Thrombotic Microangiopathies - TMA

  • Diagnosis
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • Presence of hemolytic anemia and thrombocytopenia with a clinical presentation suspicious for a thrombotic microangiopathy (TMA)

Laboratory Testing

  • Initial hematologic testing
    • Hemolytic testing
      • CBC – usually demonstrates thrombocytopenia and anemia
      • Peripheral smear – red blood cell fragmentation (schistocytes, burr cells, helmet cells) and reticulocytes
      • Serologic testing for intravascular hemolysis – increased indirect bilirubin, negative Coombs testing, increased lactate dehydrogenase (LD), decreased haptoglobin
    • Coagulation testing
  • Other testing
    • Blood urea nitrogen (BUN)/creatinine
      • May have acute kidney injury with marked elevation
    • Hemolytic uremic syndrome (HUS) presenting with diarrhea (Shiga-toxin mediated TMA [ST-HUS])
      • E. coli/Shigella dysentery testing
      • Complement system evaluation
    • von Willebrand factor testing for thrombotic thrombocytopenic purpura (TTP)
  • Specific testing
    • ADAMTS13 activity
      • Specimen must be drawn before plasma exchange is started
      • May be low in disease states other than TTP (including other TMAs), but usually at least 25% of normal
        • <5-10% of normal suggests ADAMTS13 deficiency-mediated TMA
    • Anti-ADAMTS13 inhibitor/antibodies
      • Absence of antibodies in the presence of low or absent ADAMTS13 activity suggests congenital disease
      • Present in acquired TTP and may impart prognostic information
    • TMA with normal ADAMTS13 activity and no other obvious etiology, consider
      • Atypical HUS (aHUS)
        • Testing for complement abnormalities (complement factors H, I, and others) is not widely available and identifies causative abnormalities in only ~50% of cases
      • Autoimmune testing
      • HIV testing

Differential Diagnosis

  • Persistent ADAMST13 <10% of normal or presence of inhibitor or anti-ADAMST13 in clinical remission may signify risk of relapse

Thrombotic microangiopathy (TMA) syndromes can be acquired or hereditary. Primary TMAs include TMA with ADAMTS13 deficiency (commonly referred to as thrombotic thrombocytopenic purpura [TTP]), Shiga-toxin mediated TMA (also known as Shiga toxin TMA [ST-HUS]) and complement-mediated TMA (also known as atypical HUS [aHUS]). These disorders are associated with hemolysis (anemia), thrombocytopenia, and renal dysfunction in adults and children.

Epidemiology

  • Incidence of acquired TTP
    • Adults – 2.9/million
    • Children – 0.1/million
  • Age
    • TTP – usually adults, except for inherited forms
    • HUS – bimodal distribution: children (1-5 years) and older adults
    • aHUS – inherited disorder that affects children and adults; often presents in childhood
  • Sex – M:F, equal

Risk Factors

  • TTP
  • HUS
    • Gastroenteritis
    • Use of antimotility drugs or antibiotics during the course of bacterial diarrheas
  •  aHUS
    • Mutations in genes coding for complement factors H, I, membrane co-factor protein, or other complement factors or regulatory factors cause aHUS (not associated with a diarrheal prodrome)

Pathophysiology

  • Arteriolar platelet thrombi leads to thrombocytopenia, mechanical destruction of red blood cells (microangiopathic hemolytic anemia), and organ ischemia
  • Severe deficiency of ADAMTS13 (von Willebrand factor cleaving protease) in adult-acquired and pediatric hereditary deficiency TMAs
    • Severe deficiency  – <5% of normal activity
  • HUS is generally caused by bacterial infection with direct endothelial damage resulting in platelet thrombi
    • Enterohemorrhagic E. coli most common in U.S.
    • Shigella dysenteriae type I in developing countries
  • aHUS is an inherited disorder of complement dysregulation caused by mutations in complement proteins or complement regulatory proteins

Clinical Presentation

  • Primary TMA syndromes
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

ADAMTS13 Activity 0030056
Method: Chromogenic Assay

Limitations 

Specimen must be drawn prior to beginning plasma infusion or exchange

Mild to moderate ADAMTS13 deficiency may be seen in a variety of medical conditions

General References

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(4): 501-3. PubMed

Chapman K, Seldon M, Richards R. Thrombotic microangiopathies, thrombotic thrombocytopenic purpura, and ADAMTS-13. Semin Thromb Hemost. 2012; 38(1): 47-54. PubMed

de Córdoba SRodríguez, Hidalgo MSubías, Pinto S, Tortajada A. Genetics of atypical hemolytic uremic syndrome (aHUS). Semin Thromb Hemost. 2014; 40(4): 422-30. PubMed

