INTRODUCTION — Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent thrombosis and obstetric morbidity. Sometimes other manifestations such as thrombocytopenia and cardiac valve disease are present. Beyond clinical manifestations, classification criteria for APS require the persistent presence of antiphospholipid antibodies (aPL) as measured by at least one of three tests [1]:
●Lupus anticoagulant (LA) testing using a method that detects aPL interference in phospholipid-dependent functional clotting assays such as the activated partial thromboplastin time (aPTT) or dilute Russell viper venom time.
●An immunoassay for anti-beta2 glycoprotein I (anti-beta2GPI) antibodies (immunoglobulin [Ig]G or IgM).
●An immunoassay for anticardiolipin (aCL) antibodies (IgG or IgM).
APS-related thrombosis may affect vascular beds of all sizes including both arterial and venous circuits. The deep veins of the lower extremities and the cerebral circulation are the most common sites of venous and arterial thrombosis, respectively [2]. Thrombosis may also occur in unusual sites including visceral arteries and veins and the cerebral venous sinuses.
In a minority of patients, microvascular thrombosis affects microvessels in the kidney, skin, lungs, heart, eye, and other organs. Approximately 1 percent of patients develop catastrophic APS (CAPS) [3,4]. (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Definitions'.)
Obstetric complications of APS include recurrent early pregnancy losses, fetal demise beyond 10 weeks, and premature births associated with preeclampsia or placental insufficiency [1]. Other clinical findings such as thrombocytopenia, livedo reticularis/racemosa, skin ulcers, mitral and aortic valve damage, transient ischemic attacks, seizures, and premature cognitive decline may also occur in patients with APS, but are considered "non-criteria" manifestations [2].
It is generally accepted that aPL, particularly anti-beta2GPI antibodies, are central to the pathogenesis of APS. Multiple mechanisms by which aPL may induce thrombosis or obstetric morbidity have been identified and are discussed in this topic review. However, the extent to which the various distinct manifestations of APS are reflective of antibody heterogeneity or can be explained by a common central pathway remains unresolved.
For information on diagnosis, clinical manifestations, and treatment of APS and CAPS, as well as APS in pregnancy, refer to separate topic reviews:
●Diagnosis – (See "Diagnosis of antiphospholipid syndrome".)
●Clinical features – (See "Clinical manifestations of antiphospholipid syndrome".)
●Kidney manifestations – (See "Antiphospholipid syndrome and the kidney".)
●Management – (See "Management of antiphospholipid syndrome".)
●CAPS diagnosis and management – (See "Catastrophic antiphospholipid syndrome (CAPS)".)
●Pregnancy – (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)
ROLE OF ANTIPHOSPHOLIPID ANTIBODIES — Antiphospholipid antibodies (aPL) were originally thought to bind anionic phospholipids such as cardiolipin and phosphatidylserine (PS). However, it was subsequently recognized that the term "antiphospholipid" is a misnomer, since the best-characterized aPL are actually directed against specific phospholipid-binding proteins [5]. The most prominent of these proteins is beta2 glycoprotein I (beta2GPI). Anti-beta2GPI antibodies appear to be central to the pathogenesis of antiphospholipid syndrome (APS) [6,7]; however, other antigenic targets such as prothrombin (PT), PS/PT complexes, vimentin/cardiolipin complexes, annexin A2, and annexin A5 have been described [8-12].
Lupus anticoagulant — The so-called "lupus anticoagulant" (LA) effect is a functional property of a heterogenous group of antibodies, with its name derived from its original description in patients with systemic lupus erythematosus (SLE). Antibodies with LA activity interfere with clotting in in vitro assays and prolong phospholipid-dependent clotting times such as the activated partial thromboplastin time (aPTT). The first two patients with this finding also had a hemorrhagic diathesis [13]. This finding led to the initial mistaken impression that the antibodies had an anticoagulant effect, when in fact they are most commonly prothrombotic. LA activity is strongly associated with thrombosis and pregnancy loss [14-16]. (See "Clinical use of coagulation tests", section on 'Lupus anticoagulant tests'.)
