Nicoletta Di Simone1 and Silvia D’Ippolito1
Department of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore Rome, Largo Agostino Gemelli 8, Rome, 00168, Italy
Nicoletta Di Simone (Corresponding author)
The revised Sapporo criteria established that pregnancy morbidity in antiphospholipid syndrome (APS) encloses ≥3 consecutive and spontaneous early miscarriages before 10 weeks of gestation, at least one unexplained fetal death after the 10th week of gestation of a morphologically normal fetus, and a premature birth before the 34th week of gestation of a normal neonate due to eclampsia or severe preeclampsia or placental insufficiency .
During the years several researchers tried to find an etiopathogenic explanation for pregnancy morbidity in APS. The results underlined the heterogeneity of the pathogenic mechanisms involved in antiphospholipid antibody (aPL)-mediated fetal loss, all taking place within the placenta [1–5]. Actually, intraplacental thrombotic phenomena, a direct aPL-mediated placental damage, and inflammatory processes involving the complement cascade are considered the most important mechanisms underlying miscarriages in APS [3–5]. It is now well accepted that these mechanisms are not mutually exclusive and may play a role together or in different combination at different times of the pregnancy. Such a variety in the aPL-mediated action fits well with the heterogeneity of the clinical manifestations of the obstetric APS, spanning from early to late miscarriages or preeclampsia .
4.2 The Human Implantation and Placentation
Human implantation and placentation represent a complex process based on subsequent steps. In particular, trophoblast cells play a key role in placental development. After implantation, they differentiate into villous and extravillous trophoblast cells (VTC and EVTC, respectively) . VTC support the maternal-fetal exchange of nutrients and the endocrine functions of the placenta. EVTC invade the maternal endometrium and, through the formation of cellular plugs, gradually erode local spiral arteries to provide access to the maternal blood. The invasive nature of EVTC is dependent on the activity of matrix metalloproteases (MMPs) [7, 8], proteolytic enzyme degrading the extracellular matrix (ECM), and on the secretion of a number of molecules such as heparin-binding epidermal growth factor (HB-EGF), a strong mitogenic molecule expressed in VTC and EVTC, able to stimulate trophoblast differentiation, invasive phenotype, and motility [9–12].
During the early phase of pregnancy, also the endometrium of the uterus undergoes profound changes and transforms into decidua, a newly formed tissue that plays a critical role for successful embryo implantation and regular fetal growth. The decidua provides a physical anchorage for the implanted embryo tightly attached to the maternal tissue through anchoring villi which float in the intervillous space, surrounded by an outer layer of trophoblast cells. An important feature of the decidual tissue in the early phase of pregnancy is represented by the active angiogenic differentiation of endometrial endothelial cells (HEECs) and the vascular remodeling of the spiral arteries . In particular decidualizing endometrial cells produce critical angiogenic molecules, such as vascular endothelial growth factor (VEGF) able to promote the angiogenic differentiation of HEECs [14–16]. These changes facilitate a regular supply of maternal blood to the developing placenta at an optimal flow rate necessary for the adequate delivery of nutrients to the developing embryo [13–16]. Noteworthy, VTC exposed to maternal blood circulating in the intervillous space and EVTC present in human decidua, being of fetal origin, represent a real challenge for the maternal immune system. As a result, a vigorous response may be mounted against paternal antigens expressed on trophoblasts leading to potential deleterious effects on fetal survival . Trophoblast invasion of decidua results in recruitment and activation of leukocytes and precursors of endothelial cells and in the release of various cytokines, chemokines, and growth factors that promote tissue remodeling [3, 17, 18]. There is evidence for a dynamic balance between proinflammatory and anti-inflammatory mediators in normal pregnancy [3, 17–20].
Embryo implantation is, therefore, strictly based on trophoblast invasion and endometrial decidualization both associated with an inflammatory process and a highly regulated maternal immune response which rather than having deleterious effects help to promote fetal survival and allow normal progression of pregnancy [3, 17–19].
