Expert Statements on the Standard of Care in Critically Ill Adult Patients With Atypical Hemolytic Uremic Syndrome
2017; Elsevier BV; Volume: 152; Issue: 2 Linguagem: Inglês
10.1016/j.chest.2017.03.055
ISSN1931-3543
AutoresÉlie Azoulay, Paul Knoebl, José Garnacho‐Montero, Kateřina Rusínová, Gennadii M. Galstian, Philippe Eggimann, Fekri Abroug, Dominique Benoît, Michael von Bergwelt‐Baildon, Julia Wendon, Marie Scully,
Tópico(s)Hemoglobinopathies and Related Disorders
ResumoA typical hemolytic uremic syndrome (aHUS) presents similarly to thrombotic thrombocytopenic purpura (TTP) and other causes or conditions with thrombotic microangiopathy (TMA), such as disseminated intravascular coagulation or sepsis. Similarity in clinical presentation may hinder diagnosis and optimal treatment selection in the urgent setting in the ICU. However, there is currently no consensus on the diagnosis or treatment of aHUS for ICU specialists. This review aims to summarize available data on the diagnosis and treatment strategies of aHUS in the ICU to enhance the understanding of aHUS diagnosis and outcomes in patients managed in the ICU. To this end, a review of the recent literature (January 2009-March 2016) was performed to select the most relevant articles for ICU physicians. Based on the paucity of adult aHUS cases overall and within the ICU, no specific recommendations could be formally graded for the critical care setting. However, we recognize a core set of skills required by intensivists for diagnosing and managing patients with aHUS: recognizing thrombotic microangiopathies, differentiating aHUS from related conditions, recognizing involvement of other organ systems, understanding the pathophysiology of aHUS, knowing the diagnostic workup and relevant outcomes in critically ill patients with aHUS, and knowing the standard of care for patients with aHUS based on available data and guidelines. In conclusion, managing critically ill patients with aHUS requires basic skills that, in the absence of sufficient data from patients treated within the ICU, can be gleaned from an increasingly relevant literature outside the ICU. More data on critically ill patients with aHUS are needed to validate these conclusions within the ICU setting. A typical hemolytic uremic syndrome (aHUS) presents similarly to thrombotic thrombocytopenic purpura (TTP) and other causes or conditions with thrombotic microangiopathy (TMA), such as disseminated intravascular coagulation or sepsis. Similarity in clinical presentation may hinder diagnosis and optimal treatment selection in the urgent setting in the ICU. However, there is currently no consensus on the diagnosis or treatment of aHUS for ICU specialists. This review aims to summarize available data on the diagnosis and treatment strategies of aHUS in the ICU to enhance the understanding of aHUS diagnosis and outcomes in patients managed in the ICU. To this end, a review of the recent literature (January 2009-March 2016) was performed to select the most relevant articles for ICU physicians. Based on the paucity of adult aHUS cases overall and within the ICU, no specific recommendations could be formally graded for the critical care setting. However, we recognize a core set of skills required by intensivists for diagnosing and managing patients with aHUS: recognizing thrombotic microangiopathies, differentiating aHUS from related conditions, recognizing involvement of other organ systems, understanding the pathophysiology of aHUS, knowing the diagnostic workup and relevant outcomes in critically ill patients with aHUS, and knowing the standard of care for patients with aHUS based on available data and guidelines. In conclusion, managing critically ill patients with aHUS requires basic skills that, in the absence of sufficient data from patients treated within the ICU, can be gleaned from an increasingly relevant literature outside the ICU. More data on critically ill patients with aHUS are needed to validate these conclusions within the ICU setting. Thrombotic microangiopathies (TMAs) are a group of disorders characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction, in which ischemic organ injury can occur to the brain, kidneys, heart, pancreas, liver, lungs, eyes, and skin. Conditions occurring with TMAs include hemolytic uremic syndromes (HUSs) and thrombotic thrombocytopenic purpura (TTP), and a number of differential diagnoses that must also be excluded (Fig 1).1Campistol J.M. Arias M. Ariceta G. et al.An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document.Nefrologia. 