The ABCs of antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is a thromboinflammatory syndrome characterized by thrombotic, microvascular, obstetric, or non-thrombotic events in the setting of persistent antiphospholipid antibodies (aPL), namely anticardiolipin antibody (aCL), anti-β2 glycoprotein-I antibody (aβ2GPI), and lupus anticoagulant (LA). The diagnosis of APS requires careful assessment of the aPL profile, the clinical phenotype, and additional risk factors. The standard management of aPL-related thrombosis is anticoagulation, which is not effective for microvascular and non-thrombotic events. In parallel to our improved understanding of aPL-related mechanisms, the role of immunosuppression has been increasingly investigated. In this review, we summarize the basic concepts and future perspectives in APS.

Introduction

Antiphospholipid syndrome (APS) is a thromboinflammatory disease characterized by thrombosis (venous, arterial, or microvascular) or pregnancy morbidity in individuals with antiphospholipid antibodies (aPL).[1] Three main tests used to detect aPL are anticardiolipin antibody (aCL), anti-β₂ glycoprotein-I antibodies (aβ₂GPI), and lupus anticoagulant test (LA). Antiphospholipid antibody positivity alone, without aPL-related clinical symptoms, does not qualify for an APS diagnosis. Antiphospholipid syndrome may be seen in patients with other autoimmune diseases, such as systemic lupus erythematosus (SLE), or in otherwise healthy individuals (primary APS).

The prevalence and incidence of APS are difficult to accurately calculate due to the wide range of aPL-related clinical presentations, inconsistent definitions of aPL-positivity, and limited population-based studies. However, the overall prevalence of APS is about 50 per 100,000 individuals, and the estimated incidence ranges between 7.1 and 13.7 per 100,000 person-years.[2,3]

The clinical manifestations of aPL have a wide spectrum. The most common vascular events are thromboses of the lower extremity deep veins, and the arterial circulation of the brain. However, vascular events may vary from superficial venous thrombosis to small-moderatelarge vessel thrombosis to multiple simultaneous organ thromboses (catastrophic APS [CAPS]). An important obstetric manifestation of aPL is late pregnancy loss, commonly associated with placental vascular insufficiency. Microvascular manifestations such as diffuse alveolar hemorrhage (DAH), and non-thrombotic manifestations such as thrombocytopenia can also develop in aPLpositive patients.

The cornerstone of thrombosis treatment and recurrence prevention in APS is anticoagulation, usually with vitamin K antagonists. Direct oral anticoagulants (DOACs) are not recommended in APS, particularly in those with history of arterial thrombosis and triple aPL-positivity. Anticoagulation is not effective for microvascular and/or non-thrombotic manifestations for which immunosuppressive treatments are preferred. In parallel to our improved understanding of the pathophysiology of APS, novel treatment approaches targeting the immune components of the disease have been increasingly investigated.

In this review, we briefly discuss the basic concepts in APS, i.e., etiopathogenesis, clinical symptoms, diagnosis, and management, as well as the future perspectives. Detailed information can be found elsewhere.[1,4-6]

ETIOPATHOGENESIS

The interaction of aPL with plasma proteins, mainly β₂GPI, but also with others such as prothrombin, plasminogen, antithrombin III, protein C, protein S, annexin II and annexin V, triggers a proinflammatory state by activating endothelial cells, monocytes, platelets, neutrophils, complement system, and tissue factor.[7] Antiphospholipid antibodies also activate the hemostatic pathways by a variety of other mechanisms leading to a prothrombotic state. Despite this proinflammatory and prothrombotic state, thrombosis does not develop in all aPLpositive patients; thus, based on the “two-hit” hypothesis, additional risk factors are required for thrombosis in aPL-positive patients.[8]

Placenta is a major target particularly for β₂GPI-dependent antibodies that bind to human trophoblast. During trophoblast differentiation, phosphatidylserine is externalized, allowing β₂GPI to be expressed on the cell surface and becoming a target for aPL. Complement activation also plays a role in obstetric APS; when aPL binds with β₂GPI on trophoblastic cells, the complement system is activated through the classical pathway, causing placental injury, and eventually fetal loss and/or intrauterine growth restriction.[9]

Some of the recent findings contributing to our understanding of APS pathogenesis include: (i) aPL-induced release of neutrophil-extracellular traps (NETs) resulting in the upregulation of the coagulation cascade via activated complement system and thus, thrombosis formation (anti-NET immunoglobulin (Ig) G and/or IgM levels are higher in patients with primary APS compared to healthy controls, these antibodies are associated with recurrent venous thrombosis and, based on a recent multi-center study, almost half of the aPL-positive patients have high anti-NET IgG and/or IgM levels);[10-12] (ii) potential role of type-1 interferon activation (higher type-1 interferon levels correlate with aβ₂GPI, triple aPL positivity, and obstetric APS;[13,14] and (iii) aPL-induced upregulation of the mechanistic target of rapamycin (mTOR) complex on endothelial cells (mTOR is a kinase that plays a role in many signaling pathways regulating cell growth, proliferation, and survival), which may have a role in the pathogenesis of microvascular manifestations of APS.[15] Although multi-center and well-defined large-scale studies are lacking, a genetic association of HLA Class II alleles and non-HLA (STAT4 and C1D) genetic loci in APS has been suggested.[16] Detailed information on the etiopathogenesis of APS can be found elsewhere.[4]

