Title: TTP in the setting of pregnancy: The story still has to be written
Abstract: To reach strong levels of evidence in the knowledge regarding diseases is a prerequisite for the optimal management of patients. In the field of rare diseases, the scarcity of data can be a major limitation in the achievement of this goal, especially for some specific aspects involving even smaller groups of patients. This statement applies for thrombotic thrombocytopenia purpura (TTP) in the setting of pregnancy. As we increasingly reach an acceptable level of agreement in the general diagnosis and management of the disease through the efforts of international working groups (see the International Society on Thrombosis and Haemotology [ISTH] recommendations in this issue and Scully et al1.Scully M. Cataland S. Coppo P. et al.Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.J Thromb Haemost. 2017; 15: 312-322Crossref PubMed Scopus (264) Google Scholar), this area of the field still suffers from insufficient reported experience. Pregnant women with TTP, however, represent roughly 20% of all TTP cases in childbearing‐age women.2.Mariotte E. Azoulay E. Galicier L. et al.Epidemiology and pathophysiology of adulthood‐onset thrombotic microangiopathy with severe ADAMTS13 deficiency (thrombotic thrombocytopenic purpura): a cross‐sectional analysis of the French national registry for thrombotic microangiopathy.Lancet Haematol. 2016; 3: e237-e245Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Moreover, emerging topics need to be urgently addressed in this specific population at a time when new therapeutic agents (including caplacizumab, immunomodulators, and soon the recombinant ADAMTS13) are enriching our therapeutic arsenal.1.Scully M. Cataland S. Coppo P. et al.Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.J Thromb Haemost. 2017; 15: 312-322Crossref PubMed Scopus (264) Google Scholar Until more complete data are available, we summarize here the known and still unknown aspects of pregnancy‐associated TTP that should be addressed in the near future. Unexpectedly, the prevalence of late‐onset congenital TTP (cTTP) was found to be remarkably high among pregnancy‐associated TTP (~40% when considering all pregnancies and even ~60% when considering only first pregnancies), while it represents <5% of all adult‐onset TTP.3.Moatti‐Cohen M. Garrec C. Wolf M. et al.Unexpected frequency of Upshaw‐Schulman syndrome in pregnancy‐onset thrombotic thrombocytopenic purpura.Blood. 2012; 119: 5888-5897Crossref PubMed Scopus (173) Google Scholar, 4.Scully M. Thomas M. Underwood M. et al.Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes.Blood. 2014; 124: 211-219Crossref PubMed Scopus (180) Google Scholar The first pregnancy usually triggers the first TTP bout (and consequently is associated with the discovery of the disease) in patients carrying ADAMTS13 mutations linked to late‐onset cTTP. In some rare cases of late‐onset cTTP, the first pregnancy is not associated with a classical TTP bout but with a short‐term outcome combining an early miscarriage and a transient thrombocytopenia. In these particular cases, the diagnosis of TTP is most often missed during the first pregnancy. Late‐onset cTTP presenting de novo in an obstetrical context usually occurs during the second half of pregnancy and early post partum (mostly as a consequence of the progressive increase in von Willebrand factor multimer concentration throughout pregnancy), but rare cases may occur during the first trimester. The later the TTP occurs during pregnancy, the better is the fetal prognosis. In the historical patients who did not benefit from prophylactic plasmatherapy, the fetal mortality (mostly linked to placental thrombi) was >50% in pregnant women with cTTP. In contrast, the maternal prognosis was good provided curative plasmatherapy was performed quickly. Among ADAMTS13 mutations associated with late‐onset cTTP, the R1060W missense mutation is the most frequent in Caucasian women with pregnancy‐associated cTTP (prevalence ranging from 50% to 75% in cohorts from France and UK) while it is not found in Japan.3.Moatti‐Cohen M. Garrec C. Wolf M. et al.Unexpected frequency of Upshaw‐Schulman syndrome in pregnancy‐onset thrombotic thrombocytopenic purpura.Blood. 2012; 119: 5888-5897Crossref PubMed Scopus (173) Google Scholar, 4.Scully M. Thomas M. Underwood M. et al.Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes.Blood. 2014; 124: 211-219Crossref PubMed Scopus (180) Google Scholar, 5.Fujimura Y. Matsumoto M. Kokame K. et al.Pregnancy‐induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw‐Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients.Br J Haematol. 2009; 144: 742-754Crossref PubMed Scopus (102) Google Scholar, 6.Joly B.S. Boisseau P. Roose E. et al.ADAMTS13 gene mutations influence ADAMTS13 conformation and disease age‐onset in the french cohort of upshaw‐schulman syndrome.Thromb Haemost. 