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British Journal of Anaesthesia May 2018Neutralisation of systemic anticoagulation with heparin in cardiac surgery with cardiopulmonary bypass requires protamine administration. If adequately dosed, protamine... (Review)
Review
Neutralisation of systemic anticoagulation with heparin in cardiac surgery with cardiopulmonary bypass requires protamine administration. If adequately dosed, protamine neutralises heparin and reduces the risk of postoperative bleeding. However, as its anticoagulant properties are particularly exerted in the absence of heparin, overdosing of protamine may contribute to bleeding and increased transfusion requirements. This narrative review describes the mechanisms underlying the anticoagulant properties and side-effects of protamine, and the impact of protamine dosing on the activated clotting time and point-of-care viscoelastic test results, and explains the distinct protamine dosing strategies in relation to haemostatic activation and postoperative bleeding. The available evidence suggests that protamine dosing should not exceed a protamine-to-heparin ratio of 1:1. In particular, protamine-to-heparin dosing ratios >1 are associated with more postoperative 12 h blood loss. The optimal protamine-to-heparin ratio in cardiac surgery has, however, not yet been elaborated, and may vary between 0.6 and 1.0 based on the initial heparin dose.
Topics: Anticoagulants; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Dose-Response Relationship, Drug; Heparin; Heparin Antagonists; Humans; Postoperative Hemorrhage; Protamines
PubMed: 29661409
DOI: 10.1016/j.bja.2018.01.023 -
Clinical and Applied... Jul 2017Bleeding is the most common complication of all anticoagulants. Any bleeding patient on an anticoagulant should be risk-stratified based on hemodynamic instability,... (Review)
Review
Bleeding is the most common complication of all anticoagulants. Any bleeding patient on an anticoagulant should be risk-stratified based on hemodynamic instability, source of bleeding, and degree of blood loss. Although minor bleed may be managed with discontinuation of anticoagulant, major bleed may require transfusion of blood products and use of specific antidote. The residual effects of each anticoagulant may be monitored with distinct coagulation assay. Intravenous or oral vitamin K can reverse the effect of warfarin within 24 to 48 hours and is indicated for any bleeding, international normalized ratio of >10 or 4.5 to 10 in patients with other risk factors for bleeding. Fresh frozen plasma or prothrombin complex concentrate (PCC) may be necessary in major bleeding related to warfarin. Protamine sulfate reverses the effect of unfractionated heparin completely and of low-molecular-weight heparin (LMWH) partially. Idarucizumab has recently been approved in United States for dabigatran reversal, whereas andexanet alfa is expected to get approved in the near future for reversal of oral factor Xa inhibitors. The PCC may reverse the effect of rivaroxaban to some extent, but no data are available regarding reversal of apixaban and edoxaban. Aripazine has shown promising results to reverse the effects of LMWH, fondaparinux, and direct oral anticoagulants but is still in the developmental phase.
Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Blood Coagulation Factors; Blood Coagulation Tests; Hemorrhage; Humans; International Normalized Ratio; Plasma; Protamines
PubMed: 27789605
DOI: 10.1177/1076029616675970 -
Reproduction (Cambridge, England) Sep 2022Protamines package and shield the paternal DNA in the sperm nucleus and have been studied in many mouse models over decades. This review recapitulates and updates our... (Review)
Review
IN BRIEF
Protamines package and shield the paternal DNA in the sperm nucleus and have been studied in many mouse models over decades. This review recapitulates and updates our knowledge about protamines and reveals a surprising complexity in protamine function and their interactions with other sperm nuclear proteins.
