Impaired Thrombin Generation in β2-Glycoprotein I Null Mice

Abstract

Autoimmune antibodies to ␤ 2 -glycoprotein I (␤2GPI) have been proposed to be clinically relevant because of their strong association with thrombosis, miscarriage, and thrombocytopenia. By using a homologous recombination approach, ␤2GPI-null mice were generated to begin to understand the physiologic and pathologic role of this prominent plasma protein in mammals. When ␤2GPI heterozygotes on a 129/Sv/C57BL/6 mixed genetic background were intercrossed, only 8.9% of the resulting 336 offspring possessed both disrupted alleles. These data suggest that ␤2GPI plays a beneficial role in implantation and/or fetal development in at least some mouse strains. Although those ␤2GPI-null mice that were born appeared to be relatively normal anatomically and histologically, subsequent analysis revealed that they possessed an impaired in vitro ability to generate thrombin relative to wild type mice. Thus, ␤2GPI also appears to play an important role in thrombinmediated coagulation.

Beta-2 glycoprotein I and its role in antiphospholipid syndrome—lessons from knockout mice

“…When h 2 GPI heterozygotes on a 129/Sv/C57BL/6 mixed genetic background were intercrossed, only 8.9% of the resulting offspring were homozygous for the deletion, which is significantly lower than the expected 1:2:1 Mendelian ratio [83]. This finding implies that lack of h 2 GPI action confers a selective disadvantage to survival.…”

“…Perhaps surprisingly, the results show that loss is not associated with placental thrombosis or clotting changes, but rather occurs before or early after embryo implantation. This is of interest in view of the observations of early loss of h 2 GPI-deficient embryos [83]. These data, combined with the finding that h 2 GPI is not essential for successful reproductive function, imply that the mechanism of aPL-associated pregnancy loss does not involve deactivation of h 2 GPI, but rather is the consequence of an event triggered via interaction of aPL with the h 2 GPI ligand.…”

“…Mice with a deletion of the b 2 GPI gene proceed normally to adulthood and show no clear tendency to thrombosis; however, they exhibit impaired thrombin generation upon activation of the extrinsic clotting cascade in defibrinated plasma [83]. The findings from experiments with h 2 GPIdeficient mice on the role of h 2 GPI will be discussed next.…”

“…In initial experiments, normal reproductive function was observed in crosses between h 2 GPI-deficient male and female mice [83] with reproductive outcomes indistinguishable from control mice in both males and females carrying the h 2 GPI null mutation in terms of the proportion of animals that bred successfully and the number and viability of pups born at term and surviving to weaning. Furthermore, there was no evidence of altered blood platelet counts in either virgin or pregnant mice.…”

“…New perspectives into research on h 2 GPI have emerged after the recent generation and initial characterization of transgenic mice unable to express h 2 GPI [83], obtained using a homologous recombination approach [76]. Mice with a deletion of the b 2 GPI gene proceed normally to adulthood and show no clear tendency to thrombosis; however, they exhibit impaired thrombin generation upon activation of the extrinsic clotting cascade in defibrinated plasma [83].…”