Murine Severe Combined Anemia and Thrombocytopenia (SCAT), a Model for Human Juvenile Cyclic Congenital Amegakaryocytic Thrombocytopenia (cyCAMT).

Congenital inherited thrombocytopenias (CTP) are rare and often misdiagnosed in patients. SCAT is a heritable, recessive murine bleeding disorder that shares characteristics with some of the human CTPs. The disease is: present at birth, episodic, lethal unless treated and not immune-mediated. A platelet-specific antibody present in plasma of scat/+ mothers and their affected scat/scat pups initiates a short-lived platelet decrease when injected into adult +/+ mice and binds a 110 kD platelet protein on Western blots. The antibody is not responsible for the phenotype. scat/scat pups are anemic and thrombocytopenic at birth regardless of whether they and/or their scat/+ mother are immunodeficient and antibody free. Hematopoietic stem cell transplantation transmits the SCAT disease to normal mice. scat/+ x scat/+ matings generate only ½ the expected number of scat/scat neonates. Despite the deficit, the total number of live newborns from scat/+ x scat/+ matings is the same as from +/+ x +/+ matings. These observations suggest that the disease is incompletely penatrant or that scat/scat fetuses die in utero. In utero analyses indicate that the expected number of bruised scat/scat fetuses die near birth, but also an additional 24% of the total fetuses present are resorbed after implantation. Identification of the resorbed fetuses is impossible by molecular analysis, so the normal, live born survivors (?/+) were genotyped as adults by mating to a known scat/+ adult of the opposite sex. Results are consistent with early in utero loss of the scat/+ pups. Surprisingly, the scat/+ mothers and all their fetuses are platelet deficient. Platelets are more severely decreased in the live, bruised fetuses. Clearly, the scat/+ mother is more fecund and the scat/+ as well as the scat/scat fetuses are at risk. We hypothesize there is transplacental transfer of a thrombocytopenia-initiating factor between the fetuses and their mother in both directions. The putative initiator is produced only when a wild-type gene is present since scat/scat parents surviving the cyclical platelet deficiency can mate but give birth to unaffected scat/scat pups. The early onset, recessive inheritance, cyclical nature, defective stem cells and rapidly progressing marrow hypoplasia in scat/scat mice are reminiscent of juvenile cyCAMT. c-mpl, responsible for non-cyclical CAMT, is not in the scat interval on mouse Chr. 8. The scat gene must play an unpredicted role in maintaining stem cells and their progeny and could be a candidate gene for cyCAMT.