Rat Models of Thrombotic Thrombocytopenic Purpura Reveal Crucial Role of Placental ADAMTS13 in Perinatal Survival

Thrombotic thrombocytopenic purpura (TTP), a life-threatening thrombotic microangiopathy, is caused by severe deficiency of plasma ADAMTS13 activity. Pregnancy is found to be frequently associated with the onset of acute TTP. However, how pregnancy or postpartum affects the progression of TTP and how ADAMTS13 may play a role in perinatal outcome are not known. Using CRISPR/Cas9, we generated a novel rat model of TTP by deleting 13-nucleotides in the coding region for ADAMTS13 metalloprotease. ADAMTS13-deficient (KO) rats showed barely detectable plasma ADAMTS13 activity with significantly increased size of plasma von Willebrand factor (VWF) multimers. The KO rats developed severe spontaneous thrombocytopenia with a median (interquartile range) platelet count of 125 (112-145) ×10⁹/L compared with that of 481 (404-532) ×10⁹/L in wild type (WT) and that of 520 (428-575) ×10⁹/L in heterozygous (Het) rats (P<.0001). Moreover, plasma levels of lactate dehydrogenase, urea nitrogen, and creatinine were significantly elevated in KO rats compared with those in WT (P<.05) and Het (P<.05). Immunohistochemistry revealed the presence of VWF- and platelet integrin b3-rich microvascular thrombi in major organ tissues of KO rats, but not of WT controls. Unexpectedly, pregnancy or postpartum did not result in worsening thrombocytopenia, but increased the risk of death in the KO females bred with KO male rats. These female rats produced significantly fewer live offsprings than those bred with WT or Het males (P<.05). We conclude that the findings in our novel KO rats recapitulate the features of congenital TTP and underscore the importance of fetal-placental ADAMTS13 in perinatal survival.