2015; 35: 421-447Crossref PubMed Google Scholar These conditions have a similar clinical presentation of consumptive thrombocytopenia, mechanical hemolysis, and organ failure, but with distinct causes, and are typically associated with thickening and inflammation of arterioles and capillaries, detachment and swelling of endothelial cells, subendothelial widening, accumulation of proteins and cellular debris, or platelet thrombi that obstruct the vascular lumen.1Campistol J.M. Arias M. Ariceta G. et al.An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document.Nefrologia. 2015; 35: 421-447Crossref PubMed Google Scholar, 2Franchini M. Atypical hemolytic uremic syndrome: from diagnosis to treatment.Clin Chem Lab Med. 2015; 53: 1679-1688Crossref PubMed Scopus (21) Google Scholar Herein, we will focus on one of these conditions, atypical hemolytic uremic syndrome (aHUS). aHUS is a rare but life-threatening condition that affects both children and adults. It accounts for approximately 10% of cases of HUS in children, but most HUS cases in adults.3Loirat C. Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome.Orphanet J Rare Dis. 2011; 6: 60Crossref PubMed Scopus (461) Google Scholar The annual incidence of aHUS is thought to be around 1 to 2 per million in adults4Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (481) Google Scholar; however, epidemiologic data are limited.5Mele C. Remuzzi G. Noris M. Hemolytic uremic syndrome.Semin Immunopathol. 2014; 36: 399-420Crossref PubMed Scopus (114) Google Scholar aHUS is distinct from typical, or diarrhea-associated, HUS, now commonly called Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS), which is typically caused by Shiga toxin because of bacterial infection and often associated with bloody diarrhea. In most cases, aHUS is caused by the uncontrolled activation of the complement system, which leads to platelet, leucocyte, and endothelial cell activation and TMA,1Campistol J.M. Arias M. Ariceta G. et al.An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document.Nefrologia. 2015; 35: 421-447Crossref PubMed Google Scholar, 6Legendre C.M. Licht C. Loirat C. Eculizumab in atypical hemolytic-uremic syndrome.N Engl J Med. 2013; 369: 1379-1380PubMed Google Scholar, 7Riedl M. Fakhouri F. Le Quintrec M. et al.Spectrum of complement-mediated thrombotic microangiopathies: pathogenetic insights identifying novel treatment approaches.Semin Thromb Hemost. 2014; 40: 444-464Crossref PubMed Scopus (98) Google Scholar, 8Noris M. Mele C. Remuzzi G. Podocyte dysfunction in atypical haemolytic uraemic syndrome.Nat Rev Nephrol. 2015; 11: 245-252Crossref PubMed Scopus (34) Google Scholar ultimately causing thrombosis and organ dysfunction.8Noris M. Mele C. Remuzzi G. Podocyte dysfunction in atypical haemolytic uraemic syndrome.Nat Rev Nephrol. 2015; 11: 245-252Crossref PubMed Scopus (34) Google Scholar, 9Hofer J. Rosales A. Fischer C. Giner T. Extra-renal manifestations of complement-mediated thrombotic microangiopathies.Front Pediatr. 2014; 2: 97Crossref PubMed Scopus (57) Google Scholar Accordingly, it may be unmasked by conditions with enhanced complement activation, such as systemic lupus erythematosus, pregnancy, malignant hypertension, and hematopoietic stem cell transplantation. Genetic abnormalities have been found in approximately 50% to 70% of patients with aHUS,4Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (481) Google Scholar, 10Noris 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: 1844-1859Crossref PubMed Scopus (698) Google Scholar and a wide variety of mutations are associated with the condition.4Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (481) Google Scholar, 8Noris M. Mele C. Remuzzi G. Podocyte dysfunction in atypical haemolytic uraemic syndrome.Nat Rev Nephrol. 