CLINICAL PRESENTATION

Deep venous thrombosis (DVT), which is usually seen together with pulmonary embolism is the most common manifestation of APS. Unusual venous distributions may be affected, such as renal or splenic vein thrombosis. The most frequent arterial event is stroke, which accounts for approximately one-fourth of the APS presentations. However, arterial thrombosis may also develop at unusual locations such as peripheral and mesenteric thrombosis. Unexplained late fetal losses (beyond the 10^th week of gestation), associated with placental vascular problems such as preeclampsia or intrauterine growth restriction, is the most specific event for obstetric APS. Other manifestations such as pre-fetal losses are less specific.

Livedo reticularis, symmetrical mottling of the skin, has poor specificity and is common in healthy individuals, usually induced by the cold exposure. In contrast, livedo racemosa, broken asymmetrical mottling of the skin, is more specific for APS. Cutaneous necrosis or ulcerations may develop due to underlying livedoid vasculopathy.

Antiphospholipid antibodies can affect the entire renal vasculature (i.e., arteries, arterioles, and glomerular capillaries) resulting in large vessel thrombosis, as well as microvascular disease in intrarenal arteriolar and glomerular capillaries, leading to aPL-nephropathy.[17] Kidney biopsies in aPL-nephropathy patients can demonstrate: (i) acute thrombotic microangiopathy (TMA) lesions such as fibrin thrombi in arterioles or glomeruli without inflammatory cells or immune complexes; and (ii) chronic lesions, including organized microthrombi with/without recanalization, focal cortical atrophy, arterial fibrous intimal hyperplasia, fibrous/fibrocellular occlusions of arteries and arterioles, and chronic or organized glomerular thrombi.[18]

Valvular heart disease (vegetations and/or valve thickening) can occur in aPL-positive patients. Moreover, cardiac microthrombosis may cause symptoms similar to a coronary artery with normal coronary angiogram. Diffuse alveolar hemorrhage is a rare microvascular manifestation of aPL characterized by the red blood cell leak from alveolar capillaries into the intraalveolar space.[5]

Neurological involvement, particularly in the form of cognitive dysfunction independent of stroke, can develop in aPL-positive patients. Chorea, transverse myelitis, multiple sclerosis-like syndrome, and seizures are reported in aPLpositive patients; however, these features are rare and controversial.

Thrombocytopenia (usually >100x10⁹ /L) is usually mild and presents in 20 to 40% of APS patients.[19] Despite low platelet counts, APS patients remain at risk for thrombosis. Coombspositive autoimmune hemolytic anemia (without schistocytes) can also develop in less than 5% of patients with primary APS.[20]

Catastrophic APS is a rare, life-threatening subgroup of APS that multiple thromboses of small, medium, and large-size vessels occur over a period of days (further discussed below and elsewhere).[5]

DIAGNOSIS

Disease assessment in aPL-positive patients should start with the review of the aPL profile (Table 1), the clinical phenotype (Table 2), and additional venous thromboembolism (VTE) and cardiovascular disease (CVD) risk factors (approximately half of thrombotic APS patients have additional thrombosis risk factors at the time thrombosis).[5] Age, male sex, CVD risk factors, combined VTE risk factors, and additional systemic autoimmune diseases independently increase the risk of thrombosis in aPL-positive patients.[5] Since the laboratory and clinical findings vary widely, APS diagnosis may be challenging; overinterpretation of aPL results is relatively common. There are no diagnostic criteria for APS; thus, physician judgement is critical (see below).

Table 1. Diagnostic assessment of antiphospholipid antibody tests and profile

Table 2. Diagnostic assessment of antiphospholipid syndrome (APS)- and catastrophic antiphospholipid syndrome (CAPS)-related clinical symptoms

Catastrophic APS diagnosis can be also challenging given that: (i) half of CAPS patients do not have a prior APS or aPL positivity history;[5,21] (ii) false positivity of LA test may occur due to sepsis, ongoing anticoagulation treatment, and infection;[21] and (iii) CAPS may mimic or co-exist together with other systemic TMA syndromes (thrombocytopenia, microangiopathic hemolytic anemia, and organ failure - usually kidney), such as thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), complement-mediated TMA (CM-TMA), HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), sepsis, or heparin-induced thrombocytopenia. Detailed information on CAPS diagnosis can be found elsewhere.[5,22]

CLASSIFICATION

Classification criteria aim to specify homogeneous cohorts of patients for clinical and translational research, while the goal of diagnostic criteria is to identify all patients with a specific condition, including those with rare and atypical clinical manifestations of the disease.[1] Thus, classification criteria should not be used for diagnosis; however, they can serve as a guide while evaluating aPL-positive patients. Based on the revised Sapporo APS Classification Criteria, at least one clinical (thrombotic or obstetric) and one laboratory (aPL) criterion are required APS (Table 2).[23] The new APS classification criteria, supported by the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) are expected to be published this year.[24,25]

Catastrophic APS classification criteria define definite CAPS as thromboses in ≥3 organs developing in less than a week, microvascular thrombosis in ≥1 organ, and persistent aPL positivity. When only three of four requirements are met, a patient can be classified as probable CAPS (Table 2).[22] Similarly, CAPS classification criteria should not be used for diagnosis; however, they can serve as a guide while evaluating aPLpositive patients with multi-organ thrombosis.

