Diagnosis of aHUS

Patients with aHUS are at ongoing risk of systemic, life-threatening, and sudden complications1-3,6

Severe ADAMTS13 deficiency (TTP)

The underlying cause in TTP is a severe deficiency in ADAMTS13 activity (≤5%)47-50

Insufficient ADAMTS13 activity (≤5%) leaves von Willebrand (vWF) factor uncleaved, causing excessive platelet aggregation47, 50, 55, 56

Genetic, complement-mediated TMA (aHUS)

aHUS is caused by chronic, uncontrolled complement activation5, 14, 15, 26, 27, 53-55

Genetic defects in activators and/or inhibitors lead to chronic activation of the complement system, causing endothelial cell damage and continuous platelet aggregation5, 14, 15, 26, 27, 53-55

Serum creatinine levels (SCr) and platelet count can be used to predict ADAMTS13 activity in patients with TMA57,66-70

A patient with a TMA presenting with SCr >1.7 mg/dL OR platelet count >30,000/mm3 is 21.8 times less likely to have severe ADAMTS13 deficiency (TTP) than those who meet neither criteria

  • In a national registry of 214 TMA patients, baseline SCr and platelet count were identified as independently predictive values of ADAMTS13 deficiency*66.
  • Multiple studies on a total of 806 patients with TMA have demonstrated that baseline values of SCr and platelets at clinical presentation can rapidly and efficiently distinguish between sufficient and severely deficient ADAMTS13 activity57,66-70

Though not required for diagnosis, the following may help determine if aHUS is the underlying cause of TMA:

  • Patient's medical history includes previous TMA3,19
  • Patient reports family history of renal impairment6,19,40

Complement-amplifying conditions place patients with aHUS at high risk for TMA manifestations4,21,26,41

  • TMA is very rare among the general population42-44
  • A patient who presents with TMA and an identifiable complement-amplifying condition may have a defect in complement regulation4,21,26,41

aHUS has been unmasked in a percentage of patients experiencing TMA in the presence of a complement-amplifying condition5

69% of patients with aHUS showed their first clinical manifestation while experiencing one of the following complement-amplifying conditions (N=191)5

31% 20% 49%
*Eg, systemic lupus erythematosus and scleroderma.
Complement amplification occurs frequently and is not always apparent14,17,20,21
  • Complement-amplifying conditions include and are not limited to14,17,20,21
    • Bacterial, viral, and fungal infections
    • Atherosclerosis
    • Inflammatory bowel disease
    • Surgeries
    • Thyroiditis
    • Allergies
    • Asthma
    • Anaphylactic Shock

A clinical diagnosis of aHUS should be considered in patients presenting with both a complement-amplifying condition and TMA24,41,45

