�uJournal of Reproductive Immunology�v53Šª�AP.269-277, 2002”N Œf�Ú
Autoantibodies to contact proteins in patients with recurrent pregnancy losses


Toshitaka Sugi and Tsunehisa Makino

Department of Obstetrics and Gynecology, Center for Growth and Reproductive Medicine, Tokai University School of Medicine, Kanagawa, Japan

Abstract
The kallikrein-kinin system or plasma contact system consists of three essential plasma proteins. These are coagulation factor XII, prekallikrein and high molecular weight kininogen. Deficiencies of these proteins are not associated with clinical bleeding despite marked prolongation of in vitro surface-activated coagulation time. Paradoxically, studies suggest that contact proteins have anticoagulant, profibrinolytic functions in a physiologic millieu, on endothelial cells. Recently, evidence has accumulated for the presence of the kallikrein-kinin system or plasma contact system in the fetoplacental unit. Kinins which are released within the placenta may play a role in regulating placental blood flow. This suggests that the plasma contact system may also have an important role in pregnancy. Several studies have reported the presence of autoantibodies to the contact proteins in patients with recurrent early pregnancy losses. Disruption of this system may be a risk factor for early gestational losses.


1. Introduction
Antiphospholipid antibodies (aPA) to anionic phospholipids such as cardiolipin and phosphatidylserine have been described in patients with thrombosis, thrombocytopenia and recurrent fetal loss. Autoantibodies reactive to zwitterionic phospholipids such as phosphatidylethanolamine (PE) have not been studied extensively. Most lupus anticoagulant (LA) and aPA literature is limited to descriptions of anionic phospholipids such as cardiolipin, however, antiphosphatidylethanolamine antibodies (aPE) also have been described in patients with thrombotic diseases and recurrent pregnancy losses (Staub et al., 1989; Karmochkine et al., 1992, 1993; Boffa et al., 1996; Berard et al., 1995; Sugi et al., 1999; Gris et al., 2000; McIntyre and Wagenknecht, 2000). We reported that certain aPE are not specific for PE per se, but are directed to PE-binding plasma proteins, kininogens (Sugi and McIntyre, 1995a).
Recently, a surprising high prevalence of factor XII deficiency among patients with recurrent pregnancy losses and thrombosis has been reported (Gris et al., 1997; Halbmayer et al, 1992). Jones (1999) reported the presence of antibodies to factor XII in patients with aPA.
Kininogens and factor XII are known as plasma contact proteins in the intrinsic pathway of blood coagulation. Since contact proteins may play an important role in pregnancy especially in feto-placental unit, deficiencies of these proteins and/or autoantibodies to these proteins may be associated with pregnancy losses.

2. Plasma contact system and kallikrein-kinin system
The plasma contact system or kallikrein-kinin system consists of three essential plasma proteins that interact upon binding to negatively charged surfaces. These are coagulation factor XII (Hageman factor), prekallikrein (Fletcher factor), and high molecular weight kininogen (Williams, Fitzgerald factor). Factor XII can be activated by contact with negatively-charged surfaces (Griffin, 1978; Silverberg et al., 1980; Tankersley and Finlayson, 1984). Activated factor XII (factor XIIa) converts prekallikrein to kallikrein and kallikrein digests high molecular weight kininogen (HK) to liberate the vasoactive, proinflammatory mediator, bradykinin. Factor XIIa also activates factor XI to continue the intrinsic coagulation cascade (Kaplan et al., 1997).
Although there are many candidate physiologic negatively-charged surfaces that in vitro can be associated with factor XII autoactivation, the concept of autoactivation itself has never been a sufficiently convincing mechanism to explain contact system activation in vivo. In fact, it is correct to say that the so-called elusive physiologic, negatively charged surface for contact system activation is actually the assembly of contact proteins on cell membranes (Colman et al., 1997; Motta et al., 1998). Their specific interactions with biologic cell membranes such as endothelial cells and platelets indicate that assembly and activation of this system takes place in a physiologic milieu, independent of negatively charged surfaces. In vivo, a negatively charged surface is not always needed for activation.
Evidence for the presence of the kallikrein-kinin system in fetoplacental vessels has accumulated in several studies (Miatello et al., 1994; Weerasinghe and Gadsby, 1992). Mutoh et al. (1992) indicated that a kinin generating activity of the kallikrein-kinin system is localized within the uteroplacental unit. Hermann et al. (1996) reported that kininogen and plasma prekallikrein/plasma kallikrein were present at at the endothelial cells of placental villous capillaries. In larger placental blood vessels and umbilical cord, neither kininogens nor kallikreins were detected. The co-localization of kininogen and plasma prekallikrein/plasma kallikrein suggests that kinins could be generated locally in placental capillaries. The functional spectrum of biologically active kinins, such as vasodilation, vasoconstriction, smooth muscle contraction and relaxation, could influence placental blood flow regulation. Moreover, kinins could also have anti-thrombotic/profibrinolytic activities (Colman and Schmaier, 1997; Brown et al., 1997). Kinins which are released within the placenta may play a role in regulating placental blood flow and transplacental transport of substrates and metabolites (Hermann et al., 1996). To influence placental circulation and nutrient supply to the fetus effectively, components of the kallikrein-kinin system should be situated within or close to the placental vasculature.
Recently, numerous studies have suggested an associations between contact protein deficiencies and recurrent pregnancy losses (Schved et al., 1989; Braulke et al., 1993; Gris et al., 1997), and between autoantibodies to contact proteins and recurrent pregnancy losses (McIntyre et al., 1997; Sugi et al., 1995a; Sugi et al., 1995b; Gallimore et al., 1998; McIntyre and Wagenknecht, 2000; Sugi et al., 1999). Since contact proteins may play an important role in pregnancy especially in fetoplacental unit, deficiencies of these proteins and/or autoantibodies to these proteins may be associated with pregnancy losses.

