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Mechanisms of Pregnancy Loss in Antiphospholipid Syndrome

Gharavi, Azzudin E. MD,*; Pierangeli, Silvia S. PhD,*; Levy, Roger A. MD, PhD,†; Harris, E. Nigel MD*

Clinical Obstetrics and Gynecology: March 2001 - Volume 44 - Issue 1 - p 11-19
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Association of Antiphospholipid Antibodies With Pregnancy Loss

The biologically false-positive serologic test for syphilis (BFP-STS) and the lupus anticoagulant (LA), an antiphospholipid antibody (aPL) that paradoxically prolongs coagulation time in vitro but is related to a wide spectrum of thromboembolic manifestations in vivo, were first associated with recurrent intrauterine fetal death in the late 1950s. 1 This association was confirmed in several anecdotal case reports and small series. 2–4 In 1975, Nilsson et al 5 reported a young woman with circulating LA who had three consecutive intrauterine deaths at 31 and 34 weeks of gestation, suggesting a possible link between circulating anticoagulant and fetal loss caused by diffuse placental thrombosis and infarction. Large studies to determine the association between fetal loss and aPL were hindered by the lack of sensitivity of the BFP-STS and difficulties in performing LA tests. Only after the introduction of solid phase radioimmunoassay 6 and enzyme-linked immunosorbent assay (ELISA) 7 for aPL antibodies in the early 1980s did more extensive studies become possible, and the association of these antibodies with recurrent pregnancy loss was confirmed in large clinical series. 8–14 According to the current classification criteria for definite antiphospholipid syndrome (APS), recurrent fetal loss is an important clinical component. 15,16

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Do Antiphospholipid Antibodies Cause Fetal Death

The close association of aPL with thrombosis and recurrent fetal death strongly suggests a causative role for aPL antibodies in these complications, but does not prove it. The other evidence for the pathogenic role of aPL in recurrent fetal death has come from animal model experiments. MRL/ lpr mice, an autoimmune strain widely used as an animal model of systemic lupus erythematosus (SLE), have high levels of IgG aPL, thrombocytopenia, and intrauterine fetal death manifested by a smaller litter size compared with NZB/NZW, F1 mice, another SLE mouse model, or Balb/c, a normal strain of mice. 17 This observation further indicated a pathogenic role for aPL. The direct proof for the pathogenic role of aPL in pregnancy loss came from experiments by Branch et al, 18 who demonstrated that passive transfer of IgG fractions from women with aPL and recurrent fetal death to pregnant normal Balb/c mice (15 mg/mouse, intraperitoneal) caused intrauterine fetal death. The mice miscarried within 48 hours of injection, and no live fetuses were found when the animals were killed after 9 to 15 days of injection. Histopathologic and immunofluorescence studies revealed decidua necrosis and prominent intravascular IgG aPL and fibrin deposition. Pregnant mice injected with the same amount of IgG from normal pregnant subjects had neither fetal death, placenta necrosis, nor IgG deposition. Though reports are not consistently positive, these findings have been reproduced by other investigators using passive immunization murine models. For example, one group found that intravenous injections of affinity-purified human polyclonal or mouse monoclonal aCL (10 μg/mouse) to pregnant ICR mice, a normal strain, resulted in increased rates of embryo resorption and lower mean weights of pups and placentae in both groups. 19

Active immunization murine models also have been studied. Immunization of normal mice with purified human β2-glycoprotein I (β2GPI) induced high levels of aPL that induce pregnancy loss in some strains of mice. 20,21 Immunization with synthetic peptides representing the phospholipid-binding site of the β2GPI also produced pathogenic aPL. 22 Immunization with synthetic peptides of viral and bacterial origin with sequence and functional similarity to the phospholipid binding site of β2GPI also has induced aPL production. 23 Further, immunization with human pathogenic aPL also may induce aPL production, and some of these aPLs are pathogenic and cause intrauterine fetal death. 24 These experiments convincingly indicate that aPL antibodies are responsible for fetal death in patients with APS, but still do not explain their mechanism(s) of action. We review and analyze the possible mechanisms by which aPL antibodies may cause pregnancy loss.

