Hamostaseologie 2013; 33(02): 149-159
DOI: 10.5482/HAMO-13-01-0004
Review
Schattauer GmbH

Treatment of thrombotic microangiopathy with a focus on new treatment options

Die Therapie der thrombotischen Mikroangiopathie mit Fokus auf neue Behandlungsformen
P. Knöbl
1   Department of Medicine 1, Division of Haematology and Haemostasis, Medical University of Vienna, Vienna, Austria
› Author Affiliations
Further Information

Publication History

received: 29 January 2013

accepted in revised form: 12 April 2013

Publication Date:
05 February 2018 (online)

Summary

The thrombotic microangiopathies (TMA) are a heterogeneous group of disorders, characterized by microangiopathic haemolytic anaemia with red cell fragmentation, thrombocytopenia and signs of organ dysfunction due to disturbed microcirculation. Current laboratory methods can be used to better distinguish some of these entities. Organ dysfunction can be severe and life-threatening, and immediate start of sufficient therapy is necessary to avoid permanent damage or death. The therapeutic options, however, are often limited to symptomatic measures, and are not standardized or based on high scientific evidence. During the preceding years, not only considerable progress has been made in better diagnosis of TMA, but also new therapeutic strategies have been established. Initial treatment still is based on plasma exchange and symptomatic measures to protect organ function. New concepts (immunosuppression, targeted anti-von Willebrand factor or anti-complement therapy, replacement with recombinant enzymes) are discussed in this article.

Zusammenfassung

Die thrombotischen Mikroangiopathien sind eine heterogene Gruppe von Erkrankungen, die durch mikroangiopathische Hämolyse mit Erythrozytenfragmentation, Thrombozytopenie und Zeichen von Organschädigung durch Mikrozirkulationsstörungen charakterisiert sind. Moderne Labormethoden können die verschiedenen Entitäten besser unterscheiden. Die Organdysfunktion kann schwer und lebensbedrohlich sein, und die sofortige Einleitung einer suffizienten Therapie ist notwendig um permanente Schäden oder den Tod zu vermeiden. Die Behandlungsoptionen sind jedoch oft beschränkt auf symptomatische Maßnahmen, sind nicht standardisiert oder durch hohe wissenschaftliche Evidenz abgesichert. In den vergangenen Jahren konnten deutliche Fortschritte in der Diagnose und Behandlung der thrombotischen Mikroangiopathien erzielt werden. Etablierte Strategien, aber auch neue Behandlungsformen, die auf spezifische pathophysiologisch bedeutsame Mechanismen zielen, werden in diesem Artikel diskutiert.