2015; 11: 245-252Crossref PubMed Scopus (34) Google Scholar Although gene mutations increase the risk of aHUS, they may not be sufficient to cause overt symptoms without additional environmental triggers. These include infections, pregnancy, certain medications, malignancy, sepsis, bone marrow transplantation, and connective tissue disorders.2Franchini M. Atypical hemolytic uremic syndrome: from diagnosis to treatment.Clin Chem Lab Med. 2015; 53: 1679-1688Crossref PubMed Scopus (21) Google Scholar, 9Hofer J. Rosales A. Fischer C. Giner T. Extra-renal manifestations of complement-mediated thrombotic microangiopathies.Front Pediatr. 2014; 2: 97Crossref PubMed Scopus (57) Google Scholar, 11Mannucci P.M. Understanding organ dysfunction in thrombotic thrombocytopenic purpura.Intensive Care Med. 2015; 41: 715-718Crossref PubMed Scopus (15) Google Scholar Consequently, genetic testing is currently not useful for the acute diagnosis of aHUS (eg, in the ICU setting), but it can provide diagnostic confirmation, prognostic value, and information on long-term treatment. Furthermore, because of the severe nature of the condition, the time delay in obtaining genetic results is not consistent with the need for rapid initiation of therapy. In the absence of any fast, specific diagnostic tests for aHUS, the condition can only be diagnosed after exclusion of TTP12Scully M. Goodship T. How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome.Br J Haematol. 2014; 164: 759-766Crossref PubMed Scopus (110) Google Scholar and related TMAs. Previously, aHUS and TTP have been managed in the same way because the conditions are difficult to differentiate and only one treatment option, plasma therapy (plasma infusion or plasma exchange), was available.1Campistol J.M. Arias M. Ariceta G. et al.An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document.Nefrologia. 2015; 35: 421-447Crossref PubMed Google Scholar, 4Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (481) Google Scholar The benefits of plasma exchange, although not evaluated in prospective studies, include the removal of pathologic substances from the blood and the replacement of deficient plasma components.13Reeves H.M. Winters J.L. The mechanisms of action of plasma exchange.Br J Haematol. 2014; 164: 342-351Crossref PubMed Scopus (143) Google Scholar However, although plasma therapy has improved outcomes considerably in TTP, reducing the mortality rate from 90% to 10% to 20%,14Scully M. Hunt B.J. Benjamin S. et al.Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies.Br J Haematol. 2012; 158: 323-335Crossref PubMed Scopus (537) Google Scholar > 50% of patients with aHUS proceed to end-stage renal disease or death despite plasma therapy.8Noris M. Mele C. Remuzzi G. Podocyte dysfunction in atypical haemolytic uraemic syndrome.Nat Rev Nephrol. 2015; 11: 245-252Crossref PubMed Scopus (34) Google Scholar, 12Scully M. Goodship T. How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome.Br J Haematol. 2014; 164: 759-766Crossref PubMed Scopus (110) Google Scholar Consequently, specific, urgent, and interdisciplinary management is paramount in the treatment of patients with aHUS because of both the severity of the illness and the potential development of irreversible complications of organ involvement.1Campistol J.M. Arias M. Ariceta G. et al.An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document.Nefrologia. 2015; 35: 421-447Crossref PubMed Google Scholar Eculizumab, approved in 2011, is the first treatment for aHUS with proven efficacy and safety in prospective clinical trials.6Legendre C.M. Licht C. Loirat C. Eculizumab in atypical hemolytic-uremic syndrome.N Engl J Med. 2013; 369: 1379-1380PubMed Google Scholar This monoclonal antibody targets the complement system by blocking the cleavage of C5, avoiding the production of cleavage products C5a and C5b15Cofiell R. Kukreja A. Bedard K. et al.Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS.Blood. 2015; 125: 3253-3262Crossref PubMed Scopus (128) Google Scholar; evidence suggests that early initiation can improve renal and nonrenal recovery.16Walle J.V. Delmas Y. Ardissino G. Wang J. Kincaid J.F. Haller H. Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment.J Nephrol. 2017; 30: 127-134Crossref PubMed Scopus (61) Google Scholar, 17Zuber J. Le Q.M. Sberro-Soussan R. Loirat C. Fremeaux-Bacchi V. Legendre C. New insights into postrenal transplant hemolytic uremic syndrome.Nat Rev Nephrol. 2011; 7: 23-35Crossref PubMed Scopus (138) Google Scholar In many cases, the ICU is the only clinical environment in which such specialized urgent care can be effectively provided at any time. Based on our experience, physicians in the ICU see an average of three patients with TMA per year, many of whom are not diagnosed at the time of admission. Although treatment guidelines for aHUS are available for nephrology,14Scully M. Hunt B.J. Benjamin S. et al.Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies.Br J Haematol. 2012; 158: 323-335Crossref PubMed Scopus (537) Google Scholar, 18Sawai T. Nangaku M. Ashida A. et al.Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee of the Japanese Society of Nephrology and the Japan Pediatric Society.Pediatr Int. 2014; 56: 1-5Crossref PubMed Scopus (20) Google Scholar, 19Loirat C. Fakhouri F. Ariceta G. et al.An international consensus approach to the management of atypical hemolytic uremic syndrome in children.Pediatr Nephrol. 2016; 31: 15-39Crossref PubMed Scopus (359) Google Scholar, 20Nester C.M. Managing atypical hemolytic uremic syndrome: chapter 2.Kidney Int. 2015; 87: 882-884Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar there is currently no consensus on the diagnosis or treatment of aHUS for ICU specialists. This review aims to summarize available data on the diagnosis and treatment of aHUS in the ICU with the goal of enhancing the understanding of aHUS diagnosis and outcomes in patients managed in the ICU. The need for this article was identified by a multidisciplinary multinational expert panel of 11 members (nine intensive care physicians and two hematologists) who met in September 2015 to define unmet needs and skill priorities for ICU clinicians managing critically ill patients with aHUS and to evaluate existing recommendations outside critical care. A literature search was conducted in the National Library of Medicine database (PubMed) looking for articles published between January 2009 and March 2016, using the following search terms: "atypical haemolytic uraemic syndrome" or "atypical hemolytic uremic syndrome" or "diarrhoea negative haemolytic uraemic syndrome" or "diarrhea negative hemolytic uremic syndrome" or "aHUS" or "D-HUS," with search filters of "humans" and "English language." Additional relevant articles were also included from Internet searches using the same search terms. Articles were reviewed manually for relevance by the authors; studies concerning both transplant and native kidney patients with aHUS were permitted in this study, as were systematic literature reviews and specialist review articles. In total, 539 articles were identified, of which 56 were considered relevant (included diagnosis and/or treatment of adult patients with aHUS). Diagnosis of aHUS typically commences with the broad diagnosis of TMA (Fig 2, Table 1)21Loirat C. Saland J. Bitzan M. Management of hemolytic uremic syndrome.Presse Med. 2012; 41: e115-e135Crossref PubMed Scopus (81) Google Scholar, 22Knobl P.N. Treatment of thrombotic microangiopathy with a focus on new treatment options.Hamostaseologie. 2013; 33: 149-159Crossref PubMed Scopus (21) Google Scholar, 23Greenbaum L.A. Atypical hemolytic uremic syndrome.Adv Pediatr. 