PREVENTION AND TREATMENT

Primary thrombosis prevention

The first step in prevention is the modification of reversible VTE (such as estrogen therapy) and CVD risk factors (such as hypertension), prophylaxis during high thrombosis risk periods (such as surgical interventions), and optimal management of other systemic autoimmune diseases.

Low-dose aspirin (LDA) is not beneficial for primary thrombosis prevention based on a placebo-controlled randomized-controlled trial (RCT), as well as prospective cohort studies.[26] Nevertheless, LDA is prescribed by some physicians based on retrospective data implying that it may be protective against first thrombosis.[27] Risk stratification based on the aPL profile and concomitant risk factors is important before LDA is initiated.[28,29] Our approach is to use LDA in aPL-positive patients with additional CVD risk factors.

Hydroxychloroquine (HCQ) has antithrombotic effects in mouse models and in SLE patients through multiple mechanisms including protecting annexin A5 shield from aPL-related disruption.[30-32] However, there are no prospective, controlled studies showing the efficacy of HCQ for primary thrombosis prevention in aPL-positive patients. Our approach is to use HCQ in patients aPL-positive patients, if they have with lupus or lupus-like disease.

Secondary thrombosis prevention

Warfarin remains the cornerstone for longterm recurrent thrombosis prevention in APS patients with a target international normalized ratio (INR) of 2 to 3. Despite retrospective cohort studies demonstrating that high-intensity (INR 3-4) anticoagulation is more effective than moderate intensity (INR 2-3), two prospective RCTs of moderate- versus high-intensity warfarin did not show any difference between the treatment groups in the prevention of recurrent thrombosis.[33,34] Since the number of APS patients with arterial events were relatively low in these two RCTs, high-intensity anticoagulation is still preferred by some centers. Our approach for secondary thrombosis prevention in APS is warfarin with a target INR of 2.5 to 3, adding LDA if patients have additional CVD risk factors.

In patients who experience recurrent thrombosis despite therapeutic range INR, options include higher-intensity warfarin (INR 3-4) or switching to low-molecular-weight heparin (LMWH). Additional LDA, HCQ, a statin drug, or a combination of these drugs is also commonly used.

Direct oral anticoagulants are currently not recommended for secondary thrombosis in APS. An open-label, non-inferiority RCT of aPL-positive VTE patients demonstrated that rivaroxaban was inferior to warfarin with respect to the percentage change in endogenous thrombin potential (a quantitative measurement of thrombin generation) on Day 42, which was the primary outcome measure of the study.[35] However, no patients in either group developed thrombosis or major bleeding during the sixmonth safety period. A subsequent open-label, multi-center, non-inferiority RCT (warfarin vs. rivaroxaban), investigating triple aPL-positive patients with history of arterial or venous thrombosis, was terminated early due to the increased risk of thrombosis and bleeding in the rivaroxaban group.[36] A three-year open-label randomized non-inferiority study of rivaroxaban vs. warfarin demonstrated approximately two times increased risk of recurrent thrombosis, particularly arterial thrombosis and stroke, in the rivaroxaban group, although it was not statistically significant.[37] An RCT of apixaban vs. warfarin was terminated early due to the higher occurrence of stroke in patients randomized to apixaban (6/23 patients) compared to warfarin group (0/25).[38] Thus, as emphasized by the 16^th International Congress on aPL Task Force on Treatment Trends, DOACs should be avoided in APS patients with arterial thrombosis, and in patients with recurrent thrombosis while on standard intensity warfarin.[39] In triple aPLpositive thrombotic APS patients, if the patient is already on DOAC following the first VTE, then switching to vitamin K antagonists is recommended. If a patient declines the switch, close clinical surveillance while on DOAC is important, which also includes the magnetic resonance imaging of the brain for ischemic lesions.[39]

Microvascular and non-thrombotic manifestations

There is no uniform approach to the management of microvascular APS due to heterogeneous organ involvement, and the lack of controlled studies and strong literature supporting any treatment strategy.[5] Microvascular manifestations of APS do not respond to anticoagulation, and may develop while patients are on therapeutic anticoagulation. Given the increasing awareness of the mechanisms involved in APS pathogenesis as discussed above, both glucocorticoids and immunosuppressive agents (traditional agents such as azathioprine or mycophenolate mofetil [MMF], or biologic agents such as rituximab [RTX] or eculizumab) are increasingly used in the management of patients with microvascular disease or non-thrombotic manifestations, mostly based on case reports or series.[40-42] Details are discussed elsewhere.[6]

