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Utility of ADAMTS13 Assays in Diagnosing Thrombotic Thrombocytopenic Purpura.

To the Editor.--Thrombotic thrombocytopenic purpura (TTP) is an uncommon disorder, classified as a thrombotic microangiopathy (TMA) based on clinical findings of hemolytic anemia, thrombocytopenia, neurologic symptoms, fever, and renal dysfunction. (1) Unfortunately, several other TMAs have similar features (typical and atypical hemolytic uremic syndromes, disseminated intravascular coagulation, among others). An assay of ADAMTS13 is useful for distinguishing TTP from the other TMA disorders, thus identifying those patients who will benefit from plasma exchange (PE). (2)

Barrows and Teruya (3) reported their institution's experience using the ADAMTS13 assay, confirming that the test correctly identifies appropriate patients for PE. However, even with an in-house assay available, it may take hours to days to determine the ADAMTS13 result. Even that brief delay in making or refuting a diagnosis of TTP may be unacceptable to most physicians because urgent PE is the appropriate therapy.

There are 2 solutions to this problem. One option is to subject all patients suspected of having TTP to PE until the ADAMTS13 result returns; however, that approach means that most patients who receive PE will be unnecessarily treated. More important, appropriate treatment for the underlying TMA disorder will be delayed. Another approach that we use at our institution is the establishment of clinical criteria for rapidly identifying patients who have a high probability, intermediate probability, or low probability of TTP. (4) This clinical prediction score uses easily obtainable laboratory results (platelet count, Ddimer, creatinine, reticulocyte count, indirect bilirubin). Patients with a very low likelihood of TTP are not given PE, and alternative diagnoses are considered in those patients. Patients with an intermediate or a high likelihood of having TTP should receive PE. Results of this clinical prediction score were validated in a second cohort of patients with TMA. (5)

We agree with Barrows and Teruya that ADAMTS13 testing is useful in diagnosing TTP. However, we disagree that "... the presence of thrombocytopenia and hemolytic anemia are generally sufficient for starting empiric treatment with TPE." (p548) Patients with TTP represent only a few of the patients with TMA (5% in the authors' study, 10% in our studies), so exclusion of patients without TTP from receiving PE improves the efficiency of PE use and appropriate TMA management.

Christopher M. Lehman, MD

Department of Pathology

George M. Rodgers, MD, PhD

Department of Hematology University of Utah Salt Lake City, UT 84112

(1.) Osborn JD, Rodgers GM. Update on thrombotic thrombocytopenic purpura. Clin Adv Hematol Oncol. 2011;9(7):531-536.

(2.) Groot E, Hulstein JJJ, Rison CN, De Groot PG, Fijnheer R. FRETS-VWF73: a rapid and predictive tool for thrombotic thrombocytopenic purpura. / Thromb Haemost. 2006:4(3):698-699.

(3.) Barrows BD, Teruya J. Use of the ADAMTS13 activity assay improved the accuracy and efficiency of the diagnosis and treatment of suspected acquired thrombotic thrombocytopenic purpura. Arch Pathol Lab Med. 2014; 138(4):546-549.

(4.) 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):1654-1664.

(5.) 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):313-318.

doi: 10.5858/arpa.2014-0225-LE

In Reply.--We thank the authors for the letter in response to our recent article describing our experience using disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTs13) assays to assist in the efficient use of plasma exchange (PE). (1)

We suggested that thrombotic microangiopathy (TMA), without evidence of other possible cause, is generally viewed as sufficient to consider the diagnosis of acquired thrombotic thrombocytopenic purpura (ATTP), which could warrant the initiation of PE. occasional difficulties differentiating A-TTP from hemolytic uremic syndrome (HUs), and the implications for misdiagnosis (up to 90% fatality rate) have influenced empiric use of PE. (2) We agree this is not the best approach, which is why we have instituted ADAMTS13 assays as in-house tests.

We use the ADAMTS13 assays as a screen for patients presenting with TMA (Figure). Pediatric patients with ADAMTS13 activity less than 20% and associated inhibitor are diagnosed with A-TTP and started on PE. When the mixing study is negative, a non neutralizing inhibitor must be ruled out. Newborns and older infants presenting with TMA and low ADAMTS13, without evidence of an inhibitor, are diagnosed with congenital TTP and started on plasma transfusion therapy.

