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M. Rijkers et al.
rected count increments one hour after transfusion com- pared to placebo; however, no beneficial effects were observed 24 hours after transfusion.37 Thus, IVIg might be an effective way to prevent rapid platelet clearance induced by HLA antibodies. Similarly, Eculizumab could block formation of a MAC.38,39 Preliminary data of a clini- cal trial showed that Eculizumab could overcome platelet transfusion refractoriness in patients with HLA-alloanti- bodies.40 The C3 inhibitor Compstatin was not tested here, but is also used in clinical practice already41 and might have a beneficial effect for patients refractory for platelet transfusion caused by HLA alloantibodies. Also, C1 esterase inhibitor, which blocks complement activa- tion at the beginning of the complement cascade, inhibit- ed C3b and C4b deposition induced by HLA mAbs. Blocking complement activation at this point might be even more beneficial than blocking after formation of C4b and C3b. The potential beneficial effect of complement inhibitors in refractory patients receiving platelet transfu- sions needs to be confirmed in clinical studies.
In conclusion, in this study we have shown that HLA antibodies can induce complement activation on platelets
through the classical complement pathway, as is schemat- ically represented in the visual abstract. We propose that C3b complement deposition induced by HLA alloantibod- ies in refractory patients might contribute to platelet clear- ance through their binding to C11b/CD18 on myeloid cells. Ongoing complement activation on HLA-sensitized platelets will lead to formation of a MAC allowing for Ca2+-influx and subsequent platelet activation. Importantly, these effects of HLA antibodies may not only be prevented via HLA-matching between donors and recipient antibodies, but also by functional matching, since not all HLA antibodies are capable of inducing com- plement activation. Furthermore, inhibition of comple- ment activation, as currently studied in clinical trials, may be of benefit to further optimize platelet support in HLA immunized patients.
Funding
Supported by grant PPOC-2013-019 and PPOC-2015- 024P (Netherlands Ministry of Health). AJGJ is supported by a Clinical Fellowship of the European Hematology Association. We thank Diana Wouters for critical feedback on the experiments.
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