Francesca Dall’Ara1 , Cecilia Nalli1 and Laura Andreoli1
Department of Clinical and Experimental Sciences, Rheumatology and Clinical Immunology, Spedali Civili of Brescia, University of Brescia, Piazzale Spedali Civili, 1, Brescia, 25123, Italy
Laura Andreoli (Corresponding author)
Antiphospholipid antibodiesaPL carriersPrimary thromboprophylaxisPregnancyAntiaggregation
Antiphospholipid antibodies (aPL) are a group of heterogeneous antibodies, detected by different assays (lupus anticoagulant, LA; anticardiolipin antibodies, aCL; and anti-β2-glycoprotein I antibodies, anti-β2GPI) . These autoantibodies are directly involved in pathogenesis of severe clinical manifestations such as thrombosis (either venous or arterial) and pregnancy morbidity (not only pregnancy loss but also life-threatening conditions like preeclampsia) . These manifestations are the hallmark of the antiphospholipid syndrome (APS) .
However, aPL have been increasingly detected in subjects who do not display the classical features of APS . In fact, aPL may be found in patients with “non-criteria” manifestations (thrombocytopenia, hemolytic anemia, livedo reticularis) or women undergoing investigations for infertility. The presence of aPL can be discovered before a surgical procedure because of a prolonged thromboplastin time. Are these subjects at risk for thrombosis and pregnancy adverse outcomes? The answer is for sure “yes,” since we know that aPL are pathogenic antibodies. However, observational studies did not report a high incidence of events in aPL carriers, ranging from 0 to 3.8 % annually . This apparent discrepancy can be explained by the fact that the relationship between aPL and thrombosis is not “all or nothing.”
17.1 aPL as Risk Factors
Circulating aPL should be better considered as thrombotic risk factors, with several other variables modulating the final clinical expression [6, 7]. Among these factors, the most important are the aPL profile, the coexistence of other thrombotic risk factors, and the presence of an underlying autoimmune disease, mainly systemic lupus erythematosus (SLE).
In terms of aPL profile, the patients may have single, double, or triple aPL; single or multiple isotypes (IgG, IgM, and IgA, although the last one is not included in the criteria); and low vs. medium to high titers of antibodies. Taken as a whole, this information means that clinicians deal every day with a wide variety of “aPL profiles” and not all antibody profiles confer the same degree of risk. According to special task forces at the 13th International Congress on Antiphospholipid Antibodies [8, 9], a high-risk profile can be defined as LA positivity, or “triple positivity” (LA + aCL + anti-β2GPI) or the isolated but persistent positivity for aCL at medium-high titers. A multicenter prospective Italian study  observed that the occurrence of a first thrombotic event in carriers of high-risk aPL profile is considerable and it is more frequent among male patient and in the presence of additional risk factor for venous thrombosis.
Recently, a meta-analysis  concluded that LA and aCL were the tests significantly associated with an increased risk of thrombosis, especially arterial thrombosis in patients without SLE. A possible limitation of this work is that the relationship with clinical manifestations was searched for single tests (either aCL or LA or anti-β2GPI) and no analysis of the aPL profile was performed. It should be actually recognized that the concept of “high-risk profile” is rather new, so many of the studies included in the meta-analysis did not apply such a definition. In any case, the international consensus of experts felt that patients with isolated aCL or anti-b2GPI at low to medium titer could be considered at low risk for future thrombosis .
17.2 Risk Assessment for Thrombosis in aPL-Positive Subjects
aPL alone are not sufficient to generate thrombosis. According to the “two-hit hypothesis,” aPL represent only the “first hit,” decreasing the thrombophilic threshold by inducing a prothrombotic and proinflammatory phenotype in endothelial cells, but a “second hit”  may be required as a triggering event. In fact, retrospective, cross-sectional, and prospective cohort studies demonstrated that at least half of APS patients with vascular events showed other non-aPL, reversible thrombosis risk factors at the time of the event . In the general population, the thrombosis risk rises with increasing number of risk factors and age, therefore also in aPL carriers all these variables may be responsible for triggering acute events. For this reason management of aPL carriers should take into account any possible second hit, namely :
In addition to those “classic” risk factors, it is also important to consider the presence of an underlying systemic autoimmune disease that may also increase the risk of thrombosis. A higher incidence of vascular events, which is not completely explained by traditional vascular risk factors, is observed in patients with SLE. The inflammatory phenotypes of systemic autoimmune diseases are able to induce perturbation of the endothelium and to initiate the action of aPL, regardless of the underlying disease. Because aPL are risk factors, their assessment should become part of the routine workup of patients with a diagnosis of systemic autoimmune disease .
