbidity rate as it frequently affects the cerebrovascular bed, usually causing strokes and transient ischemic attacks [6, 9]. Vascular occlusions may present in any form and combination in the same patient with time intervals between vascular events showing variation from weeks to months, or even years .
Pregnancy-related complications are one of the hallmarks of APS and include early to late fetal loss, premature birth, and preeclampsia .
The most severe life-threatening form of APS is called catastrophic antiphospholipid syndrome (CAPS). Although the prevalence of CAPS is less than 1%, it has high mortality rate due to a rapid onset microthrombosis involving multiple organs resulting in multiorgan failure . Table 2 shows various clinical characteristics of APS related with venous and arterial thrombosis as well as non-thrombotic manifestations.
Recently, arterial and venous thromboses have been described as severe complications of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory system coronavirus (SARS-CoV-2). The underlying mechanism of COVID-19-related coagulopathy remains unclear [27,28,29]. However, studies have shown elevated aPL levels in a considerable number of patients with severe COVID-19 [27,28,29,30,31]. Elevated NET levels from neutrophils have also been reported in severe COVID-19 patients . Infection-induced aPL is usually transient and may disappear in a couple of weeks [27,28,29,30,31]. Although the clinical significance of this associated transient increase in aPL levels has not been well-defined, these transient findings may play a role in the development of thrombotic events and may lead to APS in particularly severe COVID-19 cases. Thus far, there have been no reports of APS or APS-like disease affecting the eye that was deemed to be secondary to or associated to COVID-19 infection.
Antiphospholipid syndrome can affect any part of the eye including the anterior and posterior segments, as well as visual pathways in the central nervous system . Therefore, ocular involvement of APS may show up with a wide range of clinical manifestations and symptoms. Patients with ocular involvement typically present with visual symptoms such as monocular or binocular blurring of vision, amaurosis fugax, transient diplopia and transient visual field losses [3, 11, 32]. Headaches and migraine-like visual symptoms have also been reported . Table 3 demonstrates the various documented ocular manifestations of APS.
Anterior segment involvement of APS is relatively rare compared to posterior segment diseases. Clinical findings seen in the anterior segment include conjunctivitis sicca, conjunctival vascular telangiectasias and microaneurysms, punctate epithelial keratopathy, and limbal keratitis [11, 32, 33]. Anterior uveitis associated with retinal vasculitis, episcleritis, and scleritis have been described as clinical findings of APS [32, 34].
Antiphospholipid syndrome more commonly presents with posterior segment involvement and is typically associated with vaso-occlusive conditions. Common retinal findings seen in APS include venous tortuosity, retinal hemorrhages, microaneurysms, and cotton-wool spots, the latter of which is most likely attributable to microvascular occlusion (Fig. 2) [3, 33, 35]. The use of spectral domain optical coherence tomography (SD-OCT) has shown retinal ischemia (paracentral acute middle maculopathy, PAMM) in patients with primary APS as hyperreflective, band-like lesions located in the inner or outer retinal layers [36, 37]. Optical coherence tomography angiography (OCTA) has likewise demonstrated evidence of superficial and deep capillary deficits with signal attenuation artifacts .
Other vaso-occlusive pathologies that are also common in APS include: central retinal vein occlusion (CRVO), central retinal artery occlusion (CRAO), branched retinal vein occlusion (BRVO), and branched retinal artery occlusion (BRAO) [11, 32]. Left untreated, vaso-occlusive retinopathies may lead to several complications such as neovascularization, vitreous hemorrhage, neovascular glaucoma, and tractional retinal detachment . Choroidal infarction and cilioretinal infarction can also be seen in APS (Fig. 3) [11, 32].
Instead of retinal venous occlusions occurring at arterial/venous crossings as seen in atherosclerosis-related vasculopathy, APS-related venous occlusions may be seen in multiple areas in the same eye [3, 33, 35]. Similarly, retinal arterial occlusions do not usually occur at bifurcations as seen in embolic situations [3, 33, 35].
