C-reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia

Abstract

Key Points• CRP enhances IgG-mediated respiratory burst and phagocytosis of platelets in vitro and their clearance in vivo.• CRP levels are increased in ITP patients and correlate with platelet counts and bleeding severity and predict time to recovery.Immune-mediated platelet destruction is most frequently caused by allo-or autoantibodies via Fcg receptor-dependent phagocytosis. Disease severity can be predicted neither by antibody isotype nor by titer, indicating that other factors play a role. Here we show that the acute phase protein C-reactive protein (CRP), a ligand for Fc receptors on phagocytes, enhances antibody-mediated platelet destruction by human phagocytes in vitro and in vivo in mice. Without antiplatelet antibodies, CRP was found to be inert toward platelets, but it bound to phosphorylcholine exposed after oxidation triggered by antiplatelet antibodies, thereby enhancing platelet phagocytosis. CRP levels were significantly elevated in patients with allo-and autoantibody-mediated thrombocytopenias compared with healthy controls. Within a week, intravenous immunoglobulin treatment in children with newly diagnosed immune thrombocytopenia led to significant decrease of CRP levels, increased platelet numbers, and clinically decreased bleeding severity. Furthermore, the higher the level of CRP at diagnosis, the longer it took before stable platelet counts were reached. These data suggest that CRP amplifies antibody-mediated platelet destruction and may in part explain the aggravation of thrombocytopenia on infections. Hence, targeting CRP could offer new therapeutic opportunities for these patients. (Blood. 2015;125(11): 1793-1802 IntroductionFetal or neonatal alloimmune thrombocytopenia (FNAIT) and immune thrombocytopenia (ITP) are both antibody-mediated disorders in which platelets are destroyed mainly through activating immunoglobulin (IgG) Fc receptors on phagocytes in the spleen and liver, eventually resulting in thrombocytopenia. 1 In childhood, ITP is characterized by a typical history of acute development of purpura and bruising in an otherwise healthy child, caused by development of platelet autoantibodies, with an incidence of ;5 in 100 000 children.2 Most children with newly diagnosed ITP will not suffer from serious bleeding and will recover within 12 months. In ;60% of ITP, there is a history of a prior infection. [1][2][3] FNAIT is a potentially destructive disease in pregnancies, with intracerebral hemorrhage (ICH) of the fetus or neonate as the most feared complication, resulting in perinatal death in 1% to 7% or in severe neurological impairments in 14% to 26% of affected pregnancies. [4][5][6][7] FNAIT is caused by maternal IgG platelet alloantibodies, in whites mainly directed against human platelet antigen (HPA)-1a (85%), that cross the placenta and destroy the platelets of the fetus or newborn. Immunization against HPA-1a occurs in ;1:450 random pregnancies. [8][9][10] Although platelet decrement is related to antibody titer in FNAIT, 8,11,12 this correlation is not strict, as cas...

Nouvelle Cuisine: Platelets Served with Inflammation

“…CRP was found to be increased in children with ITP, and treatment with IVIg was associated with increased platelet counts, decreased CRP levels, and reduced clinical bleeding severity (142). Moreover, elevated CRP at diagnosis corresponded to slower platelet count recovery after 3 mo (142). The suggested mechanism of action was independent of platelet FcgRIIA but based on platelet oxidation (triggered by anti-platelet Abs and the phagocyte NADPH oxidase system), which resulted in exposure of platelet phosphorylcholine residues to which CRP could bind and, thereby, enhance IgG-mediated platelet phagocytosis via interaction with phagocytic FcRs (142).…”

“…Moreover, elevated CRP at diagnosis corresponded to slower platelet count recovery after 3 mo (142). The suggested mechanism of action was independent of platelet FcgRIIA but based on platelet oxidation (triggered by anti-platelet Abs and the phagocyte NADPH oxidase system), which resulted in exposure of platelet phosphorylcholine residues to which CRP could bind and, thereby, enhance IgG-mediated platelet phagocytosis via interaction with phagocytic FcRs (142). Therefore, CRP could be an important factor in Ab-mediated platelet destruction in bacterial (Gramnegative and/or Gram-positive) or viral infections associated with ITP.…”

“…CRP is an acute-phase protein, also present in healthy individuals, which increases rapidly during acute infections. CRP was found to be increased in children with ITP, and treatment with IVIg was associated with increased platelet counts, decreased CRP levels, and reduced clinical bleeding severity (142). Moreover, elevated CRP at diagnosis corresponded to slower platelet count recovery after 3 mo (142).…”

“…Therefore, LPS may be an important mediator of Ab-mediated platelet clearance during Gram-negative infections; despite not knowing the exact working mechanism, triggering of phagocyte and/or platelet TLR4 could be relevant. Recently, C-reactive protein (CRP) was identified as a novel pathogenic serum factor that enhances IgG-mediated platelet destruction in vitro and in vivo (142). CRP is an acute-phase protein, also present in healthy individuals, which increases rapidly during acute infections.…”

TRALI: hit by CRP

“…The study does not exclude the possibility that CRP may also be involved in other inflammatory processes leading to TRALI, including enhancing antibody-mediated respiratory burst by neutrophils, 9 synergizing with MHC class I antibodies in binding to the endothelium, 5,10 and causing pulmonary vascular leakage and/or complement cascade activation. The source of the MIP-2 secretion was not shown; however, their previous work demonstrated the source of MIP-2 secretion to be blood monocytes.…”