A common risk factor is cigarette smoking. A recent study  explored the association between smoking, aPL, and vascular events. Only aPL, among a large set of commonly occurring autoantibodies in SLE, were positively associated with a history of smoking. Among ever regular smokers who were aPL positive, a higher frequency of former venous events was observed. Smoking was shown to double the risk of stroke in LA-positive women younger than 50 years in the RATIO study (risk of arterial thrombosis in relation to oral contraceptives) . Interestingly, this case-control study also found that the use of oral contraceptive multiplied sevenfold the risk of stroke.
Also genetic factors seem to play a role in risk stratification. Lundstrom  and coworkers described that HLA-DRB*04/*13 alleles are associated with vascular events and aPL-positive immune phenotype in SLE and demonstrated that a subset of SLE patients is genetically disposed to vascular vulnerability. Another recent work  investigated the role of genetic factors in arterial thrombosis in APS. No association was found between platelet glycoprotein polymorphisms and arterial thrombosis, but it was confirmed anyway that APS patients with aCL IgG antibodies, livedo reticularis, and suffering from hypertension and hypercholesterolemia are at the increased risk of arterial thrombosis.
17.3 Primary Thromboprophylaxis in aPL Carriers
Issues regarding the role of prophylaxis for patients with aPL in the absence of clinical events have long been debated . Keeping in mind all previous considerations, the first approach to patients with aPL antibodies should be risk stratification. As general measures, modifiable risk factors (hypertension, diabetes mellitus, proatherogenic lipid profile, obesity, smoking) should be corrected, estrogen-containing oral contraceptives avoided, and there is a strong suggestion to thromboprophylaxis with low molecular weight heparin (LMWH) in acute high-risk situations such as surgical procedures, long periods of immobilizations, puerperium, and in less frequent conditions such as ovarian stimulation .
Retrospective and prospective observational studies and controlled trials of aspirin for the prevention of thrombotic events in people with aPL without history of arterial or venous thrombosis have yielded discordant results [20–22]. Up to now only one randomized, double-blind, placebo-controlled trial  (APLASA trial) is available in aPL-positive subjects. In this study, persistently aPL-positive patients were enrolled and they were given placebo or 81 mg/day aspirin, and a low annual incidence of acute thrombosis was observed. The APLASA trial concluded that asymptomatic individuals who are persistently positive for aPL do not benefit from low-dose aspirin since thrombotic events in this population are unlikely in the absence of additional risk factors for thrombosis. Recently, a meta-analysis of observational studies showed that the risk of first thrombotic event is significantly decreased by low-dose aspirin among asymptomatic aPL individuals with or without SLE . However, no significant risk reduction was retained when considering only prospective studies or those with the best methodological quality. Furthermore, the estimated incidence of thrombosis in unselected cases (about 1 % patient-years) is equivalent to that of major bleeding associated with the use of aspirin . So the dilemma is to correctly select those aPL carriers for whom the expected benefit of low-dose aspirin outweighs the risk.
The international consensus  on primary prevention in asymptomatic APL carriers proposed strict control of cardiovascular risk and prophylaxis with LMWH only in high-risk situations (e.g., surgery, immobilization, pregnancy). Aspirin may be useful for some subsets of APL patients at particularly high risk of arterial thrombosis, such as those with SLE or special antibody patterns such as triple positivity or isolated, persistently positive aCL at medium to high levels .
Also the use of warfarin has been proposed in primary thromboprophylaxis . The ALIWAPAS trial compared the efficacy low-dose aspirin (LDA) with LDA in association with low-intensity warfarin. This study faced different problems, but probably the major one was the low recruitment rate because many patients refused to participate. The most likely reason for that could be that aPL carriers did not feel motivated to comply with a drug regimen that carries the risk of bleeding and requires frequent blood sampling and lifestyle modifications. Therefore the lesson to be learned is that a drug used in primary prophylaxis should be acceptable to people who carry a risk factor, not a disease .
