Thrombotic Thrombocytopenic Purpura and Atypical Hemolytic Uremic Syndrome Microangiopathy in Pregnancy

 

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Abstract

Thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) are thrombotic microangiopathies (TMAs) that can present in pregnancy. The presentation can be with typical microangiopathic features and thrombocytopenia, but there is also a significant risk of in-utero fetal loss. TTP presents most commonly in the third trimester and aHUS in the postpartum period. On presumptive diagnosis, plasma exchange should be started and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity measured. An activity of < 10% is in keeping with TTP, which may be late-onset congenital TTP or acquired disease: the former will require regular plasma therapy and the latter immunosuppression. In aHUS, eculizumab is the therapy of choice. In future pregnancies, follow-up with a multidisciplinary team including fetomaternal and specialist obstetrics should be undertaken.

• References

• 1 Scully M, Goodship T. How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome. Br J Haematol 2014; 164 (6) 759-766
  CrossrefPubMedGoogle Scholar
• 2 Levy GG, Nichols WC, Lian EC , et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413 (6855) 488-494
  CrossrefPubMedGoogle Scholar
• 3 Furlan M, Robles R, Solenthaler M, Wassmer M, Sandoz P, Lämmle B. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 1997; 89 (9) 3097-3103
  PubMedGoogle Scholar
• 4 Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339 (22) 1585-1594
  CrossrefPubMedGoogle Scholar
• 5 Scully M, Yarranton H, Liesner R , et al. Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features. Br J Haematol 2008; 142 (5) 819-826
  CrossrefPubMedGoogle Scholar
• 6 Thomas MR, Robinson S, Scully MA. How we manage thrombotic microangiopathies in pregnancy. Br J Haematol 2016; 173 (6) 821-830
  CrossrefPubMedGoogle Scholar
• 7 Kavanagh D, Goodship TH. Atypical hemolytic uremic syndrome, genetic basis, and clinical manifestations. Hematology (Am Soc Hematol Educ Program) 2011; 2011: 15-20
  CrossrefPubMedGoogle Scholar
• 8 Tsai HM, Kuo E. From Gestational Hypertension and Preeclampsia to Atypical Hemolytic Uremic Syndrome. Obstet Gynecol 2016; 127 (5) 907-910
  CrossrefPubMedGoogle Scholar
• 9 Salmon JE, Heuser C, Triebwasser M , et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med 2011; 8 (3) e1001013
  CrossrefPubMedGoogle Scholar
• 10 Mannucci PM, Canciani MT, Forza I, Lussana F, Lattuada A, Rossi E. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001; 98 (9) 2730-2735
  CrossrefPubMedGoogle Scholar
• 11 Sánchez-Luceros A, Farías CE, Amaral MM , et al. von Willebrand factor-cleaving protease (ADAMTS13) activity in normal non-pregnant women, pregnant and post-delivery women. Thromb Haemost 2004; 92 (6) 1320-1326
  PubMedGoogle Scholar
• 12 Regal JF, Gilbert JS, Burwick RM. The complement system and adverse pregnancy outcomes. Mol Immunol 2015; 67 (1) 56-70
  CrossrefPubMedGoogle Scholar
• 13 Baines MG, Millar KG, Mills P. Studies of complement levels in normal human pregnancy. Obstet Gynecol 1974; 43 (6) 806-810
  PubMedGoogle Scholar
• 14 Mohlin FC, Mercier E, Fremeaux-Bacchi V , et al. Analysis of genes coding for CD46, CD55, and C4b-binding protein in patients with idiopathic, recurrent, spontaneous pregnancy loss. Eur J Immunol 2013; 43 (6) 1617-1629
  CrossrefPubMedGoogle Scholar
• 15 Burwick RM, Easter SR, Dawood HY, Yamamoto HS, Fichorova RN, Feinberg BB. Complement activation and kidney injury molecule-1-associated proximal tubule injury in severe preeclampsia. Hypertension 2014; 64 (4) 833-838
  CrossrefPubMedGoogle Scholar
• 16 Cataland SR, Holers VM, Geyer S, Yang S, Wu HM. Biomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP. Blood 2014; 123 (24) 3733-3738
  CrossrefPubMedGoogle Scholar
• 17 Fang CJ, Richards A, Liszewski MK, Kavanagh D, Atkinson JP. Advances in understanding of pathogenesis of aHUS and HELLP. Br J Haematol 2008; 143 (3) 336-348
  CrossrefPubMedGoogle Scholar
• 18 Fakhouri F, Jablonski M, Lepercq J , et al. Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome. Blood 2008; 112 (12) 4542-4545
  CrossrefPubMedGoogle Scholar