Rituximab is a monoclonal antibody against CD-20 on B-cells, which causes depletion of CD-20 expressing B-cells.[43] A small (n=19) openlabel study of RTX for aPL-positive patients with thrombocytopenia or microvascular disease demonstrated no change in the aPL profile during 12 months of follow-up; however, some patients with thrombocytopenia, aPL-nephropathy, skinulcers, and cognitive dysfunction had complete or partial response without major adverse events.[44] Belimumab, which is a B-lymphocyte stimulator neutralizing monoclonal antibody, was used in two primary APS patients with DAH and recurrent skin ulcers with a partial clinical response.[45]

Eculizumab is a C5 monoclonal antibody and is approved for the treatment of atypical hemolytic uremic syndrome and paroxysmal nocturnal hematuria.[46] When eculizumab binds to complement protein C5, it inhibits its cleavage to C5a and C5b and prevents the assembly of terminal complement complex C5b-9. In several case reports or studies, eculizumab was shown to be effective for the improvement of thrombocytopenia, hemolytic anemia, and renal function in APS patients with systemic TMA.[46,47]

In a study of APS patients requiring renal transplantation, the inhibition of mTOR pathway by sirolimus prevented the recurrence of vascular lesions by inhibiting the vascular proliferation, and improved the survival of the renal allografts.[15] A recent case report also showed that sirolimus successfully inhibited the mTOR pathway, and was associated with significant improvement in kidney function and kidney findings in a patient with active aPLnephropathy.[48]

Our approach for the management of selected microvascular and non-thrombotic manifestations can be summarized as follows:[5] (i) for DAH and aPL-nephropathy, glucocorticoids, MMF with/without RTX, and adding intravenous IG (IVIG) for DAH and switching to sirolimus for aPL-nephropathy if the disease activity persists; (ii) for livedoid vasculopathy-related skin ulcers, RTX; (iii) for platelet counts less than 50x10⁹/L, glucocorticoids, IVIG, and/or RTX; and (iv) for hemolytic anemia, glucocorticoids with RTX, azathioprine, or MMF.

In all aPL-positive patients with microvascular disease, despite the lack of strong clinical support, adding HCQ as discussed above and a statin drug to the main treatment regimen should be considered. In mouse models, fluvastatin reduced the leucocyte adhesion to endothelial cells, and also the thrombus size.[49] Although there are no controlled data to show the efficacy of statins on primary or secondary prevention in APS patients with normal lipid levels, they may be beneficial as a concomitant therapy for patients with anticoagulant-refractory disease.[39] Of note, a recent meta-analysis did not show an association between congenital malformation and statins; however, statins are still accepted to be teratogenic and contraindicated during pregnancy.[39,50]

CATASTROPHIC APS

Catastrophic APS management requires a multidisciplinary team approach. Early treatment is critical; the highest survival rate is achieved with the combination of anticoagulation (unfractionated intravenous heparin), glucocorticoids, and plasma exchange and/or IVIG.[5]

Based on the McMaster RARE-Best Practices Clinical Practice Guideline on the diagnosis and management of CAPS, for first-line treatment, combination therapy with heparin, glucocorticoids, and either IVIG or plasma exchange is recommended over single agents or other combinations of therapies.[51] Given the small number of CAPS patients treated with rituximab and based on limited data on long-term outcomes, the guideline does not recommend rituximab for the first-line treatment. However, rituximab use was supported by the panel members in refractory cases and in those with thrombocytopenia.[51]

Our approach for CAPS management is also anticoagulation, glucocorticoids, and IVIG and/or plasma exchange. If clinical improvement is not achieved, second-line treatment depends on if a patient has prominent systemic TMA symptoms, microvascular disease, and/or thrombocytopenia. Complement inhibition is chosen for those with well-defined systemic TMA, whereas RTX is preferred for those without systemic TMA but with microvascular disease or thrombocytopenia.[5]

OBSTETRIC MANIFESTATIONS

In patients with obstetric APS who have not experienced thrombosis, LDA and prophylactic doses of LMWH during pregnancy, and in the 8- to 12-week postpartum period are recommended. In women with a history of thrombosis and APS, LDA and therapeutic dose LMWH should be used during pregnancy, even in the absence of any history of pregnancy complications. In aPL-positive patients who have never experienced pregnancy complications or thromboses, a prophylactic dose of LMWH is recommended during the 8- to 12-week postpartum period, but not during pregnancy. Low-dose aspirin has been generally used in this setting without strong supportive prospective data.