In retinal vein occlusion, the presence of aPLs has been reported as higher compared with population-based controls [38,39,40,41]. A recent systemic review and meta-analysis assessing the risk of retinal vein occlusion showed a significant association between aPLs and risk of developing retinal vein occlusion (OR = 5.18, 95% CI = [3.37, 7.95]) . The British Committee for Standards in Haematology released guidelines in 2012 suggesting that all patients with unprovoked episodes of venous occlusion without other underlying systemic of local causes be tested for aPLs after a sufficient period of removing anticoagulation treatment . Though venous occlusion involving the eye was not specifically mentioned, given the higher prevalence of aPLs in patients with retinal vein occlusion [38,39,40,41] and increased risk of developing of retinal vein occlusion in the presence of aPLs [42, 44, 45] that has been reported in several studies, aPLs are potential targets to detect and measured in patients with newly diagnosed retinal vein occlusion, especially in patients without any known systemic underlying conditions such as hypertension, diabetes, hyperlipidemia, and cardiovascular disease.
In a descriptive study of 13 patients positive for aCL, retinal vasculitis, vitritis, and posterior scleritis have been seen despite no other diagnosable etiology . Serpiginous-like choroidopathy due to both retinal and choroidal vaso-occlusion accompanied by vitritis and vasculitis was also described in APS . Wood and et al. presented a case of iritis in the right eye and bilateral vitritis with diffuse retinal peri-phlebitis resembling frosted branch angiitis in a patient with primary APS, All ocular findings resolved with oral prednisone treatment  Fig. 4 depicted a frosted branch angiitis in a patient with antiphospholipid syndrome.
APS can present in a wide range of neuro-ophthalmologic disorders such as non-arteritic or arteritic ischemic optic neuropathy, extraocular motility disorders, and central nervous system (CNS) infarctions along the visual pathway [3, 11, 32].
Optic disc findings due to non-arteritic and arteritic ischemic optic neuropathy are common neuro-ophthalmologic presentations in APS patients . Retrobulbar optic neuropathy with normal fundus examination accompanied by decreased visual acuity and visual field defects have been shown in primary APS patients .
Ocular motility disorders due to extraocular muscle nerve palsies have been reported in APS patients in the settings of idiopathic intracranial hypertension and cerebral sinus thrombosis [49, 50]. Superior ophthalmic vein thrombosis is another pathology that can also cause ophthalmoplegia as well as proptosis in APS patients .
Prevention of aPL-induced coagulation is the main goal in the treatment of thrombotic events in APS. Initial therapy for patients with venous thrombosis consists of unfractionated or low-molecular-weight heparin (LMWH) for 5 days followed by anticoagulation therapy with warfarin [9, 12]. The international normalized ratio (INR) target ranges between 2.0 and 3.0. High intensity anticoagulation, in which the INR target is between 3 and 4, has not shown superiority in terms of preventing recurrent thrombosis in patients with APS [52, 53].
Oral anticoagulation therapy with a target INR of 2.0–3.0 is also recommended for patients with arterial non-cerebral events [1, 17]. Higher intensity anticoagulation is preferred in some centers because some studies have shown that moderate intensity anticoagulation was not able to prevent recurrences in arterial thrombosis [9, 12]. Low-dose aspirin therapy with moderate intensity anticoagulation therapy is suggested for APS patients with cerebral events [17, 54].
Regarding APS associated with pure ophthalmic manifestations however, there are no current guidelines nor any therapeutic actions suggested other than for preventing subsequent events. Furthermore, systemic anticoagulation, particularly with warfarin, has been linked to increased risk of subsequent retinal vein and arterial occlusion, even at therapeutic dosages [55,56,57].
Recently, direct oral anticoagulants (DOACs) have been developed. These direct FXa inhibitors include rivaroxaban, apixaban and edoxaban and a direct thrombin inhibitor named dabigatran [1, 12, 58, 59]. All of these DOACs are reversible, competitive, and dose dependent and have not shown inferiority to Vitamin K antagonists (VKA) in terms of secondary prevention of venous thrombosis and stroke in patients with nonvalvular atrial fibrillation [12, 59]. Furthermore, they have some advantages over VKAs because they are used as a fixed dose, do not need monitoring, and show fewer drug interactions. However, there are ongoing clinical trials comparing DOACs and warfarin in APS patients and we have limited data regarding the overall safety DOACs in treatment compared to VKAs [1, 12, 58].