Antibodies against beta2GPI or PT are the most common cause of an LA effect [17]. Overall, LA associated with anti-beta2GPI antibodies appears to confer greater thrombotic risk than does beta2GPI-independent LA (odds ratio [OR] 42.3, 95% CI 9.9-194.3, versus 1.6, 95% CI 0.8-3.9) [18]. Furthermore, the risk of thrombosis increases with the number of positive tests for aPL. In particular, patients with positive tests for LA, anticardiolipin (aCL) antibodies, and anti-beta2GPI antibodies (referred to as "triple positive" APS) have a higher risk of a first or recurrent thrombotic event than patients having only one or two positive tests [19-22]. (See "Management of antiphospholipid syndrome", section on 'Risk of a first thrombosis with aPL'.)
Anti-beta2 glycoprotein I antibodies — Beta2GPI is the best-defined antigenic target of pathogenic aPL. Anti-beta2GPI antibodies are associated with both thrombosis and pregnancy loss in individuals with APS [6,15]. Affinity-purified anti-beta2GPI antibodies also potentiate thrombosis in mice [23].
Beta2GPI is a circulating glycoprotein. The crystal structure has demonstrated a series of five "sushi" domains arranged like beads on a string in a "J"-shaped molecule that includes four complement control domains followed by a positively charged fifth domain that associates with phospholipids [24].
These beta2GPI domains exist in at least two configurations [25]:
●Closed configuration – A closed/circular form circulates in plasma. In this form, domain 5 associates with domain 1, essentially hiding domain 1 from autoantibodies.
●Open configuration – An open conformation is created when domain 5 binds to anionic phospholipids on the surface of various cells (endothelial cells, monocytes, platelets). This "opens" the molecule into a linear string, exposing domain 1 and allowing the binding of the aPL autoantibodies.
The presence of the closed configuration of beta2GPI that cannot be bound by autoantibodies in the circulation may explain the absence of circulating beta2GPI-containing immune complexes in patients with APS. Antibodies directed against beta2GPI appear to recognize beta2GPI only when it binds to anionic surfaces and assumes the open conformation, although the mechanisms underlying this conformational change are poorly understood [26].
Subsequent studies have suggested that domain 1-specific beta2GPI antibodies are the aPL most likely to cause thrombosis. IgG antibodies against the Gly40-Arg43 epitope in domain 1 (referred to as anti-beta2GPI-domain 1 antibodies) often cause the LA effect. (See 'Lupus anticoagulant' above.)
Anti-beta2GPI-domain 1 antibodies are more strongly associated with both thrombosis and obstetric morbidity than are antibodies directed against other regions of beta2GPI [27,28]. Anti-beta2GPI-domain 1 antibodies are also more likely to persist at 12 weeks [29] and to associate with triple positivity [30].
The clinical significance of IgA isotypes of anti-beta2GPI and aCL remains under investigation, and these antibodies are not included in the classification criteria for APS (see "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing' and "Diagnosis of antiphospholipid syndrome", section on 'Classification criteria'). IgA antibodies from patients with APS have been shown to induce thrombosis in a mouse model [31]. IgA anti-beta2GPI have also been associated with thrombotic events, particularly in individuals with SLE [32,33].
Non-criteria autoantibodies — Antibodies against other targets have been identified in patients with APS. These antibodies are not included in the classification criteria for APS (unless they act as an LA), and their role in APS pathogenesis is under study. (See "Diagnosis of antiphospholipid syndrome", section on 'Classification criteria'.)
●Other phospholipid-binding proteins – aPL directed against a variety of other phospholipid-binding proteins and phospholipid/protein complexes have been detected in sera of patients with APS. These proteins include:
•PT and PS/PT complexes [34-36]
•Phosphatidylethanolamine (PE) [37]
•Annexin A2 [8,9]
•Annexin A5 [10]
•Vimentin/cardiolipin complexes [11]
•Endosomal lysobisphosphatidic acid (LBPA) associated with the endothelial receptor for protein C (endothelial protein C receptor [EPCR]) [38]
Some of these antibodies, particularly anti-PS/PT, have been associated with thrombosis and LA activity [39,40]. However, the clinical significance of most non-criteria aPL remains uncertain. Rigorous mechanistic studies are lacking.
●Neutrophil extracellular traps – Neutrophil extracellular traps (NETs) are structures released from dying neutrophils that have antimicrobial properties. (See "An overview of the innate immune system", section on 'Neutrophil extracellular traps'.)
