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First use of the anti‐VWF nanobody caplacizumab to treat iTTP in pregnancy

2021; Wiley; Volume: 196; Issue: 3 Linguagem: Inglês

10.1111/bjh.17833

1365-2141

Lucas Kühne, Linus A. Völker, Henning Hagmann, Holger Hägele, Thomas Osterholt, Dennis A. Eichenauer, Andreas Thomas, Johanna Breuer, Berthold Grüttner, Ingo Gottschalk, Martin Kann, Thomas Benzing, Mario Thevis, Annette Müller, Paul T. Brinkkoetter,

Blood Coagulation and Thrombosis Mechanisms

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.1 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.2, 3 The standard treatment of pregnancy-associated iTTP is immediate plasma exchange (PEX) and steroids with high response rates.1 The therapeutic repertoire for iTTP has recently been expanded by caplacizumab, directed against platelet-binding sites on VWF and limiting fatal microthrombi formation.4-10 To date, no data on the use of caplacizumab for pregnancy-associated iTTP are available.1 Animal data in guinea pigs did not report adverse effects.11 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.2 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).12 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 notching. The fetal growth curve had further flattened, potentially deriving from early-onset placental insufficiency. A rebounding albuminuria to 647 mg/g creatinine, together with new onset hypertension and an elevated sFlt-1/PlGF ratio, led to the suspicion of preeclampsia resulting from placental iTTP manifestation. One week later, severe early-onset IUGR was diagnosed, with almost no interval growth and oligohydramnios and placental hydrops being present. Given the poor fetal prognosis, termination of pregnancy was agreed upon with the patient, to prevent potentially life-threatening iTTP and preeclampsia sequelae. Vaginal delivery was favoured and intrauterine fetocide by intracordal potassium injection was performed prior to labour at the patient's request. After the patient's informed consent, placental tissue, amniotic fluid and fetal blood samples were collected and further analysed. Placental histology revealed villous retardation, fetal vascular thrombosis, (maternal) intervillous thrombosis and fibrin deposition in decidual arterioles corresponding to atherosis, as in preeclampsia. However, mural hypertrophy of arterioles (characteristic of preeclampsia) was absent, suggesting chronic placental insufficiency and fetal thrombosis as major causes for severe early-onset IUGR. Whether thrombi in fetal vessels indicate a fetal iTTP manifestation remains elusive. The transplacental transfer of maternal anti-ADAMTS13 antibodies has been described before, but to our knowledge there are no reports of a fetal iTTP.13 There were no apparent bleeding complications, especially no signs of retroplacental haematoma. With the help of LC-HR-MS/MS analysis, we documented the transplacental transfer of caplacizumab (for methods see supplemental material). Caplacizumab was qualitatively identified in amniotic fluid and fetal blood above the assay's limit of detection, as illustrated in Fig 1D. The estimated drug concentration was 50 ng/ml. The estimated concentration in maternal blood was within the expected range, according to published pharmacokinetics, and hence five- to tenfold higher.5 Whether the caplacizumab dose was insufficient to prevent any fetal thrombosis or whether the histologically proven thrombosis results from pre-caplacizumab microthrombi formation remains elusive. In conclusion, caplacizumab treatment in our patient appeared to be safe and effective, with a rapid platelet count normalisation within three days. The treatment rapidly improved the mother's condition, but may have been applied too late to save fetal life. From our experience, what lessons can be learned with regard to future cases of iTTP in early pregnancy? First, iTTP is a devastating disease affecting the mother and the fetus, with a high risk of adverse outcomes. Even timely initiation of standard therapy – which was effective in previous acute iTTP episodes in the same patient – could not prevent IUGR and fetal loss. Therefore, in individual cases, rapid and determined initiation of caplacizumab treatment to prevent thrombotic microangiopathy seems reasonable, albeit off-label. Second, although caplacizumab may potentially increase the risk for pregnancy-specific haemorrhagic complications, e.g. a retroplacental haematoma, we believe that placental damage by ongoing TMA with an impaired placental perfusion poses a much greater risk to the fetus. In a prospective patient with iTTP in early pregnancy and high risk for miscarriage, we would administer caplacizumab as early as possible, flanked by glucocorticoids and PEX. Undoubtedly, this treatment must be based on shared decision-making, after thorough risk-benefit discussion. We would then stop PEX once TMA resolves and continue caplacizumab, depending on ADAMTS13 activity, disease severity, and drug tolerability. Dr. Völker reports grants from the Else-Kroener-Fresenius Stiftung (2015_A224) and speaker honoraria from Sanofi-Genzyme. Prof. Brinkkötter declares grants from the German Research Foundation (BR2955/8) and personal fees from Alexion, Sanofi-Genzyme, Bayer, Vifor, and Pfizer (speaker honoraria, advisory boards). All other authors declare no competing financial interest. L.K., L.A.V., M.T. and P.T.B. drafted the manuscript and prepared the figures. A.T., J.B. and M.T. designed and performed LC-MS/MS experiments. A.M. performed the histopathological analysis of the placenta. L.K., L.A.V., H. Hagmann, H. Hägele, T.O., I.G., B.G., M.K., T.B., P.T.B. were involved in patient management. All authors were involved in data collection and proofreading. The manuscript has been read and approved for submission to BJH by all authors. Written informed consent was obtained from the patient for publication of this short report and any accompanying images. A copy of the written consent is available for review by the corresponding author. 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