FUTURE DIRECTIONS

There have been ongoing efforts to develop new APS classification criteria,[24] disease activity index, as well as updating the current APS damage index.[52] All these efforts are expected to increase the quality of APS research, with the ultimate goal of improving patient care, and the number of APS clinical trials. Based on mouse models and/or case reports, anti-tumor necrosis factor (TNF) agents,[53] daratumumab (anti-CD38 human monoclonal antibody targeting CD38 molecule on plasmablasts and plasma cells; approved for multiple myeloma),[54] chimeric antigen receptor T-cell (CART) therapy,[55] adenosine receptor agonists such as defibrotide and dipyridamole,[56] and coenzyme Q10[57] were suggested as potential future treatments.

Two ongoing APS clinical trials that deserve attention:

• The IMProve Pregnancy in APS with Certolizumab Therapy (IMPACT: ClinicalTrials.gov Identifier: NCT031 52058) in patients with obstetric APS investigating the efficacy of an anti-TNF agent in obstetric APS (increased levels of TNF-α is associated with pregnancy loss in mouse models;[58] a case series of 18 anti-TNF-treated [16 adalimumab and 2 certolizumab] obstetric APS patients [despite LMWH, LDA, and HCQ] showed favorable obstetric outcomes in 70% of patients without any congenital malformations.[53]

• A Phase 1b open-label study of daratumumab in APS (DARE-APS: ClinicalTrials.gov Identifier: NCT05671757) (daratumumab resulted in clinical improvement and significant reduction in anti-double stranded levels in two SLE patients;[59] another SLE patient with cerebral vasculitis was successfully treated with daratumumab without any significant adverse effects;[60] and a triple aPL-positive patient with refractory VTE despite anticoagulation received daratumumab and plasma exchange in addition to heparin [there was partial improvement of aPL]).[54]

Conclusion

In conclusion, APS is a thromboinflammatory syndrome with systemic clinical manifestations. Primary thrombosis prevention needs a riskstratified approach and LDA is considered in selected patients with additional CV risk factors. Anticoagulation remains as the cornerstone of thrombosis treatment and recurrence prevention; however, DOACs are not recommended. With our increasing knowledge on APS pathogenesis and molecular mechanisms, novel immunosuppressive approaches are emerging, particularly for patients with microvascular disease.

Citation: Keleşoğlu Dinçer AB, Erkan D. The ABCs of antiphospholipid syndrome. Arch Rheumatol 2023;38(2):163-173. doi: 10.46497/ArchRheumatol.2023.41875.

All authors contributed equally to the article.

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

The authors received no financial support for the research and/or authorship of this article.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