George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014; 371(7): 654-66. PubMed

Hofer J, Giner T, Józsi M. Complement factor H-antibody-associated hemolytic uremic syndrome: pathogenesis, clinical presentation, and treatment. Semin Thromb Hemost. 2014; 40(4): 431-43. PubMed

Hofer J, Giner T, Safouh H. Diagnosis and treatment of the hemolytic uremic syndrome disease spectrum in developing regions. Semin Thromb Hemost. 2014; 40(4): 478-86. PubMed

Kiss JE. Thrombotic thrombocytopenic purpura: recognition and management. Int J Hematol. 2010; 91(1): 36-45. PubMed

Knöbl P. Inherited and acquired thrombotic thrombocytopenic purpura (TTP) in adults. Semin Thromb Hemost. 2014; 40(4): 493-502. PubMed

Orth-Höller D, Würzner R. Role of complement in enterohemorrhagic Escherichia coli-Induced hemolytic uremic syndrome. Semin Thromb Hemost. 2014; 40(4): 503-7. PubMed

Peyvandi F, Palla R, Lotta LA, Mackie I, Scully MA, Machin SJ. ADAMTS-13 assays in thrombotic thrombocytopenic purpura. J Thromb Haemost. 2010; 8(4): 631-40. PubMed

Riedl M, Fakhouri F, Le Quintrec M, Noone DG, Jungraithmayr TC, Fremeaux-Bacchi V, Licht C. Spectrum of complement-mediated thrombotic microangiopathies: pathogenetic insights identifying novel treatment approaches. Semin Thromb Hemost. 2014; 40(4): 444-64. PubMed

Sethi S, Fervenza FC. Pathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS). Semin Thromb Hemost. 2014; 40(4): 416-21. PubMed

Shenkman B, Einav Y. Thrombotic thrombocytopenic purpura and other thrombotic microangiopathic hemolytic anemias: diagnosis and classification. Autoimmun Rev. 2014; 13(4-5): 584-6. PubMed

Smock KJ, Perkins SL. Thrombocytopenia: an update. Int J Lab Hematol. 2014; 36(3): 269-78. PubMed

Tsai H. Autoimmune thrombotic microangiopathy: advances in pathogenesis, diagnosis, and management. Semin Thromb Hemost. 2012; 38(5): 469-82. PubMed

Tsai H. Thrombotic thrombocytopenic purpura and the atypical hemolytic uremic syndrome: an update. Hematol Oncol Clin North Am. 2013; 27(3): 565-84. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Bentley MJ, Lehman CM, Blaylock RC, Wilson AR, Rodgers GM. The utility of patient characteristics in predicting severe ADAMTS13 deficiency and response to plasma exchange. Transfusion. 2010; 50(8): 1654-64. PubMed

Bentley MJ, Rodgers GM. Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity: comment J Thromb Haemost. 2015; 13(8): 1524-5. PubMed

Bentley MJ, Wilson AR, Rodgers GM. Performance of a clinical prediction score for thrombotic thrombocytopenic purpura in an independent cohort. Vox Sang. 2013; 105(4): 313-8. PubMed

Heikal NM, Smock KJ. Laboratory testing for platelet antibodies. Am J Hematol. 2013; 88(9): 818-21. PubMed

Kling SJ, Judd CA, Warner KB, Rodgers GM. Regulation of ADAMTS13 expression in proliferating human umbilical vein endothelial cells. Pathophysiol Haemost Thromb. 2008; 36(5): 233-40. PubMed

Lee M, Rodansky ES, Smith JK, Rodgers GM. ADAMTS13 promotes angiogenesis and modulates VEGF-induced angiogenesis. Microvasc Res. 2012; 84(2): 109-15. PubMed

Spahr JE, Rodgers GM. Treatment of immune-mediated thrombocytopenia purpura with concurrent intravenous immunoglobulin and platelet transfusion: a retrospective review of 40 patients. Am J Hematol. 2008; 83(2): 122-5. PubMed

Werner TL, Agarwal N, Carney HM, Rodgers GM. Management of cancer-associated thrombotic microangiopathy: what is the right approach? Am J Hematol. 2007; 82(4): 295-8. PubMed

Medical Reviewers

Last Update: August 2016