Plasma contact system, kallikrein-kinin system and antiphospholipid-protein antibodies in thrombosis and pregnancy
「Journal of Reproductive Immunology」Vol.47 2000

Tsunehisa Makino and Toshitaka Sugi
Department of Obstetrics and Gynecology, Tokai University School of Medicine, Kanagawa, Japan


 Coagulation factor XII, prekallikrein and high molecular weight kininogen are known as plasma contact proteins in the intrinsic pathway of blood coagulation. Deficiencies of these proteins are not associated with clinical bleeding despite marked prolongation of in vitro surface-activated coagulation time. Paradoxically, studies suggest that these proteins have anticoagulant and profibrinolytic activities. In fact, association between deficiencies of these proteins as well as recurrent thrombosis has been reported. Also deficiencies of these proteins and antiphospholipid antibodies are frequent haemostasis-related abnormalities found in unexplained recurrent aborters. Recently, evidence has accumulated for the presence of the kallikrein-kinin system or plasma contact system in the fetoplacental unit. 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 SLE, thrombosis and recurrent pregnancy loss. These autoantibodies are often in association with antiphospholipid antibodies and lupus anticoagulants. Contact proteins may be added to the list of proteins to which autoantibodies are produced in patients assigned to antiphospholipid antibody syndrome.


1. Introduction

 The 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 et al., 1978; Silverberg et al., 1980; Tankersley et al., 1984). Activated factor XII (factor XIIa) converts prekallikrein (PK) to kallikrein and kallikrein digests high molecular weightkininogen (HK) to liberate the vasoactive, proinflammatory mediator, bradykinin (BK). Factor XIIa also activates factor XI to continue the intrinsic coagulation cascade.


2. Factor XII (Hageman factor)

 A surprisingly high prevalence of factor XII deficiency among patients with recurrent thrombosis has been reported (Mannhalter et al, 1987; Halbmayer et al, 1992). Factor XII deficiency is autosomal recessive (Halbmayer et al, 1994). Homozygous factor XII deficiencies with factor XII activities below 1% are often detected during routine laboratory testing by markedly prolonged aPTT. Heterozygous factor XII deficiencies with factor XII activities of 25-50% show only minor prolongation of or normal aPTT.

 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 recurrent aborters. They found 9.4% of the patients with an isolated factor XII deficiency, 7.4% of the patients with primary aPA and isolated hypofibrinolysis (mainly high plasminogen activator inhibitor) was found in 42.6% of the patients (reference groups: respectively 0/150, 3/150, 2/150, p<0.001).

Bick and Ancypa (1995) described factor XII deficiency as one of the rare congenital blood protein defects associated with thrombosis in contrast to the more common deficiencies of antithrombin III, protein C and protein S. However, the prevalence of factor XII deficiency among patients with recurrent venous and/or arterial thromboembolism was described to be 8-20% (Halbmayer et al, 1992). Since little was known about the prevalence of factor XII deficiency among the normal population, Halbmayer (1994) studied 300 healthy blood donors for factor XII deficiency and reported an incidence of factor XII deficiency of 2.3%. Among the 300 healthy donors, 16 (5.3%) subjects with prolonged aPTT were identified. Causes for aPTT-prolongation are factor XII deficiency (7/16), lupus anticoagulant (6/16), mild factor VIII deficiency (1/16) and hepatic disorder (1/16). Their data suggest that factor XII deficiency is a relatively frequent defect rather than other blood protein deficiencies.



 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.




Bick, R.L., Ancypa, D., 1995. Blood protein defects associated with thrombosis. Laboratory assessment.Clin Lab Med 15, 125-163.

Braulke, I., Hinney, B., Pruggmayer, M., Kostering, H., Melloh, P., Gunther, E., 1993. Factor XII (Hageman) deficiency in women with habitual abortion: new subpopulation of recurrent aborters? Fertil Steril 59, 98-101.

Cowchock, S., Smith, J.B., Gocial, B., 1986. Antibodies to phospholipids and nuclear antigens in patients with repeated abortions. Am J Obstet Gynecol 155, 1002-10.

Griffin, J.H., 1978. Role of surface in surface-dependent activation of Hageman factor (blood coagulation factor XII). Proc Natl Acad Sci USA 75, 1998-2002.

Gris, J.C., Neveu, S.R., Maugard, C., Tailland M.L., Brun, S., Courtieu, C., Biron, C., Hoffet, M., Hedon, B., Mares, P., 1997. Prospective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. Thromb Haemost 77, 1096-103.

Halbmayer, W.M., Haushofer, A., Schon, A., Mannhalter, C., Stromer, E., Baumgarter, K., Fischer, M., 1994. The prevalence of moderate and severe factor XII (Hageman factor) deficiency among the normal population: Evaluation of the incidence of factor XII deficiency among 300 healthy blood donors. Thromb Haemost 71, 68-72.

Halbmayer, W.M., Mannhalter, C., Feichtinger, C., Rubi, K., Fisher, M., 1992. The prevalence of factor XII deficiency in 103 orally anticoagulated outpatients suffering from recurrent venous and/or arterial thromboembolism. Thromb Haemost 68, 285-290.

Hermann, A., Buchinger, P., Somlev, B., Rehbock, J., 1996. High and low molecular weight kininogen and plasma prekallikrein/plasma kallikrein in villous capillaries of human term placenta. Placenta 17, 223-230.

Mannhalter, C., Fischer, M., Hopmeier, P., Deutsch, E., 1987. Factor XII activity and antigen concentrations in patients suffering from recurrent thrombosis. Fibrinolysis 1, 259-263.

Schved, J.F., Dupaigne, D., Gris, J.C., Mares, P., Neveu, S., 1989. Factor XII congenital deficiency and early spontaneous abortion. Fertil Steril 52, 335 336.

Silverberg, M., Dunn, J.T., Garen, L., Kaplan, A.P., 1980. Autoactivation of human Hageman factor: Demonstration utilizing a synthetic substrate. J Biol Chem 255, 7281-7286.

Sugi, T., Katsunuma, J., Izumi, S., McIntyre, J.A., Makino, T., 1999. Prevalence and heterogeneity of antiphosphatidylethanolamine antibodies in patients with recurrent early pregnancy losses. Fertil Steril (in press).

Tankersley, D.L., Finlayson, J.S., 1984. Kinetics of activation and autoactivation of human factor XII. Biochemistry 23, 273-279.