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ADAMTS13 and Thrombotic Microangiopathy

High antibody titers and persistence of undetectable ADAMTS13 activity during remission indicate poor prognosis and predict relapse.

The enzyme ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats) cleaves large multimers of von Willebrand factor (vWF), which decreases their activity. Congenital or acquired deficiency of ADAMTS13 is associated with an increase in ultra-large multimers of vWF, formation of platelet aggregates, thrombocytopenia, and vascular occlusion, resulting in microangiopathic hemolytic anemia. Some patients with idiopathic thrombotic microangiopathy (TMA) have autoantibodies against ADAMTS13, but the relation among vWF, ADAMTS13 activity, and ADAMTS13 autoantibodies has been unclear.

In a retrospective study review of data from 35 consecutive French patients with first episodes of TMA and no history of sepsis, cancer, HIV infection, or transplantation, researchers noted undetectable ADAMTS13 activity in 31 patients (89%) and the presence of ADAMTS13 antibodies in 33 (94%). Levels of vWF antigen were higher than normal in 91% of patients and exceeded 200 IU/dL in 31% of patients. However, not all patients with very low levels of ADAMTS13 antigen (<750 ng/mL) had elevated vWF levels, and no correlation was found between the two measures. Anti-ADAMTS13 titers ranged from 20 to >10,000, and all immunoglobulin classes were represented. No correlation was observed between ADAMTS13 antigen levels and antibody titers.

All patients were treated with steroids and plasma exchange, and 32 patients survived their initial TMA episodes. The three patients who died had neurologic dysfunction, renal impairment, or both; hemoglobin levels lower than 6.5 g/dL; and <15,000 platelets/µL. Levels of vWF antigen ranged from 150 to 540 IU/dL, ADAMTS13 antigen levels ranged from <62.5 to 85.0 ng/mL, and antibody IgA titers ranged from 3200 to 10,000. Among survivors, levels of ADAMTS13 after remission were >15% in 19 patients but remained undetectable in 13. Six patients suffered relapses during the next 18 months; the rate of relapse was higher in patients whose ADAMTS13 activity levels were undetectable during remission (5 of 13) than in those with detectable levels (1 of 19).

Comment: Plasma exchange is effective for treating TMA. The rationale for its use is to remove antibodies against ADAMTS13 along with the thrombogenic high-molecular-weight multimers of vWF and also to replenish depleted ADAMTS13. The principal findings of this study, that high antibody titers and persistence of undetectable ADAMTS13 activity during remission indicate poor prognoses and predict relapse, support the logic of plasma exchange. However, the lack of correlation between vWF and ADAMTS13 antigen and antibody levels suggests that the pathogenesis of this disease is more complex than currently is appreciated, and further research is needed.

— David Green, MD, PhD

Published in Journal Watch Oncology and Hematology May 7, 2007

Citation(s):

Ferrari S et al. Prognostic value of anti-ADAMTS13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS13 activity. Blood 2007 Apr 1; 109:2815-22.

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