Thrombotic Microangiopathies - TMA

Thrombotic microangiopathy (TMA) syndromes can be acquired or hereditary. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are two prototypes of TMAs, although TMAs may occur secondarily to multiple other systemic disorders (eg, malignant hypertension, medications). These disorders are associated with hemolysis (anemia), thrombocytopenia, and renal dysfunction in adults and children. TTP should be distinguished from other TMA syndromes, as patients with ADAMTS13 deficiency are likely to respond to therapeutic plasma exchange (TPE) whereas those without ADAMTS13 severe deficiency require treatments other than TPE (Joly, 2016).

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

Indications for Testing

Definitions (Scully, 2016)

  • Thrombotic thrombocytopenic purpura (TTP)
    • MAHA
    • Moderate or severe thrombocytopenia
    • Associated organ dysfunction
    • Severe deficiency (<10%) of ADAMTS13 activity
    • Subtypes of TTP
      • Congenital TTP (cTTP, or Upshaw-Schulman syndrome)
        • Persistent severe deficiency (<10%) of ADAMTS13 activity with no evidence of anti-ADAMTS13 inhibitory autoantibodies, confirmed by molecular analysis of ADAMTS-13 gene mutations
      • Immune-mediated TTP (iTTP) – acquired TTP
        • Primary iTTP – no obvious underlying precipitating cause/disease
          • Due to immune inhibitor of ADAMTS13
          • Accounts for the majority of cases of TTP
        • Secondary iTTP – underlying disorder or trigger can be identified (eg, infectious disease, drugs, pregnancy)
  • Hemolytic uremic syndrome (HUS)
    • Microangiopathic hemolytic anemia and thrombocytopenia (MAHAT)
    • Renal injury
    • Subtypes of HUS
      • Infection-associated HUS/classical (IA-HUS or STEC-HUS)
        • Infectious etiology typically associated with E. coli, which expresses Shiga toxin
      • Complement mediated/atypical (CM-HUS or aHUS)
        • Results from defective regulation of the alternative complement pathway
        • May be triggered by infection, vaccinations, or pregnancy

Laboratory Testing

  • Specific testing
    • ADAMTS13 investigation – sensitive and specific marker for TTP
      • Activity testing
        • Severe deficiency (<10%) – essentially diagnostic of TTP
        • Specimen must be drawn before plasma exchange is started; samples taken following plasma therapy may give a falsely raised ADAMTS13 activity (Scully, 2016)
        • May be low in disease states other than TTP (including other thrombotic microangiopathies [TMAs]), but usually at least 25% of normal
      • Antibody testing
        • ADAMTS13 autoantibodies can neutralize ADAMTS13 function (found in ~2/3 of idiopathic cases), increase clearance (found in ~1/3 of idiopathic cases), or both
        • Absence of antibodies in the presence of severely deficient ADAMTS13 activity suggests congenital disease
        • Inhibitor testing
          • Present in majority of acquired TTP and may impart prognostic information
        • Antibody testing
          • Not recommended as initial test for identification of autoantibodies to ADAMTS13 – antibody test is less specific for acquired TTP than inhibitor test
          • Consider when acquired TTP is suspected but antibodies are not identified by inhibitor testing
  • Nonspecific testing
    • Intravascular hemolysis testing
      • Bilirubin (increased), Coombs testing (negative), haptoglobin (decreased/absent), lactate dehydrogenase (LDH) (elevated)
    • Organ dysfunction testing
      • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT), creatinine
    • Coagulation testing
      • Prothrombin time (PT)/partial thromboplastin time (PTT)/d-dimer – usually normal
    • Hematology testing
      • CBC – demonstrates thrombocytopenia (typically <30 X 109/L) (Joly, 2016)
      • Blood smear – red blood cell fragmentation (schistocytes), high reticulocyte count (>120 X 109/L)
    • Other testing as needed
      • Antinuclear antibodies (ANA)
      • Stool culture
      • Shiga toxin stool polymerase chain reaction (PCR) – for patients presenting with diarrhea
      • Complement testing if aHUS suspected
  • Molecular analysis
    • ADAMTS13 testing
      • May be useful in suspected hereditary TTP (Upshaw-Schulman syndrome)
      • Suspected in patients with family history or when ADAMTS13 activity <10% and an inhibitor is not detected (Joly, 2016)

