Late onset and pregnancy-induced congenital thrombotic thrombocytopenic purpura

Summary

We report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a spontaneous abortion in the 30^th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her second pregnancy from a second acute TTP episode. Diagnosis: In 2013 a severe ADAMTS13 deficiency of <10% without detectable ADAMTS13 inhibitor was repeatedly found. Investigation of the ADAMTS13 gene showed that the severe ADAMTS13 deficiency was caused by compound heterozygous ADAMTS13 mutations: a premature stop codon in exon 2 (p.Q44X), and a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity. Conclusion: Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded.

Zusammenfassung

Wir berichten von unserer Patientin (Fall 2), die 1976 im Alter von 19 Jahren ihren ersten akuten Schub einer thrombotisch thrombozytopenischen Purpura (TTP) während ihrer ersten Schwangerschaft erlitt und ihr Kind in der 30. Schwangerschaftswoche verlor. Ery-throzytenkonzentrate wurden transfundiert und eine Splenektomie vorgenommen. Nach mehreren TTP-Schüben 1977, möglicherweise partiell mitigiert durch Acetylsalicylsäure, konnte ein weiterer Schub in der zweiten Schwangerschaft 1980 durch Interruptio und Tuben ligatur verhindert werden. Ihre ältere Schwester (Fall 1) hatte 1974 während ihrer ersten Schwangerschaft auch einen akuten TTP-Schub erlitten. Sie verstarb in der zweiten Schwangerschaft 1977 in Folge ihres zweiten akuten TTP-Schubes. Diagnostik: Im Jahr 2013 wurde eine schwere ADAMTS13-Defizienz von <10% festgestellt ohne nachweisbaren ADAMTS13-Inhibitor. Die Untersuchung des ADAMTS13-Gens zeigte, dass der schwere Mangel durch zwei heterozygote ADAMTS13-Mutationen verursacht wird: ein vorzeitiges Stopp-Codon in Exon 2 (p.Q44X) und eine Punktmutation in Exon 24 (p.R1060W), die eine geringe ADAMTS13-Restaktivität zeigt. Schlussfolgerung: Die genetische Analyse von ADAMTS13 bei TTP-Patienten aller Altersgruppen ist wichtig zur korrekten Diagnose einer hereditären TTP, wenn ein ADAMTS13-Inhibitor ausgeschlossen wurde.

Keywords

Hereditary TTP - pregnancy - ADAMTS13 activity - ADAMTS13 mutation

Schlüsselwörter

Hereditäre TTP - Schwangerschaft - ADAMTS13-Aktivität - ADAMTS13-Mutationen

• References

• 1 Tsai HM. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol 2010; 91: 1-19.
• 2 Falter T, Alber KJ, Scharrer I. Long term outcome and sequelae in patients after acute thrombotic thrombocytopenic purpura episodes. Hämostaseologie 2013; 33: 113-120.
• 3 Moake JL. Thrombotic microangiopathies. N Engl J Med 2002; 347: 589-600.
• 4 Hellmann M, Hallek M, Scharrer I. Thromboticthrombocytopenic purpura. Internist 2010; 51 1136 8-44.
• 5 Kiss JE. Thrombotic thrombocytopenic purpura: recognition and management. Int J Hematol 2010; 91: 36-45.
• 6 Furlan M, Lämmle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol 2001; 14: 437-454.
• 7 Upshaw Jr JD. Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J Med 1978; 298: 1350-1352.
• 8 Antoine G, Zimmermann K, Plaimauer B. et al. ADAMTS13 gene defects in two brothers with constitutional thrombotic thrombocytopenic purpura and normalization of von Willebrand factorcleaving protease activity by recombinant human ADAMTS13. Br J Haematol 2003; 120: 821-824.
• 9 Camilleri RS, Cohen H, Mackie IJ. et al. Prevalence of the ADAMTS-13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura. J Thromb Haemost 2008; 06: 331-338.
• 10 Moatti-Cohen M, Garrec C, Wolf M. et al. Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. Blood 2012; 119: 5888-5897.
• 11 Lotta LA, Wu HM, Mackie IJ. et al. Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura. Blood 2012; 120: 440-448.
• 12 Von Krogh AS, Kremer JAHovinga, Tjonnfjord GE. et al. The impact of congenital thrombotic thrombocytopenic purpura on pregnancy complications. Thromb Haemost 2014; 111: 1180-1183.
• 13 Kentouche K, Voigt A, Schleussner E. et al. Pregnancy in Upshaw-Schulman syndrome. Hämostaseologie 2013; 33: 144-148.
• 14 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: 742-754.
• 15 Schneppenheim R, Budde U, Oyen F. et al. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood 2003; 101: 1845-1850.
• 16 Ducloy-Bouthors AS, Caron C, Subtil D. et al. Thrombotic thrombocytopenic purpura: medical and biological monitoring of six pregnancies. Eur J Obstet Gynecol Reprod Biol 2003; 111: 146-152.
• 17 Veyradier A. ADAMTS, thrombotic thrombocytopenic purpura and pregnancy. Hereditary Genetics. 2013 01. 01
• 18 Tanaka H, Tenkumo C, Mori N. et al. Case of maternal and fetal deaths due to severe congenital thrombotic thrombocytopenic purpura (UpshawSchulman syndrome) during pregnancy. J Obstet Gynaecol Res 2014; 40: 247-249.
• 19 Yamamoto T, Fujimura Y, Emoto Y. et al. Autopsy case of sudden maternal death from thrombotic thrombocytopenic purpura. J Obstet Gynaecol Res 2013; 39: 351-354.
• 20 Mannucci PM, Capoferri C, Canciani MT. Plasma levels of von Willebrand factor regulate ADAMTS-13, its major cleaving protease. Br J Haematol 2004; 126: 213-218.
• 21 Kremer JAHovinga, Zeerleder S, Kessler P. et al. ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock. J Thromb Haemost 2007; 05: 2284-2290.
• 22 Reiter RA, Varadi K, Turecek PL. et al. Changes in ADAMTS13 (von-Willebrand-factor-cleaving protease) activity after induced release of von Willebrand factor during acute systemic inflammation. Thromb Haemost 2005; 93: 554-558.
• 23 Loirat C, Girma JP, Desconclois C. et al. Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatr Nephrol 2009; 24: 19-29.
• 24 Camilleri RS, Scully M, Thomas M. et al. A phenotype-genotype correlation of ADAMTS13 mutations in congenital thrombotic thrombocytopenic purpura patients treated in the United Kingdom. J Thromb Haemost 2012; 10: 1792-1801.
• 25 Lotta LA, Garagiola I, Palla R. et al. ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura. Hum Mutat 2010; 31: 11-19.
• 26 Tao Z, Anthony K, Peng Y. et al. Novel ADAMTS-13 mutations in an adult with delayed onset thrombotic thrombocytopenic purpura. J Thromb Haemost 2006; 04: 1931-1935.
• 27 Scully M, Thomas M, Underwood M. et al. Congenital and acquired thrombotic thrombocytopenic purpura and pregnancy: presentation, management and outcome of subsequent pregnancies. Blood. 2014 http://dx.doi.org/10.1182/blood-2014-02-553131