2018; 118: 1902-1917Crossref PubMed Scopus (28) Google Scholar The ADAMTS13 R1060W sequence variation causes severe intracellular retention of ADAMTS13, which impairs secretion; it is strongly associated with both the R7W and A1033T modifying single nucleotide polymorphisms. Practically, the ADAMTS13 R1060W sequence variation could be screened to help distinguish cTTP from those with immune‐mediated TTP (iTTP) with no detectable anti‐ADAMTS13 antibodies in a patient with an inaugural acute TTP occurring during a first pregnancy. Here, the most important challenge is to identify TTP in a context of maternal thrombotic microangiopathy (TMA), which means to differentiate TTP from other obstetrical TMAs like pre‐eclampsia (PE); hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome; or acute fatty liver (AFL) syndrome and from other diseases like hemolytic uremic syndrome, antiphospholipid syndrome, or disseminated intravascular coagulation (Figure 1). These differential diagnoses may be tricky for several reasons: first, obstetrical TTP and its differential diagnoses may have similar prevalence/clinical presentation; second, TTP sometimes presents with unusual symptoms classically observed in other TMAs (hypertension, acute kidney injury, or abdominal pain); third, TTP may be associated with PE/HELLP, sepsis, and auto‐immune diseases in ~25% of cases. Clinical features more in favor of TTP are the occurrence during the first trimester of pregnancy, a normal clotting screen at presentation, and a failure to improve within 48 hours after delivery. However, only an ADAMTS13 activity < 10% will definitely confirm TTP diagnosis. The curative treatment of the inaugural TTP episode revealing a late‐onset cTTP triggered by a first pregnancy is an emergency. This management relies on a multidisciplinary approach to facilitate complex clinical decision making. Following heightened clinical suspicion, and prior to getting the result of the ADAMTS13 activity, plasma exchange (PEX) has to be initiated urgently and the patient transferred to a specialized center with an obstetrical department for high‐risk pregnancies and a neonatal pediatric department, as well as an intensive care unit. The timing of delivery should be decided on fetal features (well‐being and viability). The diagnosis of cTTP has important consequences. First, it is crucial to take into consideration that women with child‐onset cTTP reaching childbearing age may also become pregnant, exposing the patient to a relapse, in the absence of prophylactic treatment. Second, the management of subsequent pregnancies in late‐onset cTTP is based on the fact that the relapse risk is ~100%. Consequently, prophylactic replacement therapy with a regular monitoring (maternal blood cell count/lactate dehydrogenase [LDH], fetal ultrasound, and uterine artery Doppler) is mandatory both to prevent a maternal TTP bout and to guarantee normal fetal growth. Plasma infusion with a minimal volume of 10 to 15 ml/kg may be started as soon as the first trimester but will usually be required later in pregnancy and post partum, with an optimal plasma infusion frequency of one session every 1‐2 weeks. Delivery is also usually scheduled at a maximum of 37 weeks of gestation.3.Moatti‐Cohen M. Garrec C. Wolf M. et al.Unexpected frequency of Upshaw‐Schulman syndrome in pregnancy‐onset thrombotic thrombocytopenic purpura.Blood. 2012; 119: 5888-5897Crossref PubMed Scopus (173) Google Scholar, 4.Scully M. Thomas M. Underwood M. et al.Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes.Blood. 2014; 124: 211-219Crossref PubMed Scopus (180) Google Scholar, 5.Fujimura Y. Matsumoto M. Kokame K. et al.Pregnancy‐induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw‐Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients.Br J Haematol. 2009; 144: 742-754Crossref PubMed Scopus (102) Google Scholar The ideal monitoring and replacement therapy schedule is not known with certainty. However, this empirical approach led for the last 10 years by multidisciplinary staff in specialized centers has been shown to be successful in virtually all cases with a favorable prognosis in both the mother and the newborn.3.Moatti‐Cohen M. Garrec C. Wolf M. et al.Unexpected frequency of Upshaw‐Schulman syndrome in pregnancy‐onset thrombotic thrombocytopenic purpura.Blood. 2012; 119: 5888-5897Crossref PubMed Scopus (173) Google Scholar, 4.Scully M. Thomas M. Underwood M. et al.Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes.Blood. 2014; 124: 211-219Crossref PubMed Scopus (180) Google Scholar, 5.Fujimura Y. Matsumoto M. Kokame K. et al.Pregnancy‐induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw‐Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients.Br J Haematol. 2009; 144: 742-754Crossref PubMed Scopus (102) Google Scholar In patients with child‐onset cTTP reaching childbearing age, the same primary prophylactic management is recommended for the first pregnancy and for all subsequent pregnancies. Third, as cTTP is transmitted as a recessive autosomal disorder, the newborn from an affected mother is usually healthy (heterozygous carrier of a recessive autosomal trait and thus not clinically affected by the disease). However, particularly in the case of late‐onset cTTP, genetic counseling is indicated in all siblings of the index patient and especially in her childbearing‐age sisters, as they have a 25% probability to be affected and will thus require a primary prophylactic ADAMTS13 replacement therapy (ie, as soon as their first pregnancy). The treatment of iTTP during pregnancy, and the management of subsequent pregnancies in these