Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura
ABSTRACT The quantification of residual plasmatic ADAMTS13 activity in congenital thrombotic thrombocytopenic purpura (TTP) patients is constrained by limitations in sensitivity and reproducibility of commonly used assays at low levels of ADAMTS13 activity, blunting efforts to establish genotype-phenotype correlations. In the present study, the residual plasmatic activity of ADAMTS13 was measured centrally by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (limit of detection = 0.5%) in 29 congenital TTP patients. The results were used to study correlations among ADAMTS13 genotype, residual plasmatic activity, and clinical phenotype severity. An ADAMTS13 activity above 0.5% was measured in 26 (90%) patients and lower levels of activity were associated with earlier age at first TTP episode requiring plasma infusion, more frequent recurrences, and prescription of fresh-frozen plasma prophylaxis. Receiver operating characteristic curve analysis showed that activity levels of less than 2.74% and 1.61% were discriminative of age at first TTP episode requiring plasma infusion < 18 years, annual rate of TTP episodes > 1, and use of prophylaxis. Mutations affecting the highly conserved N-terminal domains of the protein were associated with lower residual ADAMTS13 activity and a more severe phenotype in an allelic-dose dependent manner. The results of the present study show that residual ADAMTS13 activity is associated with the severity of clinical phenotype in congenital TTP and provide insights into genotype-phenotype correlations.
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ABSTRACT: Patients with thrombotic thrombocytopenic purpura (TTP) and severe ADAMTS13 deficiency are often considered to have typical clinical features. However, our experience is that there is extraordinary diversity of the presenting features and the clinical courses of these patients. This diversity is illustrated by descriptions of 10 patients. The patients illustrate that ADAMTS13 activity may be normal initially but severely deficient in subsequent episodes. Patients with established diagnoses of systemic infection as the cause of their clinical features may have undetectable ADAMTS13 activity. Patients may have a prolonged prodrome of mild symptoms with only microangiopathic hemolytic anemia and thrombocytopenia or they may have the sudden onset of critical illness with multiple organ involvement. Patients may die rapidly or recover rapidly; they may require minimal treatment or extensive and prolonged treatment. Patients may have acute and severe neurologic abnormalities before microangiopathic hemolytic anemia and thrombocytopenia occur. Patients may have concurrent TTP and systemic lupus erythematosus. Patients may have hereditary ADAMTS13 deficiency as the etiology of their TTP rather than acquired autoimmune ADAMTS13 deficiency. These patients' stories illustrate the clinical spectrum of TTP with ADAMTS13 deficiency and emphasize the difficulties of clinical diagnosis. J. Clin. Apheresis, 2012. © 2012 Wiley Periodicals, Inc.Journal of Clinical Apheresis 01/2012; 27(6). DOI:10.1002/jca.21248 · 1.58 Impact Factor
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ABSTRACT: Hereditary thrombotic thrombocytopenic purpura (TTP) may be rare, but it is forever. What is the future for our patients?Blood 07/2012; 120(2):243-4. DOI:10.1182/blood-2012-05-427419 · 10.43 Impact Factor
- Blood Cells Molecules and Diseases 09/2012; DOI:10.1016/j.bcmd.2012.08.001 · 2.33 Impact Factor