Studies on the neutralizing mechanism of antithrombin activity of heparin by protamine

Okajima, Yasushi; Kanayama, Shunyo; Maeda, Yoshiharu; Urano, S.; Kitani, Teruo; Watada, Mitsuro; Nakagawa, Masao; Ijichi, Hamao

doi:10.1016/0049-3848(81)90028-1

Cited by 49 publications

(21 citation statements)

References 7 publications

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“…Although few authors have described con comitant reversal of anti-lla and anti-Xa ac tivity for standard heparin [9], our in vitro results are in agreement with the literature regarding the unfractionated molecule. Prot amine sulfate corrects both the thrombin time and the APTT, which is logical and sup ports its clinical use in these circumstances [10].…”

Section: Discussionsupporting

confidence: 81%

Partial Reversal of Low Molecular Weight Heparin (PK 10169) Anti-Xa Activity by Protamine Sulfate: In vitro and in vivo Study during Cardiac Surgery with Extracorporeal Circulation

Massonnet-Castel¹,

Pelissier²,

Bara³

et al. 1986

Pathophysiol Haemos Thromb

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Neutralization of a low molecular weight (LMW) heparin fraction by protamine sulfate was evaluated in vitro and in vivo. Anti-Xa and anti-IIa activities were measured by amidolytic and coagulation methods (activated partial thromboplastin time, APTT). Fifteen patients (4 males and 11 females) underwent surgery with extracorporeal circulation. In vitro, anti-Xa and anti-IIa activities and APTT of unfractionated heparin were neutralized with a protamine/heparin (P/H) gravimetric ratio of 1.6, 1.33 and about 2, respectively. Anti-IIa activity and APTT induced by PK 10169 were completely corrected at a P/H ratio of 1 and 2, respectively, while anti-Xa activity was incompletely neutralized at a ratio of 5. In vivo, in 9 patients who did not receive intravenous protamine sulfate, a good correlation was found between doses of PK 10169 infused, anti-IIa plasma level and blood loss. In 3 patients who were treated prophylactically with protamine, bleeding was normal or only slightly increased. In 3 patients who received protamine because of hemorrhage, mean anti-Xa and anti-IIa were 2.3 and 0.54 U before and 1.32–0.06 U after neutralization. Bleeding was stopped by a second dose of protamine in 1 patient, but blood loss was abnormal in the other patients. However, a correlation between bleeding and anti-Xa or anti-IIa activities was not clearly evident.

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Section: Discussionsupporting

confidence: 81%

Partial Reversal of Low Molecular Weight Heparin (PK 10169) Anti-Xa Activity by Protamine Sulfate: In vitro and in vivo Study during Cardiac Surgery with Extracorporeal Circulation

Massonnet-Castel¹,

Pelissier²,

Bara³

et al. 1986

Pathophysiol Haemos Thromb

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“…The degradation product, FXaγ, is visualized Protamine sulfate has been shown to neutralize heparin by binding to heparin's sulfuric acid groups and thus forming a stable complex that lacks anticoagulant activity [15,18]. PS can also dissociate the ATIII/H complex, without itself binding to ATIII, and allow the ATIII to retain its activity [18].…”

Section: Discussionmentioning

confidence: 99%

“…The FXa/ATIII/H reaction is several hundred-fold faster when also in the presence of physiological levels of Ca 2+ [8][9][10]. The Ca 2+ binds to the Gla region of FXa and allows the heparin to bind to FXa [18].…”

Section: Discussionmentioning

confidence: 99%

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The Modification of Xa-ATIII-Heparin Dynamics by Protamine Sulfate

Coggin

Brecher

2012

ISRN Cell Biology

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Heparin promotes the formation of 1∘FXaα-ATIII and FXaβ-ATIII complexes from the free enzymes and antithrombin III. It further stimulates the transformations of the 1∘complexes into the corresponding 3∘complexes. Additionally, it stimulates the degradation of the 1∘FXaα-ATIII and FXaβ-ATIII complexes into free FXaα, FXaβand ATIIIM. Protamine sulfate (PS) stimulates the transformation of FXaαinto FXaβand hence to FXaγ. It also stimulates the transformation of the 1∘-, 2∘-, and 3∘- FXα-ATIII complexes into their correspondingβ-complexes. It further promotes the degradation of the 1∘FXaα- and FXaβ-ATIII complexes into their corresponding 3∘- FXaα- and FXaβ-ATIII complexes, with the concommittant release of FXaγ. The addition of PS to FXa/ATIII/H mixtures results in a reduction in free FXa, ATIII, and 1∘Xa-ATIII complex formation, together with the concommittant increase in 3∘-FXa- ATIII complex formation and release of FXaγ. The likeliest explanation of these results resides in the removal of the effective free heparin as a consequence of the generation of a stable heparin/PS salt upon the addition of the PS to the FXa/ATIII/H mixtures, thereby effectively lowering clotting times.

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“…Meanwhile, there is strong affinity between protamine and heparin, which has been used in clinical and experimental observation. 33 In the presence of heparin, the Raman enhancement effect of 4-MPY functionalized Ag NPs induced by protamine would be decreased. The experiment results proved that this sensing strategy provided a good performance in terms of sensitivity, selectivity, linearity, and limits detection of heparin in both standard aqueous solution and fetal bovine serum sample.…”

Section: ■ Introductionmentioning

confidence: 99%

Highly Sensitive Surface-Enhanced Raman Scattering Sensing of Heparin Based on Antiaggregation of Functionalized Silver Nanoparticles

Wang

Chen

et al. 2013

ACS Appl. Mater. Interfaces

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We report a simple and sensitive surface-enhanced Raman scattering (SERS) platform for the detection of heparin, based on antiaggregation of 4-mercaptopyridine (4-MPY) functionalized silver nanoparticles (Ag NPs). Here, protamine was employed as a medium for inducing the aggregation of negatively charged 4-MPY functionalized Ag NPs through surface electrostatic interaction, which resulted in significantly enhanced Raman signal of the Raman reporter. However, in the presence of heparin, the interaction between heparin and protamine decreased the concentration of free protamine, which dissipated the aggregated 4-MPY functionalized Ag NPs and thus decreased Raman enhancement effect. The degree of aggregation and Raman enhancement effect was proportional to the concentration of added heparin. Under optimized assay conditions, good linear relationship was obtained over the range of 0.5−150 ng/mL (R 2 = 0.998) with a minimum detectable concentration of 0.5 ng/mL in standard aqueous solution. Furthermore, the developed method was also successfully applied for detecting heparin in fetal bovine serum samples with a linear range of 1−400 ng/mL.

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Studies on the neutralizing mechanism of antithrombin activity of heparin by protamine

Cited by 49 publications

References 7 publications

Partial Reversal of Low Molecular Weight Heparin (PK 10169) Anti-Xa Activity by Protamine Sulfate: In vitro and in vivo Study during Cardiac Surgery with Extracorporeal Circulation

Partial Reversal of Low Molecular Weight Heparin (PK 10169) Anti-Xa Activity by Protamine Sulfate: In vitro and in vivo Study during Cardiac Surgery with Extracorporeal Circulation

The Modification of Xa-ATIII-Heparin Dynamics by Protamine Sulfate

Highly Sensitive Surface-Enhanced Raman Scattering Sensing of Heparin Based on Antiaggregation of Functionalized Silver Nanoparticles

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