1. Garcia D, Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med 2018;378:2010-21. doi: 10.1056/NEJMra1705454. DOI: 10.1056/NEJMra1705454
2. Ioannou Y, Beukelman T, Murray M, Erkan D. Incidence of antiphospholipid syndrome: Is estimation currently possible? Eur J Rheumatol 2023;10:39-44. doi: 10.5152/eurjrheum.2023.22012. DOI: 10.5152/eurjrheum.2023.22012
3. Duarte-García A, Pham MM, Crowson CS, Amin S, Moder KG, Pruthi RK, et al. The epidemiology of antiphospholipid syndrome: A population-based study. Arthritis Rheumatol 2019;71:1545-52. doi: 10.1002/art.40901. DOI: 10.1002/art.40901
4. Knight JS, Branch DW, Ortel TL. Antiphospholipid syndrome: Advances in diagnosis, pathogenesis, and management. BMJ 2023;380:e069717. doi: 10.1136/bmj-2021-069717. DOI: 10.1136/bmj-2021-069717
5. Erkan D. Expert perspective: Management of microvascular and catastrophic antiphospholipid syndrome. Arthritis Rheumatol 2021;73:1780-90. doi: 10.1002/art.41891. DOI: 10.1002/art.41891
6. Erton ZB, Erkan D. Treatment advances in antiphospholipid syndrome: 2022 update. Curr Opin Pharmacol 2022;65:102212. doi: 10.1016/j. coph.2022.102212. DOI: 10.1016/j.coph.2022.102212
7. Zuo Y, Shi H, Li C, Knight JS. Antiphospholipid syndrome: A clinical perspective. Chin Med J (Engl) 2020;133:929-40. doi: 10.1097/ CM9.0000000000000705. DOI: 10.1097/CM9.0000000000000705
8. Meroni PL, Riboldi P. Pathogenic mechanisms mediating antiphospholipid syndrome. Curr Opin Rheumatol 2001;13:377-82. doi: 10.1097/00002281- 200109000-00006. DOI: 10.1097/00002281-200109000-00006
9. Rote NS, Vogt E, DeVere G, Obringer AR, Ng AK. The role of placental trophoblast in the pathophysiology of the antiphospholipid antibody syndrome. Am J Reprod Immunol 1998;39:125-36. doi: 10.1111/ j.1600-0897.1998.tb00344.x. DOI: 10.1111/j.1600-0897.1998.tb00344.x
10. Yalavarthi S, Gould TJ, Rao AN, Mazza LF, Morris AE, Núñez-Álvarez C, et al. Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: A newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol 2015;67:2990-3003. doi: 10.1002/art.39247. DOI: 10.1002/art.39247
11. Zuo Y, Yalavarthi S, Gockman K, Madison JA, Gudjonsson JE, Kahlenberg JM, et al. Anti-neutrophil extracellular trap antibodies and impaired neutrophil extracellular trap degradation in antiphospholipid syndrome. Arthritis Rheumatol 2020;72:2130-5. doi: 10.1002/art.41460. DOI: 10.1002/art.41460
12. Zuo Y, Navaz S, Tsodikov A, Kmetova K, Kluge L, Ambati A, et al. Anti-neutrophil extracellular trap antibodies in antiphospholipid antibodypositive patients: Results from the Antiphospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking Clinical database and repository. Arthritis Rheumatol 2023. doi: 10.1002/ art.42489.
13. Grenn RC, Yalavarthi S, Gandhi AA, Kazzaz NM, Núñez-Álvarez C, Hernández-Ramírez D, et al. Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome. Ann Rheum Dis 2017;76:450-7. doi: 10.1136/annrheumdis-2016-209442. DOI: 10.1136/annrheumdis-2016-209442
14. Palli E, Kravvariti E, Tektonidou MG. Type I interferon signature in primary antiphospholipid syndrome: Clinical and laboratory associations. Front Immunol 2019;10:487. doi: 10.3389/fimmu.2019.00487. DOI: 10.3389/fimmu.2019.00487
15. Canaud G, Bienaimé F, Tabarin F, Bataillon G, Seilhean D, Noël LH, et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med 2014;371:303-12. doi: 10.1056/ NEJMoa1312890. DOI: 10.1056/NEJMoa1312890
16. Ortiz-Fernández L, Sawalha AH. Genetics of antiphospholipid syndrome. Curr Rheumatol Rep 2019;21:65. doi: 10.1007/s11926-019-0869-y. DOI: 10.1007/s11926-019-0869-y
17. Scheen M, Adedjouma A, Esteve E, Buob D, Abisror N, Planche V, et al. Kidney disease in antiphospholipid antibody syndrome: Risk factors, pathophysiology and management. Autoimmun Rev 2022;21:103072. doi: 10.1016/j.autrev.2022.103072. DOI: 10.1016/j.autrev.2022.103072
18. Barbhaiya M, Taghavi M, Zuily S, Domingues V, Chock EY, Tektonidou M, et al. Efforts to Better Characterize “Antiphospholipid Antibody Nephropathy” for the New Antiphospholipid Syndrome Classification Criteria: Renal Pathology Subcommittee Report. J Rheum 2023 [In Press] DOI: 10.3899/jrheum.2022-1200
19. El Hasbani G, Saliba AN, Uthman I, Taher AT. Hematological manifestations of antiphospholipid syndrome: Going beyond thrombosis. Blood Rev 2023;58:101015. doi: 10.1016/j.blre.2022.101015. DOI: 10.1016/j.blre.2022.101015
20. Ames PRJ, Merashli M, Bucci T, Pastori D, Pignatelli P, Arcaro A, et al. Antiphospholipid antibodies and autoimmune haemolytic anaemia: A systematic review and meta-analysis. Int J Mol Sci 2020;21:4120. doi: 10.3390/ijms21114120. DOI: 10.3390/ijms21114120
21. Vora SK, Asherson RA, Erkan D. Catastrophic antiphospholipid syndrome. J Intensive Care Med 2006;21:144-59. doi: 10.1177/0885066606287041. DOI: 10.1177/0885066606287041
22. Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic antiphospholipid syndrome: International consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530-4. doi: 10.1191/0961203303lu394oa. DOI: 10.1191/0961203303lu394oa
23. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306. doi: 10.1111/j.1538- 7836.2006.01753.x. DOI: 10.1111/j.1538-7836.2006.01753.x
24. Barbhaiya M, Zuily S, Ahmadzadeh Y, Amigo MC, Avcin T, Bertolaccini ML, et al. Development of a new international antiphospholipid syndrome classification criteria phase I/II report: Generation and reduction of candidate criteria. Arthritis Care Res (Hoboken) 2021;73:1490-501. doi: 10.1002/ acr.24520. DOI: 10.1002/acr.24520
25. Barbhaiya M, Zuily S, Naden R, Hendry A, Manneville F, Alessandro C, et al. 2023 ACR/ EULAR Antiphospholipid Syndrome Classification Criteria. Arthritis & Rheum 2023 [In Press] DOI: 10.1136/ard-2023-225074
26. Erkan D, Harrison MJ, Levy R, Peterson M, Petri M, Sammaritano L, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: A randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals. Arthritis Rheum 2007;56:2382-91. doi: 10.1002/art.22663. DOI: 10.1002/art.22663
27. Arnaud L, Mathian A, Ruffatti A, Erkan D, Tektonidou M, Cervera R, et al. Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: An international and collaborative meta-analysis. Autoimmun Rev 2014;13:281-91. doi: 10.1016/j.autrev.2013.10.014. DOI: 10.1016/j.autrev.2013.10.014
28. Zuo Y, Barbhaiya M, Erkan D. Primary thrombosis prophylaxis in persistently antiphospholipid antibodypositive individuals: Where do we stand in 2018? Curr Rheumatol Rep 2018;20:66. doi: 10.1007/s11926- 018-0775-8. DOI: 10.1007/s11926-018-0775-8
29. Tektonidou MG, Andreoli L, Limper M, Amoura Z, Cervera R, Costedoat-Chalumeau N, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019;78:1296-304. doi: 10.1136/ annrheumdis-2019-215213. DOI: 10.1136/annrheumdis-2019-215213
30. Edwards MH, Pierangeli S, Liu X, Barker JH, Anderson G, Harris EN. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation 1997;96:4380-4. doi: 10.1161/01.cir.96.12.4380. DOI: 10.1161/01.CIR.96.12.4380
31. Tektonidou MG, Laskari K, Panagiotakos DB, Moutsopoulos HM. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum 2009;61:29-36. doi: 10.1002/art.24232. DOI: 10.1002/art.24232
32. Rand JH, Wu XX, Quinn AS, Ashton AW, Chen PP, Hathcock JJ, et al. Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: Evidence for a novel effect for an old antimalarial drug. Blood 2010;115:2292-9. doi: 10.1182/blood-2009-04-213520. DOI: 10.1182/blood-2009-04-213520
33. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003;349:1133-8. doi: 10.1056/NEJMoa035241. DOI: 10.1056/NEJMoa035241
34. Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, et al. 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 2005;3:848- 53. doi: 10.1111/j.1538-7836.2005.01340.x. DOI: 10.1111/j.1538-7836.2005.01340.x
35. Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): A randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016;3:e426-36. doi: 10.1016/S2352-3026(16)30079-5. DOI: 10.1016/S2352-3026(16)30079-5
36. Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, et al. Rivaroxaban vs warfarin in highrisk patients with antiphospholipid syndrome. Blood 2018;132:1365-71. doi: 10.1182/blood-2018-04- 848333. DOI: 10.1182/blood-2018-04-848333
37. Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, Vidal X, Riera-Mestre A, Castro-Salomó A, et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: A randomized noninferiority trial. Ann Intern Med 2019;171:685-694. doi: 10.7326/M19-0291. DOI: 10.7326/M19-0291
38. Woller SC, Stevens SM, Kaplan D, Wang TF, Branch DW, Groat D, et al. Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: A randomized trial. Blood Adv 2022;6:1661- 70. doi: 10.1182/bloodadvances.2021005808. DOI: 10.1182/bloodadvances.2021005808
39. Cohen H, Cuadrado MJ, Erkan D, Duarte-Garcia A, Isenberg DA, Knight JS, et al. 16th International Congress on Antiphospholipid Antibodies task force report on antiphospholipid syndrome treatment trends. Lupus 2020;29:1571-93. doi: 10.1177/0961203320950461. DOI: 10.1177/0961203320950461
40. Niki T, Kawamura Y. Hematological remission of primary myelofibrosis with antiphospholipid antibody following treatment of azathioprine. Rinsho Ketsueki 1995;36:141-6.
41. Alba P, Karim MY, Hunt BJ. Mycophenolate mofetil as a treatment for autoimmune haemolytic anaemia in patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus 2003;12:633-5. doi: 10.1191/0961203303lu419cr. DOI: 10.1191/0961203303lu419cr
42. Agmon-Levin N, Berman M, Harel L, Lidar M, Drori T, Hajyahia S, et al. Rituximab for refractory manifestations of the antiphospholipid syndrome: A multicentre Israeli experience. Clin Exp Rheumatol 2021;39:1049-55. doi: 10.55563/clinexprheumatol/ cc5taf. DOI: 10.55563/clinexprheumatol/cc5taf
