Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP)

Abstract

SummaryThe clinical presentation of thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies (TMAs) can often be similar. The role of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in diagnosing TTP is accepted by most researchers but continues to be debated in a few studies. We report the experience of our single-centre academic institution, where ADAMTS13 is used to diagnose TTP and guide plasma exchange (PLEX). Patients presenting to our institution with thrombotic microangiopathy (60 patients) between January 2006 and December 2012 were divided into two groups based on ADAMTS13 activity and clinical history. Patients with ADAMTS13 activity <10% were included in the TTP (n = 30) cohort while patients with activity >11% were classified as 'other microangiopathies' (TMA, n = 30). PLEX was only initiated in patients with a high likelihood of TTP and discontinued when the baseline ADAMTS13 activity was >11%. Patients with severe ADAMTS13 deficiency (TTP group) showed significant presenting differences: lower platelet counts, less renal dysfunction, higher presence of neurological abnormalities, and greater haemolysis markers as compared to non-deficient patients (TMA group). Most importantly, patients without severe ADAMTS13 deficiency were safely managed without increased mortality despite receiving no PLEX or discontinuing PLEX after a short course (upon availability of ADAMTS13 results). In conclusion, ADAMTS13 can be used to diagnose TTP and guide appropriate PLEX therapy.

Thrombotic Thrombocytopenic Purpura Refractory to Plasmapheresis Treated Successfully with Vincristine: A Case Report

“…The immediate administration of plasma exchange has been the essential and urgent treatment for patients with a clinical diagnosis of TTP since the publication of the randomized clinical trial by the Canadian Apheresis Group in 1991 [12]. The reported incidence of patients who do not respond to PE (refractory TTP) and require additional therapy varies between 10% and 42 % [13][14][15][16]. In much of that literature, refractory TTP is defined as a failure of platelet response after 4 to 7 days of PE, or a clinical deterioration in a patient receiving standard therapy [17].…”

Thrombotic microangiopathy and indications for therapeutic plasma exchange

“…Renal failure and fever are not prominent features of TTP. 2,5,9 The vast majority of TTP cases are acquired and due to an autoantibody against the VWF-cleaving protease, ADAMTS13. 10,11 Congenital TTP, also known as Upshaw-Schulman syndrome, accounts for ϳ5% of TTP cases and is caused by mutations in the ADAMTS13 gene that result in persistently low levels or activity of the enzyme.…”

“…14 In general, a diagnosis of TTP can be made by demonstrating a profoundly low, usually Ͻ10%, ADAMTS13 activity in the plasma from patients with clinical features consistent with TTP. 5,10,11 This assay can be used to distinguish between TTP and HUS, and ADAMTS13 activity levels Ͻ5% are 90% specific for TTP. 15 A majority of these patients will also have an identifiable autoantibody directed against the enzyme.…”

“…Some experts in TTP diagnostics believe that mildly reduced or even normal levels of ADAMTS13 are possible in the setting of TTP 16 ; however, this idea remains controversial and may be a consequence of laboratory testing errors or misclassification of the TMA due to referral center reporting. 5 Other reports of ADAMTS13 deficiency in non-TMA conditions, for example, fulminant hepatic failure and systemic infections, raise questions regarding the diagnostic utility of ADAMTS13 testing and highlight the importance of interpreting the results within the appropriate clinical context. 17 Functional assays to measure the activity of ADAMTS13 are based on the detection of cleaved VWF multimers or recombinant VWF peptides in the presence of patient plasma.…”

“…Rare cases of significant morbidity and mortality in the setting of TPE have been reported, but most of these instances were due to the patient's underlying medical condition or the risks associated with central line placement. 4,5 TPE is commonly requested when a patient is discovered to have TMA, often before the underlying cause is elucidated. In many clinical settings, this request is appropriate, but there are other clinical scenarios for which TPE has little to no benefit or may actually be harmful to the patient either directly or indirectly by substituting for a more efficacious therapy.…”