ABSTRACT
The packaging and safeguarding of paternal DNA in the sperm cell nucleus is a critical feature of proper sperm function. Histones cannot mediate the necessary hypercondensation and shielding of chromatin required for motility and transit through the reproductive tracts. Paternal chromatin is therefore reorganized and ultimately packaged by protamines. In most mammalian species, one protamine is present in mature sperm (PRM1). In rodents and primates among others, however, mature sperm contain a second protamine (PRM2). Unlike PRM1, PRM2 is cleaved at its N-terminal end. Although protamines have been studied for decades due to their role in chromatin hypercondensation and involvement in male infertility, key aspects of their function are still unclear. This review updates and integrates our knowledge of protamines and their function based on lessons learned from mouse models and starts to answer open questions. The combined insights from recent work reveal that indeed both protamines are crucial for the production of functional sperm and indicate that the two protamines perform distinct functions beyond simple DNA compaction. Loss of one allele of PRM1 leads to subfertility whereas heterozygous loss of PRM2 does not. Unprocessed PRM2 seems to play a distinct role related to the eviction of intermediate DNA-bound proteins and the incorporation of both protamines into chromatin. For PRM1, on the other hand, heterozygous loss leads to strongly reduced sperm motility as the main phenotype, indicating that PRM1 might be important for processes ensuring correct motility, apart from DNA compaction.
Topics: Animals; Chromatin; DNA; Male; Mammals; Mice; Protamines; Semen; Sperm Motility; Spermatozoa
PubMed: 35900356
DOI: 10.1530/REP-22-0107 -
Journal of Cardiothoracic and Vascular... Apr 2023The common conception of "heparin rebound" invokes heparin returning to circulation in the postoperative period after apparently adequate intraoperative reversal with... (Review)
Review
The common conception of "heparin rebound" invokes heparin returning to circulation in the postoperative period after apparently adequate intraoperative reversal with protamine. This is believed to portend increased postoperative bleeding and provides the rationale for administering additional empiric doses of protamine in response to prolonged coagulation tests and/or bleeding. However, the relevant literature of the last 60+ years provides only a weak level of evidence that "rebounded" heparin itself is a significant etiology of postoperative bleeding after cardiac surgery with cardiopulmonary bypass. Notably, many of the most frequently cited heparin rebound investigators ultimately concluded that although exceedingly low levels of heparin activity could be detected by anti-Xa assay in some (but not all) patients postoperatively, there was no correlation with actual bleeding. An understanding of the literature requires a careful reading of the details because the investigators lacked standardized definitions for "heparin rebound" and "adequate reversal" while studying the phenomenon with significantly different experimental methodologies and laboratory tests. This review was undertaken to provide a modern understanding of the "heparin rebound" phenomenon to encourage an evidence-based approach to postoperative bleeding. Literature searches were conducted via PubMed using the following MeSH terms: heparin rebound, heparin reversal, protamine, platelet factor 4, and polybrene. Relevant English language articles were reviewed, with subsequent references obtained from the internal citations. Perspective is provided for both those who use HepCon-guided management and those who do not, as are practical recommendations for the modern era based on the published data and conclusions of the various investigators.
Topics: Humans; Heparin; Blood Coagulation Tests; Protamines; Postoperative Hemorrhage; Heparin Antagonists; Cardiopulmonary Bypass; Anticoagulants
PubMed: 36641308
DOI: 10.1053/j.jvca.2022.12.019 -
Journal of Cardiothoracic and Vascular... Aug 2022Perioperative myocardial infarction is a serious complication affecting a significant portion of patients undergoing coronary artery bypass graft surgery. This may arise... (Review)
Review
Perioperative myocardial infarction is a serious complication affecting a significant portion of patients undergoing coronary artery bypass graft surgery. This may arise due to coronary graft thrombosis, a rare but potentially fatal phenomenon associated with both congenital and acquired risk factors. Multiple case reports implicate the role of protamine in the development of such thromboses. The role of protamine in facilitating the regulation of hemostasis by reversing the anticoagulant effects of heparin in patients undergoing cardiopulmonary bypass is well-recognized. However, discussion of its potential contribution to coronary graft thrombosis and mechanisms by which this may occur is lacking. Furthermore, its narrow therapeutic index and side effect profile are such that its appropriateness as a universal reversal agent to heparin requires reconsideration. This article reviews the current body of evidence regarding the use of protamine in cardiac surgery and the limited case reports pertaining to its potential role in the pathophysiology of coronary graft thrombosis.