4.3 aPL and Intraplacental Thrombotic Phenomena
In line with the thrombogenic effect of aPL, intraplacental thrombotic phenomena and the subsequent impaired maternal-fetal blood exchange were initially suggested as the main pathogenic mechanism underlying the poor obstetric outcome [21, 22]. Accordingly placental thrombosis and infarction were reported. It was suggested that such an effect might be due to the in vitro ability of aPL, mainly anti-ß2 glycoprotein 1 antibodies (anti-ß2GP1), to induce a procoagulant state via disruption of annexin A5 shield on trophoblast and endothelial cell monolayers. These findings were supported by the observation of reduced annexin A5 expression in placentas from aPL-positive women compared to those lacking the autoantibodies [23, 24]. However further histological studies revealed that neither thrombosis nor infarction is common in the placentas of patients with APS [25, 26]. Specifically, the prevalence of intervillous thrombosis in women with aPL was similar to that found in aPL-negative pregnancies. Moreover, due to the presence of trophoblast plugs in the uterine spiral arteries, significant maternal blood flow does not occur in the intervillous space until the end of the first trimester, suggesting that placental thrombosis and infarction are unlikely causes of embryonic or early fetal loss in APS patients.
4.4 aPL and Direct Placental Damage
Besides thrombosis, several evidence indicated that alternative aPL-mediated pathogenic mechanisms directly affect placental tissue. The observation of β2GPI reactivity with trophoblast cell membranes, human stromal decidual cells, and HEECs suggested the placental tropism of anti-β2GPI antibodies [15, 27, 28]. β2GPI has been shown to bind to target cells through the phospholipid-binding site in the fifth domain of the molecule [4, 19, 28]. Accordingly polyclonal IgG antibodies from APS patients and human IgM monoclonal antibodies with anti-β2GPI activity can react in vitro with β2GPI both at the fetal side of human placenta (i.e., on trophoblast cells) and at the maternal one (i.e., on stromal decidual cells and HEECs) [15, 27, 28]. Subsequent studies demonstrated that, after reacting with target cells, aPL are able to:
· Inhibit trophoblast differentiation, as shown by the reduced secretion of human chorionic gonadotrophin (hCG) [28, 29].
· Impair EVTC invasiveness in an in vitro Matrigel assay. This effect is well correlated with a significant inhibition of expression/activity of MMPs [28, 29] and of HB-EGF production .
· Induce trophoblast injury and apoptosis .
· Be endocytosed into the human syncytiotrophoblast in a ß2GPI-dependent process, disrupting the normal apoptotic turnover and to induce the extrusion of necrotic trophoblast debris which are able to activate the maternal endothelium .
· Induce a proinflammatory phenotype in stromal decidual cells .
· Block endometrial angiogenesis both in vitro and in vivo, by inhibiting the HEECs angiogenic differentiation and the production of specific factors upregulated during angiogenesis, such as VEGF .
As a whole, all of these aPL-mediated effects might contribute to a final functional cellular damage resulting in a defective placentation and eventually in the poor obstetric outcome. Furthermore these findings suggest that APS-associated pregnancy complications can be mediated by several distinct pathogenic events not necessarily related to the procoagulant action of aPL [3, 4, 19].
The above results suggest β2GPI-dependent aPL as the main pathogenic autoantibodies in obstetric APS. Accordingly, it has been hypothesized that most of these potentially pathogenic autoantibodies should be absorbed at the placental level (where β2GPI is expressed) and should not be transferred to the fetus. This mechanism would explain why thrombotic events are rarely reported in babies born to aPL-positive mothers, in spite of the high thrombophilic profile of neonates.
