Thrombocytopenia and complement activation under recombinant TNFα/IFNγ therapy in man

Abstract

Infusions of recombinant human tumor necrosis-alpha plus recombinant human interferon-gamma (rhTNF alpha/rhIFN gamma) were assessed in two patients with Ewing's sarcoma. We analyzed platelet count, coagulation and the terminal complement complex (TCC). During cycles with continuous rhTNF alpha-infusions we found a rapid, marked decrease of platelet count (minus 90% of initial values) and a simultaneous increase of TCC (plus 84% of initial values) at day 4. At days 5-7 a spontaneous increase of platelet count and decrease of TCC were visible. Short-term infusion led to a milder, continuous decrease of platelet counts and to a moderate, progressive increase of TCC at days 5-7. Bleeding occurred only as petechia and mild hemoglobinuria. There was no effect related to the dosage of rhTNF alpha or rhIFN gamma. Relevant differences were seen only in the variable time courses of rhTNF alpha application. Ex vivo analysis of one patient's platelets showed no cytokine-related effect on induced aggregation according to Born. Additionally, we analyzed in vitro effects of the cytokines on platelet count, platelet aggregation, and the assembly of TCC in platelet membranes. No effects were found after incubation of platelet-rich plasma (PRP) with 1000 pg/ml rhTNF alpha and/or 50 pg/ml rhIFN gamma. Fluid-phase and membrane-bound TCC did not change after incubation of PRP with cytokines. A slightly time-dependent increase of TCC without alteration of platelet count and platelet function did not agree with the assumption of a direct injury to platelets. We assume a cytokine-mediated role of the endothelium in platelet loss.

Rituximab-induced Acute Thrombocytopenia in Granulomatosis with Polyangiitis

“…Since platelets do not express CD20 receptor, there is no association between RTX therapy and the direct platelet destruction or the induction of antiplatelet autoantibodies (13). Complement activation could cause acute thrombocytopenia through a direct degradation of platelets (25) or a downstream effect and the accumulation of some cytokines such as TNF-α (26). In our patient's case, a positive correlation between platelets and complement values was observed, suggesting that complement activation is involved in the pathogenesis of RIAT.…”

Differing Influences of Virus Burden and Immune Activation on Disease Severity in Secondary Dengue‐3 Virus Infections

“…The degree of thrombocytopenia was related to both virus burden and host factors affecting IL-10 or TNF-a (and sTNFR-II) production. Administration of recombinant IL-10 or TNF-a to human subjects has produced thrombocytopenia because of decreased platelet production (IL-10) [50] or increased platelet consumption (TNF-a) [51,52].…”

Unexpected Hematologic Effects of Biotherapeutics in Nonclinical Species and in Humans

“…The thrombocytopenia can be moderate or profound depending on the duration of the infusion. Thrombocytopenia is considered secondary to complement activation, with possible contribution from endothelial activation (Michelmann et al 1997). Complement activation is also a factor in cytopenias associated with rituximab (see 5.2.2.…”