Hydroxychloroquine (HCQ) is an antimalarial drug that is typically used in SLE patients which has anti-inflammatory as well as anti-thrombotic effects [12, 17, 26]. It has been shown that HCQ has anti-thrombotic effects based on inhibition of glycoprotein IIb/IIIa (GPIIb/IIIa) expression on aPL activated platelets , preventing aPL-β2GPI-phospholipid formation, and aPL-mediated Annexin A5 shield disruption (Fig. 1) [61,62,63]. Furthermore, HCQ is known to have immunomodulatory effects including prevention of Toll-like receptor 3 (TLR3), Toll-like receptor 7 (TLR7) (Fig. 1) and Toll-like receptor 9 (TLR9) activation as well as reduction in IFN signature and aPL titers [64,65,66]. On the basis of anti-thrombotic and immunomodulatory properties, HCQ can be considered as an adjunctive therapy for APS patients who have recurrent thrombotic events despite being on adequate anticoagulation therapy [5, 12, 58]. However, further clinical studies are needed supporting the clinical antithrombotic effects of HCQ in patients with APS.
Statins, also known as hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are a type of cholesterol lowering agent. In addition to a lipid-lowering effect, statins have demonstrated anti-thrombotic and anti-inflammatory properties such as inhibition of tissue factor production in endothelial cells and prevention of anti-β2GPI antibody-mediated endothelial adherence (Fig. 1) [67, 68]. Fluvastatin treatment has been proposed to decrease proinflammatory and prothrombotic mediators in aPL positive patients and to inhibit several mediators in monocytes that may be pro-thrombotic in APS patients [69, 70].
Rituximab is a chimeric monoclonal antibody against CD 20 expressed on B cells that was originally developed for the treatment of non-Hodgkin’s B-cell lymphoma. In the last several years, B-cell targeting therapies have been approved for the treatment of various autoimmune diseases . Anti-CD20 monoclonal therapy has been shown to decrease aPL titers and prevent new thrombotic events (Fig. 1) . Moreover, in a non-randomized prospective pilot study, rituximab was found to be effective in the treatment of non-criteria aPL manifestations in a persistently aPL positive patients . It has also been a safe and effective therapeutic option for patients with refractory catastrophic APS .
Eculizumab is a humanized monoclonal antibody against complement C5 that inhibits C5 cleavage into C5a and C5b, thus preventing membrane attack complex formation. It is currently used for paroxysmal nocturnal hemoglobinuria [75, 76]. C5 is a strong proinflammatory, chemotactic, and anaphylatoxic molecule that also shows prothrombotic effect by regulating many mediators from numerous cells . It induces tissue factor expression on endothelial cells, neutrophils, and monocytes [77,78,79]. Figure 1 depicted mechanism action of eculizumab in endothelial cells. Eculizumab has been used in treatment of refractory CAPS [76, 80,81,82,83,84] and aPL-mediated acute thrombotic microangiopathy after renal transplantations [76, 83, 85].
Inhibition of mammalian target of rapamycin (mTOR) pathway can prevent APS-related vasculopathy by inhibiting proliferation of endothelial and vascular smooth muscle cells (Fig. 1) . Sirolimus, an mTOR inhibitor, reduced the development of intimal hyperplasia and showed better graft survival in patients with APS who underwent renal transplantation . It has also been shown that anti-β2GPI results in mTOR activation as well as tissue factor and Interleukin-8 (IL-8) expression in monocytes . Based on these findings, mTOR inhibition can be considered as a useful therapeutic option in the future in terms of preventing aPL-mediated thrombosis and inflammation in APS patients.
Future therapeutic targets
TIFI is a 20-amino acid peptide derived from cytomegalovirus, which shows similarities with the PL-binding site of β2GPI [12, 88]. TIFI inhibits the binding of β2GPI to human endothelial cells and murine monocytes in vitro in a dose-dependent manner (Fig. 1). TIFI has also been demonstrated to reverse aPL-induced thrombosis in mice . It was also shown to inhibit binding of monoclonal human β2GPI to human trophoblast in vitro as well as to reverse aPL-induced fetal loss and growth retardation in pregnant mice . Similarly, recombinant β2GPI -DI abrogates aPL-induced thrombus formation and inhibits production of vascular cell adhesion molecule-1 (VCAM-1) in aortic endothelial cells and macrophage tissue factor in mice .
Inhibitors of intracellular signaling pathways in APS pathogenesis are also promising therapeutic targets as inhibition of nuclear factor kappa-light-chain-enhancer of B cells (NFκB) reduces proinflammatory and prothrombotic features of aPL as well as reverses aPL-induced thrombosis in mice [92, 93]. Moreover, inhibition of Toll-like receptor 4 (TLR4) (Fig. 1) by an intracellular domain of TLR4 prevents anti-β2GPI/β2GPI-induced tissue factor (TF) and tumor necrosis factor-alpha (TNF-α) productions, which may contribute to thrombus formation .