4.5 aPL and Inflammation-Mediated Damage
Acute inflammatory events can be responsible for a negative pregnancy outcome via the activity of proinflammatory mediators, such as complement, tumor necrosis factor-α [TNF-α], and chemokines that have been shown to have a role in animal models of aPL-induced fetal loss [3, 4, 19, 20]. Evidence from experimental animal models confirmed the ability of human IgG with aPL activity, passively infused after implantation (10 mg/mouse per injection), to induce fetal resorption and growth retardation. The decidual immunohistochemical and histological demonstration of human IgG and mouse complement deposition, neutrophil infiltration, and local TNF-α secretion suggested a placental inflammatory damage [33–35]. The involvement of the complement system, in particular the cleaved product C5a, was supported by the observation that complement-deficient animal models are protected from pregnancy complications [20, 36–39]. In another experimental model of fetal loss, mice deficient in chemokine-binding protein D6, a placental scavenger receptor which controls local inflammation by degrading the majority of inflammatory chemokines, are more susceptible to fetal loss when passively infused with a small amount of human aPL IgG than wild-type mice or mice infused with normal IgG . Further in vitro studies reported the ability of aPL to directly induce human first trimester trophoblasts to generate a potent proinflammatory and potentially damaging cytokine, interleukin-1ß (IL-1ß). This is possible via the aPL-mediated activation of the uric acid response which in turn activates the inflammasome, a protein complex containing the Nod-like receptor and the apoptosis-associated speck-like protein (Nalp3/ASC) able to facilitate pro-IL-1ß processing in the trophoblast .
Altogether, these findings suggest that a local acute inflammatory response might have a role in experimental aPL-mediated fetal loss.
In spite of the experimental results, the role of inflammation in determining APS pregnancy complications still remains a debated issue. In APS placentas a strong infiltration of complement components, as well as histopathological findings of deciduitis and villous infiltration, has been found more frequently compared to normal controls [42–45]. On the contrary, further ex vivo examinations of APS placentas and subsequent in vivo studies, using another model of fetal resorption and growth retardation, injected with small amount of human aPL IgG (10–50 μg/mouse) before implantation, failed to show any sign of acute placental inflammatory events and complement deposition . These discrepancies in the results might be due to the different experimental models used and to the fact that experimental observations are often restricted to a given period of the pregnancy, that is, when the investigation is performed or at the time of autoantibody passive infusion. For the same reason, histological examination of human term placentae may show only the resulting damage without providing any insight on the events taking place at the beginning of the aPL-mediated insult.
4.6 Conclusions and Implications from a Practical Point of View
Taken together, the above reported findings suggest that numerous, heterogeneous and complex events underlie pregnancy complications in APS patients. However several aspects with regard to the events that break out the aPL activity and precipitate the different clinical manifestations of obstetric APS are still debated and need further investigation. Nevertheless, it is nowadays well established the ability of aPL to directly target both the invading trophoblasts and the maternal decidua/endometrial endothelial cells in the human placenta and, then, to induce a negative effect on placentation not necessarily related to prothrombotic or inflammatory events.
From a practical point of view, the knowledge of the aPL-mediated placental action has allowed important therapeutical implications. In clinical practice, several strategies have been proposed to improve the pregnancy outcome, including combinations of aspirin and unfractionated (UFH) or low molecular weight (LMWH) heparin [47–49]. Treatment with heparin is mainly based on the initial assumption that thrombotic events played the major role in APS pregnancy morbidity [46, 47]. However the evidence of alternative mechanisms of aPL-induced placental damage and the success of treatment with heparin on the pregnancy outcome suggested additional mechanisms of action for the drug [50, 51]. Actually it has been demonstrated the ability of LMWH to prevent the aPLs binding to trophoblast cells and to restore in vitro placental invasiveness and differentiation . Accordingly, heparin has been shown to prevent the binding of β2GPI to negatively charged phospholipids (PL), which in turn prevents the deposition of the anti-β2GPI in tissues. Subsequent studies reported the ability of heparin to block the aPL-mediated inhibition of HEEC angiogenic differentiation . As a whole, these results suggest that heparin, by interfering with the aPL binding, is able to prevent the aPL pathogenic action not only on the fetal side of the placenta (trophoblast cells) but also on the maternal one (HEECs).