1. Laurence J. Atypical hemolytic uremic syndrome (aHUS): making the diagnosis. Clin Adv Hematol Oncol. 2012;10(suppl 17):1-12. 2. Legendre CM, Licht C, Muus P, et al. N Engl J Med. 2013;368:2169-2181. 3. Sellier-Leclerc A-L, Frémeaux-Bacchi V, Dragon-Durey MA, et al; French Society of Pediatric Nephrology. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18:2392-2400. 4. Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol. 2012;8:622-633. 5. 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;5:1844-1859. 6. Caprioli J, Noris M, Brioschi S, et al; for the International Registry of Recurrent and Familial HUS/TTP. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108:1267-1279. 14. Hirt-Minkowski P, Dickenmann M, Schifferli JA. Atypical hemolytic uremic syndrome: update on the complement system and what is new. Nephron Clin Pract. 2010;114:c219-c235. 15. Loirat C, Noris M, Frémeaux-Bacchi V. Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2008;23:1957-1972. 17. Ricklin D, Hajishengallis G, Yang K, et al. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785-797. 19. Barbour T, Johnson S, Cohney S, et al. Thrombotic microangiopathy and associated renal disorders. Nephrol Dial Transplant. 2012;27:2673-2685. 20. Wagner E, Frank MM. Therapeutic potential of complement modulation. Nat Rev Drug Discov. 2010;9:43-56. 21. Liszewski MK, Atkinson JP. Too much of a good thing at the site of tissue injury: the instructive example of the complement system predisposing to thrombotic microangiopathy. Hematology Am Soc Hematol Educ Program. 2011;2011:9-14. 23. Kavanagh D, Goodship THJ. Atypical hemolytic uremic syndrome, genetic basis, and clinical manifestations. Hematology Am Soc Hematol Educ Program. 2011;2011:15-20. 24. Kavanagh D, Goodship THJ, Richards A. Atypical haemolytic uraemic syndrome. Br Med Bull. 2006;77-78:5-22. 26. Fang CJ, Richards A, Liszewski MK, et al. Advances in understanding of pathogenesis of aHUS and HELLP. Br J Haematol. 2008;143:336-348. 27. Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60. 32. Neuhaus TJ, Calonder S, Leumann EP. Heterogeneity of atypical haemolytic uraemic syndromes. Arch Dis Child. 1997;76:518-521. 33. Ohanian M, Cable C, Halka K. Clin Pharmacol. 2011;3:5-12. 34. Sallée M, Daniel L, Piercecchi M-D, et al. Myocardial infarction is a complication of factor H-associated atypical HUS. Nephrol Dial Transplant. 2010;25:2028-2032. 36. Dragon-Durey M-A, Sethi SK, Bagga A, et al. Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol. 2010;21:2180-2187. 37. Zuber J, Le Quintrec M, Sberro-Soussan R, et al. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol. 2011;1:23-35. 40. Saland JM, Shneider BL, Bromberg JS, et al. Successful split liver-kidney transplant for factor H associated hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2009;4:201-206. 41. Campistol JM, Arias M, Ariceta G, et al. An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document. Nefrologia. 2013;33:27-45. 42. Chen M-H, Chen M-H, Chen W-S, et al. Thrombotic microangiopathy in systemic lupus erythematosus: a cohort study in North Taiwan. Rheumatol. 2011;50:768-775. 43. Ardalan MR. Review of thrombotic microangiopathy (TMA), and post-renal transplant TMA. Saudi J Kidney Dis Transplant. 2006;17:235-244. 44. Izzedine H, Isnard-Bagnis C, Launay-Vacher V, et al. Gemcitabine-induced thrombotic microangiopathy: a systematic review. Nephrol Dial Transplant. 2006;21:3038-3045. 45. Totina A, Iorember F, El-Dahr SS, et al. Atypical hemolytic-uremic syndrome in a child presenting with malignant hypertension. Clin Pediatr (Phila). 2011;52:183-186. 47. Tsai H-M. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol. 2010;91:1-19. 48. Bianchi V, Robles R, Alberio L, et al. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood. 2002;100:710-713. 49. Barbot J, Costa E, Guerra M, et al. Ten years of prophylactic treatment with fresh-frozen plasma in a child with chronic relapsing thrombotic thrombocytopenic purpura as a result of a congenital deficiency of von Willebrand factor-cleaving protease. Br J Haematol. 2001;113:649-651. 50. Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood. 2008;112:11-18. 53. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676-1687. 54. Holers VM. The spectrum of complement alternative pathway-mediated diseases. Immunol Rev. 2008;223:300-316. 55. Tsai H-M. Untying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome. Am J Med. 2013;126:200-209. 56. Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347:589-600. 57. Bentley MJ, Lehman CM, Blaylock RC, et al. The utility of patient characteristics in predicting severe ADAMTS13 deficiency and response to plasma exchange. Transfusion. 2010;50:1654-1664. 58. Data on file. Alexion Pharmaceuticals, Inc.; 2014. 59. Noris M, Bucchioni S, Galbusera M, et al. Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement. J Am Soc Nephrol. 2005;16:1177-1183. 60. Davin JC, Gracchi V, Bouts A, et al. Am J Kidney Dis. 2010;55:708-711. 61. Al-Akash SI, Almond PS, Savell VH Jr, et al. Pediatr Nephrol. 2011;26:613-619. 64. Bitzan M, Schaefer F, Reymond D. Treatment of typical (enteropathic) hemolytic uremic syndrome. Semin Thromb Hemost. 2010;36:594-610. 65. Zuber J, Fakhouri F, Roumenina LT, et al. Nat Rev Nephrol. 2012;8:643-657. 66. Coppo P, Schwarzinger M, Buffet M, et al. Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience. PLOS ONE. 2010;5:e10208. 67. Kremer Hovinga JA, Vesely SK, Terrell DR, et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115:1500-1511. 68. George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010;116:4060-4069. 69. Cataland SR, Yang S, Wu HM. The use of ADAMTS13 activity, platelet count, and serum creatinine to differentiate acquired thrombotic thrombocytopenic purpura from other thrombotic microangiopathies. Br J Haematol. 2012;157:501-503. 70. Shah N, Rutherford C, Matevosyan K, et al. Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP). Br J Haematol. 2013;163:514-519.