Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura

Abstract

Therapeutic plasma exchange is an effective empiric treatment for thrombotic thrombocytopenic purpura (TTP), but how therapy affects the level of a disintegrin and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) or inhibitor has not been reported in many patients. We prospectively analyzed ADAMTS13 activity and inhibitor levels in 37 adults with TTP. ADAMTS13 level at presentation was lower than 5% in 16 of 20 patients with idiopathic TTP and in none of 17 patients with TTP associated with hematopoietic stem cell transplantation, cancer, drugs, or pregnancy (P <.00001). Seven of the 16 patients with ADAMTS13 activity lower than 5% ( approximately 44%) had inhibitors. For 8 patients followed serially with ADAMTS13 activity lower than 5% but no inhibitor at presentation, plasma exchange led to complete clinical remission and a rise in ADAMTS13 level. In contrast, 4 patients with low ADAMTS13 activity but high-titer inhibitor (> 5 units/mL) had neither a rise in ADAMTS13 activity nor a reduction in the inhibitor titer: 3 had recurrent disease and 1 died. Among 17 patients with AD-AMTS13 activity at presentation higher than 25%, 10 died. Mortality rate for idiopathic TTP was 15%, whereas mortality for nonidiopathic TTP was 59% (P <.02). We conclude that assays of ADAMTS13 activity and inhibitors in addition to the clinical categories (idiopathic TTP and nonidiopathic TTP) are predictive of outcome and may be useful to tailor patient treatment.

Figure 1.. Clinical response in patients with idiopathic TTP and severe ADAMTS13 deficiency but without detectable inhibitor.

Platelet count is shown in the top row and ADAMTS13 activity in bottom row as labeled. All data points of ADAMTS13 in each patient represented the means of 2 separate assays. The thick solid bar indicates daily plasma exchange (PEx); thick dashed bar, taper of plasma exchange; thin solid line, prednisone (P) administration; and thin dashed line, taper of prednisone. Other adjunctive therapies such as vincristine (V), splenectomy (S), and a combination of cyclophosphamide, vincristine and prednisone (CVP) are indicated with arrows in the top panel of the figure of each patient.

Figure 2.. Clinical response in patients with idiopathic TTP, severe ADAMTS13 deficiency, and a high-titer inhibitor.

ADAMTS13 inhibitor screen was positive on the initial plasma samples prior to plasma exchange therapy and inhibitor titer was determined. All patients represented in this figure had inhibitor titer of more than 5 units/mL on presentation. The thick solid bar indicates daily plasma exchange; and thick dashed bar, tapering of plasma exchange. Other adjunctive therapies were given during the period of observation as indicated. However, patient 10 had a more than 10-year history of TTP and received plasma exchange (PEx) in addition to prednisone (P), splenectomy (S), and a combination of prednisone, vincristine, and cyclophosphamide (CVP) prior to this admission. Patient 12 was reported previously and whose therapies with splenectomy (S), vincristine (V), rituximab (R), and rituximab plus cyclophosphamide (R+) are shown as indicated. Patient 13 received only plasma exchange and prednisone and is in remission.

Figure 3.. Clinical response in patients with nonidiopathic and normal or mildly reduced ADAMTS13 activity.

Six patients in this category were serially studied. All patients had plasma ADAMTS13 activity higher than 25% and no ADAMTS13 inhibitor on admission. Patients 21, 24, and 25 had hematopoietic stem cell transplantation–associated TTP. Patient 29 had idiopathic pulmonary sclerosis on FK506. Patients 31 and 33 had cancer- and clopidogrel-associated TTP, respectively. Patient 33 received 3 doses of vincristine (V) treatment prior to the study. All patients (except patient 24) died despite temporary recovery of platelet count in some patients (patients 29 and 31). The data shown are from the initial hospitalization. The ADAMTS13 activity shown in the figure was the mean of 2 independent analyses. PEx indicates plasma exchange; P, prednisone; and S, splenectomy.