patients, remain a major challenge with very few reported data in the literature. The term of occurrence of iTTP during pregnancy is more variable than for cTTP and it can be observed until the post‐partum period. As rituximab is of limited use in pregnancy, the treatment of acute iTTP is still mostly based on PEX, possibly associated with corticosteroids. In the mother, the usual response of iTTP to PEX is apparently not changed by pregnancy (with reported complete remission rates of 80%‐90%). In the most desperate cases not responding to PEX, however, salvage therapies should be proposed with the same modalities as for iTTP out of pregnancy. Intrauterine fetal deaths or prematurity were reported.6.Joly B.S. Boisseau P. Roose E. et al.ADAMTS13 gene mutations influence ADAMTS13 conformation and disease age‐onset in the french cohort of upshaw‐schulman syndrome.Thromb Haemost. 2018; 118: 1902-1917Crossref PubMed Scopus (28) Google Scholar, 7.Chakravarty E.F. Murray E.R. Kelman A. Farmer P. Pregnancy outcomes after maternal exposure to rituximab.Blood. 2011; 117: 1499-1506Crossref PubMed Scopus (388) Google Scholar As for cTTP, fetal prognosis of iTTP depends on the term of occurrence, with a better prognosis when iTTP occurs during late pregnancy. So far, no cases of fetal or neonatal iTTP via transplacental cross of anti‐ADAMTS13 IgGs have been recorded. In women with a history of iTTP and who consider a pregnancy, the risk of pregnancy‐related relapse must be weighed on the basis of ADAMTS13 activity. Here, the importance of pre‐conception counseling for disease control is mandatory. In our experience, the recurrence of iTTP is unusual in a patient who becomes pregnant while ADAMTS13 activity is normal; in this scenario, the assessment of ADAMTS13 activity at regular time‐points of pregnancy typically displays normal values. In contrast, a pregnancy should be discouraged when pre‐conception ADAMTS13 activity is found to be severely decreased (<10%). In patients with a low but detectable pre‐conception ADAMTS13 activity (between 10% and 50%), the risk of relapse is less predictable.3.Moatti‐Cohen M. Garrec C. Wolf M. et al.Unexpected frequency of Upshaw‐Schulman syndrome in pregnancy‐onset thrombotic thrombocytopenic purpura.Blood. 2012; 119: 5888-5897Crossref PubMed Scopus (173) Google Scholar, 4.Scully M. Thomas M. Underwood M. et al.Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes.Blood. 2014; 124: 211-219Crossref PubMed Scopus (180) Google Scholar, 8.Jiang Y. McIntosh J.J. Reese J.A. et al.Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura.Blood. 2014; 123: 1674-1680Crossref PubMed Scopus (45) Google Scholar, 9.Thomas M.R. Robinson S. Scully M.A. How we manage thrombotic microangiopathies in pregnancy.Br J Haematol. 2016; 173: 821-830Crossref PubMed Scopus (42) Google Scholar The best option to improve ADAMTS13 activity in those patients with a severe deficiency (rituximab, azathioprine, or corticosteroids), as well as the optimal target of ADAMTS13 activity to give a green light to conception, remain open questions. Also, whether prophylactic plasmatherapy during pregnancy should be offered is unclear: not only its benefit has never been definitely demonstrated but the risk of boosting anti‐ADAMTS13 IgGs synthesis cannot be excluded. The use of rituximab during pregnancy in general (ie, regardless of the indication) exposes newborns to lymphopenia and possibly other cytopenias; especially, peripheral B‐cells may be undetectable at delivery, although recovery (including mature B‐cells) was observed by month 6. No hypogammaglobulinemia was recorded, and vaccine responses were normal.7.Chakravarty E.F. Murray E.R. Kelman A. Farmer P. Pregnancy outcomes after maternal exposure to rituximab.Blood. 2011; 117: 1499-1506Crossref PubMed Scopus (388) Google Scholar, 10.Klink D.T. van Elburg R.M. Schreurs M.W. van Well G.T. Rituximab administration in third trimester of pregnancy suppresses neonatal B‐cell development.Clin Dev Immunol. 2008; 2008Crossref PubMed Scopus (142) Google Scholar The fetal risk from drug therapy must therefore be weighed against the risk for both the mother and the fetus from the occurrence of an acute iTTP relapse. Last, the contraceptive modalities following a pregnancy‐induced iTTP remain here again to be accurately defined. In conclusion, pregnancy‐associated TTP remains a life‐threatening condition for both the mother and the fetus. These statements highlight that more experience is urgently needed in pregnancy‐associated TTP to improve the still highly empirical management of these patients. Given the rarity of the patients and the wide range of scenarios, this challenging goal should involve large concerted international studies. PC is member of the advisory board of Sanofi, Alexion, Takeda, and Roche. AV is a member of the advisory board of Sanofi and Roche. P. Coppo and A. Veyradier wrote the manuscript and approved the final version. The authors acknowledge the following contributors who reviewed this manuscript, and who were members of the ISTH expert panel: Rawan Al Tarawneh, Spero Cataland, Brian Geldziler, Masanori Matsumoto, Reem Mustafa, Flora Peyvandi, Gail Rock, Leen Russel, Julie Valdes, Sara Vesely, and X. Long Zheng, as well as the patients and their families.