When ADAMTS13 is not decreased, workup for HUS is started. Currently, 3 variants of HUS should be considered: diarrhea-associated HUS (Shiga toxin-producing, enterohemorrhagic Escherichia coli-associated [STECHUS]), atypical HUS (complementactivating [aHUS]), and Streptococcus pneumoniae-associated HUS (SPHUS). (3)

Thrombotic microangiopathy with history of diarrhea and identification of Shiga toxin suggests a diagnosis of STEC-HUS. Treatment is generally limited to supportive therapy. However, recent reports have shown that the monoclonal anti-C5 antibody (eculizumab) can be of benefit in severe STEC-HUS. (3) Shiga toxin has been shown to activate complement by binding regulatory factor H. (4) We recommend consideration of eculizumab for severe presentations of STECHUS when it is unresponsive to supportive care.

When aHUS is suspected, we advise consideration of PE because of the potential presence of anti-complement factor H, which contributes to complement activation. Initial PE can aid by removing activated complement proteins and clearing potential anti-complement antibodies. (3) Initiation of eculizumab therapy should also be considered. Because the etiology of aHUS can be variable--such as through loss-of-function mutations of factor H or factor I, or gain-of-function mutations of C3 or factor B--there is no single rapid-assay method to make a diagnosis of aHUS. (5) It depends on the result of ADAMTS13 level, which should not be decreased.

Another form of HUS has been described to arise from Streptococcus pneumoniae infection. In SP-HUS, bacterial neuraminidase is thought to cleave N-acetyl neuraminic acid from the surface of red blood cells, platelets, and endothelium, exposing the Thomsen-Friedenreich (T) cryptantigen. Similar to other subtypes of HUS, overactivation of complement has been demonstrated. (6) The use of eculizumab has shown potential benefit in SP-HUS; however, additional evidence is required to support its use. (6) Because all blood components contain anti-T antigens, the washing of red blood cells and platelet units may be considered when transfusion is required.

In conclusion, we believe in-house ADAMTS13 assays, which can be performed quickly within 1 hour, are useful to differentiate TTP from HUS in order to either initiate PE or administer eculizumab without delay.

Please Note: Illustration(s) are not available due to copyright restrictions.

Brad D. Barrows, DO, MS Department of Pathology & Immunology Baylor College of Medicine Houston, Texas

Jun Teruya, MD, DSc Departments of Pathology & Immunology, Pediatrics, and Medicine Baylor College of Medicine Houston, Texas Texas Children's Hospital Houston, Texas

(1.) Barrows BD, Teruya J. Use of the ADAMTS13 activity assay improved the accuracy and efficiency of the diagnosis and treatment of suspected acquired thrombotic thrombocytopenic purpura. Arch Pathol Lab Hed. 2014; 138(4):546-549.

(2.) Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. Am Soc Nephrol. 2003; 14(4): 1072-1081.

(3.) Mele C, Remuzzi G, Noris M. Hemolytic uremic syndrome. Semin Immunopathol. 2014; 36(4):399-420.

(4.) Orth D, Khan AB, Naim A, et al. Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome. Immunol. 2009; 182(10):63946400.

(5.) Cataland SR, Holers VM, Geyer S, Yang S, Wu HM. Biomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP. Blood. 2014; 123(24):3733-3738.

(6.) Szilagyi A, Kiss N, Bereczki C, et al. The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome. Nephrol Dial Transplant. 2013; 28(9):2237-2245.

doi: 10.5858/arpa.2014-0452-LE

Caption: Algorithm for diagnosis and treatment of thrombotic microangiopathy (THA). * Nonneutralizing inhibitor. ** Hay require washed blood products if Thomsen-Friedenreich antigen (T antigen) positive, and plasma exchange (PE) trial if severe. *** PE trial to remove active complement and anti-complement antibodies. **** Eculizumab trial if severe. Abbreviations: ADAHTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS, atypical hemolytic uremic syndrome; A-TTP, acquired thrombotic thrombocytopenic purpura; CTTP, congenital thrombotic thrombocytopenic purpura; HUS, hemolytic uremic syndrome; SPHUS, Streptococcus pneumoniae-associated hemolytic uremic syndrome; STEC-HUS, Shiga toxin-producing, Escherichia coli-associated hemolytic uremic syndrome; TPE, therapeutic plasma exchange.
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Title Annotation:Letters to the Editor
Author:Lehman, Christopher M.; Rodgers, George M.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Letter to the editor
Date:Apr 1, 2015
Words:1371
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