 
  • References

  • 1 Scully M, Hunt BJ, Benjamin S. et al. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 2012; 158: 323-335.
  • 2 Lämmle B, Kremer JAHovinga, Alberio L. Thrombotic thrombocytopenic purpura. J Thromb Haemost 2005; 03: 1663-1675.
  • 3 Chapman K, Seldon M, Richards R. Thrombotic microangiopathies, thrombotic thrombocytopenic purpura, and ADAMTS-13. Semin Thromb Hemost 2012; 38: 47-54.
  • 4 Schneppenheim R, Budde U. Interaction of von Willebrand factor and ADAMTS13 in thrombotic thrombocytopenic purpura and von Willebrand disease. in preparation.
  • 5 Kokame K, Kokubo Y, Miyata T. Polymorphisms and mutations of ADAMTS13 in the Japanese population and estimation of the number of patients with Upshaw-Schulman syndrome. J Thromb Haemost 2011; 09: 1654-1656.
  • 6 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.
  • 7 Mansouri MTaleghani, von Krogh AS. et al. Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry. Hämostaseologie 2013; 33: 138-143.
  • 8 Cataland SR, Scully MA, Paskavitz J. et al. Evidence of persistent neurologic injury following thrombotic thrombocytopenic purpura. Am J Hematol 2011; 86: 87-89.
  • 9 Tsai HM. Autoimmune thrombotic microangiopathy: advances in pathogenesis, diagnosis, and management. Semin Thromb Hemost 2012; 38: 469-482.
  • 10 Schaller M, Studt JD, Voorberg J, Kremer JAHovinga. Acquired thrombotic thrombocytopenic purpura. Hämostaseologie 2013; 33: 121-130.
  • 11 Ferrari S, Knöbl P, Kolovratova V. et al. Inverse correlation of free and immune complex-sequestered anti-ADAMTS13 antibodies in a patient with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost 2012; 10: 156-158.
  • 12 Beloncle F, Buffet M, Coindre JP. et al. for the Thrombotic Microangiopathies Reference Center. Splenectomy and/or cyclophosphamide as salvage therapies in thrombotic thrombocytopenic purpura: the French TMA Reference Center experience. Transfusion 2012; 52: 2436-2444.
  • 13 Zipfel PF, Wolf G, John U. et al. Novel developments in thrombotic microangiopathies: is there a common link between hemolytic uremic syndrome and thrombotic thrombocytic purpura?. Pediatr Nephrol 2011; 26: 1947-1956.
  • 14 Tarr PI, Gordon CA, Chandler WL. Shiga-toxin producing Escherichia coli and haemolytic uraemic syncrome. Lancet 2004; 365: 1073-1086.
  • 15 Hauswaldt S, Nitschke M, Sayk F. et al. Lessons Learned From Outbreaks of Shiga Toxin Producing Escherichia coli. Curr Infect Dis Rep. 2012 05.
  • 16 Menne J, Nitschke M, Stingele R. et al. for EHECHUS consortium. Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study. BMJ 2012; 345: e4565.
  • 17 Greinacher A, Friesecke S, Abel P. et al. Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104 : H4-associated haemolytic uraemic syndrome: a prospective trial. Lancet 2011; 378: 1166-1173.
  • 18 Noris M, Caprioli J, Bresin E. et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010; 05: 1844-1859.
  • 19 Kavanagh D, Anderson HE. Interpretation of genetic variants of uncertain significance in atypical hemolytic uremic syndrome. Kidney Int 2012; 81: 11-13.
  • 20 Karpman D, Tati R. Complement activation in thrombotic mictoangiopathy. Hämostaseologie 2013; 33: 96-104.
  • 21 Prohászka Z, Varga L, Füst G. The use of ‘real-time’ complement analysis to differentiate atypical haemolytic uraemic syndrome from other forms of thrombotic microangiopathies. Br J Haematol 2012; 158: 424-425.
  • 22 Kim JJ, Goodship TH, Tizard J, Inward C. Plasma therapy for atypical haemolytic uraemic syndrome associated with heterozygous factor H mutations. Pediatr Nephrol 2011; 26: 2073-2076.
  • 23 Salant DJ. Targeting complement C5 in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2011; 22: 7-9.
  • 24 Blanc C, Roumenina LT, Ashraf Y. et al. Overall neutralization of complement factor H by autoantibodies in the acute phase of the autoimmune form of atypical hemolytic uremic syndrome. J Immunol 2012; 189: 3528-3537.
  • 25 Strobel S, Abarrategui-Garrido C, Fariza-Requejo E. et al. Factor H-related protein 1 neutralizes antifactor H autoantibodies in autoimmune hemolytic uremic syndrome. Kidney Int 2011; 80: 397-404.
  • 26 Ariceta G, Besbas N, Johnson S. et al. European Paediatric Study Group for HUS. Guideline for the investigation and initial therapy of diarrheanegative hemolytic uremic syndrome. Pediatr Nephrol 2009; 24: 687-696.
  • 27 Taylor CM, Machin S, Wigmore SJ, Goodship TH. working party from the Renal Association the British Committee for Standards in Haematology and the British Transplantation Society. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 2010; 148: 37-47.