43. van den Hoogen LL, Bisoendial RJ. B-cells and BAFF in primary antiphospholipid syndrome, targets for therapy? J Clin Med 2022;12:18. doi: 10.3390/ jcm12010018. DOI: 10.3390/jcm12010018
44. Erkan D, Vega J, Ramón G, Kozora E, Lockshin MD. A pilot open-label phase II trial of rituximab for noncriteria manifestations of antiphospholipid syndrome. Arthritis Rheum 2013;65:464-71. doi: 10.1002/ art.37759. DOI: 10.1002/art.37759
45. Yazici A, Yazirli B, Erkan D. Belimumab in primary antiphospholipid syndrome. Lupus 2017;26:1123-4. doi: 10.1177/0961203316682102. DOI: 10.1177/0961203316682102
46. Wright RD, Bannerman F, Beresford MW, Oni L. A systematic review of the role of eculizumab in systemic lupus erythematosus-associated thrombotic microangiopathy. BMC Nephrol 2020;21:245. doi: 10.1186/s12882-020-01888-5. DOI: 10.1186/s12882-020-01888-5
47. Kello N, Khoury LE, Marder G, Furie R, Zapantis E, Horowitz DL. Secondary thrombotic microangiopathy in systemic lupus erythematosus and antiphospholipid syndrome, the role of complement and use of eculizumab: Case series and review of literature. Semin Arthritis Rheum 2019;49:74-83. doi: 10.1016/j. semarthrit.2018.11.005. DOI: 10.1016/j.semarthrit.2018.11.005
48. Dufour I, Venot Q, Aydin S, Demoulin N, Canaud G, Morelle J. mTORC pathway activation and effect of sirolimus on native kidney antiphospholipid syndrome nephropathy: A case report. Am J Kidney Dis 2020;76:288-91. doi: 10.1053/j. ajkd.2019.08.032. DOI: 10.1053/j.ajkd.2019.08.032
49. Ferrara DE, Liu X, Espinola RG, Meroni PL, Abukhalaf I, Harris EN, et al. Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model. Arthritis Rheum 2003;48:3272-9. doi: 10.1002/ art.11449. DOI: 10.1002/art.11449
50. Karalis DG, Hill AN, Clifton S, Wild RA. The risks of statin use in pregnancy: A systematic review. J Clin Lipidol 2016;10:1081-90. doi: 10.1016/j. jacl.2016.07.002. DOI: 10.1016/j.jacl.2016.07.002
51. Legault K, Schunemann H, Hillis C, Yeung C, Akl EA, Carrier M, et al. McMaster RARE-Bestpractices clinical practice guideline on diagnosis and management of the catastrophic antiphospholipid syndrome. J Thromb Haemost 2018;16:1656-64. doi: 10.1111/ jth.14192. DOI: 10.1111/jth.14192
52. Amigo MC, Goycochea-Robles MV, Espinosa-Cuervo G, Medina G, Barragán-Garfias JA, Vargas A, et al. Development and initial validation of a damage index (DIAPS) in patients with thrombotic antiphospholipid syndrome (APS). Lupus 2015;24:927-34. doi: 10.1177/0961203315576858. DOI: 10.1177/0961203315576858
53. Alijotas-Reig J, Esteve-Valverde E, Llurba E, Gris JM. Treatment of refractory poor aPL-related obstetric outcomes with TNF-alpha blockers: Maternalfetal outcomes in a series of 18 cases. Semin Arthritis Rheum 2019;49:314-318. doi: 10.1016/j. semarthrit.2019.02.006. DOI: 10.1016/j.semarthrit.2019.02.006
54. Pleguezuelo DE, Díaz-Simón R, Cabrera-Marante O, Lalueza A, Paz-Artal E, Lumbreras C, et al. Case report: Resetting the humoral immune response by targeting plasma cells with daratumumab in anti-phospholipid syndrome. Front Immunol 2021;12:667515. doi: 10.3389/fimmu.2021.667515. DOI: 10.3389/fimmu.2021.667515
55. Schmelz JL, Navsaria L, Goswamy R, Chuang HH, Miranda RN, Lee HJ. Chimeric antigen receptor T-cell therapy's role in antiphospholipid syndrome: A case report. Br J Haematol 2020;188:e5-e8. doi: 10.1111/ bjh.16266. DOI: 10.1111/bjh.16266
56. Ali RA, Estes SK, Gandhi AA, Yalavarthi S, Hoy CK, Shi H, et al. Defibrotide inhibits antiphospholipid antibody-mediated neutrophil extracellular trap formation and venous thrombosis. Arthritis Rheumatol 2022;74:902-7. doi: 10.1002/art.42017. DOI: 10.1002/art.42017
57. Pérez-Sánchez C, Aguirre MÁ, Ruiz-Limón P, Ábalos-Aguilera MC, Jiménez-Gómez Y, Arias-de la Rosa I, et al. Ubiquinol effects on antiphospholipid syndrome prothrombotic profile: A randomized, placebo-controlled trial. Arterioscler Thromb Vasc Biol 2017;37:1923-32. doi: 10.1161/ ATVBAHA.117.309225. DOI: 10.1161/ATVBAHA.117.309225
58. Gelber SE, Brent E, Redecha P, Perino G, Tomlinson S, Davisson RL, et al. Prevention of defective placentation and pregnancy loss by blocking innate immune pathways in a syngeneic model of placental insufficiency. J Immunol 2015;195:1129-38. doi: 10.4049/jimmunol.1402220. DOI: 10.4049/jimmunol.1402220
59. Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, et al. Targeting CD38 with daratumumab in refractory systemic lupus erythematosus. N Engl J Med 2020;383:1149-55. doi: 10.1056/NEJMoa2023325. DOI: 10.1056/NEJMoa2023325
60. Yalcin Mutlu M, Wacker J, Tascilar K, Taubmann J, Manger B, Krönke G, et al. Effective and safe treatment of anti-CD38 therapy in systemic lupus erythematosus-associated refractory cerebral vasculitis induces immune tolerance. Rheumatology (Oxford) 2023;62:e21-e23. doi: 10.1093/ rheumatology/keac393. DOI: 10.1093/rheumatology/keac393