Autoantibodies to heparin from patients with antiphospholipid antibody syndrome inhibit formation of antithrombin III-thrombin complexes.
The antiphospholipid antibody syndrome (APS) is characteristically associated with thrombosis. Heparan sulfate (HS) is a physiologic endothelial cell surface modulator of normal anticoagulation, containing a specific oligosaccharide sequence that binds antithrombin III with high affinity and also is present in heparin, a related glycosaminoglycan. We hypothesized that a subset of antiphospholipid antibodies with high affinity for heparan sulfate/heparin epitopes may inhibit the function of HS, promoting a procoagulant state. Purified IgG from all seven patients with APS studied were reactive with heparin by enzyme-linked immunosorbent assay, whereas none of five controls had antiheparin reactivity. IgG antiheparin antibodies were purified from two APS patients by affinity chromatography on heparin-Sepharose. Specificity studies showed that low-affinity electrostatic interactions clearly did not account for the observed reactivity with heparin, and that APS IgG antiheparin antibodies were specifically reactive with a disaccharide present in the heparin pentasaccharide that binds antithrombin III. Furthermore, APS IgG antiheparin antibodies inhibited heparin-accelerated formation of antithrombin III-thrombin complexes. We conclude that antiheparan sulfate/heparin antibodies may be a cause of autoimmune vascular thrombosis in the antiphospholipid antibody syndrome.
Shibata
S
S
Department of Geriatrics, Mount Sinai Medical Center, New York, NY 10029.
Harpel
P C
PC
Gharavi
A
A
Rand
J
J
Fillit
H
H
D000328:Adult; D016736:Antiphospholipid Syndrome / Q000276:immunology*; D000990:Antithrombin III / Q000378:metabolism*; D001323:Autoantibodies / Q000097:blood* / Q000302:isolation & purification / Q000494:pharmacology; D002308:Cardiolipins / Q000276:immunology; D002846:Chromatography, Affinity; D004563:Electrochemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006493:Heparin / Q000276:immunology*; D006497:Heparan Sulfate / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D013917:Thrombin / Q000378:metabolism*
D000990:Antithrombin III; D001323:Autoantibodies; D002308:Cardiolipins; D006493:Heparin; D006497:Heparan Sulfate; D007074:Immunoglobulin G; D013917:Thrombin