• 19 Crovetto F, Borsa N, Acaia B , et al. The genetics of the alternative pathway of complement in the pathogenesis of HELLP syndrome. J Matern Fetal Neonatal Med 2012; 25 (11) 2322-2325
  CrossrefPubMedGoogle Scholar
• 20 Lynch AM, Gibbs RS, Murphy JR, Giclas PC, Salmon JE, Holers VM. Early elevations of the complement activation fragment C3a and adverse pregnancy outcomes. Obstet Gynecol 2011; 117 (1) 75-83
  CrossrefPubMedGoogle Scholar
• 21 Dashe JS, Ramin SM, Cunningham FG. The long-term consequences of thrombotic microangiopathy (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) in pregnancy. Obstet Gynecol 1998; 91 (5 Pt 1): 662-668
  CrossrefPubMedGoogle Scholar
• 22 Fakhouri F, Roumenina L, Provot F , et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol 2010; 21 (5) 859-867
  CrossrefPubMedGoogle Scholar
• 23 Girardi G, Salmon JB. The role of complement in pregnancy and fetal loss. Autoimmunity 2003; 36 (1) 19-26
  CrossrefPubMedGoogle Scholar
• 24 Moatti-Cohen M, Garrec C, Wolf M , et al; French Reference Center for Thrombotic Microangiopathies. Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. Blood 2012; 119 (24) 5888-5897
  CrossrefPubMedGoogle Scholar
• 25 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 (5) 742-754
  CrossrefPubMedGoogle Scholar
• 26 Delmas Y, Helou S, Chabanier P , et al. Incidence of obstetrical thrombotic thrombocytopenic purpura in a retrospective study within thrombocytopenic pregnant women. A difficult diagnosis and a treatable disease. BMC Pregnancy Childbirth 2015; 15: 137
  CrossrefPubMedGoogle Scholar
• 27 Scully M, Thomas M, Underwood M , et al; collaborators of the UK TTP Registry. Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes. Blood 2014; 124 (2) 211-219
  CrossrefPubMedGoogle Scholar
• 28 von Krogh AS, Kremer Hovinga JA, Tjønnfjord GE , et al. The impact of congenital thrombotic thrombocytopenic purpura on pregnancy complications. Thromb Haemost 2014; 111 (6) 1180-1183
  Article in Thieme ConnectPubMedGoogle Scholar
• 29 Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab. Blood 2011; 117 (5) 1499-1506
  CrossrefPubMedGoogle Scholar
• 30 Legendre CM, Licht C, Muus P , et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368 (23) 2169-2181
  CrossrefPubMedGoogle Scholar
• 31 De Sousa Amorim E, Blasco M, Quintana L, Sole M, de Cordoba SR, Campistol JM. Eculizumab in pregnancy-associated atypical hemolytic uremic syndrome: insights for optimizing management. J Nephrol 2015; 28 (5) 641-645
  CrossrefPubMedGoogle Scholar
• 32 Delmas Y, Bordes C, Loirat C, Frémeaux-Bacchi V, Combe C. Post-partum atypical haemolytic-uraemic syndrome treated with eculizumab: terminal complement activity assessment in clinical practice. Clin Kidney J 2013; 6 (2) 243-244
  CrossrefPubMedGoogle Scholar
• 33 Cañigral C, Moscardó F, Castro C , et al. Eculizumab for the treatment of pregnancy-related atypical hemolytic uremic syndrome. Ann Hematol 2014; 93 (8) 1421-1422
  PubMedGoogle Scholar
• 34 Ardissino G, Wally Ossola M, Baffero GM, Rigotti A, Cugno M. Eculizumab for atypical hemolytic uremic syndrome in pregnancy. Obstet Gynecol 2013; 122 (2 Pt 2): 487-489
  CrossrefPubMedGoogle Scholar
• 35 Zschiedrich S, Prager EP, Kuehn EW. Successful treatment of the postpartum atypical hemolytic uremic syndrome with eculizumab. Ann Intern Med 2013; 159 (1) 76
  CrossrefPubMedGoogle Scholar
• 36 Phillips EH, Westwood JP, Brocklebank V , et al. The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies. J Thromb Haemost 2016; 14 (1) 175-185
  CrossrefPubMedGoogle Scholar
• 37 Kelly R, Arnold L, Richards S , et al. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J Haematol 2010; 149 (3) 446-450
  CrossrefPubMedGoogle Scholar
• 38 Hallstensen RF, Bergseth G, Foss S , et al. Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn. Immunobiology 2015; 220 (4) 452-459
  CrossrefPubMedGoogle Scholar
• 39 Kelly RJ, Höchsmann B, Szer J , et al. Eculizumab in Pregnant Patients with Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med 2015; 373 (11) 1032-1039
  CrossrefPubMedGoogle Scholar
• 40 Mussoni MP, Veneziano FA, Boetti L , et al. Innovative therapeutic approach: sequential treatment with plasma exchange and eculizumab in a pregnant woman affected by atypical hemolytic-uremic syndrome. Transfus Apheresis Sci 2014; 51 (2) 134-136
  CrossrefPubMedGoogle Scholar