Protamine‐induced immune thrombocytopenia

Abstract

Background Protamine is widely used to reverse the anticoagulant effects of heparin. Although mild thrombocytopenia is common in patients given protamine after cardiac procedures, acute severe thrombocytopenia has not been described. We encountered a patient who experienced profound thrombocytopenia and bleeding shortly after administration of protamine and performed studies to characterize the responsible mechanism. Study design and methods Patient serum was studied for antibodies that recognize protamine, heparin/protamine complexes and platelets pre-treated with protamine using flow cytometry, ELISA and serotonin release from labeled platelets. Results A high titer IgG antibody was detected in patient serum that recognizes protamine in a complex with heparin or platelet surface glycosaminoglycans (GAG) and activates platelets pre-treated with protamine at concentrations achieved in vivo following protamine infusion. The antibody is distinctly different from those found in patients with heparin-induced thrombocytopenia on the basis of its failure to recognize heparin in a complex with platelet factor 4 (PF4) and to release serotonin from labeled platelets in the absence of protamine. Conclusions Findings made suggest that the patient’s antibody is specific for conformational changes induced in protamine when it reacts with heparin or a platelet surface GAG. Development of severe thrombocytopenia following treatment of this patient with protamine defines a previously undescribed mechanism of drug-induced immune thrombocytopenia. Patients given protamine who produce this type of antibody may be at risk to experience thrombocytopenia if given the drug a second time while antibody is still present.

Approach to the Diagnosis and Management of Drug-Induced Immune Thrombocytopenia

“…Antibodies bind to the PF4/heparin complex by their Fab portion and to the surface of platelets and monocytes by their Fc portion causing intense platelet activation and release of procoagulant microparticles [35,36]. A similar syndrome has recently been described following exposure to protamine used to reverse the effects of heparin after cardiac surgery [37][38][39]. Protamine binds heparin to form antigenic complexes that are immunogenic in mice and humans.…”

Serologic characterization of anti-protamine/heparin and anti-PF4/heparin antibodies

“…2 Similarly, a recent study of 24 patients with preformed anti-PRT/heparin antibodies who were re-exposed to drug during CPB found no association of anti-PRT/heparin antibodies with perioperative outcomes, including thrombocytopenia, hemorrhage, or thromboembolic events. 4 In contrast, other studies have noted serious clinical complications in seropositive patients, including severe thrombocytopenia 5 and arterial thrombosis in association with platelet-activating antibodies. 3,6 The disease heterogeneity associated with anti-PRT/heparin antibodies suggests that these antibodies may exhibit biologic heterogeneity as well.…”

Małopłytkowość indukowana protaminą — nowy problem czy inny typ małopłytkowości poheparynowej?

“…Istnieją przypadki kliniczne, w których wystąpienie trombocytopenii jest ściśle związane z obecnością aktywujących płytki PIT abs [19,20]. Odnotowano historię czterech pacjentów z gwałtownym spadkiem liczby płytek krwi poniżej 50 tys./µl w przeciągu 2 dni od zakończenia operacji oraz w 5 przypadkach wystąpiły powikłania zakrzepowo-zatorowe [19].…”