Anti-NET antibodies have been identified at higher levels in patients with aPLs and APS when compared with healthy controls [41]. In a cohort of patients with persistently elevated aPLs and/or APS, positive testing for anti-NET IgG was associated with white matter lesions in the brain, even after adjusting for other aPLs (odds ratio 11, 95% CI 1.9-62) [41]. The level of anti-NET IgM was inversely correlated with levels of complement components C3 and C4, and serum with high anti-NET IgM levels had higher C3d deposition on NETs compared with serum from controls, suggesting that anti-NET IgM may activate the complement cascade. (See 'Activation of vascular and immune cells' below and 'Complement activation' below.)
MECHANISMS OF THROMBOTIC ANTIPHOSPHOLIPID SYNDROME — The earliest identified prothrombotic effects of antiphospholipid antibodies (aPL) were inhibition of natural anticoagulant systems [42], along with other direct procoagulant and antifibrinolytic properties [43]. However, subsequent studies indicate that aPL-induced activation of several types of cells, resulting in multiple procoagulant and proinflammatory effects, and activation of complement are the major drivers of the vascular and obstetric complications of antiphospholipid syndrome (APS). The major pathogenic mechanisms are summarized in a table (table 1) and discussed further below.
Activation of vascular and immune cells — Activation of vascular and immune cells by aPL potentiates thrombosis through upregulation of surface adhesion molecules and release of proinflammatory cytokines and procoagulant substances including extracellular vesicles and other cellular remnants.
Cells that are activated in response to aPL include endothelial cells, monocytes, neutrophils, and platelets. The relative importance of each cell type in promoting thrombosis likely depends on the specific vascular bed.
●Endothelial cells – aPL, particularly anti-beta2 glycoprotein I (anti-beta2GPI) antibodies, activate endothelial cells in vitro, leading to expression of tissue factor and adhesion molecules [44,45]. The antibodies simultaneously downregulate the expression of vasoprotective endothelial nitric oxide synthase (eNOS) [46].
Anti-beta2GPI antibodies recognize beta2GPI complexed with coreceptors such as annexin A2 [47] and apoER2 [46] to activate intracellular signaling through toll-like receptor (TLR)-like and Krüppel-like factor (KLF) transcription factor-mediated pathways [48-50]. In mice, blocking E-selectin, P-selectin, and endothelial integrin ligands (vascular cell adhesion molecule 1 [VCAM-1] and intercellular adhesion molecule 1 [ICAM-1]) protects against aPL-mediated thrombosis [51,52].
●Monocytes – In vitro, aPL activate monocytes and cause them to express tissue factor [53-56] and other proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL) 1 beta [57-59]. Monocyte tissue factor expression is increased in patients with systemic lupus erythematosus (SLE) and aPL [60] and in patients with primary thrombotic APS [61-63].
Monocytes from patients with APS also express higher levels of the proangiogenic cytokine vascular endothelial growth factor (VEGF) and its receptor Flt-1 [64], as well as proinflammatory mediators such as TLR8, CD14, and proteins associated with oxidative stress [65,66]. Several studies demonstrate increased levels of monocyte-derived microparticles in patients with APS [67,68], which may be an important source of tissue factor [69].
●Neutrophils – Neutrophils contribute to thrombosis in arterial [70,71], venous [72,73], and microvascular beds [74,75]. aPL, particularly anti-beta2GPI antibodies [76-79], induce neutrophil tissue factor expression (similar to monocytes) [78] and the release of prothrombotic neutrophil extracellular traps (NETs) [79]. NETs are elongated extracellular "spiderwebs" composed of neutrophil-derived chromatin and microbicidal proteins; they can bind bacteria and other organisms, and they have a variety of immune functions [80,81]. (See "An overview of the innate immune system", section on 'Neutrophils'.)
NETs circulate at elevated levels in patients with APS [79]. NETs activate platelets and endothelial cells and ultimately form an integral part of venous [72,73,82,83] and arterial clots [70,84,85]. In mice, aPL-mediated large vein thrombosis is dependent on NETs [86,87] and neutrophil adhesion to the vessel wall [88,89]. Anti-NET antibodies are also elevated in patients with APS, and anti-NET IgM is inversely correlated with levels of complements C3 and C4, suggesting that anti-NET antibodies may activate the complement cascade [41]. (See 'Non-criteria autoantibodies' above and 'Complement activation' below.)