Antiphospholipid syndrome is characterized by both arterial and venous thrombosis, fetal loss, and thrombocytopenia in the presence of antiphospholipid bodies [1, 2]. It may present in various clinical forms with different thrombotic events as well as non-thrombotic events . Ocular involvements can occur in 15–88% of patients with APS and clinical findings may vary depending on the affected part of the eye including: anterior segment, posterior segment and the visual pathway along the central nervous system [3, 11]. Since APS is common and has a variety of ocular findings, early recognition of the ocular manifestations related with APS syndrome is crucial in order to prevent future thrombotic events and life-threatening morbidities.
The mechanism of the APS syndrome has not been fully understood, but recent studies have shown that aPL-induced cell activation plays an important role in the pathogenesis of APS more so than antibody-mediated coagulation. Antiphospholipid antibodies, especially anti-β2GPI antibodies, contribute to thrombosis formation by activating different cell types including endothelial cells, monocytes, platelets, neutrophils, fibroblasts, and trophoblasts, leading to induction of various pathways [10, 11]. Although anticoagulation therapy is still the standard treatment method in the management of APS, better understanding of the mechanism and identifying more specific tools in the pathogenesis of APS may provide target-specific therapy and better control of disease in patients who are refractory to standard therapy.
Systemic lupus erythematosus
Mammalian target of rapamycin
Neutrophils release neutrophil extracellular traps
P-selectin glycoprotein ligand-1
Catastrophic antiphospholipid syndrome
Coronavirus disease 2019
Severe acute respiratory system coronavirus
Spectral domain optical coherence tomography
Central retinal vein occlusion
Central retinal artery occlusion
Branched retinal vein occlusion
Branched retinal artery occlusion
International normalized ratio
Direct oral anticoagulants
Vitamin K antagonists
Hydroxymethylglutaryl coenzyme A
Vascular cell adhesion molecule-1
Nuclear factor kappa-light-chain-enhancer of B cells
Tumor necrosis factor-alpha
Gomez-Puerta JA, Cervera R (2014) Diagnosis and classification of the antiphospholipid syndrome. J Autoimmun 48-49:20–25
Chaturvedi S, McCrae KR (2017) Diagnosis and management of the antiphospholipid syndrome. Blood Rev 31(6):406–417
Durrani OM, Gordon C, Murray PI (2002) Primary anti-phospholipid antibody syndrome (APS): current concepts. Surv Ophthalmol 47(3):215–238
Espinosa G, Cervera R, Font J, Shoenfeld Y (2003) Antiphospholipid syndrome: pathogenic mechanisms. Autoimmun Rev 2(2):86–93
Cavazzana I, Andreoli L, Limper M, Franceschini F, Tincani A (2018) Update on Antiphospholipid syndrome: ten topics in 2017. Curr Rheumatol Rep 20(3):15
Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, Jacobsen S, Lakos G, Tincani A, Kontopoulou-Griva I et al (2002) Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 46(4):1019–1027
Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, Ramire de Jesus G, Erkan D (2013) Estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. Arthritis Care Res 65(11):1869–1873
Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DEG PG, Koike T, Meroni PL et al (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4(2):295–306
Garcia D, Erkan D (2018) Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med 378(21):2010–2021
de Groot PG, de Laat B (2017) Mechanisms of thrombosis in systemic lupus erythematosus and antiphospholipid syndrome. Best Pract Res Clin Rheumatol 31(3):334–341
Yang P, Kruh JN, Foster CS (2012) Antiphospholipid antibody syndrome. Curr Opin Ophthalmol 23(6):528–532
Chighizola CB, Ubiali T, Meroni PL (2015) Treatment of thrombotic Antiphospholipid syndrome: the rationale of current management-an insight into future approaches. J Immunol Res 2015:951424