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Placental Histopathology Of Patients With Fetal Death Associated With Antiphospholipid Syndrome

One of the major targets of aPL antibodies is the placenta. Second or third trimester fetal death is widely considered most specific for APS. First-trimester spontaneous abortion is not uncommon, however, and when anatomic and chromosomal abnormalities are excluded, recurrent first trimester pregnancy loss is a clinical criterion for APS in women with moderate or high titers aCL or circulating LA. 15 Fetal death in APS usually is preceded by intrauterine growth retardation, oligohydramnios, and fetal heart rate abnormalities indicating fetal hypoxia, all of which usually are caused by uteroplacental insufficiency. Uteroplacental insufficiency often is attributed to vasculopathy involving the terminal branches of the uterine arteries (spiral arteries) that nourish the intervillous space of the placenta. 25 Regardless of the gestational age at which APS-related fetal death occurs, placental histopathologic findings are suggestive of immaturity.

In normal pregnancy, the muscular and elastic tissue are completely absent throughout the tunica media of the distal arterial wall. 25 The lumen is dilated and tortuous, resembling the corresponding venous structure. The endothelial lining is not continuous, and there is no well-defined internal elastic lamina, although some small fragments may be present. This process reduces the arterial blood flow resistance. Large cells with imprecise cytoplasmic outlines and large vesicular nuclei often are found in the walls of the vessels with these physiologic changes. A typical spiral artery vasculopathy has been associated with preeclampsia, fetal growth retardation, and fetal death. This vasculopathy is characterized by absence of normal physiologic changes in the myometrial segments of the spiral arteries underlying the placenta and accumulation of lipid-laden macrophages in the intima, fibrinoid necrosis of the media, and intimal fibroblastic proliferation. In addition, a mononuclear infiltrate often is present. Because of the presence of lipid-laden macrophages, reminiscent of atherosclerotic vascular lesions, the term “acute atherosis” is used to describe this vasculopathy. 25 The spiral artery vasculopathy generally restricts maternal blood flow to the intervillous space, and hence restricts gas exchange and nutrient supply to the fetus, a condition clinically manifest as uteroplacental insufficiency. A lesser degree of uteroplacental insufficiency may lead to fetal growth retardation. The worst pregnancy outcomes are associated with multifocal uteroplacental thrombosis and placental infarction, both of which may be considered extreme expressions of the vasculopathy.

Unfortunately for the sake of study, there is no histopathologic feature specific only for APS. Gross examination and histologic findings in a woman with APS and mid-second-trimester fetal death showed massive infarction that involved more than 50% of the placental surface. 26 The more remarkable finding was the relative absence of the normal physiologic changes in the spiral arteries throughout the decidua. These vessels had small diameter and demonstrated intimal thickening, fibrinoid necrosis, and intraluminal thrombosis consistent with spiral artery vasculopathy. A postmortem examination after a fetal death at 30 weeks of gestation of a woman who died during attempted delivery from widespread infarction and intravascular thrombosis showed 30% of the placental tissue infarcted. 27 The infarcted region showed villous congestion and hemorrhage, agglutination of villi, and early trophoblastic coagulation necrosis with neutrophils infiltration. There was no evidence of intravascular thrombosis in the fetus. Several other studies have found placental infarction, thrombosis, and perivillous fibrin deposition in APS cases. In some cases in which placental bed biopsy were performed, evidence of decidua vascular atherosis, indicative of spiral artery vasculopathy, were seen. In a large comparison study of patients who had had fetal death at 16 to 39 weeks of gestation, 47 placentae from 45 women, 16 of whom had APS, were studied. 28 The pathologists were not told about the underlying disease. In placentae from patients with aPL antibodies, a decrease in vasculosyncytial membranes, fibrosis mainly in infarcted areas, hypovascular villi, and thrombosis or infarction was seen significantly more often than in placentae from women without these antibodies.

