title: Significance of platelet and monocyte activation for therapeutic immunoglobulin-induced thromboembolism.
abstract: OBJECTIVE
  Thromboembolic events (TEE) in patients receiving infusions of intravenous immunoglobulin (IVIG) products have recently been associated with contaminating factor XIa. We studied whether platelet and monocyte activation could also be involved.
  
  
  METHODS
  Twenty IVIG samples from five manufacturers were tested for the induction of visible whole blood clot formation. A selection of TEE-associated and not associated lots was further analyzed for effects on thromboelastometry, platelet activation and adhesion, as well as monocyte tissue factor surface expression. Pure factor XIa was included for comparison. Western blotting was applied to analyze anti-CD154-reactive proteins in IVIG.
  
  
  RESULTS
  In whole blood, IVIG enhanced macroscopic clotting additively with factor XIa. In monocytes, all IVIG products induced the FcγRII-dependent tissue factor expression to a similar extent, which was not affected by addition of factor XIa. Testing platelet aggregation, IVIG strengthened the ADP and TRAP-6-elicited response. Furthermore, IVIG increased platelet-monocyte adhesion and annexin V binding to platelet microvesicles, and promoted platelet adhesion to IVIG-coated surfaces. The strongest effects were observed with TEE-associated lots. CD154-related proteins were detected in all IVIG products. CD154-related high molecular weight complexes were particularly found in the TEE-associated IVIG. In platelet aggregation, recombinant soluble CD154 enhanced aggregate formation and stability.
  
  
  CONCLUSIONS
  Our data demonstrate that IVIG modulate platelet and monocyte activation and can thereby affect the hemostatic balance. These effects are either additive to or independent from factor XIa. CD154-related proteins are assumed to be involved in these interactions, the mechanism of which needs to be elucidated in further studies.
authors.affiliation: Division of Hematology and Transfusion Medicine, Paul-Ehrlich-Institut, Langen, Germany. Electronic address: Ursula.Salge-Bartels@pei.de.
authors.forename: Ursula
authors.initials: U
authors.lastname: Salge-Bartels
authors.affiliation: Division of Hematology and Transfusion Medicine, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Margarethe
authors.initials: M
authors.lastname: Heiden
authors.affiliation: Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Nannette
authors.initials: N
authors.lastname: Groß
authors.affiliation: Division of Hematology and Transfusion Medicine, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Seitz
mesh_terms: D061605:Administration, Intravenous; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015945:Factor XIa / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000008:administration & dosage / Q000009:adverse effects*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects; D013923:Thromboembolism / Q000139:chemically induced*; D013925:Thromboplastin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007136:Immunoglobulins; D013925:Thromboplastin; D048051:p38 Mitogen-Activated Protein Kinases; D015945:Factor XIa
keywords: ADP; BSA; CD40 Ligand; CT; Coagulation factor XI; ECL; FIIa; FITC; FXIa; HBS; HSA; Hepes-buffered saline; IVIG; Intravenous immunoglobulins (IVIG); LPS; MAPK; MCF; MFI; MNC; Mean fluorescence intensity; PE; TEE; TF; TRAP-6; Thromboelastometry; Thromboembolic events; Thromboplastin; WB; Western blot; adenosine diphosphate; bovine serum albumin; clotting time; coagulation factor XIa; enhanced chemiluminescence; fluorescein isothiocyanate; human serum albumin; intravenous immunoglobulin; lipopolysaccharide; maximum clot firmness; mitogen-activated protein kinase; mononuclear cells; phycoerythrin; recombinant soluble human CD154; rshCD154; thrombin; thrombin receptor activating peptide; thromboembolic events; tissue factor