Raschi E, Testoni C, Bosisio D, Borghi MO, Koike T, Mantovani A, Meroni PL (2003) Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. Blood 101(9):3495–3500
Allen KL, Fonseca FV, Betapudi V, Willard B, Zhang J, McCrae KR (2012) A novel pathway for human endothelial cell activation by antiphospholipid/anti-beta2 glycoprotein I antibodies. Blood 119(3):884–893
Wu M, Barnard J, Kundu S, McCrae KR (2015) A novel pathway of cellular activation mediated by antiphospholipid antibody-induced extracellular vesicles. J Thromb Haemost 13(10):1928–1940
Canaud G, Legendre C, Terzi F (2015) AKT/mTORC pathway in antiphospholipid-related vasculopathy: a new player in the game. Lupus 24(3):227–230
Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA (2010) Antiphospholipid syndrome. Lancet 376(9751):1498–1509
Meng H, Yalavarthi S, Kanthi Y, Mazza LF, Elfline MA, Luke CE, Pinsky DJ, Henke PK, Knight JS (2017) In vivo role of neutrophil extracellular traps in Antiphospholipid antibody-mediated venous thrombosis. Arthritis Rheum 69(3):655–667
Martinod K, Wagner DD (2014) Thrombosis: tangled up in NETs. Blood 123(18):2768–2776
von Bruhl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, Khandoga A, Tirniceriu A, Coletti R, Kollnberger M et al (2012) Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 209(4):819–835
Gould TJ, Vu TT, Swystun LL, Dwivedi DJ, Mai SH, Weitz JI, Liaw PC (2014) Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol 34(9):1977–1984
Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD (2010) Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 107(36):15880–15885
Knight JS, Meng H, Coit P, Yalavarthi S, Sule G, Gandhi AA, Grenn RC, Mazza LF, Ali RA, Renauer P et al (2017) Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target. JCI Insight 2:18
Abrahams VM, Chamley LW, Salmon JE (2017) Emerging treatment models in rheumatology: Antiphospholipid syndrome and pregnancy: pathogenesis to translation. Arthritis Rheum 69(9):1710–1721
Cervera R (2017) Antiphospholipid syndrome. Thromb Res 151(Suppl 1):S43–S47
Negrini S, Pappalardo F, Murdaca G, Indiveri F, Puppo F (2017) The antiphospholipid syndrome: from pathophysiology to treatment. Clin Exp Med 17(3):257–267
Xiao M, Zhang Y, Zhang S, Qin X, Xia P, Cao W, Jiang W, Chen H, Ding X, Zhao H et al (2020) Antiphospholipid antibodies in critically ill patients with COVID-19. Arthritis Rheum 72(12):1998–2004
Gkrouzman E, Barbhaiya M, Erkan D, Lockshin MD (2020) Reality check on antiphospholipid antibodies in COVID-19-associated coagulopathy. Arthritis Rheum 73(1):173
Zuo Y, Estes SK, Gandhi AA, Yalavarthi S, Ali RA, Shi H, Sule G, Gockman K, Madison JA, Zuo M et al (2020) Prothrombotic antiphospholipid antibodies in COVID-19. medRxiv [Preprint]. https://doi.org/10.1101/2020.06.15.20131607
Devreese KMJ, Linskens EA, Benoit D, Peperstraete H (2020) Antiphospholipid antibodies in patients with COVID-19: a relevant observation? J Thromb Haemost 18(9):2191–2201
Hasan Ali O, Bomze D, Risch L, Brugger SD, Paprotny M, Weber M, Thiel S, Kern L, Albrich WC, Kohler P et al (2020) Severe COVID-19 is associated with elevated serum IgA and antiphospholipid IgA-antibodies. Clin Infect Dis 1:ciaa1496
Utz VM, Tang J (2011) Ocular manifestations of the antiphospholipid syndrome. Br J Ophthalmol 95(4):454–459
Lima Cabrita FV, Foster CS (2005) Anticardiolipin antibodies and ocular disease. Ocul Immunol Inflamm 13(4):265–270
Miserocchi E, Baltatzis S, Foster CS (2001) Ocular features associated with anticardiolipin antibodies: a descriptive study. Am J Ophthalmol 131(4):451–456
Bolling JP, Brown GC (2000) The antiphospholipid antibody syndrome. Curr Opin Ophthalmol 11(3):211–213
Trese MG, Thanos A, Yonekawa Y, Randhawa S (2017) Optical coherence tomography angiography of Paracentral acute middle Maculopathy associated with primary Antiphospholipid syndrome. Ophthal Surg Lasers Imaging Retina 48(2):175–178