2014; 61: 335-356Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 24Hunt B.J. Bleeding and coagulopathies in critical care.N Engl J Med. 2014; 370: 2153Crossref PubMed Scopus (19) Google Scholar and implicates the involvement of not only the ICU physician but also other specialists, notably hematologists and nephrologists. Clinical suspicion of a TMA is based on clinical findings, including microangiopathic hemolytic anemia, thrombocytopenia, low haptoglobin, elevated lactate dehydrogenase, elevated reticulocytes, fragmented red cells, and schistocytes on peripheral blood smear. Acute kidney injury is common in aHUS, but other organ involvement, including cardiac, gastrointestinal, or neurological damage, may be present and can dominate the clinical picture1Campistol J.M. Arias M. Ariceta G. et al.An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document.Nefrologia. 2015; 35: 421-447Crossref PubMed Google Scholar, 5Mele C. Remuzzi G. Noris M. Hemolytic uremic syndrome.Semin Immunopathol. 2014; 36: 399-420Crossref PubMed Scopus (114) Google Scholar, 25Sallee M. Ismail K. Fakhouri F. et al.Thrombocytopenia is not mandatory to diagnose haemolytic and uremic syndrome.BMC Nephrol. 2013; 14: 3Crossref PubMed Scopus (29) Google Scholar, 26Nester C.M. Barbour T. de Cordoba S.R. et al.Atypical aHUS: state of the art.Mol Immunol. 2015; 67: 31-42Crossref PubMed Scopus (192) Google Scholar, 27Laurence J. Atypical hemolytic uremic syndrome (aHUS): making the diagnosis.Clin Adv Hematol Oncol. 2012; 10: 1-12PubMed Google Scholar, 28Shenkman B. Einav Y. Thrombotic thrombocytopenic purpura and other thrombotic microangiopathic hemolytic anemias: diagnosis and classification.Autoimmun Rev. 2014; 13: 584-586Crossref PubMed Scopus (54) Google Scholar (Fig 2, Table 1). Once suspicion of TMA has been established, further investigations, including a full patient medical and family history, are required to exclude other potential causes of TMA, including TTP, STEC-HUS, or TMA as a transient manifestation of another condition (eg, malignancy, autoimmune disease) or adverse drug effect; however, identification of one of these modulating factors does not preclude development of aHUS in individuals with a genetic predisposition. Additionally, an HIV test and a pregnancy test in women of child-bearing age should be performed to account for these potential triggers.21Loirat C. Saland J. Bitzan M. Management of hemolytic uremic syndrome.Presse Med. 2012; 41: e115-e135Crossref PubMed Scopus (81) Google ScholarTable 1Recommended Tests for the Differential Diagnosis of aHUS1Campistol J.M. Arias M. Ariceta G. et al.An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document.Nefrologia. 2015; 35: 421-447Crossref PubMed Google Scholar, 12Scully M. Goodship T. How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome.Br J Haematol. 2014; 164: 759-766Crossref PubMed Scopus (110) Google Scholar, 14Scully M. Hunt B.J. Benjamin S. et al.Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies.Br J Haematol. 2012; 158: 323-335Crossref PubMed Scopus (537) Google Scholar, 21Loirat C. Saland J. Bitzan M. Management of hemolytic uremic syndrome.Presse Med. 2012; 41: e115-e135Crossref PubMed Scopus (81) Google Scholar, 22Knobl P.N. Treatment of thrombotic microangiopathy with a focus on new treatment options.Hamostaseologie. 2013; 33: 149-159Crossref PubMed Scopus (21) Google Scholar, 23Greenbaum L.A. Atypical hemolytic uremic syndrome.Adv Pediatr. 2014; 61: 335-356Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 24Hunt B.J. Bleeding and coagulopathies in critical care.N Engl J Med. 2014; 370: 2153Crossref PubMed Scopus (19) Google ScholarIdentify TMATestOutcome in aHUSAlternative Diagnosis Reticulocyte countsIncreased Free serum hemoglobinIncreased LDHIncreased HaptoglobinDecreasedOften decreased in TMAs, normal in DIC and sepsis SchistocytesPresentCan be present in all TMAs Platelet countDecreased (most of the time)Can be reduced in all TMAs HemoglobinDecreasedCan be decreased in all TMAs Serum creatinineIncreased (most of the time)Can be increased in all TMAs Hematuria and proteinuriaPresent (most of the