Background/Purpose: Annexins are a family of structurally related proteins that bind to phospholipids in a calcium dependant manner. Annexin A5 (AnxA5), present on the surfaces of human endothelial cells, platelets and trophoblasts has potent anticoagulant activity that is a consequence of its forming 2-dimensional crystals over phospholipid bilayers, shielding the phospholipids from availability for coagulation. Antiphospholipid antibodies (aPL) disrupt the crystallization of AnxA5 over phospholipid membrane and expose the underlying phospholipid membrane for coagulation reactions. aPL-mediated disruption of AnxA5 has been correlated with thrombosis in the antiphospholipid syndrome. We investigated the association of resistance to AnxA5 anticoagulant activity (A5R assay) with thrombosis in SLE, compared with the lupus anticoagulant (LAC).
Methods: Stored plasma samples from 296 SLE patients, 150 of whom had prior thrombosis, were assayed for annexin 5 resistance. The A5R assay was performed as previously described (Blood. 2007; 109: 1490-94). We considered assay results that were < 3 SD below the mean (<140%) of 30 normal healthy control plasmas to be abnormal, and between 2-3 SD (147-153) to be borderline. The lupus anticoagulant (LAC) was detected using dRVVT with confirmatory testing.
Results: Resistance to AnxA5 anticoagulant activity was found in 45 SLE patients (15%). Table 1 shows the association of any thrombosis, venous thrombosis and stroke with A5R and with LAC. A5R was consistently associated with increased risk for thrombosis. A5R was also highly associated with a positive LAC (p<0.0001). In the small number of SLE patients with negative LAC, no association between A5R and thrombosis was found.
Table 1: Association of AnxA5 Resistance and Lupus Anticoagulant with Thrombosis
|
|
|
Thrombosis
|
No thrombosis
|
Odds Ratio
|
95% CI |
P-value when age, sex, and race were controlled |
|
|
Assay |
Number (%) positive |
Number (%) positive |
|
|
|
|
Any Thrombosis |
A5R |
27 (18%) |
18 (13%) |
2.1 |
(0.90, 5.20) |
0.097 |
|
LAC |
50 (39%) |
14 (11%) |
0.96 |
(0.94, 0.98) |
<0.0001 |
|
|
Venous Thrombosis |
A5R |
22 (23%) |
23 (12%) |
2.3 |
(0.90, 5.90) |
0.070 |
|
LAC |
34 (41%) |
30 (17%) |
0.97 |
(0.95, 0.98) |
<0.0001 |
|
|
Stroke |
A5R |
10 (20%) |
35 (14%) |
2.7 |
(0.80, 8.40) |
0.095 |
|
LAC |
18 (43%) |
46 (22%) |
0.98 |
(0.96, 0.99) |
0.0021 |
Conclusion: We found that, in SLE patients, the lupus anticoagulant by dRVVT was a stronger predictor of any thrombosis, venous thrombosis and stroke than A5R. Annexin A5 resistance was strongly associated with the lupus anticoagulant. In patients negative for lupus anticoagulant, there was no association of A5R and thrombosis. In summary, A5R identifies a subset of about half of of SLE patients with thrombosis in whom this specific mechanism for thrombosis is operative. We speculate that this finding may allow the development of treatments that target this specific mechanism.
Disclosure:
E. Akhter,
None;
H. Fang,
None;
X. X. Wu,
None;
J. Rand,
AnxA5 Resistance assay,
9;
M. Petri,
None.
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