Arf S, Sayman Muslubas I, Hocaoglu M, Karacorlu M (2018) Retinal deep capillary plexus ischemia in a case with Antiphospholipid syndrome. Retinal Cases Brief Rep 12(2):106–110
Hernandez JL, Sanles I, Perez-Montes R, Martinez-Taboada VM, Olmos JM, Salmon Z, Sierra I, Escalante E, Napal JJ (2020) Antiphospholipid syndrome and antiphospholipid antibody profile in patients with retinal vein occlusion. Thromb Res 190:63–68
Sartori MT, Barbar S, Dona A, Piermarocchi S, Pilotto E, Saggiorato G, Prandoni P (2013) Risk factors, antithrombotic treatment and outcome in retinal vein occlusion: an age-related prospective cohort study. Eur J Haematol 90(5):426–433
Glueck CJ, Hutchins RK, Jurantee J, Khan Z, Wang P (2012) Thrombophilia and retinal vascular occlusion. Clin Ophthalmol 6:1377–1384
Paccalin M, Manic H, Bouche G, Landron C, Mercie M, Boinot C, Gombert JM, Roblot P, Dighiero P (2006) Antiphospholipid syndrome in patients with retinal venous occlusion. Thromb Res 117(4):365–369
Zhu W, Wu Y, Xu M, Wang JY, Meng YF, Gu Z, Lu J (2014) Antiphospholipid antibody and risk of retinal vein occlusion: a systematic review and meta-analysis. PLoS One 10(4):e0122814
Keeling D, Mackie I, Moore GW, Greer IA, Greaves M, British Committee for Standards in H (2012) Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol 157(1):47–58
Janssen MC, den Heijer M, Cruysberg JR, Wollersheim H, Bredie SJ (2005) Retinal vein occlusion: a form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors. Thromb Haemost 93(6):1021–1026
Rehak M, Muller M, Scholz M, Wiercinska J, Niederwieser D, Wiedemann P (2009) Antiphospholipid syndrome and retinal vein occlusion. Meta-analysis of published studies. Ophthalmologe 106(5):427–434
Tang J, Fillmore G, Nussenblatt RB (2009) Antiphospholipid antibody syndrome mimicking serpiginous choroidopathy. Ocul Immunol Inflamm 17(4):278–281
Wood EH, Wong RW (2016) Bilateral frosted branch angiitis as the presenting sign of antiphospholipid antibody syndrome. J Ophthal Inflamm Infect 6(1):20
Marie I, Herve F, Borg JY, Levesque H (2007) Retrobulbar optic neuritis revealing primary anti-phospholipid antibody syndrome. Scand J Rheumatol 36(2):156–157
Shin SY, Lee JM (2006) A case of multiple cranial nerve palsies as the initial ophthalmic presentation of antiphospholipid syndrome. Korean J Ophthalmol 20(1):76–78
Sakamoto S, Akutsu K, Kawase K, Takada T, Seyama H, Takahashi J, Miyamoto S, Nonogi H, Takeshita S (2008) Simultaneous presentations of deep vein thrombosis and cerebral sinus thrombosis in a case of primary antiphospholipid syndrome. Angiology 59(6):765–768
Dey M, Charles Bates A, McMillan P (2013) Superior ophthalmic vein thrombosis as an initial manifestation of antiphospholipid syndrome. Orbit 32(1):42–44
Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, Baudo F, Berrettini M, Testa S, D'Angelo A et al (2005) A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 3(5):848–853
Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C et al (2003) A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 349(12):1133–1138
Chang AE, Karnell LH, Menck HR (1998) The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 83(8):1664–1678
Salim S, Lam WC, Hanna W (2009) Central retinal vein occlusion with therapeutic level of anticoagulation. Case Rep Med 2009:827982
Mruthyunjaya P, Wirostko WJ, Chandrashekhar R, Stinnett S, Lai JC, Deramo V, Tang J, Dev S, Postel EA, Connor TB et al (2006) Central retinal vein occlusion in patients treated with long-term warfarin sodium (Coumadin) for anticoagulation. Retina 26(3):285–291
Chang IB, Lee JH, Kim HW (2019) Combined central retinal vein and artery occlusion in a patient with elevated level of factor VIII: a case report. Int Med Case Rep J 12:309–312
Houghton DE, Moll S (2017) Antiphospholipid antibodies. Vasc Med 22(6):545–550