In addition, other researchers, in line with the aPL/complement-mediated pathogenic action, demonstrated that the protective effect of heparin in the mouse model is linked to its anticomplement activity .
The likelihood of a good pregnancy outcome in women with APS is around 75–80 % under correct management. Unfortunately, a significant proportion of women, about 20–21 %, does not respond to the standard treatment and still suffer from miscarriages and adverse pregnancy events [53, 54]. The role of glucocorticoids remains still worthy of further assessment. The addition of 40–60 mg of prednisolone to aspirin alone or associated to heparin during gestation has shown no clear benefits in APS pregnant women in spite of important side effects, such as preterm delivery because of premature rupture of membranes or preeclampsia [55–57]. By contrast, a recent study by Brahman et al. seems to suggest that the addition of low-dose prednisolone (10 mg) from the time of positive pregnancy test up to 14 weeks of gestation may be effective in increasing live birth rate . The addition of intravenous immunoglobulin (IVIg) has not been shown to be superior to heparin and aspirin in unselected patients, while it seems to be efficacious in obstetric APS patients selected for poor prognosis or autoimmune phenomena .
A possible explanation for the high proportion of refractory APS might be that not all the mechanisms underlying aPL-mediated pregnancy complications have been clarified. Novel alternative therapies are urgently needed . Given the evidence that β2GPI and the related autoantibodies play a central role in aPL-mediated obstetric manifestations, new molecules able to interfere with β2GPI expression at the placental level have been recently investigated. This is the case of a synthetic peptide, TIFI, sharing structural similarity with the PL-binding site of β2GPI. Through this similarity, TIFI can compete with the β2GPI PL-binding site and displace the molecule from the cell surface, ultimately inhibiting the aPL reaction with the target tissues . Accordingly, this peptide is able to prevent aPL-mediated thrombosis in vivo and to inhibit the in vitro binding of β2GPI to human endothelial cells, murine monocytes, trophoblast cells, and HEECs [46, 61, 62]. Furthermore, when passively infused in naïve pregnant mice, TIFI prevents the aPL-mediated fetal loss . As a whole, these results show how molecules, possibly disrupting the β2GPI placental expression, can inhibit the binding of β2GPI-dependent aPL and, in turn, the aPL-mediated placental damage. At the same time, these results lead to investigate a further and more specific therapeutical approach able to abrogate the aPL pathogenic effects. Indeed, the observation that mice lacking β2GPI show a compromised early pregnancy suggested that functional β2GPI is necessary for optimal implantation and placental morphogenesis . This has led researchers to conceive novel and promising biological therapies useful for refractory APS patients and based on the use of immunomodulatory drugs  or a monoclonal antibody which are able to prevent the aPL-mediated activation of the complement and the procoagulant and pro-abortive effects, without interfering with the expression of the placental β2GPI [65, 66].