The placental histopathologic similarities of APS and preeclampsia are reflected in their uteroplacental insufficiency complications, such as fetal growth retardation, fetal distress, and intrauterine death, suggesting that spiral artery vasculopathy may be a common pathway for poor pregnancy outcome in both conditions. 25 The major findings in placentae from APS patients are ischemic–hypoxic changes caused by thrombosis/decidual vasculopathy, decidual thrombi, chronic villitis, fibrosis, hypovascular villi and decreased placental weight, acute atherosis, a decreased number of syncytiovascular membranes, and increased number of syncytial knots. 29 These findings are not specific to APS and do not always correlate with the fetal outcome. In a recent study of 36 placentae from women with SLE and APS, SLE without APS, and preeclampsia without APS, the conventional histopathologic comparative studies of placentae could not distinguish between APS and preeclampsia, whereas immunohistochemical studies of local placental extracellular matrix proteins contributed to this differential diagnosis. Placenta of APS patients presented a significantly increased deposition of laminin and collagen in vitro, compared with placentae obtained healthy normal women and from those that had preeclampsia without APS. 30 Placental bed biopsies with evaluation of maternal uterine spiral artery changes may be required to understand the pathophysiology of APS and to assist in the differential diagnosis of preeclampsia.

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Histopathologic findings in gestational tissue from women with fetal loss caused by APS may be attributed to the aPL-induced hypercoagulable state affecting the uteroplacental circulation. The mechanisms by which aPL antibodies may cause a hypercoagulable state are not clearly understood, but several hypotheses have been proposed, some of which may be involved in aPL-associated placenta thrombosis. These are described and summarized in Table 1.

Table 1

Table 1

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Effect of Antiphospholipid Antibody on Eicosanoid Balance

An old and popular hypothesis to explain thrombosis in placenta is eicosanoid balance alteration mediated by aPL antibodies. Prostacyclin (PGI2) dilates blood vessels and inhibits platelet aggregation. In contrast, thromboxane A2 (TXA2) is a potent vasoconstrictor that enhances platelet aggregation. Inhibition of endothelial cell production of PGI2 by plasma or purified IgG from aPL-positive patients has been demonstrated. 31,32 IgG from women with APS increased placental TXA2 production without affecting PGI2 production. 33 Some other authors have not been able to consistently reproduce these findings. 34

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Effect of Antiphospholipid Antibody on Glycosaminoglycans and Antithrombin III

The cross-reactivity between aPL and glycosaminoglycans (GAG) provides a possible mechanism for thrombosis. 35 Glycosaminoglycans, a family of heparin-like substances, are major determinants of the lining of the vascular endothelium’s nonthrombotic properties. Inhibition of this function by aPL may explain, in part, the thrombosis associated with them. It has been noted that 11% of the autoimmune aPL cross-reacts with heparan sulfate; one sample was shown to inhibit the heparin-dependent activation of antithrombin III (AT III) by up to 80%. 36 Heparin-specific antibodies that inhibited heparin-accelerated formation of thrombin–AT III complexes in the serum of APS patients have been reported, suggesting that antiheparan sulfate/heparin activity of aPL may be responsible for autoimmune vascular thrombosis in some patients with APS. 37

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Antiphospholipid Antibody and the Protein-C–Protein-S Pathway

Antiphospholipid antibodies could exert a procoagulant effect by inhibiting the phospholipid-dependent activation of the protein-C–protein-S pathway at two levels: the thrombin–thrombomodulin activation of protein-C, or the protein-C/protein-S degradation of activated factor V. Endothelial cells are capable of inhibiting protein C activation in the presence of aPL. 38 A decreased factor Va degradation in the plasma of 15 patients with lupus anticoagulant has been demonstrated. 39 IgG fractions from some patients with aPL inhibited the degradation of factor Va by protein-S. The antibodies responsible for this inhibition are directed against phospholipid-bound protein-C or protein-S, suggesting a pathogenic mechanism. 40