Aside from drugs acting on platelets and on the coagulation system, there is evidence that immunomodulatory agents may be beneficial in primary prophylaxis of aPL carriers.
Many studies have investigated whether hydroxychloroquine (HCQ) could be useful in the prevention of thromboembolic events in patients with aPL and SLE. In fact it is well known that HCQ has several different function: may benefit patients who have aPL and high risk of vascular events through antiplatelet effects by reducing homocysteine levels, lupus disease activity titers, hyperlipidemia , and aPL titers [18, 28]. HCQ was also associated with lower odds of having persistently positive aPL, adjusted for age, ethnicity, and gender . Several studies on SLE patients have shown a protective effect of the drug against thrombosis: prospective cohort [29, 30] and cross-sectional  studies suggested that HCQ decreases the risk of first thrombosis in SLE patients. In a prospective cohort study conducted by Tektonidou et al. , it was shown that HCQ might reduce the thrombosis risk in both aPL-positive (hazard ratio, 0.99; 95 % CI, 0.98–1.00) and aPL-negative (hazard ratio, 0.98; 95 % CI, 0.95–0.98) patients. In another recent, case-control study, Jung et al.  also demonstrated that HCQ is protective against thrombosis in SLE patients (OR, 0.32; 95 % CI, 0.14–0.74). However, this potentially protective effect of HCQ was not confirmed by two other prospective cohort studies in lupus patients [34, 35]. Anyway in patients with systemic autoimmune diseases (particularly SLE), HCQ is commonly used for disease control and should be considered independently of the patients’ aPL status. However, further controlled studies are needed to determine the effectiveness of HCQ for primary prophylaxis in aPL-positive patient .
Also statins may be useful in aPL carriers for different reasons. In the first place, statins are recommended for patients with a proatherogenic lipid profile. Secondly, they might be beneficial because of their anti-inflammatory effects and their ability to interfere with aPL-induced endothelial activation. They also have multiple effects on monocytes and lymphocytes, contributing to thrombosis prevention in APS patients . In the third place statins seem to reduce the occurrence of the first major cardiovascular event and symptomatic thromboembolism also in the general population . So far, two prospective studies have shown the efficacy of fluvastatin in reducing proinflammatory and prothrombotic biomarkers in persistently aPL-positive patients [38, 39].
Vitamin D deficiency was described to be common among APS patients, and it seems to be associated with a history of thrombotic events . Given that vitamin D can inhibit anti-β2GPI-mediated tissue factor (TF) expression in vitro, its deficiency might be associated with decreased inhibition of TF expression and increased coagulation in APS . So vitamin D supplementation could be considered as a safe and cheap complement to standard therapy in APS patients (Table 17.1).
Proposed strategies of primary thrombosis prophylaxis for patients with clinically significant antiphospholipid antibody (aPL) profile
Management of aPL carriers:
Identify and reverse traditional cardio vascular risk factors
Identify concomitant systemic autoimmune diseases
Consider drugs acting on platelet and coagulation system:
LMWH [8, 19]
Consider drugs with immunomodulatory properties:
HCQ [27, 28]
Vitamin D [40, 41]
17.4 aPL Carriers and Pregnancy Morbidity
Besides thrombosis, aPL are known risk factors for a wide range of obstetric morbidity, such as recurrent pregnancy losses, late fetal losses, preeclampsia, placental abruption, and intrauterine growth restriction. The strength of association between aPL and single manifestations may vary from study to study, mainly for “methodological” problems: most of the data are derived from small case-control studies, often results are not conclusive, and there are no large controlled-randomized trials . In any case, the management of aPL carriers should include prophylaxis, not only for pregnancy outcome itself but also for maternal protection, being pregnancy and puerperium as high-risk periods for the occurrence of thrombosis.
17.5 Role of aPL in Pregnancy Morbidity: Pathogenesis
Pregnancy morbidity is not uncommon in the general population and can be due to multiple causes (anatomical defects, chromosomal aberrations, endocrine factors, subclinical infections, and, finally, immunological disturbances), but more than 50 % of the cases remain idiopathic after conventional investigations .
