For the past two decades, ADAMTS13 activity has been the backbone of diagnosis for thrombotic thrombocytopenic purpura (TTP); however, a long-term registry study published in Blood Advances emphasizes the need for clinical judgement in addition to ADAMTS13 measurement in establishing a TTP diagnosis.
“The most important point [from the study] is that TTP remains a clinical diagnosis,” co-author James N. George, MD, from the Departments of Epidemiology and Biostatistics at the University of Oklahoma Health Sciences Center, told ASH Clinical News.
“Documentation of ADAMTS13 deficiency is a critical component of the diagnosis, but the measurement of ADAMTS13 alone is not sufficient. I support the current understanding that severe ADAMTS13 deficiency (described as activity <10%) is the definition of TTP, but the ‘definition’ does not equal the ‘diagnosis.’”
Lead author Evaren E. Page, MPH, from the Department of Medicine at the University of Oklahoma Health Sciences Center, and co-authors analyzed data collected between 1989 and 2005, from patients with clinically suspected TTP who received plasma exchange (PEX) treatment by the Oklahoma Blood Institute and were enrolled in the Oklahoma TTP Registry.
As part of the registry, ADAMTS13 activity was measured in serum samples once yearly; samples were collected immediately prior to the first PEX beginning in 1995. ADAMTS13 assays were conducted on all samples once yearly. “We did not know the results of our ADAMTS13 activity measurements at the time of the patients’ initial hospitalization; therefore, diagnostic decisions were based on clinical evaluations,” the authors explained. “Patients were evaluated for a diagnosis of TTP if they had microangiopathic hemolytic anemia characterized by schistocytes on the peripheral blood smear, thrombocytopenia, and no evidence for disseminated intravascular coagulation.”
The analysis included 412 patients with serum samples collected through 2015; all patients were followed prospectively. Ninety-four percent of all patients had ADAMTS13 activity measured, and an additional 26 patients were excluded from the trial (because of a diagnosis of a different etiology of thrombotic microangiopathy [TMA] or an initial TTP episode occurring outside of the sample period), resulting in a final cohort of 363 patients.
ADAMTS13 activity was measured in all patients via two methods: Fluorescence resonance energy transfer (FRET) and immunoblotting (IB). Among the 363 patients with an initial episode of clinically suspected TTP, the diagnosis was confirmed in 78 patients (21%) by both an ADAMTS13 activity <10 percent and clinical features of initial episodes of TTP that served as the basis for the TTP diagnosis, including:
- Fever: Eight patients (10%) had fever associated with chills prior to admission.
- Neurologic abnormalities: 41 patients (53%) had severe neurologic abnormalities, nine of whom developed the abnormalities only after PEX began.
- Hematologic abnormalities: All patients (n=78) had thrombocytopenia and microangiopathic hemolytic anemia. The median platelet count was 10,000/μL and the median hematocrit was 21%.
- Kidney function: 37 patients had serum creatinine concentrations <1.5 mg/dL, whereas 37 patients had serum creatinine concentrations ≥1.5 mg/dL but no criteria for severe acute kidney injury.
Sixty patients had ADAMTS13 activity <10 percent confirmed by both methods, 15 had ADAMTS13 <10 percent only by FRET, and three had ADAMTS13 <10 percent only by IB. Five patients had ADAMTS13 activity <10 percent reported by one measure but had a diagnosis other than TTP (including sepsis, disseminated intravascular coagulation, transplant-associated TMA, and systemic malignancy).
“Laboratory reports of ADAMTS13 activity <10 percent are neither absolutely necessary nor sufficient for the diagnosis of TTP,” the authors concluded. “These limitations emphasize the importance of clinical judgment in the evaluation and management of patients with suspected TTP.”
Of the 78 patients with TTP, 74 achieved an initial response (defined as the achievement of a platelet count of ≥150 000/mL) and 10 died. Two of the 68 surviving patients were lost to follow-up, and 45 are still living within the registry region. Including relapse episodes, the annual TTP prevalence in Oklahoma is 19 patients per one million.
The researchers also assessed outcomes before and after rituximab treatment became available in December 2003.
They found no difference in the occurrence of severe neurologic abnormalities, frequency of responses and exacerbations, or death between patients whose initial episode occurred before December 2003 and patients who presented after. Following the introduction of rituximab, however, the number of PEX treatments required to achieve remission and frequency of relapse decreased. Before 2003, only 62 percent of patients received corticosteroids (p value not provided); after 2003, all but one patient was treated with corticosteroids.
“When TTP is clinically suspected, PEX treatment is appropriate, [and] ADAMTS13 activity measurements provide supportive evidence,” said Dr. George.
The study is limited by its small patient population and its single-center design.
Page EE, Hovinga JAK, Terrell DR, et al. Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015. Blood Adv. 2017;1:590-600.