Miyakis S, Lockshin MD, Atsumi T et al (2006) International classification consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4:295–306PubMedCrossRef
Gómez-Puerta JA, Cervera R (2014) Diagnosis and classification of the antiphospholipid syndrome. J Autoimmun 48:20–25PubMedCrossRef
Meroni PL, Borghi MO, Raschi E et al (2011) Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 7:330–339PubMedCrossRef
Pierangeli SS, Chen PP, Raschi E et al (2008) Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin Thromb Hemost 34:236–250PubMedCrossRef
Meroni PL, Raschi E, Grossi C et al (2012) Obstetric and vascular APS: same autoantibodies but different diseases? Lupus 21:708–710PubMedCrossRef
D’Ippolito S, Meroni PL, Koike T et al (2014) Obstetric antiphospholipid syndrome: a recent classification for an old defined disorder. Autoimmunity Reviews 13:901–908
Chen JZ, Sheehan PM, Brennecke SP et al (2012) Vessel remodelling, pregnancy hormones and extravillous trophoblast function. Mol Cell Endocrinol 349:138–144PubMedCrossRef
Cohen M, Meisser A, Bischof P (2006) Metalloproteinases and human placental invasiveness. Placenta 27:783–793PubMedCrossRef
Ferretti C, Bruni L, Dangles-Marie V et al (2007) Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts. Hum Reprod Update 13:121–141PubMedCrossRef
Raab G, Klagsbrun M (1997) Heparin binding EGF growth factor. Biochim Biophys Acta 1333:F179–F199PubMed
Jessmon P, Leach RE, Randal Armant D (2009) Diverse functions of HBEGF during pregnancy. Mol Reprod Dev 76:1116–1127PubMedCentralPubMedCrossRef
Chen Y, Xiao-Xia W, Tan J et al (2012) Effect of low molecular weight heparin and heparin-binding epidermal growth factor on human trophoblast in first trimester. Fertil Steril 97:764–770PubMedCrossRef
Lyall F, Bulmer JN, Duffie E et al (2001) Human trophoblast invasion and spiral artery transformation: the role of PECAM- 1 in normal pregnancy, preeclampsia, and fetal growth restriction. Am J Pathol 158:1713–1721PubMedCentralPubMedCrossRef
Yagel S (2011) Angiogenesis in gestational vascular complications. Thromb Res 127:S64–S66PubMedCrossRef
Di Simone N, Di Nicuolo F, D’Ippolito S et al (2010) Antiphospholipid antibodies affect human endometrial angiogenesis. Biol Reprod 83:212–219PubMedCrossRef
Pijnenborg R, Vercruysse L, Hanssens M (2006) The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 27:939–958PubMedCrossRef
Bulla R, Bossi F, Tedesco F (2012) The complement system at the embryo implantation site: friend or foe. Front Immunol 3:55PubMedCentralPubMedCrossRef
Chaouat G (2007) The Th1/Th2 paradigm: still important in pregnancy? Semin Immunopathol 29:95–113PubMedCrossRef
Meroni PL, Tedesco F, Locati M et al (2010) Antiphospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view. Lupus 19:453–456PubMedCrossRef
Girardi G, Yarilin D, Thurman JM et al (2006) Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med 203:2165–2175PubMedCentralPubMedCrossRef
De Wolf F, Carreras FO, Moernan P et al (1982) Decidual vasculopathy and extensive placental infarction in a patient with repeated thromboembolic accidents, recurrent fetal loss, and a lupus anticoagulant. Am J Obstet Gynecol 142:829–834PubMed
Out HJ, Kooijman CD, Bruinse HW (1991) Histopathological finding from patient with intrauterine fetal death and antiphospholipid antibodies. Eur J Obstet Gynecol Reprod Biol 41:179–186PubMedCrossRef
Rand JH, Wu XX, Quinn AS et al (2010) The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis. Lupus 19:460–469PubMedCrossRef
Rand JH, Wu XX, Guller S et al (1994) Reduction of annexin-V (placental anticoagulant protein-I) on placental villi of women with antiphospholipid antibodies and recurrent spontaneous abortion. Am J Obstet Gynecol 171:1566–1572PubMedCrossRef
Sebire NJ, Fox H, Backos M et al (2002) Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early 1078 pregnancy failure. Hum Reprod 17:1067–1071PubMedCrossRef