Antiphospholipid antibodies were shown to be pathogenic in several models of pregnancy wastage, both in vitro and in vivo [reviewed in [44, 45]. In particular, aPL specifically target the placenta by binding β2GPI, which is constitutively expressed on the trophoblast cell surface. This interaction may alter first-trimester human trophoblast modulating several cell biological pathways and, finally, causing unfavorable outcome [46, 47].
Suggested pathogenic mechanisms mediated by aPL are :
· Placental thrombosis and infarction.
· Acute inflammation and complement activation: the complement system has been identified to be critical for the pathogenic effects of aPL, both for excessive activation or inadequate regulation ;
· Defective placentation due to the evidence that placenta is a major target for aPL, in particular b2GPI-dependent antibodies, which bind to human trophoblast . Additional manifestations were placental tissue thrombosis, syncitium-throphoblast differentiation inhibition, decidual cell inflammatory phenotype induction, complement activation, and embryo and/or placental apoptosis.
· aPL, especially anti-β2GPI, are able to disrupt the anticoagulant annexin A5 shield on trophoblast and endothelial cell monolayers .
A peculiar pathogenic model for aPL-induced pregnancy morbidity is preeclampsia. Preeclampsia is a vasospastic hypertensive disorders marked by abnormal maternal arteriolar reactivity to vasoactive agents such as prostacyclin, thromboxane A2, nitric oxide, and endothelins. Moreover, defective regulation of the complement system, allowing for excessive complement activation which leads to abnormal placental development and abnormal trophoblast invasion, placental damage, generalized endothelial activation, and release of antiangiogenic factors toxic to glomerular endothelium and liver sinusoids, seems to be involved in this complex model .
17.6 Stratification of Obstetric Risk
Association between aPL single test and pregnancy morbidity is not well defined, mainly because of lacking in randomized controlled trials and heterogeneity of design studies. Most studies are underpowered with high heterogeneity regarding association with aPL and pregnancy morbidity: there are only few studies which meet Sapporo/Sydney criteria and support association between clinical events and laboratory criteria [51, 52].
As previously discussed for the risk of thrombosis, also on the obstetric side, it is important to identify patients at high risk taking into account many variables. First of all, general obstetric risk should be assessed, taking into consideration age, concomitant autoimmune disease, previous thrombosis, family history (autoimmunity, thrombosis, abortions), hypertension, obesity, acquired thrombophilia, and so forth.
It is currently under discussion whether different aPL profiles confer the same degree of obstetric risk, and it is not easy to stratify patients into “risk classes.” Routine screening for aPL antibodies is not recommended in healthy pregnant women, because they occur infrequently, at low levels, and are rarely associated with adverse pregnancy outcome. An original report at the beginning of the 1990s found that greater than 50 % of such women will go on to have uncomplicated pregnancies without any additional treatment .
At the moment, it is recommended to test all three validated antibodies (aCL, anti-β2GPI, LA) included in the revised Sydney criteria. There are few studies evaluating a possible role of nonclassical aPL (anti-phosphatidylcholine, anti-phosphatidylethanolamine, anti-phosphatidylinositol, anti-phosphatidylserine, and anti-sphingomyelin) in obstetric complications. They seem not to be an independent risk factor in the prediction of miscarriage in women with recurrent pregnancy loss and to have no clinical significance in obstetric complications .
Available meta-analysis studies evaluating the association between different aPL tests and pregnancy morbidity showed divergent results. Opatrny et al. concluded that high-risk patients are those carrying LA and IgG aCL antibodies (especially at high titers) . Abou-Nassar and coworkers concluded that the association between each single aPL test and placenta-mediated complications was inconsistent and debatable . However, it should be considered that most of the studies included in the meta-analysis did not test for a complete aPL profile but rather for one or two aPL tests.
More recently, some studies took into consideration a complete aPL profile and its relationships with pregnancy outcome.
The PROMISSE study (Predictors of Pregnancy Outcome: BioMarkers In Antiphospholipid Syndrome and Systemic Lupus Erythematosus), a large, multicenter observational study on pregnancies of patients with APS and/or SLE, described the pregnancy outcome of 144 aPL-positive patients. Poor pregnancy outcome was observed mainly in LAC-positive women and in women with moderate- to high-titer IgG aCL; other aPL did not independently predict adverse pregnancy outcome .
