Abstract

Abstract 3323

Background:

Although severe deficiency(<10%) of the ADAMTS13 protease is central to the pathophysiology of acquired TTP, recently published data have suggested a role for complement activation in the pathogenesis of acquired TTP (Reti et al, JTH 2012; 10:791–798).

Patients:

We performed a retrospective study in longitudinally banked plasma samples from 9 patients with acquired TTP and severely deficient ADAMTS13 activity at presentation. Patients were randomly selected from our cohort of acquired TTP patients who achieved remission and were followed longitudinally with plasma samples banked at regular intervals. The presenting platelet count, LDH, serum creatinine, and ADAMTS13 activity of these 9 subjects were comparable to the entire cohort of acquired TTP patients in our research program at the time of their initial presentation.

Methods:

Samples were obtained at the time of their initial presentation prior to the initiation of plasma exchange therapy (PEX), at remission (median 2 weeks after the last PEX), and at sustained remission (median 2 months after remission sample) were utilized in this study. The complement proteins Bb (alternative pathway), C3a and C3 (all pathways of complement activation), and C5b-9 (terminal pathway) were measured.

Results:

At presentation, 4 subjects had evidence of complement activation as defined by increased levels of C3a and decreased C3, and all 9 subjects exhibited activation of the alternative pathway (Bb). In serially measured samples, the complement protein Bb was significantly higher, and C3 significantly lower, at presentation, returning to normal at the time of sustained remission (Table 1). C5b-9 and C3a demonstrated similar trends as Bb. ADAMTS13 activity, severely deficient in all subjects at presentation, was also significantly higher at remission and sustained remission.

Conclusions:

These data from a cohort of ADAMTS13 deficient, acquired TTP patients provide additional evidence for the role of complement activation in the pathogenesis of acquired TTP. Further study of our complete cohort of patients with acquired TTP is presently underway to better define the role complement activation in patients with acquired TTP.

Table 1.

Serial analysis of markers of complement activation in patients with acquired TTP. Median of data shown with associated range.

 Pretreatment Remission1 Sustained Remission2 
Markers of Complement Activation (range of normal) n=9 n=9 n=8 
Bb (460–1167 ng/ml) 4035 (321–6071) 769 (537–1284) 979 (505–1627) 
 p-value <0.0001 <0.0001 
C3a (<325 ng/ml) 2220 (146–>3300) 400 (240–>3300) 292 (138–>3300) 
 p-value 0.72 0.18 
C5b-9 (101–276 ng/ml) 555 (239–3733) 349 (270–945) 305 (115–974) 
 p-value 0.23 0.14 
C3 (970–1576 ng/ml) 860 (429–1472) 1118 (544–2202) 1336 (990–1550) 
 p-value 0.19 0.013 
ADAMTS13 % 1.3 (<0.5–2.5) 13.6 (<2.5–79.0) 60.6 (13.0–71.9) 
 p-value 0.002 <0.0001 
 Pretreatment Remission1 Sustained Remission2 
Markers of Complement Activation (range of normal) n=9 n=9 n=8 
Bb (460–1167 ng/ml) 4035 (321–6071) 769 (537–1284) 979 (505–1627) 
 p-value <0.0001 <0.0001 
C3a (<325 ng/ml) 2220 (146–>3300) 400 (240–>3300) 292 (138–>3300) 
 p-value 0.72 0.18 
C5b-9 (101–276 ng/ml) 555 (239–3733) 349 (270–945) 305 (115–974) 
 p-value 0.23 0.14 
C3 (970–1576 ng/ml) 860 (429–1472) 1118 (544–2202) 1336 (990–1550) 
 p-value 0.19 0.013 
ADAMTS13 % 1.3 (<0.5–2.5) 13.6 (<2.5–79.0) 60.6 (13.0–71.9) 
 p-value 0.002 <0.0001 
1

Samples obtained a median 2 weeks since last PEX.

2

Samples obtained a median of 5 weeks after remission sample.

p-value comparison to pre-treatment sample.

Disclosures:

Cataland:Alexion: Consultancy, Research Funding. Holers:Alexion: Consultancy. Lundberg:Alexion: Employment. Wu:Alexion: Consultancy, Research Funding.

Supported by Food and Drug Administration Grant R01-FD003932 (S.C. and H.W.)

Author notes

*

Asterisk with author names denotes non-ASH members.