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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 -
Canadian Medical Association Journal May 1973Protamine is used for titration of heparin in vitro for diagnosis of hemorrhagic states and for neutralization of heparin in vivo to terminate heparinization. The... (Review)
Review
Protamine is used for titration of heparin in vitro for diagnosis of hemorrhagic states and for neutralization of heparin in vivo to terminate heparinization. The protamine equivalent varies with the heparin preparation, conditions of testing and, in vivo, with the amount of heparin present in the circulation. The latter depends on time after administration and the hemodynamic and metabolic state of the patient. Protamine, when injected rapidly, will release histamine and agglutinate platelets. Bleeding (spontaneous hemorrhage) demonstrates a multiple breakdown of hemostatic mechanisms due to surgical stress, drugs, exposure of the blood to foreign surfaces, etc. Simple rules for the amount of protamine required for an individual patient based on clinical judgement will be satisfactory in most cases. When hemostasis is not achieved, it must be appreciated that heparin and protamine are only part of a complex deteriorating situation.
Topics: Hemorrhage; Hemostasis; Heparin; Heparin Antagonists; Histamine Release; Humans; Hypotension; In Vitro Techniques; Neutralization Tests; Protamines; Thrombocytopenia
PubMed: 4122234
DOI: No ID Found -
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 -
Transfusion Oct 2013Protamine is widely used to reverse the anticoagulant effects of heparin. Although mild thrombocytopenia is common in patients given protamine after cardiac procedures,...
BACKGROUND
Protamine is widely used to reverse the anticoagulant effects of heparin. Although mild thrombocytopenia is common in patients given protamine after cardiac procedures, acute severe thrombocytopenia has not been described. We encountered a patient who experienced profound thrombocytopenia and bleeding shortly after administration of protamine and performed studies to characterize the responsible mechanism.
STUDY DESIGN AND METHODS
Patient serum was studied for antibodies that recognize protamine, heparin-protamine complexes, and platelets (PLTs) treated with protamine using flow cytometry, enzyme-linked immunosorbent assay, and serotonin release from labeled PLTs.
RESULTS
A high-titer immunoglobulin G antibody was detected in patient serum that recognizes protamine in a complex with heparin or PLT surface glycosaminoglycans (GAGs) and activates PLTs treated with protamine at concentrations achieved in vivo after protamine infusion. The antibody is distinctly different from those found in patients with heparin-induced thrombocytopenia on the basis of its failure to recognize heparin in a complex with PLT factor 4 (PF4) and to release serotonin from labeled PLTs in the absence of protamine.
CONCLUSIONS
Findings made suggest that the patient's antibody is specific for conformational changes induced in protamine when it reacts with heparin or a PLT surface GAG. Development of severe thrombocytopenia after treatment of this patient with protamine defines a previously undescribed mechanism of drug-induced immune thrombocytopenia. Patients given protamine who produce this type of antibody may be at risk of experiencing thrombocytopenia if given the drug a second time while antibody is still present.
Topics: Aged; Blood Platelets; Female; Heparin; Heparin Antagonists; Humans; Platelet Activation; Protamines; Receptors, IgG; Thrombocytopenia
PubMed: 23384227
DOI: 10.1111/trf.12112 -
BioMed Research International 2014Drug repositioning is one of the most rapidly emerging fields of study. This concept is anchored on the principle that diseases have similar damaged or affected... (Review)
Review
Drug repositioning is one of the most rapidly emerging fields of study. This concept is anchored on the principle that diseases have similar damaged or affected signaling pathways. Recently, drugs have been repositioned not only for their alternative therapeutic uses but also for their applications as biomaterials in various fields. However, medical drugs as biomaterials are rarely focused on in reviews. Fragmin and protamine have been recently the sources of increasing attention in the field of tissue engineering and regenerative medicine. Fragmin and protamine have been manufactured primarily as a safe antidote for the circulating heparin. Lately, these drugs have been utilized as either micro- or nanoparticle biomaterials. In this paper, we will briefly describe the concept of drug repositioning and some of the medical drugs that have been repurposed for their alternative therapeutic uses. Also, this will feature the historical background of the studies focused on fragmin/protamine micro/nanoparticles (F/P M/NPs) and their applications as biomaterials in tissue engineering, stem cell therapy, and regenerative medicine.
Topics: Cell- and Tissue-Based Therapy; Dalteparin; Drug Repositioning; Heparin; Humans; Nanoparticles; Protamines; Regenerative Medicine; Signal Transduction; Stem Cells; Tissue Engineering
PubMed: 24995338
DOI: 10.1155/2014/936196 -
PLoS Genetics Jun 2022Protamines are unique sperm-specific proteins that package and protect paternal chromatin until fertilization. A subset of mammalian species expresses two protamines...
