Low-dose protamine based on heparin-protamine titration method reduces platelet dysfunction after cardiopulmonary bypass

Shigeta, Osamu; Kojima, Hiroshi; Hiramatsu, Yuji; Jikuya, Tomoaki; Terada, Yasushi; Atsumi, N; Sakakibara, Yuzuru; Nagasawa, Toshiro; Mitsui, T.

doi:10.1016/s0022-5223(99)70227-8

Cited by 83 publications

(33 citation statements)

References 21 publications

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“…This acute heparin‐like anticoagulant activity is well known, and multiple points along the coagulation cascade are suspected targets;39 in the aPTT assay, thrombin inhibition is the likely mechanism 40. The clinical consequence of administering protamine to parients is careful titration and constant adjustment of the heparin/protamine ratio 41. Such complications are not specific to protamine, but instead appear to be a general feature of cationic polymers 42.…”

Section: Resultsmentioning

confidence: 99%

Heparin Antagonism by Polyvalent Display of Cationic Motifs on Virus‐Like Particles

et al. 2009

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Polyvalent interactions allow biological structures to exploit low-affinity ligand–receptor binding events to affect physiological responses. We describe here the use of bacteriophage Qβ as a multivalent platform for the display of polycationic motifs that act as heparin antagonists. Point mutations to the coat protein allowed us to generate capsids bearing the K16M, T18R, N10R, or D14R mutations; because 180 coat proteins form the capsid, the mutants provide a spectrum of particles differing in surface charge by as much as +540 units (K16M vs. D14R). Whereas larger poly-Arg insertions (for example, C-terminal Arg8) did not yield intact virions, it was possible to append chemically synthesized oligo-Arg peptides to stable wild-type (WT) and K16M platforms. Heparin antagonism by the particles was evaluated by using the activated partial thrombin time (aPTT) clotting assay; this revealed that T18R, D14R, and WT-(R8G2)95 were the most effective at disrupting heparin-mediated anticoagulation (>95 % inhibition). This activity agreed with measurements of ζ potential (ZP) and retention time on cation exchange chromatography for the genetic constructs, which distribute their added positive charge over the capsid surface (+180 and +360 for T18R and D14R relative to WT). The potent activity of WT-(R8G2)95, despite its relatively diminished overall surface charge is likely a consequence of the particle’s presentation of locally concentrated regions with high positive charge density that interact with heparin’s extensively sulfated domains. The engineered cationic capsids retained their ability to inhibit heparin at high concentrations and showed no anticlotting activity of the kind that limits the utility of antiheparin polycationic agents that are currently in clinical use.

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Section: Resultsmentioning

confidence: 99%

Heparin Antagonism by Polyvalent Display of Cationic Motifs on Virus‐Like Particles

et al. 2009

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“…Aziza et al performed a review of the literature and selected 14 papers: the studies selected did not show any differences concerning postoperative bleeding, but did have numerous biases 8 . Indeed, the studies of Yamanishi et al 11 , Sakurada et al 12 , and Shigeta et al 13 , only included a small number of patients; 32, 34 and 34, respectively. Those small cohorts did not allow for the finding of a significant difference.…”

Section: Discussionmentioning

confidence: 99%

Anticoagulation monitoring during extracorporeal circulation with the Hepcon/HMS device

et al. 2012

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“…Protamine reactions are of three general types: systemic hypotension, pulmonary hypertension, and anaphylaxis [74]. Excess protamine may exacerbate bleeding tendencies by interfering with platelet function [63,75].…”

Section: Anticoagulation For Bypassmentioning

confidence: 99%

Cardiopulmonary Bypass

McLean¹,

Lombardi²,

Pearl³

2008

Cardiovascular Pediatric Critical Illness and Injury

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Low-dose protamine based on heparin-protamine titration method reduces platelet dysfunction after cardiopulmonary bypass

Cited by 83 publications

References 21 publications

Heparin Antagonism by Polyvalent Display of Cationic Motifs on Virus‐Like Particles

Heparin Antagonism by Polyvalent Display of Cationic Motifs on Virus‐Like Particles

Anticoagulation monitoring during extracorporeal circulation with the Hepcon/HMS device

Cardiopulmonary Bypass

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