Salafia CM, Cowchock FS (1997) Placental pathology and antiphospholipid antibodies: a descriptive study. Am J Perinatol 14:435–441PubMedCrossRef
Borghi MO, Meroni PL, Raschi E et al (2009) Antiphospholipid antibodies reactivity with human decidual cells: an additional mechanism of pregnancy complications in APS and a potential target for innovative therapeutic intervention. Ann Rheum Dis [abstract OP-0119] 68(Suppl 3):109
Di Simone N, Raschi E, Testoni C et al (2005) Pathogenic role of anti-β2-glycoprotein I antibodies in antiphospholipid-associated fetal loss: characterisation of β2-glycoprotein I binding to trophoblast cells and functional effects of anti-β2-glycoprotein I antibodies in vitro. Ann Rheum Dis 64:462–467PubMedCrossRef
Di Simone N, Meroni PL, del Papa N et al (2000) Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I. Arthritis Rheum 43:140–150PubMedCrossRef
Di Simone N, Marana R, Castellani R et al (2010) Decreased expression of heparin-binding epidermal growth factor-like growth factor as a newly identified pathogenic mechanism of antiphospholipid-mediated defective placentation. Arthritis Rheum 62:1504–1512PubMedCrossRef
Di Simone N, Castellani R, Raschi E et al (2006) Anti-beta-2 glycoprotein I antibodies affect Bcl-2 and Bax trophoblast expression without evidence of apoptosis. Ann N Y Acad Sci 1069:364–376PubMedCrossRef
Viall CA, Chen Q, Liu B et al (2013) Antiphospholipid antibodies internalised by human syncytiotrophoblast cause aberrant cell death and the release of necrotic trophoblast debris. J Autoimmun 47:45–57PubMedCrossRef
Holers VM, Girardi G, Mo L et al (2002) Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 195:211–220PubMedCentralPubMedCrossRef
Girardi G, Berman J, Redecha P et al (2003) Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 112:1644–1654PubMedCentralPubMedCrossRef
Berman J, Girardi G, Salmon JE (2005) TNF-α is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol 174:485–490PubMedCrossRef
Thurman JM, Kraus DM, Girardi G et al (2005) A novel inhibitor of the alternative complement pathway prevents antiphospholipid antibody-induced pregnancy loss in mice. Mol Immunol 42:87–97PubMedCrossRef
Redecha P, Tilley R, Rencati M et al (2007) Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood 110:2423–2431PubMedCentralPubMedCrossRef
Redecha P, Franzke CW, Ruf W et al (2008) Neutrophil activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome. J Clin Invest 118:3453–3461PubMedCentralPubMed
Seshan SV, Franzke CW, Redecha P et al (2009) Role of tissue factor in a mouse model of thrombotic microangiopathy induced by antiphospholipid antibodies. Blood 114:1675–1683PubMedCentralPubMedCrossRef
Martinez de la Torre Y, Buracchi C, Borroni EM et al (2007) Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6. Proc Natl Acad Sci U S A 104:2319–2324PubMedCentralPubMedCrossRef
Mulla MJ, Salmon JE, Chamley LW et al (2013) A role for uric acid and the Nalp3 inflammasome in antiphospholipid antibody-induced IL-1β production by human first trimester trophoblast. PLoS One 8:e65237PubMedCentralPubMedCrossRef
Park AL (2006) Chapter 28. Placental pathology in antiphospholipid syndrome. In: Khamashta MA (ed) Hughes’ syndrome. Springer, London, pp 362–374CrossRef
Shamonki JM, Salmon JE, Hyjek E et al (2007) Excessive complement activation is associated with placental injury in patients with antiphospholipid antibodies. Am J Obstet Gynecol 196:e1–e5PubMedCrossRef
Cavazzana I, Nebuloni M, Cetin I et al (2007) Complement activation in anti-phospholipid syndrome: a clue for an inflammatory process? J Autoimmun 28:160–164PubMedCrossRef
Meroni PL, Tincani A, Alarcón-Riquelme ME et al (2009) European Forum on Antiphospholipid Antibodies: research in progress. Lupus 18:924–929PubMedCrossRef
