Diagnosis of thrombotic thrombocytopenic purpura among patients with ADAMTS13 Activity 10%-20%
Authors: Adanma Ayanambakkam, Johanna A. Kremer Hovinga, Sara K. Vesely, James N. George
Journal: American Journal of Hematology (2017)

Thrombotic thrombocytopenic purpura (TTP) is defined by a severe deficiency of ADAMTS13 activity and ADAMTS13 deficiency is responsible for the clinical features of TTP. Severe deficiency of ADAMTS13 activity has been defined as activity less than 10%.1 For the diagnosis of TTP in patients enrolled in the Oklahoma TTP Registry, we have previously required ADAMTS13 activity <10% by either of the two methods that are performed in all patients: FRETS, the common commercial method, and quantitative immunoblotting (IB), the original method for measuring ADAMTS13 activity.2 Among 363 patients enrolled in the Registry, 1995–2015, 78 patients were diagnosed with TTP by both ADAMTS13 activity <10% and clinical evaluation.3 ADAMTS13 activity was <10% by both methods in 60 patients. In 15 patients, ADAMTS13 activity was <10% only with the FRETS method; activity was 10%-68% by the IB method. Among these 15 patients, the three with the highest ADAMTS13 activities by IB measurements (35%-68%) have all relapsed, confirming their diagnosis of TTP. At the time of their relapse, the IB measurement was <10% in two patients and 18% in the third. In three other patients, ADAMTS13 activity was <10% only with the IB assay; activity was 11%-23% by the FRETs method.3 To determine whether additional patients who did not have ADAMTS13 activity <10% by either method had characteristic clinical features of TTP, we reviewed the presenting features, clinical courses, and outcomes of the 22 Registry patients who presented with ADAMTS13 activity of 10%-20%. The Oklahoma TTP Registry with continuing long-term follow-up of all Registry patients is approved by the institutional review boards of the University of Oklahoma Health Sciences Center and participating hospitals. Two of the authors (AA, JNG) independently reviewed the complete medical records, including all follow-up data through 2017 or until their death, for each of the 22 patients to determine the probability of the diagnosis of TTP. To support our clinical judgment, we also developed an algorithm of clinical features of TTP, similar to previously published algorithms,4 based on the presenting features and clinical course of our cohort of the 78 previously diagnosed TTP patients.3 Supporting Information Table 1 presents demographic and initial laboratory data, and days in the hospital until plasma exchange (PEX) treatment began, for the 22 patients, with a concise description of their presenting clinical features. Although all patients had anemia with features of microangiopathic hemolysis and thrombocytopenia, their diversity was extreme. Some had previously been in excellent health; others had been hospitalized for several weeks–months before the diagnosis of TTP was suspected. One patient had minimal symptoms and was managed initially with corticosteroids as an outpatient for assumed ITP; other patients were critically ill. Supporting Information Table 2 presents their clinical course and outcomes with ADAMTS13 activity and functional inhibitor measurements. Ten patients died during the hospitalization. In six (27%) patients, both ADAMTS13 methods reported ≤20% activity. In 10 patients, only the FRET activity was ≤20%; in six patients, only the IB activity was ≤20%. Three patients appeared to have a high-titer functional inhibitor (≥2 BU). These three patients had very high serum bilirubin concentrations (36–53 mg/dL) which could cause falsely low ADAMTS13 activity by the FRET assay (12%-15%) with the apparent functional inhibitor.5 Their ADAMTS13 activities by the IB assay were 40%-80%. Supporting Information Table 3 compares the four patients whom we considered to have an appropriate clinical diagnosis of TTP to the other 18 patients. Patients with an appropriate clinical diagnosis of TTP had lower platelet counts, lower serum creatinine values, and all responded to PEX. Three other features may have been significantly different if the number of patients had been greater: patients' ages, frequency of exacerbation, and death. Other presenting features (race, gender, hematocrit, and LDH) were similar, consistent with the primary clinicians' initial suspicion of TTP. Table 1 presents the scores for clinical features that are characteristic of TTP. The four patients with an appropriate clinical diagnosis of TTP met six or seven of the seven criteria. The other 18 patients met two to four criteria. The cohort of 78 TTP patients3 met a mean of six criteria. Five Registry patients with ADAMTS13 activity <10% who were not clinically diagnosed as having TTP because an alternative diagnosis was established3 met two to four criteria. One previously reported Registry patient,6 not included in Table 1, had characteristic clinical features of TTP but his initial ADAMTS13 activities were 53% by the FRET measurement and 60% by the IB measurement; he subsequently had five relapses. With his last three episodes, both ADAMTS13 measurements reported activities <10%. He met six criteria. The basis for the occurrence of patients with characteristic clinical features and an appropriate clinical diagnosis of TTP without ADAMTS13 activity <10% is not known. Measures of higher ADAMTS13 activity may result from dissociation of neutralizing autoantibodies from ADAMTS13, allowing its activity, during in vitro incubation.3, 6 The discrepancies between two different methods of ADAMTS13 activity support the hypothesis that the presence of ADAMTS13 activity ≥10% in patients who have characteristic clinical features of TTP is an in vitro phenomenon. Because these 22 patients had ADAMTS13 activity ≥10%, it would be initially assumed that they did not have TTP. Therefore we required clear clinical evidence for the diagnosis of TTP and also the absence of an alternative etiology. Other clinicians may have had other interpretations and made different decisions about who among these 22 patients should be considered to have an appropriate clinical diagnosis of TTP. We acknowledge that clinical judgment, even with the assistance of diagnostic algorithms,4 is not precise. Because the characteristics of patients with TTP can be extremely variable, the diagnosis of TTP is often uncertain. A strength of these data is that one of the authors (JNG) saw 19 of these patients during their initial hospitalization for suspected TTP and was involved in the care of all 22 patients. Our conclusion is that a report of ADAMTS13 activity >10% should not exclude consideration of the diagnosis of TTP. The diagnosis of TTP requires both measurement of ADAMTS13 activity and the physician's clinical judgment. This project had no external support. The authors have no conflicts with the topic or data in this manuscript. Adanma Ayanambakkam http://orcid.org/0000-0001-8070-7927 James N. George http://orcid.org/0000-0002-4243-2691 Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information Table S1 Supporting Information Table S2 Supporting Information Table S3 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.