Heparin-induced thrombocytopenia: laboratory studies.
This report describes studies into the pathophysiology of heparin-induced thrombocytopenia. The IgG fraction from each of nine patients with heparin-induced thrombocytopenia caused heparin-dependent platelet release of radiolabeled serotonin. Both the Fc and the Fab portions of the IgG molecule were required for the platelet reactivity. The platelet release reaction could be inhibited by the Fc portion of normal human or goat IgG, and patient F(ab')2, but not F(ab')2 from healthy controls. These results suggested that the Fab portion of IgG binds to heparin forming an immune complex and the immune complexes initiate the platelet release reaction by binding to the platelet Fc receptors. To directly challenge this hypothesis, we preincubated the serotonin-labeled platelets with the monoclonal antibody against the platelet Fc receptor (IV.3). This monoclonal antibody completely inhibited the release reaction caused by heparin and patient sera, as well as heat aggregated IgG, but did not block collagen or thrombin-induced platelet release. Heparin-dependent platelet release also could be inhibited in vitro by the addition of monocytes and neutrophils, but not by red cells, presumably because the Fc receptors on the phagocytic cells have a higher binding affinity for IgG complexes than do platelets. Platelets from patients with congenital deficiencies of specific glycoproteins Ib and IX (Bernard-Soulier syndrome) and IIb and IIIa (Glanzmann's thrombasthenia) displayed normal heparin-dependent release indicating that the release reaction did not require the participation of these glycoproteins. These studies indicate that heparin-induced thrombocytopenia is an IgG-heparin immune complex disorder involving both the Fab and Fc portion of the IgG molecule.
Department of Medicine, McMaster University Medical Centre, Hamilton, Ontario, Canada.
J G
JG
Kelton
D
D
Sheridan
A
A
Santos
J
J
Smith
K
K
Steeves
C
C
Smith
C
C
Brown
W G
WG
Murphy
D000911:Antibodies, Monoclonal / Q000502:physiology; D000936:Antigen-Antibody Complex / Q000032:analysis; D001606:Bernard-Soulier Syndrome / Q000097:blood; D001773:Blood Cells / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000172:deficiency; D011961:Receptors, Fc / Q000276:immunology; D013915:Thrombasthenia / Q000097:blood; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced*
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D010980:Platelet Membrane Glycoproteins; D011961:Receptors, Fc; D006493:Heparin