Recent Experiences with Hexadimethrine for Neutralizing Heparin after Cardiopulmonary Bypass

Cooney, Allyson; Tj, Mann

doi:10.1177/0310057x9902700314

Cited by 12 publications

(4 citation statements)

References 13 publications

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“…A number of other substances or devices have been shown to neutralize the anticoagulant effects of UFH. These include hexadimethrine (Polybrene), 102,103 heparinase (Neutralase), 104 PF4, 105,106 extracorporeal heparin removal devices, 107 and synthetic protamine variants. 108 None of these is approved for clinical use.…”

Section: Limitations Of Heparinmentioning

confidence: 99%

Parenteral Anticoagulants

García

Baglin

Weitz

et al. 2012

Chest

870

480

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This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.

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Section: Limitations Of Heparinmentioning

confidence: 99%

Parenteral Anticoagulants

García

Baglin

Weitz

et al. 2012

Chest

870

480

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“…Hexadimethrine bromide has previously been safely and extensively used as an antiheparin agent in cardiopulmonary bypass surgery in doses up to 5 mg/kg ( 52 – 61 ). Therefore, a safety profile exists clinically for HDMBr which could allow a feasible translation of its use as a NASP in trauma hemorrhage.…”

Section: Discussionmentioning

confidence: 99%

Scavenging Circulating Mitochondrial DNA as a Potential Therapeutic Option for Multiple Organ Dysfunction in Trauma Hemorrhage

et al. 2018

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Trauma is a leading cause of death worldwide with 5.8 million deaths occurring yearly. Almost 40% of trauma deaths are due to bleeding and occur in the first few hours after injury. Of the remaining severely injured patients up to 25% develop a dysregulated immune response leading to multiple organ dysfunction syndrome (MODS). Despite improvements in trauma care, the morbidity and mortality of this condition remains very high. Massive traumatic injury can overwhelm endogenous homeostatic mechanisms even with prompt treatment. The underlying mechanisms driving MODS are also not fully elucidated. As a result, successful therapies for trauma-related MODS are lacking. Trauma causes tissue damage that releases a large number of endogenous damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs released in trauma, such as mitochondrial DNA (mtDNA), could help to explain part of the immune response in trauma given the structural similarities between mitochondria and bacteria. MtDNA, like bacterial DNA, contains an abundance of highly stimulatory unmethylated CpG DNA motifs that signal through toll-like receptor-9 to produce inflammation. MtDNA has been shown to be highly damaging when injected into healthy animals causing acute organ injury to develop. Elevated circulating levels of mtDNA have been reported in trauma patients but an association with clinically meaningful outcomes has not been established in a large cohort. We aimed to determine whether mtDNA released after clinical trauma hemorrhage is sufficient for the development of MODS. Secondly, we aimed to determine the extent of mtDNA release with varying degrees of tissue injury and hemorrhagic shock in a clinically relevant rodent model. Our final aim was to determine whether neutralizing mtDNA with the nucleic acid scavenging polymer, hexadimethrine bromide (HDMBr), at a clinically relevant time point in vivo would reduce the severity of organ injury in this model. Conclusions: We have shown that the release of mtDNA is sufficient for the development of multiple organ injury. MtDNA concentrations likely peak at different points in the early postinjury phase dependent on the degree of isolated trauma vs combined trauma and hemorrhagic shock. HDMBr scavenging of circulating mtDNA (and nuclear DNA, nDNA) is associated with rescue from severe multiple organ injury in the animal model. This suggests that HDMBr could have utility in rescue from human trauma-induced MODS.

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“…In this context, fondaparinux was recently proposed to treat patients with past history of HIT and appeared as a good alternative to UFH in CBP, provided that a rapid and effective antidote is available. A variety of molecules, including hexadimethrine , platelet factor 4 , heparinase I or polycationic peptides , have been evaluated. All are active towards UFH, some can partially reverse LMWH , but none is able to neutralize fondaparinux, allowing the evaluation of fondaparinux in cardiopulmonary bypass procedures.…”

Section: Discussionmentioning

confidence: 99%

A chemically-modified inactive antithrombin as a potent antagonist of fondaparinux and heparin anticoagulant activity

Fazavana

Bianchini

Saller

et al. 2013

Journal of Thrombosis and Haemostasis

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To cite this article: Fazavana J, Bianchini EP, Saller F, Smadja C, Picard V, Taverna M, Borgel D. A chemically-modified inactive antithrombin as a potent antagonist of fondaparinux and heparin anticoagulant activity. J Thromb Haemost 2013; 11: 1128-36.Summary. Background: Heparin and its analogs, mediating their anticoagulant activity through antithrombin (AT) activation, remain largely used for the preventive and curative treatment of thrombosis. The major adverse reaction of these drugs is the bleeding risk associated with overdose. Unfractionnated heparin (UFH) can be efficiently and rapidly neutralized by protamine sulfate, but this reversal partially neutralizes low-molecular-weight heparin (LMWH) and is inefficient in reversing fondaparinux. To secure administration of AT-mediated anticoagulants and counteract bleeding disorders, we previously designed a recombinant inactive AT as an antidote to heparin derivatives. Objectives: To get around the limited production level of recombinant AT, we propose in this study an alternative strategy to produce a chemically modified inactive AT, exhibiting increased heparin affinity, as an antagonist of heparin analogs. Methods: Plasma-derived AT was chemically modified with 2,3 butanedione, a diketone known to specifically react with the arginine side chain. The chemical reaction was conducted in the presence of heparin to preserve basic residues within the heparin binding site from modifications. Results: AT treated by butanedione and selected for its high heparin affinity (AT-BD) was indeed modified on reactive Arg393 and thus exhibited decreased anticoagulant activity and increased heparin affinity. AT-BD was able to neutralize anticoagulant activity of heparin derivatives in vitro and in vivo and was devoid of intrinsic anticoagulant activity, as assessed by activated partial thromboplastin time assay. Conclusions: AT-BD appears to be as efficient as protamine to neutralize UFH in vivo but could be more largely used because it also reverses fondaparinux and LMWH.

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Recent Experiences with Hexadimethrine for Neutralizing Heparin after Cardiopulmonary Bypass

Cited by 12 publications

References 13 publications

Parenteral Anticoagulants

Parenteral Anticoagulants

Scavenging Circulating Mitochondrial DNA as a Potential Therapeutic Option for Multiple Organ Dysfunction in Trauma Hemorrhage

A chemically-modified inactive antithrombin as a potent antagonist of fondaparinux and heparin anticoagulant activity

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