Martinez de la Torre Y, Pregnolato F, D’Amelio F et al (2012) Anti-phospholipid induced murine fetal loss: novel protective effect of a peptide targeting the β2 glycoprotein I phospholipid-binding site. Implications for human fetal loss. J Autoimmun 38:J209–J215CrossRef
Arnaud L, Mathian A, Ruffatti A et al (2014) Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: an international and collaborative meta-analysis. Autoimmun Rev 13:281–291PubMedCrossRef
Branch W, Obstetric Task Force (2011) Report of the Obstetric APS Task Force: 13th International Congress on Antiphospholipid Antibodies, 13th April 2010. Lupus 20:158–164PubMedCrossRef
Hoppe B, Burmester GR, Dörner T (2011) Heparin or aspirin or both in the treatment of recurrent abortions in women with antiphospholipid antibody syndrome. Curr Opin Rheumatol 23:299–304PubMedCrossRef
Girardi G, Redecha P, Salmon JE (2004) Heparin prevents antiphospholipid antibody induced fetal loss by inhibiting complement activation. Nat Med 10:1222–1226PubMedCrossRef
Di Simone N, Caliandro D, Castellani R (1999) Low molecular weight heparin restores in vitro trophoblast invasiveness and differentiation in presence of immunoglobulin G fractions obtained from patients with antiphospholipid syndrome. Hum Reprod 14:489–495PubMedCrossRef
D’Ippolito S, Marana R, Di Nicuolo F et al (2012) Effect of Low molecular weight heparins (LMWHs) on antiphospholipid antibodies (aPL)—mediated inhibition of endometrial angiogenesis. PLoS One 7:e29660PubMedCentralPubMedCrossRef
Ziakas PD, Pavlou M, Voulgarelis M (2010) Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol 115:1256–1262PubMedCrossRef
Ruffatti A, Tonello M, Visentin MS et al (2011) Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case–control study. Rheumatology 50:1684–1689PubMedCrossRef
Lockshin MD, Drunzin M, Qamar T (1989) Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. Am J Obstet Gynecol 160:439–443PubMedCrossRef
Silver RK, MacGregor SN (1993) Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of anticardiolipin antibody-positive obstetric patients. Am J Obstet Gynecol 169:1411–1417PubMedCrossRef
Cowchock FS, Reece EA, Balaban D (1992) Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin. Am J Obstet Gynecol 166:1318–1323PubMedCrossRef
Bramham K, Thomas M, Nelson-Piercy C et al (2011) First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood 117:6948–6951PubMedCrossRef
Carp HJ, Sapir T, Shoenfeld Y (2005) Intravenous immunoglobulin and recurrent pregnancy loss. Clin Rev Allergy Immunol 29:327–332PubMedCrossRef
Erkan D, Aguiar CL, Andrade D et al (2014) 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev 13:685–696PubMedCrossRef
Ostertag MV, Liu X, Henderson V, Pierangeli SS (2006) A peptide that mimics the Vth region of beta-2-glycoprotein I reverses antiphospholipid-mediated thrombosis in mice. Lupus 15:358–365PubMedCrossRef
Di Simone N, D’Ippolito S, Marana R et al (2013) Antiphospholipid antibodies affect human endometrial angiogenesis: protective effect of a synthetic peptide (TIFI) mimicking the phospholipid binding site of β2 glycoprotein I. Am J Reprod Immunol 70:299–308PubMedCrossRef
Miyakis S, Robertson SA, Krilis SA (2004) Beta-2 glycoprotein I and its role in antiphospholipid syndrome-lessons from knockout mice. Clin Immunol 112:136–143PubMedCrossRef
Comarmond C, Cacoub P (2013) Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev 12:752–757PubMedCrossRef
Berman H, Rodríguez-Pintó I, Cervera R et al (2013) Catastrophic Antiphospholipid Syndrome (CAPS) Registry Project Group (European Forum on Antiphospholipid Antibodies). Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab. Autoimmun Rev 12:1085–1090PubMedCrossRef
Agostinis C, Durigutto P, Sblattero D et al (2014) A non complement-fixing antibody to β2 glycoprotein I as a novel therapy to control abortions and thrombosis in antiphospholipid syndrome. Blood 123:3478–3487PubMedCrossRef