●Platelets – While beta2GPI and anti-beta2GPI antibodies do not appear to bind to unstimulated platelets, under shear stress, anti-beta2GPI antibodies may trigger platelet activation through binding of beta2GPI to surface ApoER2 and GPIb receptors [90]. aPL also activate platelets in the presence of low levels of thrombin through a mitogen-activated protein kinase (MAP kinase)-dependent pathway [91]. In mouse models of APS, aPL-activated platelets may be preferentially required for fibrin generation in the expanding thrombus [92]. Increased platelet-leukocyte aggregates are detected in the blood of patients with APS, consistent with low-grade platelet activation [93]. The extent to which thrombocytopenia in APS is attributable to platelet activation (and subsequent removal) or to clearance via antiplatelet antibodies likely varies from patient to patient [94-96].
Interactions with coagulation and fibrinolytic systems — aPL appear to interfere with the activity of natural anticoagulant proteins including proteins S and C, as well as with the fibrinolytic system, which breaks down fibrin. (See "Overview of hemostasis", section on 'Control mechanisms and termination of clotting'.)
●Protein C – Inhibition of anticoagulant activity in vitro was one of the earliest identified prothrombotic mechanisms in APS. aPL inhibit the activation of protein C and the ability of activated protein C to inactivate factors V and VIII (ie, activated protein C resistance) [42,97-100].
●Antithrombin activity – aPL also reduce antithrombin (AT) activity by inhibiting the heparin binding required for full activation of AT [101]. aPL with activity against thrombin may further reduce the inactivation of thrombin by AT [102], while antibodies against activated factors X and IX also interfere with negative regulation by AT [103,104].
●Fibrinolysis – aPL may inhibit fibrinolysis by neutralizing the ability of beta2GPI to stimulate tissue plasminogen activator (tPA)-mediated plasminogen activation and fibrinolysis [105]. In addition, inhibitory antibodies against tPA and other components of the fibrinolytic system are reported in patients with APS [106,107].
●Interactions with procoagulant pathways – Tissue factor activity may be potentiated in APS via inhibition of tissue factor pathway inhibitor (TFPI) in patients with a positive lupus anticoagulant (LA) and/or anti-beta2GPI antibodies [108,109]. Anti-beta2GPI antibodies have also been reported to impair the ability of beta2GPI to inhibit von Willebrand factor (VWF)-dependent platelet aggregation [110]. Elevated levels of factor XI have been identified as a risk factor for thrombosis in the general population [111]. Patients with APS have higher levels of the active free thiol form of factor XI than age- and sex-matched controls [112].
●Annexin A5 – Annexin A5 binds to phosphatidylserine (PS) to form a two-dimensional lattice, or "anticoagulant shield," over exposed phospholipids on cell surfaces [113]. The complex of beta2GPI and anti-beta2GPI disrupts this protective shield, exposing procoagulant PS and promoting thrombosis [114,115]. Interestingly, the antimalarial drug hydroxychloroquine has been reported to stabilize the annexin V shield in vitro [116,117] and has shown efficacy against aPL-mediated thrombosis in a murine model [118].
Complement activation — Complement consists of a system of over 50 proteins involved in innate immunity that link the inflammatory response to coagulation pathways [119]. In mice, thrombotic APS can be modeled by direct vessel injury or infusion of lipopolysaccharide followed by passive transfer of patient-derived aPL. In these models, aPL-augmented thrombosis is attenuated in the presence of complement inhibitors or by gene knockout to prevent expression of complement proteins such as C3, C5, and C6 [120-122]. The C5b-9 protein complex, also called the membrane attack complex (MAC), creates transmembrane channels (holes) in cellular membranes. (See "Complement pathways", section on 'Attack (the membrane attack complex)'.)
In clinical studies, higher levels of C5b-9 are reported in patients with APS and stroke [123]. Many patients with APS have hypocomplementemia (suggestive of complement consumption) [124] and/or elevated levels of complement activation products Bb and C3a [125]. A study using sera and purified anti-beta2GPI antibodies from patients with APS demonstrated that these could cause enhanced complement-mediated cell death via C5b-9 deposition on the cell surface [126]. The assay, referred to as the modified Ham test, measures complement-mediated cell lysis. Complement activation in the modified Ham test correlates with triple positivity (presence of three types of aPL, a marker of severe disease) and recurrent thrombosis.
