A pilot study indicating that bradykinin B2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass

Pretorius, Mias; Scholl, Frank G.; McFarlane, Julie A.; Murphey, Laine J.; Brown, Nancy J.

doi:10.1016/j.clpt.2005.08.010

Cited by 16 publications

(10 citation statements)

References 39 publications

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“…Several studies had demonstrated that treatment with B1R or B2R antagonists ameliorated tissue damage in several pathologies [23][24][25][26]. B1R ability to be expressed exclusively in traumatized tissues indicates its close relationship with inflammatory responses.…”

Section: Discussionmentioning

confidence: 98%

Influence of bradykinin B1 and B2 receptors in the immune response triggered by renal ischemia–reperfusion injury

Wang

Cenedeze

Pesquero

et al. 2006

International Immunopharmacology

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Section: Discussionmentioning

confidence: 98%

Influence of bradykinin B1 and B2 receptors in the immune response triggered by renal ischemia–reperfusion injury

Wang

Cenedeze

Pesquero

et al. 2006

International Immunopharmacology

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“…Although active thrombin seems to be the main source of t-PA release in in-vitro studies, [20] bradykinin appears to be the main stimulus for t-PA secretion during CPB. It has been shown that by blocking bradykinin receptors, [21] or by preventing the release of bradykinin by kallikrein inhibition, [22] t-PA release can be reduced. There seems to be a variability in the activation of the fibrinolytic system during CPB.…”

Section: Fibrinolysis and Surgerymentioning

confidence: 99%

Antifibrinolytics in cardiac surgery

Dhir

2013

Ann Card Anaesth

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Cardiac surgery exerts a significant strain on the blood bank services and is a model example in which a multi-modal blood-conservation strategy is recommended. Significant bleeding during cardiac surgery, enough to cause re-exploration and/or blood transfusion, increases morbidity and mortality. Hyper-fibrinolysis is one of the important contributors to increased bleeding. This knowledge has led to the use of anti-fibrinolytic agents especially in procedures performed under cardiopulmonary bypass. Nothing has been more controversial in recent times than the aprotinin controversy. Since the withdrawal of aprotinin from the world market, the choice of antifibrinolytic agents has been limited to lysine analogues either tranexamic acid (TA) or epsilon amino caproic acid (EACA). While proponents of aprotinin still argue against its non-availability. Health Canada has approved its use, albeit under very strict regulations. Antifibrinolytic agents are not without side effects and act like double-edged swords, the stronger the anti-fibrinolytic activity, the more serious the side effects. Aprotinin is the strongest in reducing blood loss, blood transfusion, and possibly, return to the operating room after cardiac surgery. EACA is the least effective, while TA is somewhere in between. Additionally, aprotinin has been implicated in increased mortality and maximum side effects. TA has been shown to increase seizure activity, whereas, EACA seems to have the least side effects. Apparently, these agents do not differentiate between pathological and physiological fibrinolysis and prevent all forms of fibrinolysis leading to possible thrombotic side effects. It would seem prudent to select the right agent knowing its risk-benefit profile for a given patient, under the given circumstances.

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“…It remains a standard of care in numerous cardiac surgical procedures, including aortic aneurysm repairs and bypass surgeries . Despite its widespread use, protamine sulfate suffers from a poor therapeutic index, increased incidences of hypersensitivity, and adverse outcomes such as vasoconstriction, arterial hypertension, hemorrhage, pulmonary edema, pulmonary hypertension, and bradychardia of the lungs by induction of classical complement activation, recruitment of inflammatory cells, and release of oxygen-free radicals. − …”

Section: Polyanions That Inhibit Blood Coagulationmentioning

confidence: 99%

Targeting Biological Polyanions in Blood: Strategies toward the Design of Therapeutics

Takeuchi

Abbina

et al. 2020

Biomacromolecules

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In this Review, we highlight well-described and emerging polyanions, and the way these molecules can be targeted in the design of potential therapeutics (synthetic and biologics) with applications in thrombosis and hemostasis. It is important to strike a balance between bleeding and clotting. In thrombosis, unwanted blood clots are formed in the lumen of a blood vessel, obstructing the flow of blood through the circulatory system. Over many years of research, several polyanionic biopolymers that can either impede (anticoagulant) or promote (procoagulant) blood clotting have been identified. Mediators impeding blood clotting, including polyanionic polysaccharides such as heparins and heparin mimics, are widely used as antithrombotics, although they impart adverse complications such as bleeding. Emerging synthetic polycations and well-described cationic proteins that are specifically designed to neutralize the biological activity of heparins to prevent bleeding complications are discussed. On the other hand, there is growing evidence that several polyanions bear a procoagulant nature in blood; polyphosphate (polyP), neutrophil extracellular traps (NETs), extracellular RNA, and cell-free DNA are shown to promote blood clotting. Recent research highlights the use of polycations and enzymes that either inhibit or cleave these procoagulant polyanions and demonstrates the proof-of-concept design of new antithrombotics without bleeding side effects. Additional studies have shown that some of these procoagulant polyanions can be used as a hemostat to prevent bleeding in an emergency. There are significant opportunities for chemists in the design of new inhibitors and agents with improved selectivity toward these biological polyanions, furthering the development of novel therapeutics.

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A pilot study indicating that bradykinin B2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass

Abstract: Increased bradykinin contributes to protamine-related hypotension through its B(2) receptor in ACE inhibitor-treated patients.

Cited by 16 publications

References 39 publications

Influence of bradykinin B1 and B2 receptors in the immune response triggered by renal ischemia–reperfusion injury

Influence of bradykinin B1 and B2 receptors in the immune response triggered by renal ischemia–reperfusion injury

Antifibrinolytics in cardiac surgery

Targeting Biological Polyanions in Blood: Strategies toward the Design of Therapeutics

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