Long term outcome and sequelae in patients after acute thrombotic thrombocytopenic purpura episodes^[*]

Summary

We report on 21 patients with idiopathic thrombotic thrombocytopenic purpura (TTP) whose courses of disease have been followed from the respective diagnosis until now. They had a documented ADAMTS13 activity below 5%, a high autoantibody titer and detectable ultralarge von Willebrand factor (VWF) multimers during their episodes. The initial diagnosis was based on clinical symptoms and on laboratory parameters: thrombocytopenia, haemolytic anaemia, schistocytes and an increased LDH level. 103 acute clinical episodes of 21 TTPpatients during a time period of 30 years are described. Case histories, comorbidities and sequelae were retrospectively documented. Results, conclusion: Although patients are consistently in a prothrombotic status, clinical acute manifestations only occur after triggering. Most common trigger factors are gastrointestinal infections and pregnancy. The relapse risk per month is 0.026; men have a higher risk for relapses (0.044) than women (0.021). Patients recover physically well, except for renal insufficiency in four cases. Nevertheless, major portion of patients suffers persistently from depression, anxiety disorders and persistent neurocognitive impairments.

Zusammenfassung

Wir berichten über 21 Patienten mit idiopatischer thrombotisch thrombozytopenischer Purpura (TTP), deren Krankheitsverlauf von der Diagnose bis heute verfolgt wurde. Die Patienten wiesen zum Zeitpunkt der Schübe eine ADAMTS13-Aktivität unter 5%, hohe Autoantikörpertiter und ultralange VWFMultimere auf. Die initiale Diagnose erfolgte aufgrund klinischer Symptome und Labordaten: Thrombozytopenie, hämolytische Anämie, Schistozyten und LDH. Insgesamt war-den 103 Schübe von 21 TTP-Patienten über einen Zeitraum von 30 Jahren beschrieben. Krankheitsverlauf sowie Begleiterkrankungen und Folgen der TTP wurden retrospektiv erfasst. Ergebnisse, Schlussfolgerungen: Obwohl die Patienten sich in einem dauerhaft prothrombotischen Status befinden, treten TTP-Schübe meist infolge zusätzlicher Auslöser, insbesondere gastrointestinaler Infektionen sowie Schwangerschaften, auf. Das Risiko eines Rückfalls des Kollektivs beträgt 0,026 pro Monat, wobei Männer ein höheres Rückfallrisiko aufweisen (0,044) als Frauen (0,021). Bis auf vier Patienten mit chronischer Niereninsuffizienz, erholten sich die Patienten körperlich gut. Dennoch leidet ein Großteil der Patienten unter Depressionen, Angststörungen und neurokognitiven Defiziten.

Keywords

Thrombotic thrombocytopenic purpura - ADAMTS13 activity - long term outcome - neurocognitive impairment

Schlüsselwörter

Thrombotisch thrombozytopenische Purpura - ADAMTS13 Aktivität - Spätfolgen - neuro -kognitive Störungen

^* We gratefully dedicate this manuscript to Bernhard Lämmle.

^# Both authors contributed equally to this work.