Anecdotal reports of the efficacy of the terminal complement inhibitor eculizumab in treating refractory thrombosis in APS and catastrophic APS (CAPS) also support a role of complement in aPL-mediated thrombosis [127,128]. (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Eculizumab'.)
Additional information about the role of complement in CAPS is presented separately. (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Pathophysiology/mechanism of thrombosis'.)
Triggers of thrombosis — In animal models of APS, passive infusion of aPL does not cause thrombosis in the absence of mechanical or chemical vessel wall injury, disruption of blood flow, or infusion of an immune stimulant such as lipopolysaccharide. The "two-hit" model of APS proposes that aPL provide the first hit that induces a generalized procoagulant state by activating vascular cells and/or causing prothrombotic alterations in the coagulation and fibrinolytic systems. Subsequently, a second hit (often cryptic) in the form of a vascular injury or inflammatory stimulus tips the system toward thrombosis.
Although the precise initiating stimulus is not readily apparent in many cases of thrombotic APS, a precipitating factor such as infection, surgery, or pregnancy is identified most individuals with CAPS. (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Additional risk factors'.)
Additional risk factors — The presence of additional risk factors for thrombosis may further increase thrombotic risk in patients with aPL [129-131]. These factors include:
●SLE
●Inherited thrombophilia
●Cancer
●Smoking
●Pregnancy
●Use of estrogen-containing oral contraceptives
●Immobilization
●Obesity
●Hypertension
●Hypercholesterolemia
In a large population-based case-control study, the odds ratio (OR) of ischemic stroke in females with LA was 43.1 (95% CI 12.2-152.0), increasing to 87 (95% CI 14.5-523.0) in those who smoked and to 201 (95% CI 1.9-242) in those who used estrogen-containing oral contraceptives [132].
In the same study, the risk of myocardial infarction increased from 5.3 (95% CI 1.4-20.8) to 33.7 (95% CI 6.0-189.0) in females who smoked and to 21.6 (95% CI 1.9-242.0) in those who used estrogen-containing oral contraceptives [132].
In another cohort of 122 patients with aPL, hypertriglyceridemia was associated with a 6.4-fold increase in the risk of thrombosis, hereditary thrombophilia with a 7.3-fold increase, and anticardiolipin (aCL) IgG with a titer >40 IgG phospholipid units (GPL) with a 2.8-fold increase [129].
MECHANISMS OF OBSTETRIC ANTIPHOSPHOLIPID SYNDROME — Historically, impairment of fetal-maternal exchange caused by intervillous thrombosis was assumed to be the main driver of pregnancy morbidity in antiphospholipid syndrome (APS). However, thrombosis is not reliably detected in the placentae of antiphospholipid antibody (aPL)-positive pregnancies [133]. Rather, clinical and experimental observations suggest that obstetric complications in APS are mediated primarily by trophoblast dysfunction and complement activation [134].
Early versus late-term pregnancy loss — Although related, the pathogeneses of first-trimester fetal loss and late pregnancy loss associated with APS are distinct:
●Early pregnancy loss – First-trimester losses are typically attributed to direct inhibitory effects of aPL on trophoblast viability, proliferation, and invasion [135]. These derangements prevent proper anchorage of the placenta to maternal decidua, resulting in first-trimester miscarriage.
●Late-term pregnancy loss – Late-term obstetric complications of APS, such as fetal growth restriction, preeclampsia, preterm birth, and fetal demise, are likely a consequence of both trophoblast dysfunction (leading to an inadequately developed placenta), as well as direct inflammatory effects mediated by aPL and complement.
Trophoblast dysfunction — Trophoblasts constitutively express beta2 glycoprotein I (beta2GPI) on their surface [136-139]. In vitro studies of the effects of aPL (and especially anti-beta2GPI) on trophoblast function have revealed defects in several normal processes:
●Proliferation [140]
●Invasiveness [138]
●Secretion of human chorionic gonadotropin [138]
●Production of angiogenic factors such as vascular endothelial growth factor (VEGF) [141]
●Syncytialization (fusion) [142].