Dufrost V, Risse J, Zuily S, Wahl D (2016) Direct Oral anticoagulants use in Antiphospholipid syndrome: are these drugs an effective and safe alternative to warfarin? A systematic review of the literature. Curr Rheumatol Rep 18(12):74
Espinola RG, Pierangeli SS, Gharavi AE, Harris EN (2002) Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies. Thromb Haemost 87(3):518–522
Rand JH, Wu XX, Quinn AS, Chen PP, Hathcock JJ, Taatjes DJ (2008) Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers. Blood 112(5):1687–1695
Rand JH, Wu XX, Quinn AS, Ashton AW, Chen PP, Hathcock JJ, Andree HA, Taatjes DJ (2010) Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood 115(11):2292–2299
Wallace DJ, Linker-Israeli M, Metzger AL, Stecher VJ (1993) The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE. Lupus 2(Suppl 1):S13–S15
Kuznik A, Bencina M, Svajger U, Jeras M, Rozman B, Jerala R (2011) Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol 186(8):4794–4804
Broder A, Putterman C (2013) Hydroxychloroquine use is associated with lower odds of persistently positive antiphospholipid antibodies and/or lupus anticoagulant in systemic lupus erythematosus. J Rheumatol 40(1):30–33
van den Hoogen LL, Fritsch-Stork RD, Versnel MA, Derksen RH, van Roon JA, Radstake TR (2016) Monocyte type I interferon signature in antiphospholipid syndrome is related to proinflammatory monocyte subsets, hydroxychloroquine and statin use. Ann Rheum Dis 75(12):e81
Ferrara DE, Swerlick R, Casper K, Meroni PL, Vega-Ostertag ME, Harris EN, Pierangeli SS (2004) Fluvastatin inhibits up-regulation of tissue factor expression by antiphospholipid antibodies on endothelial cells. J Thromb Haemost 2(9):1558–1563
Meroni PL, Raschi E, Testoni C, Tincani A, Balestrieri G, Molteni R, Khamashta MA, Tremoli E, Camera M (2001) Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype. Arthritis Rheum 44(12):2870–2878
Lopez-Pedrera C, Ruiz-Limon P, Aguirre MA, Barbarroja N, Perez-Sanchez C, Buendia P, Rodriguez-Garcia IC, Rodriguez-Ariza A, Collantes-Estevez E, Velasco F et al (2011) Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome. Ann Rheum Dis 70(4):675–682
Erkan D, Willis R, Murthy VL, Basra G, Vega J, Ruiz-Limon P, Carrera AL, Papalardo E, Martinez-Martinez LA, Gonzalez EB et al (2014) A prospective open-label pilot study of fluvastatin on proinflammatory and prothrombotic biomarkers in antiphospholipid antibody positive patients. Ann Rheum Dis 73(6):1176–1180
Looney RJ, Srinivasan R, Calabrese LH (2008) The effects of rituximab on immunocompetency in patients with autoimmune disease. Arthritis Rheum 58(1):5–14
Khattri S, Zandman-Goddard G, Peeva E (2012) B-cell directed therapies in antiphospholipid antibody syndrome--new directions based on murine and human data. Autoimmun Rev 11(10):717–722
Erkan D, Vega J, Ramon G, Kozora E, Lockshin MD (2013) A pilot open-label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum 65(2):464–471
Berman H, Rodriguez-Pinto I, Cervera R, Morel N, Costedoat-Chalumeau N, Erkan D, Shoenfeld Y, Espinosa G (2013) Catastrophic Antiphospholipid syndrome registry project G: rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab. Autoimmun Rev 12(11):1085–1090
Schmidtko J, Peine S, El-Housseini Y, Pascual M, Meier P (2013) Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab. Am J Kidney Dis 61(2):289–299
Shapira I, Andrade D, Allen SL, Salmon JE (2012) Brief report: induction of sustained remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab. Arthritis Rheum 64(8):2719–2723
Guo RF, Ward PA (2005) Role of C5a in inflammatory responses. Annu Rev Immunol 23:821–852
Ikeda K, Nagasawa K, Horiuchi T, Tsuru T, Nishizaka H, Niho Y (1997) C5a induces tissue factor activity on endothelial cells. Thromb Haemost 77(2):394–398