Other studies found out that high-risk patients are those with aPL triple positivity (aCL, anti-β2GPI, LA) . A multicenter European study showed that independent risk factors for pregnancy failure despite treatment were the presence of SLE or other autoimmune diseases, history of both thrombosis and pregnancy morbidity, and triple aPL positivity . On the other hand, other authors observed unfavorable pregnancy outcome also in patients with a “low-risk” aPL profile (e.g., IgM isotype or medium to low aPL titers) [58, 59].
In our opinion, those risk factors identified in pregnancy failures despite treatment could be also considered as “red flags” to be applied in for primary prophylaxis. In other words, pregnant aPL carriers with either triple aPL positivity and/or a concomitant autoimmune disease should be considered at higher risk and provided with a more generous prophylaxis.
17.7 aPL and Infertility
The main scenario in which aPL can be found incidentally is during workup for infertility. The role of aPL in infertility is controversial. aPL may interfere with several steps from implantation, placentation, to early embryonic development. At present, there is no evidence to support routine screening for aPL in patients with primary infertility, and no difference in the prevalence of aPL in women with unexplained infertility compared to fertile controls were found . There is also no clear association between aPL positivity and implantation failure, clinical pregnancy, or live birth rates in women undergoing assisted reproduction.
The major point about assisted reproduction techniques is that ovarian stimulation protocols can be considered as high-risk situations for thrombosis because of artificially elevated estrogen levels . One retrospective cohort study of ten APS patients who underwent 47 cycles of ovulation induction showed that no patients experienced thrombosis during treatment; all patients were treated with prophylactic LDA with or without heparin . As a general measure, aPL-positive women, especially if high-risk profile, must be considered as a risk population, and so prophylactic treatment with LDA or LMWH should be considered during ovarian stimulation.
17.8 aPL Carriers and Pregnancy: Treatment
A key drug for primary obstetric prophylaxis is LDA. It is also indicated in women without aPL for the prevention of preeclampsia . In clinical practice, many physicians are used to pregnant aPL carriers with LDA, in particular if the patients have already experienced one or two fetal losses or if maternal risk factors coexist (age, arterial hypertension, obesity, etc.). A large retrospective observational study showed that pregnancy outcome can be favorable without LDA in those patients with a low-risk profile . According to another large cohort of pregnant aPL carriers, combination treatment of LDA and other drugs seems to be not necessary in asymptomatic pregnant aPL carriers, even in the presence of high antibody titers . Nevertheless, the experts recommend the use of LMWH in addition to LDA in selected cases (older maternal age, high-risk aPL profile, assisted reproduction techniques) .
In our opinion, pregnant women with a high-risk aPL profile should be granted a generous prophylaxis for both maternal and fetal protection, while patients with a low-risk profile could be candidate to a less aggressive approach. However, the definitions of “high” and “low” risk from the obstetric point of view still need to be validated in properly designed studies.
Another point of concern is the puerperium. It is considered a high-risk period for thrombosis for all women. Usually APS patients are posed in primary prophylaxis with LMWH for a few weeks after delivery (generally 4–6 weeks). Regarding aPL carriers, experts believe that is important to protect these women with a similar management .
Recently, a role for HCQ was proposed. Recent studies have reported that HCQ reduces the binding of aPL-β2GPI complexes in trophoblast surface . In a recent study by Albert and collaborators , authors studied a human first-trimester trophoblast cell line exposed to a β2GPI in presence or not of HCQ. HCQ was shown to partially antagonize aPL-induced inhibition of trophoblast migration, confirming the immunomodulatory properties of HCQ and suggesting beneficial effects on the placenta in patients with aPL positivity. At least from the experimental point of view, there may be a rationale for testing HCQ in clinical studies as a preventive treatment in aPL carrier’s pregnancies (Table 17.2).
Proposed strategies of pregnancy management in women with clinically significant antiphospholipid antibody (aPL) profile and no previous obstetric events
Management of aPL-positive women during pregnancy:
High-risk profile vs. low-risk profile (what is the definition? need for a consensus definition)
LDA (prevention of preeclampsia, possibly not necessary if low-risk aPL profile)
LMWH (maternal protection, e.g., during puerperium and ovarian stimulation, especially in high-risk profile women)
Combination of LDA and LMWH (selected high-risk cases)
HCQ (protective role suggested in experimental models)
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