time)Can be present in all TMAs Kidney biopsyaKidney biopsies are rarely performed because little information can be obtained above that from laboratory results; kidney biopsy in critically ill patients with low platelet counts should not be performed because of bleeding risk.Often arteriolar and/or glomerular intracapillary thrombosis if kidney affectedAdditional tests to perform to advise on other possible causes of TMA Direct antiglobulin test (Coombs test)NegativePositive in autoimmune hemolytic anemias, Evans syndrome, and pneumococcal HUS FibrinogenNormalReduced fibrinogen and elevated fibrinogen degradation products in DIC aPTT, PTNormalProlonged in DIC Plasma coagulation testsNormalReduced in DIC D-dimerNormal (can be elevated)Elevated D-dimer in DIC or TMA Liver enzyme levelsNormal (can be elevated if liver is involved)Elevated in HELLP syndrome Viral infections, including HIV, HBV, HCV, and H1N1Can be a precipitant of aHUSKnown external precipitant of TMA Pregnancy test (where appropriate)Pregnancy-triggered TMA caused by aHUS usually presents in late pregnancy or postpartumPregnancy-triggered TMA caused by TTP usually presents during pregnancy Antibody testing, including antinuclear antibody, lupus anticoagulant, and antiphospholipid antibodiesNegativePositive in systemic diseases, such as SLE, CAPS; 30% of TTP have positive antinuclear antibodiesRule out TTP and STEC-HUS STEC infection: fecal sample or rectal swab test for Escherichia coli and/or PCR for Shiga toxin, and serology of LPS of common Shiga toxin-producing strainsNegativePositive in STEC-HUS ADAMTS13> 10% activity< 10% activity in TTPThis is not an exhaustive list, but a suggestion. Further tests for conditions that can mimic TMA, such as malaria, babesiosis, and vitamin deficiency, may be warranted. ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin motifs 13; aHUS = atypical hemolytic uremic syndrome; aPTT = activated partial thromboplastin time; CAPS = cryopyrin-associated autoinflammatory syndrome; DIC = disseminated intravascular coagulation; HBV = hepatitis B virus; HCV = hepatitis C virus; HELLP = hemolysis, elevated liver enzymes, low platelet count; HUS = hemolytic uremic syndrome; LDH = lactate dehydrogenase; LPS = lipopolysaccharide; PCR = polymerase chain reaction; PT = prothrombin time; SLE = systemic lupus erythematosus; STEC = Shiga toxin-producing Escherichia coli; STEC-HUS = Shiga toxin-associated hemolytic uremic syndrome; TMA = thrombotic microangiopathy; TTP = thrombotic thrombocytopenic purpura.a Kidney biopsies are rarely performed because little information can be obtained above that from laboratory results; kidney biopsy in critically ill patients with low platelet counts should not be performed because of bleeding risk. Open table in a new tab This is not an exhaustive list, but a suggestion. Further tests for conditions that can mimic TMA, such as malaria, babesiosis, and vitamin deficiency, may be warranted. ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin motifs 13; aHUS = atypical hemolytic uremic syndrome; aPTT = activated partial thromboplastin time; CAPS = cryopyrin-associated autoinflammatory syndrome; DIC = disseminated intravascular coagulation; HBV = hepatitis B virus; HCV = hepatitis C virus; HELLP = hemolysis, elevated liver enzymes, low platelet count; HUS = hemolytic uremic syndrome; LDH = lactate dehydrogenase; LPS = lipopolysaccharide; PCR = polymerase chain reaction; PT = prothrombin time; SLE = systemic lupus erythematosus; STEC = Shiga toxin-producing Escherichia coli; STEC-HUS = Shiga toxin-associated hemolytic uremic syndrome; TMA = thrombotic microangiopathy; TTP = thrombotic thrombocytopenic purpura. The most critical and urgent differential diagnosis is to differentiate TTP from aHUS because of the urgency of specific treatment. Testing for ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) activity is recommended to differentiate between TTP and aHUS,27Laurence J. Atypical hemolytic uremic syndrome (aHUS): making the diagnosis.Clin Adv Hematol Oncol. 