title: Anti-protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis.
abstract: Protamine, which is routinely used after cardiac surgery to reverse the anticoagulant effects of heparin, is known to be immunogenic. Observing patients with an otherwise unexplained rapid decrease in platelet count directly after protamine administration, we determined the incidence and clinical relevance of protamine-reactive antibodies in patients undergoing cardiac-surgery. In vitro, these antibodies activated washed platelets in a FcγRIIa-dependent fashion. Using a nonobese diabetic/severe combined immunodeficiency mouse model, those antibodies induced thrombocytopenia only when protamine and heparin were present but not with protamine alone. Of 591 patients undergoing cardiopulmonary bypass surgery, 57 (9.6%) tested positive for anti-protamine-heparin antibodies at baseline and 154 (26.6%) tested positive at day 10. Diabetes was identified as a risk factor for the development of anti-protamine-heparin antibodies. In the majority of the patients, these antibodies were transient and titers decreased substantially after 4 months (P < .001). Seven patients had platelet-activating, anti-protamine-heparin antibodies at baseline and showed a greater and more prolonged decline in platelet counts compared with antibody-negative patients (P = .003). In addition, 2 of those patients experienced early arterial thromboembolic complications vs 9 of 584 control patients (multivariate analysis: odds ratio, 21.58; 95% confidence interval, 2.90-160.89; P = .003). Platelet-activating anti-protamine-heparin antibodies show several similarities with anti-platelet factor 4-heparin antibodies and are a potential risk factor for early postoperative thrombosis.
authors: Institute for Immunology und Transfusion Medicine, Ernst-Moritz-Arndt University Greifswald, Germany.
authors: Tamam
authors: T
authors: Bakchoul
authors: Heike
authors: H
authors: Zöllner
authors: Jean
authors: J
authors: Amiral
authors: Simon
authors: S
authors: Panzer
authors: Sixten
authors: S
authors: Selleng
authors: Thomas
authors: T
authors: Kohlmann
authors: Sven
authors: S
authors: Brandt
authors: Mihaela
authors: M
authors: Delcea
authors: Theodore E
authors: TE
authors: Warkentin
authors: Ulrich J
authors: UJ
authors: Sachs
authors: Andreas
authors: A
authors: Greinacher
mesh_terms: D000368:Aged; D000818:Animals; D000906:Antibodies / Q000097:blood*; D002315:Cardiopulmonary Bypass; D005260:Female; D006493:Heparin / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D006494:Heparin Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D006801:Humans; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000097:blood; D015994:Incidence; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D010976:Platelet Count; D010978:Platelet Factor 4 / Q000276:immunology; D017713:Platelet Transfusion / Q000379:methods; D011479:Protamines / Q000008:administration & dosage / Q000276:immunology*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000453:epidemiology / Q000276:immunology*; D013997:Time Factors; D014183:Transplantation, Heterologous
chemical_list: D000906:Antibodies; D006494:Heparin Antagonists; D007074:Immunoglobulin G; D011479:Protamines; D010978:Platelet Factor 4; D006493:Heparin