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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 -
Journal of Cardiothoracic Anesthesia Apr 1988
Review
Topics: Diabetes Complications; Drug Hypersensitivity; Humans; Hypotension; Lung; Protamines; Pulmonary Edema; Vasoconstriction
PubMed: 17171918
DOI: 10.1016/0888-6296(88)90277-3 -
Advances in Experimental Medicine and... 2014Protamines are the major nuclear proteins in sperm cells, having a crucial role in the correct packaging of the paternal DNA. The fact that protamine haploinsufficiency... (Review)
Review
Protamines are the major nuclear proteins in sperm cells, having a crucial role in the correct packaging of the paternal DNA. The fact that protamine haploinsufficiency in mice resulted in abnormal chromatin packaging and male infertility suggested that the protamines could also be important candidates in explaining some of the idiopathic male infertility cases in humans. The first clinical studies focused on analyzing protamines at the protein level. Various studies have found the presence of an altered amount of protamines in some infertile patients, in contrast to the normal situation in fertile individuals where the two protamines, protamine 1 and protamine 2, are both present in approximately equal quantities. Subsequently, the protamine genes were the subject of various mutational genetic screening studies in search of variants that could be associated with deregulation in the protamine expression observed. The results of these protamine mutational studies showed that the presence of high penetrant mutations is a very rare cause of male infertility. However, some variants and some haplotypes described may behave as risk factors for male infertility. More recently, the presence of RNA in the mature sperm cell has also been investigated. The present chapter will introduce the basic aspects of protamine evolution and function and review the various articles published to date on the relationship between the protamines studied at the DNA, RNA, and protein levels and male infertility.
Topics: Amino Acid Sequence; Animals; Evolution, Molecular; Gene Expression Regulation; Humans; Male; Mice; Molecular Sequence Data; Mutation; Protamines; Spermatozoa
PubMed: 23955674
DOI: 10.1007/978-1-4614-7783-9_6 -
Anesthesia and Analgesia Mar 1985The prospective human studies considered above reveal that in some patients protamine is associated with decreases in SBP and SVR, especially when administered rapidly.... (Review)
Review
The prospective human studies considered above reveal that in some patients protamine is associated with decreases in SBP and SVR, especially when administered rapidly. Cardiac output increases reflexly, except perhaps in patients with less compliant ventricles, which are more dependent on preload to maintain stroke volume. In the latter, decreases in filling volume associated with protamine can lower CO. Regardless of the rate of administration, protamine does not produce predictable, acute increases in PAP, although increases in PAP may occur during idiosyncratic reactions (see the section on idiosyncratic reactions below). Left atrial or aortic administration of protamine may not confer protection from its hemodynamic or idiosyncratic sequelae (see below). Little evidence exists to conclude that protamine directly depresses contractility of the human heart.
Topics: Anaphylaxis; Animals; Antibody Formation; Blood Pressure; Dogs; Drug Hypersensitivity; Heart; Hemodynamics; Heparin; Humans; Prospective Studies; Protamines; Pulmonary Circulation; Research; Thrombocytopenia; Vasoconstriction
PubMed: 3883848
DOI: No ID Found -
Human Fertility (Cambridge, England) Jun 2014Human sperm express two types of protamine: protamine 1 (P1) and the family of protamine 2 (P2) proteins, with P1 and P2 normally existing in a ratio of approximately... (Review)
Review
Human sperm express two types of protamine: protamine 1 (P1) and the family of protamine 2 (P2) proteins, with P1 and P2 normally existing in a ratio of approximately 1:1. Both the elevation and reduction of this ratio have been linked with male infertility suggesting that abnormalities in protamine expression, processing and replacement may be responsible for effects on semen parameters observed in infertile males affected by deficient protamination, along with abnormalities in associated regulatory processes. Abnormal protamination may result in insufficient condensation in the sperm nucleus, thus rendering paternal DNA susceptible to damage, which could have detrimental consequences upon embryogenesis. Consequently, it is imperative that Assisted Reproductive Technologies (ARTs) endeavour to utilise sperm devoid of protamine abnormalities, especially because retained histones are present in imprinted gene clusters. Emerging evidence indicates that abnormalities in protamine content may influence epigenetic signals transmitted via paternal DNA. Indeed, an increase in rare imprinting disorders has been observed in children conceived via in vitro fertilisation (IVF). This review examines the links between male infertility, abnormal protamine expression and replacement, the implications of abnormal sperm DNA packaging on fertility treatments and the potential iatrogenic effects of ART procedures on sperm function.
