ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission

Abstract

Background From 20 to 50% of patients who survive an acute episode of the acquired form of thrombotic thrombocytopenic purpura relapse but clinical and laboratory markers of recurrence are not well established. Design and MethodsIn 109 patients enrolled in an international registry we evaluated, in the frame of a retrospective cohort study, the predictive role of the metalloprotease ADAMTS13 as measured in plasma during remission. Anti-ADAMTS13 antibodies and von Willebrand factor were also evaluated in a smaller number of the same patients. ResultsMedian values of ADAMTS13 activity and antigen were significantly lower in patients with recurrent thrombotic thrombocytopenic purpura than in those with no recurrence (activity: 12% vs. 41%; p=0.007; antigen: 36% vs. 58%; p=0.003). A severe deficiency of ADAMTS13 activity (10% or less) was associated with a higher likelihood of recurrence (odds ratio 2.9; 95% confidence interval 1.3 to 6.8; p=0.01). Anti-ADAMTS13 antibodies were also more prevalent in patients with recurrent thrombotic thrombocytopenic purpura (odds ratio 3.1; 95% confidence interval 1.4 to 7.3; p=0.006). The presence during remission of both severe ADAMTS13 deficiency and anti-ADAMTS13 antibodies increased the likelihood of recurrence 3.6 times (95% confidence interval 1.4 to 9.0; p=0.006). The presence of ultralarge von Willebrand factor multimers and of associated diseases or conditions did not increase recurrence. ConclusionsSurvivors of an acute episode of acquired thrombotic thrombocytopenic purpura with severely reduced levels of ADAMTS13 and/or with anti-ADAMTS13 antibodies during remission have an approximately three-fold greater likelihood of developing another episode of thrombotic thrombocytopenic purpura than patients with higher protease activity and no antibody.Key words: thrombotic thrombocytopenic purpura, ADAMTS13, von Willebrand factor, risk factors, recurrence.Citation: Peyvandi F, Lavoretano S, Palla R, Feys H B., Vanhoorelbeke K, Battaglioli T, Valsecchi C, Canciani MT, Fabris F, Zver S, Réti M, Mikovic D, Karimi M, Giuffrida G, Laurenti L, antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission. Haematologica 2008 Feb; 93(2):232-239. DOI: 10.3324/haematol.11739 ©2008 Ferrata Storti Foundation. This is an open-access paper. ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission IntroductionAcquired thrombotic thrombocytopenic purpura (TTP) is a rare but severe disease characterized by microangiopathic hemolytic anemia and consumptive thrombocytopenia leading to disseminated microvascular thrombosis that causes variable signs and symptoms of organ ischemia and damage.1 The pathophysiology of TTP has become clearer after it was demonstrated that the plasma metalloprotease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin 1 repeats) cleaves the platelet-adhesive plasma protein von Willebrand factor (VWF) at the peptide bond Tyr1605-Met1...

Elevated plasma neutrophil elastase concentration is associated with disease activity in patients with thrombotic thrombocytopenic purpura

“…Furthermore, several patients may go into sustained clinical remission despite deficient ADAMTS13 activity [7,8]. In addition, although patients with acute TTP often present without acute disease in history, in the majority of TTP patients infections or pregnancy precede the acute disease flare [9].…”

Newly diagnosed versus relapsed idiopathic thrombotic thrombocytopenic purpura: a comparison of presenting clinical characteristics and response to treatment

“…Nevertheless, 20-50% of patients who attain disease remission experience one or more relapses, usually within the 2 years that follow the initial episode [18,19]. Some recent data point to an increased risk of relapse in patients with persistently inhibitory antibodies and/or severe ADAMTS13 deficiency after clinical remission [6,13].…”

The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura

“…The enzyme consists, from the N-terminus, of a relatively short propeptide, the catalytic site, the disintegrin-like (DLD), a first thrombospondin-1 (TSP1) repeat, the Cys-rich domain, the spacer domain, seven TSP1 repeats and 2 CUB (complement components C1r/C1s, urinary Epidermal Growth factor and bone morphogenetic protein-1) domains at the C-terminus (6), whose free thiols have also direct antithrombotic effects (7). When there is a deficiency of this enzyme, uncleaved, ultra large VWF multimers accumulate in microcirculation, causing increased platelet adhesion and aggregation, resulting in the formation of VWF-and platelet-rich thrombi (1,8,9). The development of microthrombi results in microangiopathic haemolytic anaemia and causes variable symptoms of organ ischemia and dysfunction (1).…”