Abstract
Introduction: Acquired thrombotic thrombocytopenic purpura (TTP) is a rare hematologic disorder whose hallmark is severe ADAMTS13 protease deficiency. Bendapudi et al. recently published a validated clinical algorithm known as the PLASMIC score which was shown to be an excellent tool to distinguish patients with severe ADAMTS13 deficiency from those without (Lancet Haematol 2017;4:e157). While the score is prognostic for survival, it remains unclear if it can also serve as a marker predictive for response to plasma exchange (PEX) such that it may be safe to withhold treatment in the lower-risk group. In this independent external validation of the PLASMIC score, we aim to reproduce its prognostic value for TTP diagnosis and examine for the first-time its predictive value for response to PEX.
Methods: We performed a retrospective study of all consecutive patients with at least 1 ADAMTS13 activity testing from 2007 to 2016 from the University of Washington Medical Center. We excluded patients who did not meet laboratory criteria of microangiopathic hemolytic anemia (MAHA) or had inappropriate assay testing (Figure 1) but included patients who received prior fresh frozen plasma (FFP). Severe deficiency was defined as an ADAMTS13 activity level <15% in this study given possible interference from FFP. We collected clinical and diagnostic information similar to the original PLASMIC score manuscript. We tested the PLASMIC score model for discrimination with c statistic (bias-corrected 95% confidence interval) and goodness-of-fit validity with calibration curve and Hosmer-Lemeshow (HL) test. Kaplan Meier estimator was used for survival analysis.
Results: We identified 112 patients who met the appropriate MAHA criteria out of 239 consecutive patients (Figure 1). Among them, 108 (96%) had complete data for all 7 components of the PLASMIC score assessment. Twenty-seven patients received FFP prior to ADAMTS13 testing. Twenty patients had severe ADAMTS13 deficiency (including 2 patients with activities >10% at 11% and 12%). The percentage of patients receiving PEX treatment and the distribution of clinical diagnoses in each group were summarized in Table 1.
The PLASMIC score stratified 108 patients into 3 risk categories (Table 1). When dichotomized at high (score 6-7) versus low-intermediate risk (score 0-5), the model predicted severe ADAMTS13 deficiency with positive predictive value of 72%, negative predictive value of 98%, sensitivity of 90%, and specificity of 92%. The 7-point PLASMIC score model had excellent discrimination with a c statistic of 0.94 (0.88-0.98). Furthermore, the 3-category risk stratification had a near-perfect moderate calibration curve (HL test P of 0.79).
We then examined the treatment effect of PEX on survival probability separately in the high-risk (6-7) and low-intermediate risk (0-5) groups (Figure 2). In the high-risk group, despite the limited numbers, treatment with PEX versus not led to significantly improved survival (log-rank P of <0.01). In contrast, in the low-intermediate risk group where patients were predicted to not have severe ADAMTS13 deficiency, treatment with PEX versus not did not have a significant impact on the survival (log-rank P of 0.50).
Conclusion: In our independent external validation study of the PLASMIC score extended to include patients with prior FFP, the high-risk group (6-7) correlated well with severe ADAMTS13 deficiency and showed the expected response to PEX. In contrast, the low-intermediate risk group (0-5) had high negative predictive value for ADAMTS13 deficiency and showed a lack of response to PEX. Given these observations, the current PLASMIC score risk categories appear to be diagnostic for TTP with severe ADAMTS13 deficiency and potentially predictive for PEX treatment response. The ease of calculating the score makes this a valuable clinical tool when ADAMTS13 testing is not available and urgent therapy is needed.
No relevant conflicts of interest to declare.
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