Ritis K, Doumas M, Mastellos D, Micheli A, Giaglis S, Magotti P, Rafail S, Kartalis G, Sideras P, Lambris JD (2006) A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol 177(7):4794–4802
Zikos TA, Sokolove J, Ahuja N, Berube C (2015) Eculizumab induces sustained remission in a patient with refractory primary catastrophic Antiphospholipid syndrome. J Clin Rheumatol 21(6):311–313
Kronbichler A, Frank R, Kirschfink M, Szilagyi A, Csuka D, Prohaszka Z, Schratzberger P, Lhotta K, Mayer G (2014) Efficacy of eculizumab in a patient with immunoadsorption-dependent catastrophic antiphospholipid syndrome: a case report. Medicine 93(26):e143
Wig S, Chan M, Thachil J, Bruce I, Barnes T (2016) A case of relapsing and refractory catastrophic anti-phospholipid syndrome successfully managed with eculizumab, a complement 5 inhibitor. Rheumatology 55(2):382–384
Lonze BE, Zachary AA, Magro CM, Desai NM, Orandi BJ, Dagher NN, Singer AL, Carter-Monroe N, Nazarian SM, Segev DL et al (2014) Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 14(2):459–465
Lonze BE, Singer AL, Montgomery RA (2010) Eculizumab and renal transplantation in a patient with CAPS. N Engl J Med 362(18):1744–1745
Canaud G, Kamar N, Anglicheau D, Esposito L, Rabant M, Noel LH, Guilbeau-Frugier C, Sberro-Soussan R, Del Bello A, Martinez F et al (2013) Eculizumab improves posttransplant thrombotic microangiopathy due to antiphospholipid syndrome recurrence but fails to prevent chronic vascular changes. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 13(8):2179–2185
Canaud G, Bienaime F, Tabarin F, Bataillon G, Seilhean D, Noel LH, Dragon-Durey MA, Snanoudj R, Friedlander G, Halbwachs-Mecarelli L et al (2014) Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med 371(4):303–312
Xia L, Zhou H, Wang T, Xie Y, Wang T, Wang X, Yan J (2017) Activation of mTOR is involved in anti-beta2GPI/beta2GPI-induced expression of tissue factor and IL-8 in monocytes. Thromb Res 157:103–110
Arachchillage DRJ, Laffan M (2017) Pathogenesis and management of antiphospholipid syndrome. Br J Haematol 178(2):181–195
Ostertag MV, Liu X, Henderson V, Pierangeli SS (2006) A peptide that mimics the Vth region of beta-2-glycoprotein I reverses antiphospholipid-mediated thrombosis in mice. Lupus 15(6):358–365
de la Torre YM, Pregnolato F, D'Amelio F, Grossi C, Di Simone N, Pasqualini F, Nebuloni M, Chen P, Pierangeli S, Bassani N et al (2012) Anti-phospholipid induced murine fetal loss: novel protective effect of a peptide targeting the beta2 glycoprotein I phospholipid-binding site. Implications for human fetal loss. J Autoimmun 38(2–3):J209–J215
Ioannou Y, Romay-Penabad Z, Pericleous C, Giles I, Papalardo E, Vargas G, Shilagard T, Latchman DS, Isenberg DA, Rahman A et al (2009) In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of beta2-glycoprotein I: proof of concept. J Thromb Haemost 7(5):833–842
Montiel-Manzano G, Romay-Penabad Z, Papalardo de Martinez E, Meillon-Garcia LA, Garcia-Latorre E, Reyes-Maldonado E, Pierangeli SS (2007) In vivo effects of an inhibitor of nuclear factor-kappa B on thrombogenic properties of antiphospholipid antibodies. Ann N Y Acad Sci 1108:540–553
Nishimura M, Nii T, Trimova G, Miura S, Umezawa K, Ushiyama A, Kubota T (2013) The NF-kappaB specific inhibitor DHMEQ prevents thrombus formation in a mouse model of antiphospholipid syndrome. J Nephropathol 2(2):114–121
Xie H, Zhou H, Wang H, Chen D, Xia L, Wang T, Yan J (2013) Anti-beta(2)GPI/beta(2)GPI induced TF and TNF-alpha expression in monocytes involving both TLR4/MyD88 and TLR4/TRIF signaling pathways. Mol Immunol 53(3):246–254
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Uludag, G., Onghanseng, N., Tran, A.N.T. et al. Current concepts in the diagnosis and management of antiphospholipid syndrome and ocular manifestations. J Ophthal Inflamm Infect 11, 11 (2021). https://doi.org/10.1186/s12348-021-00240-8
- Antiphospholipid syndrome
- Antiphospholipid antibodies
- Ocular manifestations