Topics: Animals; DNA; Epigenesis, Genetic; Humans; Infertility, Male; Male; Polymorphism, Single Nucleotide; Protamines; Spermatogenesis; Spermatozoa
PubMed: 24869677
DOI: 10.3109/14647273.2014.915347 -
ACS Nano Aug 2021Packaging paternal genome into tiny sperm nuclei during spermatogenesis requires 10-fold compaction of DNA, corresponding to a 10-20 times higher compaction than in...
Packaging paternal genome into tiny sperm nuclei during spermatogenesis requires 10-fold compaction of DNA, corresponding to a 10-20 times higher compaction than in somatic cells. While such a high level of compaction involves protamine, a small arginine-rich basic protein, the precise mechanism at play is still unclear. Effective pair potential calculations and large-scale molecular dynamics simulations using a simple idealized model incorporating solely electrostatic and steric interactions clearly demonstrate a reversible control on DNA condensates formation by varying the protamine-to-DNA ratio. Microscopic states and condensate structures occurring in semidilute solutions of short DNA fragments are in good agreement with experimental phase diagram and cryoTEM observations. The reversible microscopic mechanisms induced by protamination modulation should provide valuable information to improve a mechanistic understanding of early and intermediate stages of spermatogenesis where an interplay between condensation and liquid-liquid phase separation triggered by protamine expression and post-translational regulation might occur. Moreover, recent vaccines to prevent virus infections and cancers using protamine as a packaging and depackaging agent might be fine-tuned for improved efficiency using a protamination control.
Topics: Male; Humans; Protamines; Spermatozoa; Semen; DNA Packaging; DNA
PubMed: 34328301
DOI: 10.1021/acsnano.1c02337 -
Biophysical Journal Nov 2023DNA in sperm undergoes an extreme compaction to almost crystalline packing levels. To produce this dense packing, DNA is dramatically reorganized in minutes by protamine...
DNA in sperm undergoes an extreme compaction to almost crystalline packing levels. To produce this dense packing, DNA is dramatically reorganized in minutes by protamine proteins. Protamines are positively charged proteins that coat negatively charged DNA and fold it into a series of toroids. The exact mechanism for forming these ∼50-kbp toroids is unknown. Our goal is to study toroid formation by starting at the "bottom" with folding of short lengths of DNA that form loops and working "up" to more folded structures that occur on longer length scales. We previously measured folding of 200-300 bp of DNA into a loop. Here, we look at folding of intermediate DNA lengths (L = 639-3003 bp) that are 2-10 loops long. We observe two folded structures besides loops that we hypothesize are early intermediates in the toroid formation pathway. At low protamine concentrations (∼0.2 μM), we see that the DNA folds into flowers (structures with multiple loops that are positioned so they look like the petals of a flower). Folding at these concentrations condenses the DNA to 25% of its original length, takes seconds, and is made up of many small bending steps. At higher protamine concentrations (≥2 μM), we observe a second folded structure-the loop stack-where loops are stacked vertically one on top of another. These results lead us to propose a two-step process for folding at this length scale: 1) protamine binds to DNA, bending it into loops and flowers, and 2) flowers collapse into loop stacks. These results highlight how protamine uses a bind-and-bend mechanism to rapidly fold DNA, which may be why protamine can fold the entire sperm genome in minutes.
Topics: Protamines; Seeds; DNA; Spermatozoa; Flowers
PubMed: 37803830
DOI: 10.1016/j.bpj.2023.10.003 -
Nucleic Acids Research Jun 2020Protamine proteins dramatically condense DNA in sperm to almost crystalline packing levels. Here, we measure the first step in the in vitro pathway, the folding of DNA...