Topics: Anticoagulants; Cardiopulmonary Bypass; Coronary Thrombosis; Heparin; Heparin Antagonists; Humans; Protamines
PubMed: 34774407
DOI: 10.1053/j.jvca.2021.10.008 -
Nature Communications Dec 2023Idiopathic fertility disorders are associated with mutations in various genes. Here, we report that coiled-coil glutamate-rich protein 1 (CCER1), a germline-specific and...
Idiopathic fertility disorders are associated with mutations in various genes. Here, we report that coiled-coil glutamate-rich protein 1 (CCER1), a germline-specific and intrinsically disordered protein (IDP), mediates postmeiotic spermatid differentiation. In contrast, CCER1 deficiency results in defective sperm chromatin compaction and infertility in mice. CCER1 increases transition protein (Tnp1/2) and protamine (Prm1/2) transcription and mediates multiple histone epigenetic modifications during the histone-to-protamine (HTP) transition. Immiscible with heterochromatin in the nucleus, CCER1 self-assembles into a polymer droplet and forms a liquid-liquid phase-separated condensate in the nucleus. Notably, we identified loss-of-function (LoF) variants of human CCER1 (hCCER1) in five patients with nonobstructive azoospermia (NOA) that were absent in 2713 fertile controls. The mutants led to premature termination or frameshift in CCER1 translation, and disrupted condensates in vitro. In conclusion, we propose that nuclear CCER1 is a phase-separated condensate that links histone epigenetic modifications, HTP transitions, chromatin condensation, and male fertility.
Topics: Male; Humans; Mice; Animals; Histones; Protamines; Semen; Chromatin; Spermatozoa; Spermatogenesis; Fertility; Infertility, Male
PubMed: 38081819
DOI: 10.1038/s41467-023-43480-z -
Journal of Thrombosis and Haemostasis :... Jul 2023Protamine, a highly basic protein isolated from salmon sperm, is the only clinically available agent to reverse the anticoagulation of unfractionated heparin. Following... (Review)
Review
Protamine, a highly basic protein isolated from salmon sperm, is the only clinically available agent to reverse the anticoagulation of unfractionated heparin. Following intravenous administration, protamine binds to heparin in a nonspecific electrostatic interaction to reverse its anticoagulant effects. In clinical use, protamine is routinely administered to reverse high-dose heparin anticoagulation in cardiovascular procedures, including cardiac surgery with cardiopulmonary bypass. Despite the lack of supportive evidence regarding protamine's effectiveness to reverse low-molecular-weight heparin, it is recommended in guidelines with low-quality evidence. Different dosing strategies have been reported for reversing heparin in cardiac surgical patients based on empiric dosing, pharmacokinetics, or point-of-care measurements of heparin levels. Protamine administration is associated with a spectrum of adverse reactions that range from vasodilation to life-threatening cardiopulmonary dysfunction and shock. The life-threatening responses appear to be hypersensitivity reactions due to immunoglobulin E and/or immunoglobulin G antibodies. However, protamine and heparin-protamine complexes can activate complement inflammatory pathways and inhibit other coagulation factors. Although alternative agents for reversing heparin are not currently available for clinical use, additional research continues evaluating novel therapeutic approaches.
Topics: Humans; Male; Protamines; Heparin; Anticoagulants; Heparin Antagonists; Semen; Cardiopulmonary Bypass
PubMed: 37062523
DOI: 10.1016/j.jtha.2023.04.005 -
JAMA Surgery Mar 2016Protamine sulfate can be administered at the conclusion of carotid endarterectomy (CEA) to reverse the anticoagulant effects of heparin and to limit the risk for... (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
Protamine sulfate can be administered at the conclusion of carotid endarterectomy (CEA) to reverse the anticoagulant effects of heparin and to limit the risk for postoperative bleeding. Protamine use remains controversial owing to concern for increased thrombotic complications with its use.
OBJECTIVE
To review the evidence for and against protamine use, both in its association with increased thrombotic complications and with decreased bleeding.
DATA SOURCES
We searched Medline (1946-2014), EMBASE (1966-2014), Cochrane Library (1972-2014), clinical trial registries (World Health Organization International Clinical Trials Registry and clinicaltrials.gov), and abstracts from conferences of the Society of Vascular Surgery (2002-2014) and American Heart Association Scientific Sessions (1980-2014) in November 2014. No language restrictions were applied.
