Abstract

Introduction:

Thrombotic thrombocytopenic purpura (TTP) is a life threatening disease defined by the association of a hemolytic mechanical anemia, a profound thrombopenia and organ failure with a severe ADAMTS13 deficiency. A rapid diagnosis represents a major goal and sources of misdiagnosis need to be identified to avoid diagnostic wandering and delayed adapted treatment that may translate in increased morbi-mortality. The main objective of this study is to describe the characteristics of TTP initially misdiagnosed and analyse the impact of a late diagnosis on patient's outcomes.

Methods:

From May 2000 to May 2014, all patients with acquired TTP and severe ADAMTS13 deficiency enrolled prospectively in the French TMA Reference Centre registry were included. A misdiagnosis was retained if initial diagnosis was not TTP and if patients did not receive TPE as initial treatment.

Results:

Among the 423 studied patients, 84 (20%) were initially misdiagnosed and not received plasma exchange. Main diagnostic errors were attributed to an Evans syndrome and an auto-immune thrombopenic purpura in 51% and 37% of cases respectively. Median time to diagnosis was longer in the misdiagnosed group than in the accurately diagnosed (5 [IQR, 2-8] vs. 1 [IQR, 0-3] days, P=.008). At admission, compared to the accurately diagnosed patients, misdiagnosed patients had a higher rate of low or undetectable schizocytosis (57.5% vs. 32%, P=.001), higher hemoglobin level (8.4 [IQR, 6.7-9.7] g/dl vs. 7.7 [IQR, 6.5-9.1] g/dl, P=.008) and rate of positive DAT (18% vs. 4%, P=.008). Anti-nuclear antibodies (65% vs. 51%, P=.045) and an associated auto-immune disease (24% vs. 13%, P=.017) were also more frequent. In multivariate analysis, a positive DAT and hemoglobin level were retained as risk factor (OR= 8.71, 95% CI [1.759-43.181], P=.008 and OR= 1.27, 95% CI [1.002-1.602], P=.048), respectively. Platelet count recovery over time was significantly longer in the misdiagnosed group (log-rank test: P=.041) without any consequence on overall mortality, exacerbation and relapse. However, specific causes of death probably differed between groups: in the accurately diagnosed group, patients died more frequently on early stage from a fulminant form of TTP within the first week, whereas in the misdiagnosed group patients died later (13 [IQR, 3-20] vs. 6 [IQR, 2-9] days; P=.023), had less organ involvement at early diagnosis (49% vs.64%, P=.019) and received more salvage therapies (80% vs. 35%, P=.009), suggesting that prognosis could have been improved with an earlier treatment.

Conclusion:

TTP is frequently misdiagnosed with auto-immune cytopenias and usual biological parameters may be initially absent. In a context of hemolysis and thrombocytopenia, a low or undetectable rate of schizocytosis at admission, and a positive DAT should not rule out the diagnosis of TTP, especially when associated with organ failure. A rapid accurate diagnosis of TTP may result in a shorter time to platelet recovery and could improve prognosis.

Disclosures

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.