ADAMTS13 enzyme key to pregnancy success in TTP rat study
Lack of key enzyme led to fewer surviving pups for pregnant rats
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The lack of a key enzyme in thrombotic thrombocytopenic purpura (TTP) may threaten fetal survival during pregnancy, according to a study involving rats.
Researchers found that, while pregnancy and the postpartum period did not worsen key disease features, the absence of the ADAMTS13 enzyme in the fetus and placenta was associated with fewer surviving offspring. The findings “underscore the importance of fetal-placental ADAMTS13 in perinatal survival,” the researchers wrote.
The study, “Rat Models of Thrombotic Thrombocytopenic Purpura Reveal Crucial Role of Placental ADAMTS13 in Perinatal Survival,” was published in Blood Advances.
TTP is a blood disorder marked by a severe deficiency or complete lack of activity of ADAMTS13, an enzyme that helps regulate blood clotting. In congenital TTP, this deficiency is caused by mutations in the ADAMTS13 gene. The lack of ADAMTS13 ultimately leads to abnormal clot formation in small blood vessels.
Excessive clotting can damage organs and cause red blood cells to break apart, leading to anemia or a shortage of red blood cells. It can also deplete the body’s supply of platelets (the small cell fragments that help blood clot), resulting in low platelet levels (thrombocytopenia).
Rat study explores ADAMTS13-pregnancy link
Pregnancy and the postpartum period are known triggers of TTP. However, “how pregnancy or the postpartum period affects the progression of TTP, and how ADAMTS13 may influence perinatal outcomes, are not well understood,” the researchers wrote.
The team at the University of Kansas Medical Center developed a rat model lacking ADAMTS13 using a gene-editing technique to introduce mutations that prevented the gene from producing a working enzyme.
Unlike previous animal models, which required an additional trigger to develop TTP symptoms, the rats lacking ADAMTS13 exhibited hallmark features of TTP from birth.
These rats had severe thrombocytopenia, with low platelet counts detected as early as the first week of life, along with consistent signs of red blood cell destruction. They also showed abnormal clotting in small blood vessels across multiple organs — including the brain, heart, lungs, kidneys, and spleen — along with evidence of organ damage.
Restoring ADAMTS13 activity in these rats led to a rapid rise in platelet counts within 24 hours, with effects lasting several days, confirming that the disease was driven by the enzyme’s deficiency.
To understand how pregnancy and the postpartum period affect the disease, the researchers bred female rats lacking ADAMTS13 with males that either lacked the enzyme or had normal levels, generating offspring with varying levels of enzyme activity. Pregnancies resulting from breeding healthy rats and rats with partial ADAMTS13 activity served as controls.
They found that pregnancy did not worsen thrombocytopenia. Before pregnancy, female rats lacking ADAMTS13 had much lower platelet counts than healthy rats or those with partial enzyme activity. During pregnancy, platelet levels in these female rats increased significantly during mid to late pregnancy, but returned to pre-pregnancy levels within a few days after delivery.
However, pregnancy outcomes differed. Female rats lacking ADAMTS13 bred with males also lacking the enzyme had fewer surviving offspring, with a median litter size of 4.5 live pups. When these females were bred with healthy males, the median litter size increased to eight pups, but it remained lower than in healthy or partially deficient pairs, which had around 10 pups.
Because the females lacked ADAMTS13 in both cases, the difference in survival seemed to depend on whether the fetus could produce ADAMTS13.
Placental tissue from female rats lacking ADAMTS13 bred with males also lacking the enzyme showed abnormal clot formation in small blood vessels, indicating impaired blood flow. These findings suggest that ADAMTS13 produced by the fetus and the placenta is essential for maintaining healthy blood flow and supporting survival before birth.
“This innovative rat model demonstrates little adverse impact of pregnancy or postpartum on the severity of congenital TTP and reveals the critical role of fetal placental ADAMTS13 in perinatal survival,” the researchers wrote.