At the same time, studies using trophoblast cell lines demonstrate that aPL can cause the cells to take on a proinflammatory phenotype including activation of the NALP3 inflammasome [143] and interleukin (IL) 8 secretion [144].
These impaired cellular functions cause inadequate remodeling of uterine spiral arteries, thereby reducing maternal blood flow to the placenta and inducing hypoxic damage and reperfusion injury. A lack of well-developed vasculosyncytial membranes in the placenta of aPL-positive patients can further limit gas and nutrient exchange in the third trimester [133].
Complement activation and downstream mediators — As pregnancy progresses, it is hypothesized that recruitment of aPL to the placenta may trigger Fc-dependent inflammatory responses (activation of complement is the best characterized).
In murine "passive transfer" models, polyclonal IgG from patients with APS with high titers of aPL are administered to pregnant mice, resulting in fetal resorption and growth restriction. The seminal observations from these models were that mice deficient in complement component C3 were protected from fetal injury, and in wild-type mice, administration of C3 convertase inhibitors was protective [145].
Other mouse studies have suggested that downstream of complement, neutrophils are activated in C5a receptor-dependent fashion [146] with fetal damage further amplified by both tumor necrosis factor (TNF)-alpha [147] and tissue factor [148].
A study in a cohort of pregnant patients (487 with aPL or systemic lupus erythematosus [SLE] and 204 controls) found that circulating markers of complement activation (Bb and soluble C5b-9) were higher in the individuals with aPL or SLE, and adverse pregnancy outcomes correlated with higher levels of these circulating markers [149].
Notably, the efficacy of heparin in reducing pregnancy loss in individuals with APS is thought to be at least in part due to its ability to inhibit complement activation in the placenta [150].
PATHOGENESIS OF OTHER CLINICAL PRESENTATIONS
Catastrophic antiphospholipid syndrome — (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Pathophysiology/mechanism of thrombosis'.)
Antiphospholipid syndrome vasculopathy — In addition to thrombosis, patients with APS may also develop chronic proliferative vascular lesions that contribute to progressive organ impairment [151]. As examples, small arteries in the kidney, leptomeninges, and lungs may show concentric cellular and fibrous intimal hyperplasia (neointima formation) reminiscent of hypertensive vascular disease, without evidence of thrombotic microangiopathy [151].
A study implicated the mammalian/mechanistic target of rapamycin (mTOR, a kinase that integrates a variety of signaling pathways to regulate cellular growth, proliferation, and survival) in the chronic proliferative vasculopathy of APS [152]. In individuals with aPL-associated nephropathy, the vascular endothelium of intrarenal vessels was found to display molecular markers consistent with activation of mTOR and downstream signaling [153]. Furthermore, patients with aPL-associated nephropathy who required transplantation and were receiving sirolimus (an mTOR inhibitor) had minimal recurrence of vascular lesions, which was in contrast to matched patients with aPL who were not receiving sirolimus [153].
COVID-19 AND ANTIPHOSPHOLIPID ANTIBODIES — Similar to antiphospholipid syndrome (APS), coronavirus disease 2019 (COVID-19) is associated with a higher-than-expected incidence of thrombosis in arterial, microcirculatory, and venous vascular beds [154,155]. Mechanistic studies of COVID-19-associated thrombosis demonstrate some similarities with the pathophysiology of APS, including evidence for hyperactivation of neutrophils [156], endothelial cells [157], platelets [158], and the complement system [159]. (See "COVID-19: Hypercoagulability", section on 'Pathogenesis'.)
Reports from early in the pandemic found antiphospholipid antibodies (aPL) at high titers in a small number of patients with COVID-19 who experienced macrovascular thrombotic events [160]. In a subsequent series of 56 patients hospitalized with COVID-19, lupus anticoagulant (LA) was detected in 25 (44.6 percent), 5 of whom (8.9 percent) also had either anticardiolipin (aCL) or anti-beta2 glycoprotein I (anti-beta2GPI) antibodies [161].
Studies in COVID-19 patients have detected both traditional aPL (such as IgG and IgM isotypes of aCL) and various "non-criteria" aPL (including IgG and IgM isotypes of anti-phosphatidylserine/prothrombin [anti-PS/PT] as well as IgA isotypes of aCL and anti-beta2GPI). There is significant heterogeneity across studies in terms of both overall prevalence of aPL (some as high as 50 percent) and which particular aPL species are most commonly detected [162-164]. It is not known whether these are transient aPL, as have been reported in viral infections previously [165], or persistent aPL more likely to be associated with long-term thrombotic risk. (See "Diagnosis of antiphospholipid syndrome", section on 'Transient antiphospholipid antibodies'.)