3. Autoantibodies to factor XII and factor XII deficiency
Deficiencies of contact proteins are not associated with clinical bleeding despite marked prolonged activated partial thromboplastin time (aPTT), a surface-activated coagulation protein screening test. Paradoxically, studies suggest that contact proteins have anticoagulant, profibrinolytic functions in a physiologic milieu, on endothelial cells (Colman et al., 1975; Wuepper et al., 1975; Saito et al., 1975; Halbmayer et al., 1994; Lammle et al., 1991; Halbmayer et al., 1992). Numerous clinical studies suggest that contact protein deficiencies may be associated with impaired contact factor-dependent fibrinolysis. This result may contribute to an increased incidence of thrombosis in patients with congenital factor XII deficiency, an increased incidence of factor XII deficiency in patients with venous thrombosis, and acquired thrombotic disorders such as myocardial infarction and re-thrombosis of coronary arteries after thrombolytic therapy (Mannhalter et al., 1987; Lammle et al., 1991; Halbmayer et al., 1992; Jespersen et al., 1992).
A surprisingly high prevalence of factor XII deficiency among patients with recurrent thrombosis has been reported (Mannhalter et al, 1987; Halbmayer et al, 1992). Ten percent of factor XII deficiencies among patients with venous thrombosis has been reported by Mannhalter et al. (1987). Halbmayer et al. (1992) reported that a high prevalence of factor XII deficiency (20%) among patients with recurrent arterial thromboembolism and/or myocardial infarction and an 8% incidence of factor XII deficiency among patients with recurrent venous thrombosis. The reduced generation of bradykinin resulting in diminished release of tissue plasminogen activator is proposed as a cause of thrombosis in factor XII-deficient patients (Levi et al., 1991). Both vascular and placental thrombosis in the presence of aPA or factor XII deficiency have been reported to be associated with recurrent fetal loss (Cowchock et al., 1986; Schved et al., 1989). Schved et al. (1989) reported the cases of three young women with a factor XII deficiency (two homozygous and one heterozygous) and a clinical history of spontaneous abortion. Braulke et al. (1993) reported on 8 patients with moderately reduced level of factor XII found among 43 patients with repeated abortions. Recently, Gris et al. (1997) reported the prevalence of haemostasis abnormalities in 500 unexplained primary early recurrent aborters. They found 9.4% of the patients with an isolated factor XII deficiency, 7.4% of the patients with primary aPA and 42.6% of the patients with an isolated hypofibrinolysis (mainly high plasminogen activator inhibitor) in the patients (reference groups: respectively 0/150, 3/150, 2/150, p<0.001). Willebrand disease, fibrinogen deficiency, antithrombin, protein C or protein S deficiencies were not more frequent in recurrent aborters than in members of the reference groups.
Gallimore and Winter (1998) reported a high incidence (20.9%) of apparently true factor XII deficiency in patients who were LA positive. They have hypothesized that antibodies to factor XII might be present in some patients who are LA positive and that immune complexes may be formed leading to reduced levels of factor XII. They studied plasma samples from LA positive patients for the presence of antibodies to factor XII and reported that many patients were positive for antibodies to factor XII detected by ELISA and immunoblot (Jones et al., 1999). Factor XII may be added to the list of proteins to which antibodies are produced in LA positive patients. These antibodies may interfere with contact activated fibrinolysis in such patients. Recently, presence of autoantibodies to factor XII was reported in factor XII deficient patients with recurrent early pregnancy losses (Uchida et al., 2000).

