Neutralization of a low molecular weight heparin (LHN-1) and conventional heparin by protamine sulphate in rats

SummaryThe neutralisation by protamine sulphate (PS) of heparan sulphate (HS), a low molecular weight heparin (LMWH), and a reference preparation of unfractionated heparin (UH), was studied by activated partial thromboplastin time (APTT) and anti-Xa clotting assays. UH was most easily neutralised in the APTT assay by PS (on a weight for weight basis), followed by LMWH and HS. The neutralisation of APTT activity by PS closely followed the loss of activity in the anti-Xa clotting assay, when plasma was used as the source of At III. When the anti-Xa clotting assay was carried out using purified At III in place of plasma, HS and LMWH were neutralised by much lower amounts of PS and resembled UH neutralisation more closely. Resistance of HS anti-Xa activity to PS neutralisation decreased with increasing plasma dilution. The presence of bovine albumin with purified At III concentrate increased the resistance of HS to PS neutralisation. It is concluded that PS binding to UH, HS and LMWH is probably related more to their degree of sulphation than molecular weight and that non-specific interactions between PS and plasma proteins inhibit the binding of PS to HS and LMWH.

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PHARMACOKINETICS OF A LOW MOLECULAR WEIGHT HEPARIN (KABI 2165, FRAGMIN) ATFER INTRAVENOUS AND SUBCUTANEOUS ADMINISTRATION IN HUMAN VOLUNTEERS AND ITS IN VIVO NEUTRALIZATION BY PROTAMINE SULFATE

10.1055/s-0038-1642866 ◽

1987 ◽

Author(s):

J Albada ◽

K K Nieuwenhuis ◽

J J Sixma

Keyword(s):

Molecular Weight ◽

Healthy Volunteers ◽

Half Life ◽

Low Molecular Weight Heparin ◽

Subcutaneous Administration ◽

Low Molecular Weight ◽

Protamine Sulphate ◽

Original Curve ◽

Rebound Phenomenon

Pharmacokinetics of a low molecular weight heparin (LMWH) were studied in healthy volunteers. After an intravenous bolus injection of 5000 anti-Xa U in 5 healthy volunteers anti Xa activity disappeared according to the combination of saturable and a linear mechanism, preceded by a rapid initial disappearance. The apparent half-life of the anti Xa activity is about twice as long as that of standard heparin. In another set of experiments 5000 anti Xa U of LMWH were immediately followed by 50 mgr of Protamine Sulphate (PS). The curve of the anti Xa-activity parallelled the original curve at a level of about 30-40%. No rebound phenomenon was observed. The same dose of the LMWH followed by 100 mg of PS resulted in an anti Xa disappearance curve at an obvious higher level of about 50%. Also at this dose no rebound phenomenon was noticed.A continuous infusion of 10.000 anti Xa U/24 h during 10 hours was followed by 15.000 anti Xa U/24 h for another 10 hours after which the dose was raised to 20.000 anti Xa U/24 h for another 10 hours. Only the first infusion period resulted in a plateau fase. At the end of these experiments anti Xa activity was neutralized by 50 mg P.S. i.v. resulting in the disappearance of less than 50% of anti Xa activity. After subcutaneous administration of 15.000 anti Xa U (corresponding to the dose for i.v. treatment per day with this LMWH) peak levels of 1,1-1,8 anti Xa were reached after 3-4 hours. Supra-optimal anti Xa levels (higher than 0.9) were observed in all volunteers during a period of 5 hours. After 24 hours in none of the volunteers any anti Xa-activity could be detected.Conclusions:In contrast to previous reports pharmacokinetics of this LMWH do not essentially differ from those of standard heparin apart from its longer half-life and its high bioavialability after subcutaneous injection.

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Nursing Skill and Responsibility in Administration of Low Molecular Weight Heparin by Prefilled Syringe

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i47a32993 ◽

2021 ◽

pp. 85-92

Author(s):

Vaishali Tembhare ◽

Gaurav Mujbaile ◽

Seema Singh ◽

Achita Sawarkar ◽

Maduri Shambharkar ◽

...