STUDY SELECTION
We included clinical trials and observational studies comparing reversal of heparin with protamine sulfate vs no reversal in patients undergoing carotid revascularization and reporting stroke during hospitalization. Of 360 records screened, 12 studies (3%) of CEA were eligible for data pooling.
DATA EXTRACTION AND SYNTHESIS
Two reviewers extracted data and assessed quality. Random-effects models were used to summarize relative risks (RRs).
MAIN OUTCOME AND MEASURE
Stroke after CEA.
RESULTS
We included 12 observational studies involving 10,621 patients in the meta-analysis. Event rates did not differ significantly between patients who received protamine vs those who did not for the following outcomes: stroke (RR, 0.84; 95% CI, 0.55-1.29; I(2) = 15%; 9 studies), myocardial infarction (RR, 0.89; 95% CI, 0.53-1.51; I(2) = 0%; 3 studies), or mortality (RR, 0.9, 95% CI, 0.62-1.29; I(2) = 0%; 7 studies). The use of protamine was associated with a significant decrease in major bleeding complications requiring reoperation (RR, 0.57; 95% CI, 0.39-0.84; I(2) = 32%; 10 studies).
CONCLUSIONS AND RELEVANCE
Based on available evidence, the use of protamine following CEA is associated with a reduction in bleeding complications, without increasing major thrombotic outcomes, including stroke, myocardial infarction, or death.
Topics: Carotid Stenosis; Endarterectomy, Carotid; Heparin Antagonists; Humans; Postoperative Hemorrhage; Protamines; Registries
PubMed: 26501944
DOI: 10.1001/jamasurg.2015.3592 -
Results and Problems in Cell... 2022Sperm nuclei present a highly organized and condensed chromatin due to the interchange of histones by protamines during spermiogenesis. This high DNA condensation leads... (Review)
Review
Sperm nuclei present a highly organized and condensed chromatin due to the interchange of histones by protamines during spermiogenesis. This high DNA condensation leads to almost inert chromatin, with the impossibility of conducting gene transcription as in most other somatic cells. The major chromosomal structure responsible for DNA condensation is the formation of protamine-DNA toroids containing 25-50 kilobases of DNA. These toroids are connected by toroid linker regions (TLR), which attach them to the nuclear matrix, as matrix attachment regions (MAR) do in somatic cells. Despite this high degree of condensation, evidence shows that sperm chromatin contains vulnerable elements that can be degraded even in fully condensed chromatin, which may correspond to chromatin regions that transfer functionality to the zygote at fertilization. This chapter covers an updated review of our model for sperm chromatin structure and its potential functional elements that affect embryo development.
Topics: Male; Humans; Semen; Chromatin; Spermatozoa; Protamines; DNA
PubMed: 36348112
DOI: 10.1007/978-3-031-06573-6_10 -
Advances in Experimental Medicine and... 2019Spermatozoa genome has unique features that make it a fascinating field of investigation: first, because, with oocyte genome, it can be transmitted generation after... (Review)
Review
Spermatozoa genome has unique features that make it a fascinating field of investigation: first, because, with oocyte genome, it can be transmitted generation after generation; second, because of genetic shuffling during meiosis, each spermatozoon is virtually unique in terms of genetic content, with consequences for species evolution; and finally, because its chromatin organization is very different from that of somatic cells or oocytes, as it is not based on nucleosomes but on nucleoprotamines which confer a higher order of packaging. Histone-to-protamine transition involves many actors, such as regulators of spermatid gene expression, components of the nuclear envelop, histone-modifying enzymes and readers, chaperones, histone variants, transition proteins, protamines, and certainly many more to be discovered.In this book chapter, we will present what is currently known about sperm chromatin structure and how it is established during spermiogenesis, with the aim to list the genetic factors that regulate its organization.
Topics: Chromatin; Gene Expression Regulation, Developmental; Histones; Humans; Male; Protamines; Spermatids; Spermatogenesis; Spermatozoa
PubMed: 31301043
DOI: 10.1007/978-3-030-21664-1_1