Protamines are unique sperm-specific proteins that package and protect paternal chromatin until fertilization. A subset of mammalian species expresses two protamines (PRM1 and PRM2), while in others PRM1 is sufficient for sperm chromatin packaging. Alterations of the species-specific ratio between PRM1 and PRM2 are associated with infertility. Unlike PRM1, PRM2 is generated as a precursor protein consisting of a highly conserved N-terminal domain, termed cleaved PRM2 (cP2), which is consecutively trimmed off during chromatin condensation. The carboxyterminal part, called mature PRM2 (mP2), interacts with DNA and together with PRM1, mediates chromatin-hypercondensation. The removal of the cP2 domain is believed to be imperative for proper chromatin condensation, yet, the role of cP2 is not yet understood. We generated mice lacking the cP2 domain while the mP2 is still expressed. We show that the cP2 domain is indispensable for complete sperm chromatin protamination and male mouse fertility. cP2 deficient sperm show incomplete protamine incorporation and a severely altered protamine ratio, retention of transition proteins and aberrant retention of the testis specific histone variant H2A.L.2. During epididymal transit, cP2 deficient sperm seem to undergo ROS mediated degradation leading to complete DNA fragmentation. The cP2 domain therefore seems to be a key aspect in the complex crosstalk between histones, transition proteins and protamines during sperm chromatin condensation. Overall, we present the first step towards understanding the role of the cP2 domain in paternal chromatin packaging and open up avenues for further research.
Topics: Animals; Chromatin; Histones; Humans; Infertility, Male; Male; Mammals; Mice; Protamines; Semen; Spermatozoa
PubMed: 35763544
DOI: 10.1371/journal.pgen.1010272 -
Development (Cambridge, England) May 2023Unique chromatin remodeling factors orchestrate dramatic changes in nuclear morphology during differentiation of the mature sperm head. A crucial step in this process is...
Unique chromatin remodeling factors orchestrate dramatic changes in nuclear morphology during differentiation of the mature sperm head. A crucial step in this process is histone-to-protamine exchange, which must be executed correctly to avoid sperm DNA damage, embryonic lethality and male sterility. Here, we define an essential role for the histone methyltransferase DOT1L in the histone-to-protamine transition. We show that DOT1L is abundantly expressed in mouse meiotic and postmeiotic germ cells, and that methylation of histone H3 lysine 79 (H3K79), the modification catalyzed by DOT1L, is enriched in developing spermatids in the initial stages of histone replacement. Elongating spermatids lacking DOT1L fail to fully replace histones and exhibit aberrant protamine recruitment, resulting in deformed sperm heads and male sterility. Loss of DOT1L results in transcriptional dysregulation coinciding with the onset of histone replacement and affecting genes required for histone-to-protamine exchange. DOT1L also deposits H3K79me2 and promotes accumulation of elongating RNA Polymerase II at the testis-specific bromodomain gene Brdt. Together, our results indicate that DOT1L is an important mediator of transcription during spermatid differentiation and an indispensable regulator of male fertility.
Topics: Animals; Male; Mice; Cell Differentiation; Chromatin Assembly and Disassembly; Histone-Lysine N-Methyltransferase; Histones; Protamines; Semen; Spermatids
PubMed: 37082969
DOI: 10.1242/dev.201497 -
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 -
Molecules (Basel, Switzerland) Jan 2024Protamine is a cationic peptide derived from fish sperm and has several important functional properties: antibacterial properties, acting as a carrier for injectable...
Protamine is a cationic peptide derived from fish sperm and has several important functional properties: antibacterial properties, acting as a carrier for injectable insulin and as a heparin antagonist, combatting fatigue, etc. Thus, it has been widely used in medicinal applications and food products. Cultured is a type of pufferfish with a delicious taste that is popular in China, and its production is increasing significantly. Therefore, protamine was extracted via acid extraction from the sperm of and further isolated and purified via sephadex gel chromatography, ion exchange chromatography, and desalination chromatography. Furthermore, the physicochemical properties of protamine were investigated. The results showed that the sperm of the cultured were non-toxic, and the extracted and purified protamine had high contents of arginine (36.90%) and lysine (27.02%), respectively. The secondary structure of protamine was mainly β-folded and irregularly curled. Additionally, protamine exhibited high thermal stability with a denaturation temperature of 176 °C. This study would provide a theoretical basis for the structural analysis, bioactivity, and resource development of pufferfish protamine and help to promote the development of the pufferfish industry.
Topics: Male; Animals; Takifugu; Protamines; Semen; Heparin Antagonists; Anti-Bacterial Agents
PubMed: 38202846
DOI: 10.3390/molecules29010263 -
Current Opinion in Cell Biology Apr 2022The sperm genome is tightly packed into a minimal volume of sperm nuclei. Sperm chromatin is highly condensed by protamines (PRMs) after histone-protamine replacement,... (Review)
Review
The sperm genome is tightly packed into a minimal volume of sperm nuclei. Sperm chromatin is highly condensed by protamines (PRMs) after histone-protamine replacement, and the majority of the sperm genome forms a nucleo-protamine structure, namely, the PRM-DNA complex. The outline of sperm chromatin structure was proposed 30 years ago, and the details have been explored by approaches from several independent research fields including male reproduction and infertility, DNA biopolymer, and most recently, genome-wide sequence-based approaches. In this review, the history of research on sperm chromatin structure is briefly described, and the progress of recent related studies is summarized to obtain a more integrated view for the sperm chromatin, an extremely compacted "black box."
Topics: Chromatin; Chromatin Assembly and Disassembly; DNA; Humans; Male; Protamines; Spermatozoa
PubMed: 35344802
DOI: 10.1016/j.ceb.2022.102075