• References

• 1 Coppo P, Veyradier A. Thrombotic microangiopathies: towards a pathophysiology-based classification. Cardiovasc Hematol Disord Drug Targets 2009; 09: 36-50.
• 2 Lämmle B, Kremer JHovinga, Studt JD. et al. Thrombotic thrombocytopenic purpura. Hematol J 2004; 05 (Suppl. 03) S6-S11.
• 3 Furlan M, Robles R, Lämmle B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 1996; 87: 4223-4234.
• 4 Zheng X, Chung D, Takayama TK. et al. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 2001; 276: 41059-41063.
• 5 Tsai HM. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol 2010; 91: 1-19.
• 6 Hellmann M, Hallek M, Scharrer I. Thromboticthrombocytopenic purpura. Internist (Berl) 2010; 51 1136, 8-44.
• 7 Rock GA, Shumak KH, Buskard NA. et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med 1991; 325: 393-397.
• 8 Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 1991; 325: 398-403.
• 9 Peyvandi F, Palla R, Lotta LA. Pathogenesis and treatment of acquired idiopathic thrombotic thrombocytopenic purpura. Haematologica 2010; 95: 1444-1447.
• 10 Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of literature. Medicine (Baltimore) 1966; 45: 139-159.
• 11 George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood 2010; 116: 4060-4069.
• 12 Howard MA, Duvall D, Terrell DR. et al. A support group for patients who have recovered from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): The six-year experience of the Oklahoma TTP-HUS Study Group. J Clin Apher 2003; 18: 16-20.
• 13 George JN. The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: evaluation, management, and long-term outcomes experience of the Oklahoma TTP-HUS Registry, 1989-2007. Kidney Int Suppl. 2009: S52-S54.
• 14 Bohm M, Vigh T, Scharrer I. Evaluation and clinical application of a new method for measuring activity of von Willebrand factor-cleaving metalloprotease. Ann Hematol 2002; 81: 430-435.
• 15 Banno F, Kokame K, Okuda T. et al. Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura. Blood 2006; 107: 3161-3166.
• 16 Fujimura Y, Matsumoto M, Isonishi A. et al. Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan. J Thromb Haemost 2011; 09 (Suppl. 01) 283-301.
• 17 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.
• 18 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.
• 19 Feys HB, Deckmyn H, Vanhoorelbeke K. ADAMTS13 in health and disease. Acta Haematol 2009; 121: 183-185.
• 20 Mannucci PM, Canciani MT, Forza I. et al. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001; 98: 2730-2735.
• 21 Chauhan AK, Kisucka J, Brill A. et al. ADAMTS13: a new link between thrombosis and inflammation. J Exp Med 2008; 205: 2065-2074.
• 22 Claus RA, Bockmeyer CL, Budde U. et al. Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failure. Thromb Haemost 2009; 101: 239-247.
• 23 Vesely SK, George JN, Lämmle B. et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 2003; 102: 60-68.
• 24 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: 819-826.
• 25 George JN, Kremer JAHovinga, Terrell DR. et al. The Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome Registry: the Swiss connection. Eur J Haematol 2008; 80: 277-286.
• 26 Hovinga JA, Vesely SK, Terrell DR. et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010; 115: 1500-1511.
• 27 Kremer JAHovinga, Studt JD, Demarmels FBiasiutti. et al. Splenectomy in relapsing and plasmarefractory acquired thrombotic thrombocytopenic purpura. Haematologica 2004; 89: 320-324.
• 28 Aqui NA, Stein SH, Konkle BA. et al. Role of splenectomy in patients with refractory or relapsed thrombotic thrombocytopenic purpura. J Clin Apher 2003; 18: 51-54.
• 29 Crowther MA, Heddle N, Hayward CP. et al. Splenectomy done during hematologic remission to prevent relapse in patients with thrombotic thrombocytopenic purpura. Ann Intern Med 1996; 125: 294-296.
• 30 Allford SL, Hunt BJ, Rose P, Machin SJ. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 2003; 120: 556-573.
• 31 Altuntas F, Aydogdu I, Kabukcu S. et al. Therapeutic plasma exchange for the treatment of thrombotic thrombocytopenic purpura: a retrospective multicenter study. Transfus Apher Sci 2007; 36: 57-67.
• 32 Hagel S, Jantsch J, Budde U. et al. Treatment of acquired thrombotic thrombocytopenic purpura (TTP) with plasma infusion plus rituximab. Thromb Haemost 2008; 100: 151-153.
• 33 Fakhouri F, Vernant JP, Veyradier A. et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood 2005; 106: 1932-1937.
• 34 Scully M, Starke R, Lee R. et al. Successful management of pregnancy in women with a history of thrombotic thrombocytopaenic purpura. Blood Coagul Fibrinolysis 2006; 17: 459-463.
• 35 Schleinitz N, Ebbo M, Mazodier K. et al. Rituximab as preventive therapy of a clinical relapse in TTP with ADAMTS13 inhibitor. Am J Hematol 2007; 82: 417-418.
• 36 Chemnitz JM, Uener J, Hallek M, Scheid C. Longterm follow-up of idiopathic thrombotic thrombocytopenic purpura treated with rituximab. Ann Hematol 2010; 89: 1029-1033.
• 37 Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood 2004; 103: 4043-4049.
• 38 Strauss M, Pierer M, Schonknecht P. Adjustment disorders in internal medicine diseases. Internist (Berl) 2012; 53: 1271-1275.
• 39 Lewis QF, Lanneau MS, Mathias SD. et al. Longterm deficits in health-related quality of life after recovery from thrombotic thrombocytopenic purpura. Transfusion 2009; 49: 118-124.
• 40 Kennedy AS, Lewis QF, Scott JG. et al. Cognitive deficits after recovery from thrombotic thrombocytopenic purpura. Transfusion 2009; 49: 1092-1101.