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Although aPLs are incapable of binding to nonstimulated platelets, they are able to bind freeze-thawed platelets. 41 Increased platelet secretion of TXA2 has been reported in the presence of aPL. 42 In vitro TXA2 secretion by platelets was enhanced by IgG F(ab′)2 from six APS patients with increased TXA2:PGI2 ratios. 42 An increased TXA2:PGI2 ratio, estimated by urinary metabolites, was reported in patients with APS. 43 Immunofluorescence studies revealed up-regulation of platelet endothelial cell adhesion molecule (PECAM-1). It has been demonstrated that affinity-purified anticardiolipin antibodies from patients with APS significantly enhanced the aggregation and activation of platelets when pretreated with suboptimal doses of ADP or thrombin. 44 These findings indicate that platelet activation contributes significantly to the thrombogenic phenotype in APS. Antiphospholipid antibodies also may generate a hypercoagulable state by activating endothelial cells, and this could represent an important pathophysiologic event in thrombosis. Incubation of human umbilical vein endothelial cells (HUVEC) with IgG aPL in the presence of β2GPI-increased monocyte adherence. There was an associated increase in surface expression of PECAM-1, ICAM-1, and VCAM-1 on the endothelial cells, and in preincubation with monoclonal antibodies to these molecules inhibited monocyte binding. 45 These findings were confirmed by other investigators. 46 Human polyclonal aPL antibody isolated from APS patients significantly enhanced the expression of adhesion molecules on HUVEC in vitro (indicating endothelial cell activation); this correlated with endothelial cell activation in vivo, as indicated by increased adhesion of leukocytes to vascular endothelial cells and enhanced thrombus formation in vivo in mouse models. 47 It has been shown that a murine monoclonal aPL antibody capable of activating endothelial cells in vitro (up-regulation of adhesion molecule expression on HUVEC) caused pregnancy loss in mice. 48 The murine monoclonal antibody generated by immunization with the phospholipid binding site of β2GPI also activated endothelial cells in vitro and in vivo, and this correlated with the thrombogenic potential of the monoclonal antibody. 23

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Antiphospholipid Antibodies and Annexins

Antiphospholipid antibodies may interfere with the function of natural regulators and inhibitors of coagulation such as placental anticoagulant proteins (PAP) and other annexins. Placental anticoagulant proteins are a group of four calcium-dependent phospholipid-binding proteins that inhibit phospholipid-dependent steps of coagulation by making phospholipid inaccessible to clotting factors. 49 The major component of the PAP family, PAP-1, also called annexin V, has the greatest affinity for acidic phospholipid (up to 1,000-fold greater than clotting factors) and is most abundant in the placenta. 50,51 Annexin V and aPL compete for phospholipid in coagulation assays and in the antiphospholipid ELISA. 52,53 In a blind study using computerized morphometric analysis of placental sections stained with antiannexin V, it was shown that in eight patients with APS and recurrent spontaneous abortions, the distribution of annexin V over the intervillous surface was significantly lower compared with that in women who had only elective abortions. Further, IgG aPL significantly decreased annexin V production by cultured trophoblasts in vitro. 54 In another study, IgG fractions from patients with APS were incubated with cultured trophoblasts (BeWo cells) and human umbilical vein endothelial cells. Cells exposed to aPL had reduced levels of annexin V and increased procoagulant activity. 55 In another experiment, when a monoclonal IgM antiphosphatidylserine was incubated with trophoblasts in culture, the exposure of phosphatidylserine during activation lead to annexin V binding to phosphatidylserine. Annexin V was no longer seen on the cell surface by immunoperoxidase technique. Further, an increased binding of prothrombin to trophoblasts was observed. 56 These findings suggest that reduced annexin V production and inhibition of its anticoagulant function by aPL antibodies may play a major role in pregnancy loss in APS syndrome.

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Antiphospholipid antibodies are associated with intrauterine fetal growth retardation and fetal distress leading to premature birth or fetal death. These complications are caused by uteroplacental insufficiency that is the result of multiple placental thromboses, infarcts, and spiral artery vasculopathy, which are almost certainly provoked by the hypercoagulable state induced by aPL antibodies. Available data indicate that the thrombogenic function of aPL antibodies involves their general effect on platelets, endothelial cells, anticoagulant mechanisms, and fibrinolytic pathways, as well as their local effect on trophoblasts and villi cells, leading to reduction of annexin V (placental anticoagulant protein-I) production and inhibition of its anticoagulant function.

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