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Chemical and pharmacological aspects of neutralization of heparins from different animal sources by protamine
Author(s): ,
B. F. Glauser
Affiliations:
Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil
,
G. R. C. Santos
Affiliations:
Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil. Laboratório de Apoio ao Desenvolvimento Tecnológico, Laboratório Brasileiro de Controle de Dopagem, Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitári
,
J. D. Silva
Affiliations:
Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil
,
A. M. F. Tovar
Affiliations:
Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil
,
M. S. Pereira
Affiliations:
Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil
,
E. Vilanova
Affiliations:
Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil
P. A. S. Mourão
Affiliations:
Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil
Correspondence: Paulo A. S. Mourão, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Cidade Universitária, Caixa Postal 68041, Rio de Janeiro, RJ, 21941‐913, Brazil|Tel.: +55 21 3928 2090|E‐m
ISTH Academy. A. S. Mourão P. Sep 4, 2018; 230974
Paulo A. S. Mourão
Paulo  A. S. Mourão

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Journal Abstract
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Background
Protamine neutralization is an essential step for the safe use and inactivation of the unfractionated heparin (UFH) that is widely employed in surgical and non‐surgical procedures involving extracorporeal circulation.
Objective
To compare protamine neutralization of different pharmaceutical‐grade UFHs prepared from porcine or bovine intestine (HPI and HBI, respectively). HBI has approximately half the anticoagulant potency of HPI, mostly as consequence of its fraction enriched with N‐sulfated α‐glucosamine disaccharides.
Methods
Protamine neutralization of HPI and HBI was evaluated with in vitro, ex vivo and in vivo assays. We also performed in‐depth assessments of the complexation of protamine with these distinct UFHs by using nuclear magnetic resonance and mass spectroscopy.
Results
HPI and HBI interact similarly with protamine on a mass/mass basis; however, HBI requires more protamine than HPI to have its anticoagulant activity fully neutralized, because of its lower potency, which entails the use of higher doses. Nuclear magnetic resonance spectra revealed that HPI precipitates homogeneously with protamine. On the other hand, the low‐sulfated fraction of HBI, enriched with N‐sulfated α‐glucosamine, precipitates at higher concentrations of protamine than the fraction more like HPI, with a preponderance of N,6‐disulfated α‐glucosamine disaccharides. Finally, mass spectroscopy spectra showed that some of the different peptide components of protamine interact preferentially with the heparins, irrespective of their animal origin.
Conclusion
Our results have important medical implications, indicating that protamine neutralization of HBI, determined exclusively by point‐of‐care coagulation assessments, must fail because of its lower‐sulfated fraction with reduced anticoagulant activity that could remain in the circulation after the neutralization procedure.
Keyword(s)
anticoagulants, blood coagulation tests, hemorrhage, heparin antagonists, thrombosis
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