Pregnancy Does Not Affect The Thrombotic Thrombocytopenic Purpura (TTP) phenotype Of ADAMTS13-Deficient Mice

Thrombotic thrombocytopenic purpura (TTP) is a life threatening disease, characterized by sudden onset of the pentad of fever, hemolytic anemia, thrombocytopenia, renal dysfunction and neurological findings. Previous studies in ADAMTS13-deficient mice demonstrated a dependence on both genetic and environmental factors for the expression of the disease. Though homozygous Adamts13^-/- mice on a C57BL6/J (B6) background are indistinguishable from wild-type controls, introduction of the CAST/EiJ genetic background results in a spontaneous TTP-like syndrome in a subset of mice.

The aim of this study was to evaluate the effect of pregnancy on TTP expression in this mouse model of TTP.

Adamts13^+/- mice were backcrossed for 20 generations to C57BL/6J to generate N20 B6 Adamts13^+/- progeny. These mice were backcrossed for 2 generations into the CAST/EiJ mouse strain to generate N2F1 Adamts13^-/- female mice that were tested and compared to N20F1 B6 Adamts13^-/- female mice.

Two groups of 20 Adamts13^-/- female mice from each strain were tested. Mice from one group were mated with wild type males, and mice from the second group were housed separately from male mice. Pregnant Adamts13-/- mice were compared to control non-pregnant Adamts13^-/- female mice. Mice were monitored for a full profile of blood parameters and peripheral blood smears weekly for 10 weeks. Data was collected for mortality, pregnancy outcome and litter size. Von Willebrand factor (VWF) levels were also measured.

All Adamts13^-/- mice in the B6 non-pregnant group appeared healthy and exhibited normal blood count parameters, without microangiopathic changes on peripheral blood smears. None of Adamts13^-/- mice in the B6 pregnant group developed TTP. Mean platelet count in this group was 844,000±127,000 cells/µl compared to 666,000±56,000 cells/µl in the B6 non-pregnant group (p<0.01)

In contrast to the B6 results, Adamts13^-/- CAST/EiJ non-pregnant mice exhibited lower platelet counts 369,000±89,000 cells/µl with spontaneous TTP-like disease in 54% of mice, as expected from previous studies.

Pregnancy did not worsen TTP expression in Adamts13^-/- CAST/EiJ mice. Only 45% of mice in the CAST/EiJ pregnant group developed low platelet counts with a higher mean platelet count of 511,000±160,000 cells/µl, compared to non-pregnant group(p<0.01).

The physiological rise in VWF levels of pregnancy had no effect on TTP susceptibility in this model. VWF antigen levels were 167%, 203%, 197% and 245% in B6 non-pregnant, B6 pregnant, CAST/EiJ non-pregnant and pregnant respectively, compared to wild-type B6 levels. Four mice died during follow-up, 2 in the B6 pregnant and 2 in the CAST/EiJ non-pregnant groups.

In summary, TTP expression was unique to Adamts13^-/- CAST/EiJ mice. Pregnancy and elevated VWF levels had no deleterious effect on TTP susceptibility in this mouse model.