Elsevier

The Lancet Haematology

Volume 4, Issue 4, April 2017, Pages e157-e164
The Lancet Haematology

Articles
Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study

https://doi.org/10.1016/S2352-3026(17)30026-1Get rights and content

Summary

Background

Among the syndromes characterised by thrombotic microangiopathy, thrombotic thrombocytopenic purpura is distinguished by a severe deficiency in the ADAMTS13 enzyme. Patients with this disorder need urgent treatment with plasma exchange. Because ADAMTS13 activity testing typically requires prolonged turnaround times and might be unavailable in resource-poor settings, a method to rapidly assess the likelihood of severe ADAMTS13 deficiency is needed.

Methods

All consecutive adult patients presenting to three large academic medical centres in Boston, MA, USA, with thrombotic microangiopathy and a possible diagnosis of thrombotic thrombocytopenic purpura between Jan 8, 2004, and Dec 6, 2015, were included in an ongoing multi-institutional registry (the Harvard TMA Research Collaborative). Univariate analysis was used to identify covariates for a logistic regression model predictive of severe ADAMTS13 deficiency (≤10% activity). A clinical point score was generated, and its diagnostic performance was assessed using internal and external validation cohorts and compared to clinical assessment alone.

Findings

214 patients with thrombotic microangiopathy were included in the derivation cohort. A seven-component clinical prediction tool, termed the PLASMIC score, was developed and found to reliably assess the pretest probability of severe ADAMTS13 deficiency (C statistic 0·96, 95% CI 0·92–0·98). Our diagnostic model was reproducibly accurate in both the internal (0·95, 0·91–0·98) and external (0·91, 0·85–0·95) validation cohorts. The scoring system also more consistently diagnosed thrombotic microangiopathy due to severe ADAMTS13 deficiency than did standard clinical assessment, as measured by C statistic (0·96, 95% CI 0·92–0·98 for PLASMIC vs 0·83, 0·77–0·88 for clinical assessment; p<0·0001) and mean Brier score (0·065 for PLASMIC vs 0·111 for clinical assessment; mean paired difference 0·05, 95% CI 0·01–0·08; p<0·0001). When utilised in addition to clinical assessment, the PLASMIC score contributed significant discriminatory power (integrated discrimination improvement 0·24, 95% CI 0·11–0·37).

Interpretation

We have developed and validated a clinical prediction tool—the PLASMIC score—to stratify patients with thrombotic microangiopathy according to their risk of having severe ADAMTS13 deficiency. We have shown that this scoring system is superior to standard clinical assessment in addressing the diagnostic challenge presented by thrombotic microangiopathy. Its use, together with clinical judgment, may facilitate treatment decisions in patients for whom timely results of ADAMTS13 activity testing are unavailable.

Funding

The Luick Family Fund of Massachusetts General Hospital.

Introduction

The thrombotic microangiopathies are a disparate group of uncommon but serious disorders that present as the combination of thrombocytopenia and microangiopathic haemolytic anaemia. A range of disorders or clinical events can manifest as a thrombotic microangiopathy, including haemolytic uraemic syndrome, disseminated intravascular coagulation, malignant hypertension, and haemopoietic-stem-cell transplantation or solid-organ transplantation. Thrombotic thrombocytopenic purpura is a rare form of thrombotic microangiopathy caused by acquired or congenital deficiency of the von Willebrand factor regulatory enzyme, ADAMTS13.1, 2, 3 In patients with acquired thrombotic thrombocytopenic purpura, inhibitory autoantibodies against ADAMTS13 result in uncontrolled formation of von Willebrand factor-rich platelet thrombi in the microvasculature, with consequent end-organ dysfunction and death.

Because acquired thrombotic thrombocytopenic purpura is associated with substantial morbidity and mortality, optimum care relies on urgent diagnosis and treatment with plasma exchange,4, 5 which removes the autoantibody and repletes the missing ADAMTS13 enzyme.6 However, the lengthy turnaround times needed at most centres for ADAMTS13 activity testing render this assay unsuitable for real-time clinical decision making.7 Furthermore, the ADAMTS13 activity assay is unavailable in many developing countries, where clinicians generally must manage patients with thrombotic microangiopathy and decide on the allocation of scarce blood-product resources without objective guidance. In such settings, patients with thrombotic thrombocytopenic purpura might benefit substantially from plasma transfusion and immunosuppressive therapy, even when plasma exchange is not available.8, 9

Research in context

Evidence before this study

We reviewed relevant English language studies by searching PubMed for the terms “ADAMTS13”, “score”, and “clinical prediction tool”. We identified two studies that reported diagnostic scoring systems for severe ADAMTS13 deficiency. One was derived from a national registry experience whereas the other utilised a small single-centre case series. Neither score was validated externally or shown to add value to clinical practice.

Added value of this study

We report a clinical prediction tool for severe ADAMTS13 deficiency that was derived in a multicentre consortium and validated externally using a dataset assembled at a separate institution. This scoring system includes historical and laboratory variables that would be obtainable rapidly in a wide range of clinical settings. We showed the superiority of our prediction score to a previously proposed diagnostic score for thrombotic microangiopathy and assessed directly the potential contribution of our scoring system to clinical practice using three independent metrics.

Implications of all the available evidence

Profound thrombocytopenia associated with normal or mildly impaired renal function in patients presenting with thrombotic microangiopathy is predictive of severe ADAMTS13 deficiency. Our results indicate that a seven-component clinical prediction score containing platelet count and measures of renal function is appropriate for use in settings in which ADAMTS13 activity testing might not be available readily and that our scoring system represents an improvement over use of clinical assessment alone.

In view of the need to promptly recognise and treat patients with thrombotic thrombocytopenic purpura before knowing the level of ADAMTS13 activity, a means to rapidly identify individuals with thrombotic microangiopathy and severe ADAMTS13 deficiency would be of considerable benefit. Using a cohort of patients in the Harvard TMA Research Collaborative registry,10 we aimed to develop and validate externally a simple but accurate diagnostic scoring system capable of ascertaining the pretest probability of severe ADAMTS13 deficiency.

Section snippets

Study population and setting

The study population consisted of participants in the Harvard TMA Research Collaborative registry, an observational cohort of all patients with thrombotic microangiopathy and possible thrombotic thrombocytopenic purpura presenting to three large academic medical centres in Boston, MA, USA—Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, and Massachusetts General Hospital. Details of the registry and criteria for the assignment of diagnoses have been described previously.10

Results

Between Jan 8, 2004, and Dec 6, 2015, 647 patients were part of the Harvard TMA Research Collaborative registry, of whom 368 with thrombotic microangiopathy met inclusion criteria and were part of this analysis (figure 1). 214 consecutive cases presented between Jan 8, 2004, and May 1, 2012, and these patients formed the derivation cohort (table 1). 62 (29%) of 214 patients had an ADAMTS13 activity result of 10% or lower. Median follow-up for this cohort was 4·3 years (IQR 2·1–6·7). 154 cases

Discussion

In evaluating the range of patients who present with thrombotic microangiopathy, the ability to identify quickly those with thrombotic thrombocytopenic purpura is a key unmet clinical need. We have assembled a large multi-institutional dataset of patients with thrombotic microangiopathy and used it to derive and characterise a seven-component clinical prediction algorithm, the PLASMIC score, which is capable of distinguishing between cases of thrombotic microangiopathy with and without severe

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