Protamine proteins dramatically condense DNA in sperm to almost crystalline packing levels. Here, we measure the first step in the in vitro pathway, the folding of DNA into a single loop. Current models for DNA loop formation are one-step, all-or-nothing models with a looped state and an unlooped state. However, when we use a Tethered Particle Motion (TPM) assay to measure the dynamic, real-time looping of DNA by protamine, we observe the presence of multiple folded states that are long-lived (∼100 s) and reversible. In addition, we measure folding on DNA molecules that are too short to form loops. This suggests that protamine is using a multi-step process to loop the DNA rather than a one-step process. To visualize the DNA structures, we used an Atomic Force Microscopy (AFM) assay. We see that some folded DNA molecules are loops with a ∼10-nm radius and some of the folded molecules are partial loops-c-shapes or s-shapes-that have a radius of curvature of ∼10 nm. Further analysis of these structures suggest that protamine is bending the DNA to achieve this curvature rather than increasing the flexibility of the DNA. We therefore conclude that protamine loops DNA in multiple steps, bending it into a loop.
Topics: DNA; Microscopy, Atomic Force; Nucleic Acid Conformation; Pliability; Protamines
PubMed: 32392345
DOI: 10.1093/nar/gkaa365 -
Methods in Molecular Biology (Clifton,... 2013Protamine titration is the gold standard method for the measurement of unfractionated heparin (UFH) concentration in plasma. Protamine titration produces reliable and...
Protamine titration is the gold standard method for the measurement of unfractionated heparin (UFH) concentration in plasma. Protamine titration produces reliable and reproducible results; however it is -generally not considered a convenient assay for current clinical management of UFH as it is not readily automated (Olson et al. Arch Pathol Lab Med 122(9):782-798, 1998). Early clinical trials of UFH therapy determined that a heparin concentration of 0.2-0.4 U/ml by protamine titration correlated to an APTT of 1.5-2.5 times higher compared to baseline values produced desirable UFH safety and efficacy outcomes (Hull et al. N Engl J Med 315(18):1109-1114, 1986; Hull et al. N Engl J Med 322:1260-1264, 1990; Turpie et al. N Engl J Med 320:352-357, 1989; Brill-Edwards et al. Ann Intern Med 119(2):104-109, 1993; Hull Int Angiol 14(1):32-34, 1995). Such studies paved the way to the current view that it is no longer ideal to manage UFH based solely upon a 1.5-2.5 times prolongation of the "normal" APTT. Most advisory bodies recommend therapeutic APTTs be determined by correlating APTT results with therapeutic UFH levels as measured by anti-Xa assay (0.35-0.7 U/ml) or protamine titration (0.2-0.4 U/ml) (Hirsh and Raschke. Chest 126(3):188S-203S, 2004) (see Note 1). The concentration of UFH in a sample is measured by determining the amount of protamine required to return the thrombin clotting time (TCT) test (prolonged by UFH) to a pre-UFH level (Laffan and Manning. Dacie and Lewis: practical haematology. Churchill Livingstone: London, 2001).
Topics: Blood Coagulation; Blood Coagulation Tests; Heparin; Humans; Protamines; Thrombin
PubMed: 23546721
DOI: 10.1007/978-1-62703-339-8_21 -
The Journal of Extra-corporeal... Mar 2020Without anticoagulation, cardiopulmonary bypass would not have developed over the last nearly 60 years into one of the most influential innovations in medicine; without... (Review)
Review
Without anticoagulation, cardiopulmonary bypass would not have developed over the last nearly 60 years into one of the most influential innovations in medicine; without the ability to reverse anticoagulation, cardiac surgery might not have become the common intervention, which is now practiced globally. Despite the recent breathtaking developments in extracorporeal technology, heparin and protamine remain the pillars of anticoagulation and its reversal until this day. However, there is still much controversy in particular about protamine dosing regimens. A number of recent publications investigating various approaches to dosing protamine have rekindled this debate. This review is seeking to capture the current thinking about protamine dosing after cessation of cardiopulmonary bypass.
Topics: Animals; Anticoagulants; Cardiopulmonary Bypass; Heparin; Heparin Antagonists; Humans; Protamines
PubMed: 32280146
DOI: 10.1182/ject-1900038