The Inhibitory Effect of Protamine on Platelets is Attenuated by Heparin without Inducing Thrombocytopenia in Rodents

Mikłosz, Joanna; Kałaska, Bartłomiej; Kamiński, Kamil; Rusak, Małgorzata; Szczubiałka, Krzysztof; Nowakowska, Maria; Pawlak, Dariusz; Mogielnicki, Andrzej

doi:10.3390/md17090539

Cited by 6 publications

(5 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The others showed that blockers of vasoconstrictive mediators released from platelets only partially restored normal hemodynamic and respiratory parameters in animal models and patients [ 13 , 41 , 43 , 44 ]. The partial inhibition of PS–induced hypotension by l –NAME together with the PS antiplatelet effects previously demonstrated by us indicate the involvement of short–acting mediators such as NO in the mechanism of action [ 42 ]. The delay of hypotensive effect of PS by the neutralization with UFH may also be a result of differences in the metabolism of PS or the short action of NO.…”

Section: Discussionmentioning

confidence: 99%

“…We have recently showed that both PS alone and together with UFH did not induce thrombocytopenia, platelet activation, or aggregation in rats and mice. On the contrary, PS inhibited platelet aggregation [ 42 ]. The others showed that blockers of vasoconstrictive mediators released from platelets only partially restored normal hemodynamic and respiratory parameters in animal models and patients [ 13 , 41 , 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and Rodent Models

et al. 2021

Self Cite

View full text Add to dashboard Cite

Protamine sulfate (PS) is the only available option to reverse the anticoagulant activity of unfractionated heparin (UFH), however it can cause cardiovascular and respiratory complications. We explored the toxicity of PS and its complexes with UFH in zebrafish, rats, and mice. The involvement of nitric oxide (NO) in the above effects was investigated. Concentration–dependent lethality, morphological defects, and decrease in heart rate (HR) were observed in zebrafish larvae. PS affected HR, blood pressure, respiratory rate, peak exhaled CO2, and blood oxygen saturation in rats. We observed hypotension, increase of HR, perfusion of paw vessels, and enhanced respiratory disturbances with increases doses of PS. We found no effects of PS on human hERG channels or signs of heart damage in mice. The hypotension in rats and bradycardia in zebrafish were partially attenuated by the inhibitor of endothelial NO synthase. The disturbances in cardiovascular and respiratory parameters were reduced or delayed when PS was administered together with UFH. The cardiorespiratory toxicity of PS seems to be charge–dependent and involves enhanced release of NO. PS administered at appropriate doses and ratios with UFH should not cause permanent damage of heart tissue, although careful monitoring of cardiorespiratory parameters is necessary.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and Rodent Models

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Reoperation or reintervention is needed if bleeding happened during carotid recanalization, which is associated with the chance of perioperative stroke, MI, or even death. Miklosz et al (2019) measured the platelet numbers, collagen-induced aggregation, etc. in blood extracted from mice and rats and then furthermore found that protamine has a short-term antiplatelet activity.…”

Section: Discussionmentioning

confidence: 99%

A Meta-Analysis of Using Protamine for Reducing the Risk of Hemorrhage During Carotid Recanalization: Direct Comparisons of Post-operative Complications

et al. 2022

View full text Add to dashboard Cite

Background: Protamine can decrease the risk of hemorrhage during carotid recanalization. However, it may cause severe side effects. There is no consensus on the safety and efficacy of protamine during surgery. Thus, we conduct a comprehensive review and meta-analysis to compare the differences between the protamine and the no-protamine group.Method: We systematically obtained literature from Medline, Google Scholar, Cochrane Library, and PubMed electronic databases. All four databases were scanned from 1937 when protamine was first adopted as a heparin antagonist until February 2021. The reference lists of identified studies were manually checked to determine other eligible studies that qualify. The articles were included in this meta-analysis as long as they met the criteria of PICOS; conference or commentary articles, letters, case report or series, and animal observation were excluded from this study. The Newcastle-Ottawa Quality Assessment Scale and Cochrane Collaboration’s tool are used to assess the risk of bias of each included observational study and RCT, respectively. Stata version 12.0 statistical software (StataCorp LP, College Station, Texas) was adopted as statistical software. When I2 < 50%, we consider that the data have no obvious heterogeneity, and we conduct a meta-analysis using the fixed-effect model. Otherwise, the random-effect model was performed.Result: A total of 11 studies, consisting of 94,618 participants, are included in this study. Our analysis found that the rate of wound hematoma had a significant difference among protamine and no-protamine patients (OR = 0.268, 95% CI = 0.093 to 0.774, p = 0.015). Furthermore, the incidence of hematoma requiring re-operation (0.7%) was significantly lower than that of patients without protamine (1.8%). However, there was no significant difference in the incidence of stroke, wound hematoma with hypertension, transient ischemic attacks (TIA), myocardial infarction (MI), and death.Conclusion: Among included participants undergoing recanalization, the use of protamine is effective in reducing hematoma without increasing the risk of having other complications. Besides, more evidence-based performance is needed to supplement this opinion due to inherent limitations.

show abstract

“…PS administered alone can exhibit anticoagulant activity, inhibit thrombin and factor VII activity, impair platelet function, and negatively impact lungs and heart [ 21 , 22 ]. Those were not reported when PS was administered with UFH, which might bind PS and thus counter its effect [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Reversal Activity and Toxicity of Heparin-Binding Copolymer after Subcutaneous Administration of Enoxaparin in Mice

Swieton

Mikłosz

Yusa

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Uncontrolled bleeding after enoxaparin (ENX) is rare but may be life-threatening. The only registered antidote for ENX, protamine sulfate (PS), has 60% efficacy and can cause severe adverse side effects. We developed a diblock copolymer, heparin-binding copolymer (HBC), that reverses intravenously administered heparins. Here, we focused on the HBC inhibitory activity against subcutaneously administered ENX in healthy mice. BALB/c mice were subcutaneously injected with ENX at the dose of 5 mg/kg. After 110 min, vehicle, HBC (6.25 and 12.5 mg/kg), or PS (5 and 10 mg/kg) were administered into the tail vein. The blood was collected after 3, 10, 60, 120, 360, and 600 min after vehicle, HBC, or PS administration. The activities of antifactors Xa and IIa and biochemical parameters were measured. The main organs were collected for histological analysis. HBC at the lower dose reversed the effect of ENX on antifactor Xa activity for 10 min after antidote administration, whereas at the higher dose, HBC reversed the effect on antifactor Xa activity throughout the course of the experiment. Both doses of HBC completely reversed the effect of ENX on antifactor IIa activity. PS did not reverse antifactor Xa activity and partially reversed antifactor IIa activity. HBC modulated biochemical parameters. Histopathological analysis showed changes in the liver, lungs, and spleen of mice treated with HBC and in the lungs and heart of mice treated with PS. HBC administered in an appropriate dose might be an efficient substitute for PS to reverse significantly increased anticoagulant activity that may be connected with major bleeding in patients receiving ENX subcutaneously.

show abstract

The Inhibitory Effect of Protamine on Platelets is Attenuated by Heparin without Inducing Thrombocytopenia in Rodents

Cited by 6 publications

References 60 publications

Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and Rodent Models

Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and Rodent Models

A Meta-Analysis of Using Protamine for Reducing the Risk of Hemorrhage During Carotid Recanalization: Direct Comparisons of Post-operative Complications

Reversal Activity and Toxicity of Heparin-Binding Copolymer after Subcutaneous Administration of Enoxaparin in Mice

Contact Info

Product

Resources

About