  • 28 Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem celltransplantation-associated thrombotic microangiopathy. Blood 2011; 118: 1452-1462.
  • 29 Coppo P, Adrie C, Azoulay E. et al. Infectious diseases as a trigger in thrombotic microangiopathies in intensive care unit patients?. Intensive Care Med 2003; 29: 564-569.
  • 30 Gernsheimer T, James AH, Stasi R. How I treat thrombocytopenia in pregnancy. Blood 2013; 121: 38-47.
  • 31 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.
  • 32 Moake J, Chintagumpala M, Turner N. et al. Solvent/detergent-treated plasma suppresses shearinduced platelet aggregation and prevents episodes of thrombotic thrombocytopenic purpura. Blood 1994; 84: 490-497.
  • 33 Som S, Deford CC, Kaiser ML. et al. Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011. Transfusion 2012; 52: 2525-2532.
  • 34 Waldner H. The role of innate immune responses in autoimmune disease development. Autoimmun Rev 2009; 08: 400-404.
  • 35 Kappers-Klunne MC, Wijermans P, Fijnheer R. et al. Splenectomy for the treatment of thrombotic thrombocytopenic purpura. Br J Haematol 2005; 130: 768-776.
  • 36 Swisher KK, Terrell DR, Vesely SK. et al. Clinical outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura. Transfusion 2009; 49: 873-887.
  • 37 Scheiflinger F, Knöbl P, Trattner B. et al. Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura. Blood 2003; 102: 3241-3243.
  • 38 Coppo P, Veyradier A. Current management and therapeutical perspectives in thrombotic thrombocytopenic purpura. Presse Med 2012; 41: e163-e176.
  • 39 Plaimauer B, Kremer JAHovinga, Juno C. et al. Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies. J Thromb Haemost 2011; 09: 936-944.
  • 40 Bartunek J, Barbato E, Heyndrickx G. et al. Novel antiplatelet agents: ALX-0081, a nanobody directed towards von Willebrand factor. J Cardiovasc Transl Res 2013; 06: 355-363.
  • 41 Mayr FB, Knöbl P, Jilma B. et al. The aptamer ARC1779 blocks von Willebrand factor-dependent platelet function in patients with thrombotic thrombocytopenic purpura ex vivo. Transfusion 2010; 50: 1079-1087.
  • 42 Knöbl P, Jilma B, Gilbert JC. et al. Anti-von Willebrand factor aptamer ARC1779 for refractory thrombotic thrombocytopenic purpura. Transfusion 2009; 49: 2181-2185.
  • 43 Jilma B, Paulinska P, Jilma-Stohlawetz P. et al. A randomised pilot trial of the anti-von Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease. Thromb Haemost 2010; 104: 563-570.
  • 44 Jilma-Stohlawetz P, Knöbl P, Gilbert JC, Jilma B. The anti-von Willebrand factor aptamer ARC1779 increases von Willebrand factor levels and platelet counts in patients with type 2B von Willebrand disease. Thromb Haemost 2012; 108: 284-290.
  • 45 Cataland SR, Peyvandi F, Mannucci PM. et al. Initial experience from a double-blind, placebo-controlled, clinical outcome study of ARC1779 in patients with thrombotic thrombocytopenic purpura. Am J Hematol 2012; 87: 430-432.
  • 46 Siller-Matula JM, Merhi Y, Tanguay JF. et al. ARC15105 is a potent antagonist of von Willebrand factor mediated platelet activation and adhesion.Arterioscler Thromb Vasc Biol. 2012; 32: 902-909.
  • 47 Perosa F, Prete M, Racanelli V, Dammacco F. CD20-depleting therapy in autoimmune diseases: from basic research to the clinic. J Intern Med 2010; 267: 260-277.
  • 48 Knoebl P, Koder S, Schellongowski P. et al. Monitoring of ADAMTS13 in patients with thrombotic thrombocytopenic purpura: Prediction of response to therapy, risk of relapse, and long-term outcome. Blood 2008; 112: 2291.
  • 49 Froissart A, Buffet M, Veyradier A. et al. for the French Thrombotic Microangiopathies Reference Center. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Crit Care Med 2012; 40: 104-111.
  • 50 Scully M, McDonald V, Cavenagh J. et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood 2011; 118: 1746-1753.
  • 51 Zareba KM. Eculizumab: A novel therapy for paroxysmal nocturnal hemoglobinuria. Drugs Today (Barc) 2007; 43: 539-546.
  • 52 Kelly RJ, Hill A, Arnold LM. et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011; 117: 6786-6792.
  • 53 Vilalta R, Lara E, Madrid A. et al. Long-term eculizumab improves clinical outcomes in atypical hemolytic uremic syndrome. Pediatr Nephrol 2012; 27: 2323-2326.
  • 54 Al-Akash SI, Almond PS, Savell Jr VH. et al. Eculizumab induces long-term remission in recurrent post-transplant HUS associated with C3 gene mutation. Pediatr Nephrol 2011; 26: 613-619.