Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare thrombotic microangiopathy (TMA), caused by autoantibodies against the metalloproteinase ADAMTS13. Subsequent accumulation of ultra-large von Willebrand factor (VWF) multimers induces platelet agglutination… Click to show full abstract
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare thrombotic microangiopathy (TMA), caused by autoantibodies against the metalloproteinase ADAMTS13. Subsequent accumulation of ultra-large von Willebrand factor (VWF) multimers induces platelet agglutination and microvascular thrombosis. Pregnancy is known to precipitate iTTP episodes and poses additional challenges to physicians, e.g. the combination with features of preeclampsia or HELLP syndrome, potentially increasing maternal mortality. Index cases are more often associated with fetal demise than cases with a prior history of iTTP, and the risk of pregnancy-associated iTTP and miscarriage correlates with reduced levels of ADAMTS13 activity and the presence of anti-ADAMTS13 antibodies during pregnancy. The standard treatment of pregnancy-associated iTTP is immediate plasma exchange (PEX) and steroids with high response rates. The therapeutic repertoire for iTTP has recently been expanded by caplacizumab, directed against platelet-binding sites on VWF and limiting fatal microthrombi formation. To date, no data on the use of caplacizumab for pregnancy-associated iTTP are available. Animal data in guinea pigs did not report adverse effects. Here, we report the first use of caplacizumab in a 36-year-old pregnant woman with an acute iTTP episode. The patient was diagnosed with iTTP 13 years prior to this episode. Autoimmune activity, with ADAMTS13 activity below 10% and detectable anti-ADAMTS13 autoantibodies, had persisted since her last episode three years ago, despite intermittent rituximab treatment. The patient rejected further treatment intensification and immunosuppressive medication was discontinued one year before. During a follow-up visit, the patient reported to be pregnant at 11 + 4 weeks estimated gestational age (EGA). By then, ADAMTS13 activity was still below 10% with detectable anti-ADAMTS13 antibodies, indicating an increased risk for acute iTTP and miscarriage. With no signs of haemolytic activity or microthrombi formation, immunosuppressive medication with glucocorticoids and azathioprine was initiated. At 17 + 1 weeks EGA, the patient presented to our hospital with symptoms of a foodborne infection. Laboratory examination revealed microangiopathic haemolytic anaemia and thrombocytopenia (see Table I and Fig 1A). Ultrasound revealed a vital fetus with regular fetal growth. The patient received daily PEX and high-dose glucocorticoids, in addition to azathioprine. Platelet counts recovered within five days. After two additional sessions, PEX was discontinued, but the patient experienced an immediate exacerbation. By then, the fetus was still vital, with fetal growth within the lower limit of normal (see Fig 1B). Of note, an increased uterine vascular resistance with bilateral notching was present, indicating an increased risk for preeclampsia and severe intrauterine growth restriction (IUGR). Consequently, daily PEX was resumed but platelet count continued to decrease. Further therapeutic options including off-label therapies were thoroughly discussed. The patient emphatically expressed her firm wish to intensify treatment even if in off-label indications. Based on shared-decision making, ciclosporin, rituximab and caplacizumab were administered as off-label therapies. Platelet count normalised within three days, but ultrasound again demonstrated a noticeably high uteroplacental resistance with persistent bilateral
               
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