Differential Diagnosis (Saha, 2017)

  • Medication induced
  • Chemotherapy induced
  • Transplantation associated
  • Malignancy related
  • Infectious (eg, HIV)
  • Disseminated intravascular coagulation (DIC)
  • Malignant hypertension
  • Pregnancy associated (eg, preeclampsia/eclampsia/Hemolysis, Elevated Liver enzyme levels, Low Platelet count (HELLP)

Persistent ADAMTS13 <10% of normal or presence of inhibitor of anti-ADAMTS13 in clinical remission may signify risk of relapse

Epidemiology

  • Incidence
    • 3-11/million people (Saha, 2017)
  • Age
    • Thrombotic thrombocytopenic purpura (TTP) – first acute episode usually occurs during adulthood (~90% of all cases), except in inherited forms (Joly, 2016)
    • Hemolytic uremic syndrome (HUS) – bimodal distribution
      • Children (1-5 years)
      • Older adults
    • Complement-mediated HUS or atypical HUS (aHUS) – inherited disorder that affects children and adults; often presents in childhood
  • Sex – M<F, 1:2 (Joly, 2016)

Risk Factors

  • TTP
    • Predisposing factors (Joly, 2016)
      • Black ethnicity
      • Female gender
      • HLA-DRB1*11
      • Obesity
    • Precipitating factors (Joly, 2016)
      • Conditions increasing von Willebrand factor (VWF) levels (eg, inflammation, infections, pregnancy)
  • HUS
    • Gastroenteritis
    • Use of antimotility drugs or antibiotics during the course of bacterial diarrheas
  • aHUS
    • Variants in genes coding for complement factors H, I, membrane cofactor 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 TTP
    • Severe deficiency – <10% 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 (only rarely acquired) 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 Reflex Panel 3000239
Method: Quantitative Enzyme-Linked Immunosorbent Assay

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

ADAMTS13 Inhibitor 3000228
Method: Quantitative Enzyme-Linked Immunosorbent Assay

ADAMTS13 Antibody 3000182
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Guidelines

Go RS, Winters JL, Leung N, Murray DL, Willrich MA, Abraham RS, Amer H, Hogan WJ, Marshall AL, Sethi S, Tran CL, Chen D, Pruthi RK, Ashrani AA, Fervenza FC, Cramer CH, Rodriguez V, Wolanskyj AP, Thomé SD, Hook C, Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy Disease-Oriented Group. Thrombotic Microangiopathy Care Pathway: A Consensus Statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group. Mayo Clin Proc. 2016; 91(9): 1189-211. PubMed

Scully M, Cataland S, Coppo P, de la Rubia J, Friedman KD, Hovinga K, Lämmle B, Matsumoto M, Pavenski K, Sadler E, Sarode R, Wu H, International Working Group for Thrombotic Thrombocytopenic Purpura. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost. 2017; 15(2): 312-322. PubMed

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 SR, Hidalgo MS, 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

Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood. 2017; 129(21): 2836-2846. 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

Sadler E. Pathophysiology of thrombotic thrombocytopenic purpura. Blood. 2017; 130(10): 1181-1188. PubMed

Saha M, McDaniel JK, Zheng XL. Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics. J Thromb Haemost. 2017; 15(10): 1889-1900. 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

Smock KJ. The role of ADAMTS13 testing in the work up of suspected thrombotic thrombocytopenic purpura. American Association for Clinical Chemistry. [Published: Apr 2016; Accessed: Apr 2017]

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

Content Reviewed: 
December 2017

Last Update: January 2018