Most studies have not found a clear association of aPL with macrovascular thrombotic events in COVID-19. Furthermore, functional assays such as LA must be interpreted with caution in critically ill patients due to potential confounding by high levels of C-reactive protein, an acute phase reactant that can also prolong in vitro clotting times and lead to false-positive tests [166].
Despite these caveats, the relationship between aPL and COVID-19 is an emerging area deserving of further research. There is some evidence that IgG fractions isolated from the serum of patients with COVID-19 with high titers of aPL have prothrombotic properties in vitro and in mice [164]. Future studies are required to determine persistence of these antibodies and identify mechanistic connections that can further clarify whether aPL in patients with COVID-19 are similar to aPL seen in patients with APS.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Antiphospholipid syndrome".)
SUMMARY
●Role of antiphospholipid antibodies – Antiphospholipid antibodies (aPL), particularly anti-beta2 glycoprotein I (anti-beta2GPI) antibodies, are diverse autoantibodies central to the pathogenesis of antiphospholipid syndrome (APS). aPL directed against other antigenic targets such as prothrombin (PT), phosphatidylserine/prothrombin (PS/PT) complexes, vimentin/cardiolipin complexes, annexin A2, annexin A5, and neutrophil extracellular traps (NETs) have been detected in the sera of patients with APS. Their roles in pathogenesis are under study. (See 'Role of antiphospholipid antibodies' above.)
●Mechanisms of thrombosis – aPL-induced cellular activation resulting in multiple procoagulant and proinflammatory effects, as well as activation of complement, are the major drivers of the thrombotic complications of APS (table 1). (See 'Mechanisms of thrombotic antiphospholipid syndrome' above.)
The presence of additional risk factors such as systemic lupus erythematosus (SLE), inherited thrombophilia, cancer, smoking, pregnancy, and the use of estrogen-containing oral contraceptives further increases thrombotic risk in patients with aPL. (See 'Additional risk factors' above.)
●Mechanisms of obstetric APS – Clinical and experimental observations suggest that the pathophysiology of obstetric complications in APS is driven by trophoblast dysfunction and complement activation. (See 'Mechanisms of obstetric antiphospholipid syndrome' above.)
Although related, the pathogenesis of first-trimester fetal loss and late pregnancy morbidity associated with aPL are distinct:
•Early pregnancy loss – First-trimester losses are typically attributed to direct inhibitory effects of aPL on trophoblast viability, proliferation, and invasion. These derangements prevent proper anchorage of the placenta to maternal decidua, resulting in first-trimester miscarriage.
•Late-term pregnancy loss – Late-term obstetric complications of APS, such as fetal growth restriction, preeclampsia, preterm birth, and fetal demise, are likely a consequence of both trophoblast dysfunction (leading to an inadequately developed placenta), as well as direct inflammatory effects mediated by aPL and complement.
●Other clinical presentations – Progress has also been made in understanding the drivers of some other less common manifestations of APS:
•Catastrophic antiphospholipid syndrome (CAPS) – (See 'Catastrophic antiphospholipid syndrome' above.)
•Antiphospholipid vasculopathy – In addition to thrombosis, patients with APS may also demonstrate chronic proliferative vascular lesions that contribute to progressive organ impairment. (See 'Antiphospholipid syndrome vasculopathy' above.)
●COVID-19 and antiphospholipid antibodies (aPL) – Most studies have not found a clear association of aPL with macrovascular thrombotic events in patients with coronavirus disease 2019 (COVID-19). Functional assays such as lupus anticoagulant (LA) must be interpreted with caution in critically ill patients because of potential confounding by transient aPL positivity due to infection and by high levels of C-reactive protein, which can cause the LA phenomenon. Future mechanistic studies will be most illuminating if they define the specificity and function of aPL in COVID-19 infection in comparison to those in traditional APS. (See 'COVID-19 and antiphospholipid antibodies' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Bonnie Bermas, MD, who contributed to an earlier version of this topic review.
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