2012; 10: 1-12PubMed Google Scholar and sampling must take place prior to administration of plasma therapy. ADAMTS13 deficiency is characteristic of TTP, with levels < 10% widely considered to be diagnostic for the condition.12Scully M. Goodship T. How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome.Br J Haematol. 2014; 164: 759-766Crossref PubMed Scopus (110) Google Scholar, 14Scully M. Hunt B.J. Benjamin S. et al.Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies.Br J Haematol. 2012; 158: 323-335Crossref PubMed Scopus (537) Google Scholar, 27Laurence J. Atypical hemolytic uremic syndrome (aHUS): making the diagnosis.Clin Adv Hematol Oncol. 2012; 10: 1-12PubMed Google Scholar, 29Feng S. Eyler S.J. Zhang Y. et al.Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome.Blood. 2013; 122: 1487-1493Crossref PubMed Scopus (61) Google Scholar, 30Campistol J.M. Arias M. Ariceta G. et al.An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document.Nefrologia. 2013; 33: 27-45PubMed Google Scholar, 31Nester C.M. Thomas C.P. Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated?.Hematology Am Soc Hematol Educ Program. 2012; 2012: 617-625Crossref PubMed Google Scholar, 32Contreras E. de la Rubia J. Del Rio-Garma J. Diaz-Ricart M. Garcia-Gala J.M. Lozano M. Diagnostic and therapeutic guidelines of thrombotic microangiopathies of the Spanish Apheresis Group.Med Clin (Barc). 2015; 144 ([in Spanish]): 331Crossref PubMed Scopus (22) Google Scholar ADAMTS13, also known as von Wilbrand Factor cleavage protease, acts by cleavage of von Wilbrand Factor into smaller, less thrombotic fragments, thereby reducing platelet aggregation. Conversely, in TTP, reduced activity of ADAMTS13 results in platelet hyperadhesiveness and clumping within the microvasculature.27Laurence J. Atypical hemolytic uremic syndrome (aHUS): making the diagnosis.Clin Adv Hematol Oncol. 2012; 10: 1-12PubMed Google Scholar, 33Tsai H.M. Untying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome.Am J Med. 2013; 126: 200-209Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Somewhat reduced ADAMTS13 activity levels (> 10% of normal) may also occur in aHUS, but such levels are sufficient to exclude TTP. Although results from the ADAMTS13 assay are typically available within a few hours when the assay is established in the local laboratory, they may take some additional days when the sample has to be shipped, meaning that treatment decisions may need to be made prior to receiving the results of the test. If ADAMTS13 tests are not available within a few hours, a diagnostic algorithm developed by Coppo et al,34Coppo 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: e10208Crossref PubMed Scopus (230) Google Scholar in which TTP is suggested by low platelet count (< 30 × 109/L), mildly elevated serum creatinine (≤ 200 μmol/L), and detectable antinuclear antibodies, could help form an initial differential diagnosis. In the interim, until TTP has been excluded, patients should receive plasma exchange. The presence of associated organ involvement may be included within the diagnostic workup to provide evidence for differentiation of aHUS from TTP, but it is not conclusive. Renal impairment is the most common complication in aHUS (Fig 3), but renal function may be preserved in up to 20% of cases. Acute kidney injury may be seen in TTP, but it is typically reversible with therapy.35Zafrani L. Mariotte E. Darmon M. et al.Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity.J Thromb Haemost. 2015; 13: 380-389Crossref PubMed Scopus (38) Google Scholar The need for renal support, such as hemodialysis, is not a common feature of TTP, but it can be seen in progressive disease with multiorgan involvement. Neurologic signs (eg, confusion, focal cerebral abnormalities, seizures) and cardiovascular signs (eg, cardiomyopathy, myocardial infarction, myocarditis, heart failure) occur in 10% to 48% and 10% of aHUS cases, respectively9Hofer J. Rosales A. Fischer
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