Keyword(s):

Molecular Weight ◽

Blood Test ◽

Low Molecular Weight Heparin ◽

Occult Blood ◽

Low Molecular Weight ◽

Low Molecular Weight Heparins ◽

Protamine Sulphate ◽

Subcutaneous Tissues ◽

Skin Discoloration ◽

Medicine Administration

Abstract: Low-molecular-weight heparins (LMWHs) have proven to be effective in the prevention and treatment of thrombotic disorders, as well as substitute for unfractionated heparin (UFH). LMWHs are a diverse collection of medicines with different biochemical and pharmacological characteristics, despite the fact that they all have antithrombotic actions. Medicine is administered into the subcutaneous tissues with these injections. Small amounts of injections are delivered by the subcutaneous approach, which involves inserting a small thin needle beneath the skin and slowly injecting the medicine. Low molecular weight heparins make up dalteparin and enoxaparin, two anticoagulants. The rights of medicine administration must be followed by nurses. For patients on LMWH medication, the most essential blood test is prothrombin time. Following administration, look for any signs of bleeding, such as occult blood in the stool, malena, bleeding gums, and skin discoloration/hematoma. The antidote for low molecular weight heparin is protamine sulphate. It is effective at counteracting the effects of LMWH. 100 units of LMWH are neutralised by 1 mg of protamine sulphate.If it's been more than 8 hours since you've given LMWH, provide 0.5 mg protamin per 100 units of LMWH.

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Significant Differences in Neutralization of Heparin and Its Low Molecular Fragments by Protamine Sulfate: An In Vivo Study.

Blood ◽

10.1182/blood.v104.11.1850.1850 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1850-1850

Author(s):

Mark A. Crowther ◽

Klement Petr ◽

Liao Peng ◽

Chen Frank ◽

Berry B. Leslie ◽

...

Keyword(s):

Molecular Weight ◽

Low Molecular Weight Heparin ◽

Factor Xa ◽

In Vivo Model ◽

Low Molecular Weight ◽

Protamine Sulphate ◽

Heparin Plasma ◽

Optimal Regimen

Abstract In clinical practice, patients receiving low molecular weight heparin (LMWH) occasionally suffer bleeding. Protamine sulphate (PS) is often used to reverse the anticoagulant effect of LMWH in such cases. However, the optimal regimen of PS for complete neutralization of LMWH fragments has not been established. Results from our previous in vitro studies indicate that the ability of PS to neutralize LMWHs is inversely related to the charge of the low molecular weight heparin molecule; more heavily charged LMWHs (such as Tinzaparin) are more readily neutralized than less charged LMWHs (such as Enoxaparin). The aim of the current study was to confirm these findings using an in vivo model. Twenty minutes after administration of either saline, unfractionated heparin [UFH, 100U/kg], Tinzaparin [100U/kg] or enoxaparin [100U/kg], 50% of anesthetized rabbits received either saline or PS [1 mg/100 U of heparin or LMWH]. The efficacy of PS neutralization was assessed by serial measurements of anti-factor Xa heparin plasma levels. Results are presented as mean of the anti-factor Xa heparin activities normalized to the level at 10 minutes and summarized in the table below. As expected, PS completely neutralized the anti-factor Xa effect of UFH. However, PS was significantly less effective for neutralization of Tinzaparin (about 66%) and Enoxaparin (about 44%) at the dose tested. We conclude that when tested in an in vivo model LMWHs vary in their protamine neutralizability. More highly charged LMWHs (e.g. Tinazaparin) are more neutralizable than less highly charged products (e.g. Enoxaparin). Residual Anti-Xa heparin effect Time Enoxaparin Tinzaparin UFH Saline + PS Enoxaparin +PS Tinzaparin + PS UFH + PS 10 min 1.00 1.00 1.00 0 1.00 1.00 1.00 20 min 0.85 0.86 0.70 0 0.80 0.85 0.89 Protamine 25 min 0.71 0.75 0.69 0 0.45 0.29 0.01 35 min 0.68 0.64 0.48 0 0.40 0.28 0 50 min 0.48 0.32

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Use of low molecular weight heparin CY 222 during cardiopulmonary bypass. Experimental study and clinical application

Perfusion ◽

10.1177/026765918600100204 ◽

1986 ◽

Vol 1 (2) ◽

pp. 99-102

Author(s):

B. Touchot ◽

F. Laborde ◽

F. Dum ◽

P. Commin ◽

P. Gallix ◽

...

Keyword(s):

Molecular Weight ◽

Cardiopulmonary Bypass ◽

Low Molecular Weight Heparin ◽

Heart Surgery ◽

Open Heart Surgery ◽

Low Molecular Weight ◽

Inotropic Effects ◽

Protamine Sulphate ◽

Potential Benefits ◽

Anaphylactoid Reactions

Cardiopulmonary bypass (CPB) standard heparin and protamine therapy is a relatively satisfactory part of conventional CPB practice. However, some problems are known to result from both heparin and protamine sulphate administration. These include: allergic reaction and thrombocytopenia due to heparin, and anaphylactoid reactions, negative inotropic effects, pulmonary oedema and pulmonary hypertension due to protamine administration. Low molecular weight heparin (LMWH) should theoretically be superior decreasing the adverse effects of standard heparin. In addition, it should not require the use of protamine for heparin neutralization. These potential benefits of LMWH encourage the experimental evaluation of the use of LMWH during open-heart surgery before preliminary clinical applications.

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