Research from ASH ’ s newest peer-reviewed journal , Blood Advances in a Different Vein
CLINICAL NEWS
Long-Term Study Highlights Limitations of Current TTP Diagnostic Methods
For the past two decades , ADAMTS13 activity has been the backbone of diagnosis for thrombotic thrombocytopenic purpura ( TTP ); however , a longterm 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 , AD- AMTS13 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
“ TTP remains a clinical diagnosis . Documentation of ADAMTS13 deficiency is a critical component of the diagnosis , but the measurement of ADAMTS13 alone is not sufficient .”
— JAMES N . GEORGE , MD
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 AD- AMTS13 < 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 AD- AMTS13 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 . ●
REFERENCE
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 .
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