4. Autoantibodies to kininogen
The important function of the plasma kininogens is the delivery of bradykinin, a potent biologically active peptide. Kininogens and bradykinin contribute to vessel patency, increased blood flow, and anti-thrombotic/profibrinolytic activities. Bradykinin is a stimulator of endothelial cell prostacyclin synthesis; an inhibitor of platelet function (Hong, 1980; Crutchley et al., 1983), nitric oxide formation (Palmer et al., 1987) and tissue plasminogen activator release (Brown et al, 1997). Thus, kininogens have been shown to have antithrombin and profibrinolytic activities.
Autoantibodies reactive to zwitterionic phospholipid such as phosphatidylethanolamine (PE) have not been studied extensively. Most LA and aPA literature is limited to descriptions of anionic phospholipids such as cardiolipin, however, aPE also have been described in patients with thrombotic diseases (Staub et al., 1989; Karmochkine et al., 1992, 1993; Boffa et al., 1996; Berard et al., 1995; McIntyre and Wagenknecht, 2000). Furthermore, aPE have been reported as the sole aPA in several patients (Karmochkine et al., 1992; Karmochkine et al., 1993; Boffa et al., 1996; Berard et al., 1995). Since PE is a major component of both the outer and inner leaflet of cell plasma membranes, production of aPE may interfere with normal cell functions. Sugi and McIntyre (1995a) reported that certain aPE are not specific for PE per se, but are directed to PE-binding plasma proteins, for example, kininogens. Many aPE recognize a kininogen-PE complex and neither PE nor kininogen when they are presented independently (Sugi and McIntyre, 1995a, 1996; McIntyre et al., 1997). The kininogens bind to both negatively-charged and zwitterionic phospholipids. Despite the phospholipid-binding properties, kininogen-dependent aPE are specific for the kininogen-PE complex, as they do not recognize the kininogens when presented on other phospholipid substrates (Sugi and McIntyre, 1996a). This indicates that PE induces unique antigenic conformational changes in the kininogens which do not occur when the kininogens bind to other phospholipids.
The female reproductive tract is the second richest site for kininogen and its metabolic products in the body (Hossain et al., 1995; Hermann et al., 1996; Brann et al., 1995; Adam et al., 1989). Adam et al. (1989) measured 12.2, 10.9, 0.4 and 1.2 mg/mg T-kininogen in rat plasma, uterus, liver, and kidney, respectively. The kininogen concentration in reproductive tissues and plasma was reported to fluctuate during ovulation, pregnancy, and parturition (Hossain et al., 1995; Adam et al., 1989). Why the female reproductive system is so rich in kininogen and what governs the fluctuation of kininogen concentrations at the local level remains to be elucidated.
Because numerous studies (Branch et al., 1985; Petri et al., 1997; Katano et al., 1996) have concluded that recurrent pregnancy loss are associated with aPA to anionic phospholipids, and in view of the conspicuous presence of kininogen in reproductive tissues, we decided to test recurrent pregnancy loss patients for aPE, especially those patients who lose during the embryonic period (Branch and Silver, 1996). We reported that of 139 recurrent pregnancy loss patients, 28 (20.1%), 17 (12.2%), and 2 (1.4%) patients were positive for IgG, IgM, and IgA aPE, respectively. A positive test result for aPE was more frequent in the patients with recurrent pregnancy losses than in the members of the control group (p=0.0002). In contrast, there was no statistically significant difference in the incidence of positive test results for antibodies to anionic phospholipids between the recurrent pregnancy loss group and the control group. In this study, 21 patients were positive for plasma protein-dependent IgG aPE. Nineteen (90.5%) of these 21 patients were kininogen-dependent (Sugi et al., 1999). Our data suggest that aPE may represent a significant risk factor for early recurrent pregnancy loss. Recently Gris et al. (2000) reported that aPE were found to be independent risk factors for unexplained early fetal loss.

Conclusions
Plasma contact proteins have anticoagulant and profibrinolytic activities in vivo. In fact, an association between deficiencies of these proteins and recurrent thrombosis has been reported. Also deficiencies of these proteins and antiphospholipid antibodies are frequent haemostasis-related abnormalities found in unexplained recurrent aborters. Mid gestation pregnancy loss in primary antiphospholipid syndrome patients often is associated with anticardiolipin antibodies (Branch et al., 1985). Gris et al. (1997) reported the association between early recurrent miscarriages and factor XII deficiency. Sugi et al. (1999) reported a statistically stronger association between recurrent miscarriages and kininogen-dependent aPE than between recurrent miscarriages and antibodies to anionic phospholipids for early gestational losses. Thus, in contrast with anticardiolipin antibody associated pregnancy loss, early gestation pregnancy loss often may be associated with the disruption of plasma contact system or kallikrein-kinin system. Because the kallikrein-kinin system is localized within the uteroplacental unit, it may play a role in regulating placental blood flow and transplacental transport of subtances and metabolites (Hermann et al., 1996). Disruption of this system may be a risk factor for early gestational loss.


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