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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 -
Transfusion Oct 2020Bleeding complications are common in cardiac surgery and lead to an increase in morbidity and mortality. This is multifactorial in aetiology including the effects of... (Review)
Review
Bleeding complications are common in cardiac surgery and lead to an increase in morbidity and mortality. This is multifactorial in aetiology including the effects of cardiopulmonary bypass, the drugs given to manipulate the coagulation system and the vascular nature of the surgery itself. Viscoelastic tests provide a point of care, rapid assessment of coagulation which offer the advantage of faster turnaround times and a nuanced view of the elements of the coagulation system allowing targeted therapy to be delivered quickly. Both thomboelastography (TEG)and thromboelastometry (ROTEM) have been recommended for use in cardiac surgery, both have shown a reduction in transfusion and bleeding when used as part of a testing algorithm. They are particularly useful in assessing residual heparinisation and fibrinogen levels. Additionally, TEG allows the evaluation of the effects of anti-platelet agents on platelet function. This review discusses the mechanisms by which bleeding occurs in cardiac surgery and explores three uses of viscoelastic testing in cardiac surgery: to predict bleeding, to assess platelet function and peri-operative testing to reduce transfusion.
Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Loss, Surgical; Blood Transfusion; Cardiac Surgical Procedures; Coronary Artery Bypass; Extracorporeal Circulation; Fibrinogen; Fibrinolysis; Heparin; Humans; Hypothermia, Induced; Platelet Function Tests; Point-of-Care Systems; Postoperative Hemorrhage; Preoperative Care; Procedures and Techniques Utilization; Protamines; Randomized Controlled Trials as Topic; Thrombelastography
PubMed: 32955756
DOI: 10.1111/trf.16075 -
Clinical Pharmacokinetics Aug 2019Unfractionated heparin (UFH) is a commonly used anticoagulant therapy for the acute treatment and prevention of thrombosis. Its short duration of action, reversibility... (Review)
Review
Unfractionated heparin (UFH) is a commonly used anticoagulant therapy for the acute treatment and prevention of thrombosis. Its short duration of action, reversibility of effect by protamine sulfate, and extensive clinical experience are some of the advantages that support its use. However, the choice of dose and dosing regimen of UFH remains challenging for several reasons. First, UFH has a narrow therapeutic window and wide variability in the dose-response relationship. Second, its pharmacodynamic (PD) properties are difficult to characterise owing to the complex multidimensional mechanisms of interaction with the haemostatic system. Third, the complex heterogeneous chemical composition of UFH precludes precise characterisation of its pharmacokinetic (PK) properties. This review provides a comprehensive mechanistic approach to the interaction of UFH with the haemostatic system. The effect of chemical structure on its PK and PD properties is quantitatively described, and a framework for characterisation of the dose-response relationship of UFH for the purpose of dose optimisation is proposed.
Topics: Anticoagulants; Dose-Response Relationship, Drug; Evaluation Studies as Topic; Heparin; Humans; Protamines; Thrombosis
PubMed: 30850987
DOI: 10.1007/s40262-019-00751-7 -
Vascular Apr 2023The literature suggests that heparin reversal with protamine in transcarotid arterial revascularization (TCAR) decreases postoperative bleeding complications without an... (Observational Study)
Observational Study
OBJECTIVE
The literature suggests that heparin reversal with protamine in transcarotid arterial revascularization (TCAR) decreases postoperative bleeding complications without an increase in stroke or death. However, the dosing of protamine in TCAR has not yet been evaluated. We aimed to evaluate our experience with intraoperative heparin reversal with protamine.
METHODS
This was a single-center, retrospective, observational study that evaluated the heparin and protamine doses used during TCAR. All adult patients who underwent TCAR between 9/1/2019 and 4/2/2021 were included. Demographic data was obtained from the Vascular Quality Initiative and protamine/heparin doses were obtained from a chart review. Multivariate logistic regression models were used to assess the association between the protamine/heparin dose ratio and other variables.
RESULTS
Sixty-two patients were included. The average protamine/heparin dose ratio used was 0.96 ± 0.12 mg/U; seven had a ratio less than 0.8 mg/U, and one was greater than 1.2 mg/U. Two patients experienced bleeding complications, which were managed non-operatively. No patient with a protamine/heparin ratio greater than 0.8 mg/U had postoperative bleeding. Postoperative bradycardia was observed in 32.3% of patients and hypotension in 35%, with 19% requiring vasopressors. No relationship was identified between the protamine/heparin ratio and bleeding, bradycardia, or hypotension. No 30-day myocardial infarction, stroke or death occurred.
CONCLUSIONS
We identified a near 1:1 ratio of a protamine/heparin dosing regimen for the reversal of heparin during TCAR, with postoperative bleeding complications similar to those reported in the literature. However, patients who received a lower protamine/heparin ratio did not experience bleeding complications. In the era of protamine shortages, a future larger-scale study is needed to evaluate the impact of a lower protamine dose on postoperative complications.
Topics: Humans; Carotid Stenosis; Retrospective Studies; Bradycardia; Endovascular Procedures; Risk Factors; Treatment Outcome; Stroke; Postoperative Complications; Heparin; Stents; Risk Assessment
PubMed: 35040739
DOI: 10.1177/17085381211067047 -
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 -
Journal of Hematology & Oncology Dec 2022Acute myeloid leukemia (AML) is a fatal clonal hematopoietic malignancy, which results from the accumulation of several genetic aberrations in myeloid progenitor cells,...
BACKGROUND
Acute myeloid leukemia (AML) is a fatal clonal hematopoietic malignancy, which results from the accumulation of several genetic aberrations in myeloid progenitor cells, with a worldwide 5-year survival prognosis of about 30%. Therefore, the development of more effective therapeutics with novel mode of action is urgently demanded. One common mutated gene in the AML is the DNA-methyltransferase DNMT3A whose function in the development and maintenance of AML is still unclear. To specifically target "undruggable" oncogenes, we initially invented an RNAi-based targeted therapy option that uses the internalization capacity of a colorectal cancer specific anti-EGFR-antibody bound to cationic protamine and the anionic siRNA. Here, we present a new experimental platform technology of molecular oncogene targeting in AML.
METHODS
Our AML-targeting system consists of an internalizing anti-CD33-antibody-protamine conjugate, which together with anionic molecules such as siRNA or ibrutinib-Cy3.5 and cationic free protamine spontaneously assembles into vesicular nanocarriers in aqueous solution. These nanocarriers were analyzed concerning their physical properties and relevant characteristics in vitro in cell lines and in vivo in xenograft tumor models and patient-derived xenograft leukemia models with the aim to prepare them for translation into clinical application.
RESULTS
The nanocarriers formed depend on a balanced electrostatic combination of the positively charged cationic protamine-conjugated anti-CD33 antibody, unbound cationic protamine and the anionic cargo. This nanocarrier transports its cargo safely into the AML target cells and has therapeutic activity against AML in vitro and in vivo. siRNAs directed specifically against two common mutated genes in the AML, the DNA-methyltransferase DNMT3A and FLT3-ITD lead to a reduction of clonal growth in vitro in AML cell lines and inhibit tumor growth in vivo in xenotransplanted cell lines. Moreover, oncogene knockdown of DNMT3A leads to increased survival of mice carrying leukemia patient-derived xenografts. Furthermore, an anionic derivative of the approved Bruton's kinase (BTK) inhibitor ibrutinib, ibrutinib-Cy3.5, is also transported by this nanocarrier into AML cells and decreases colony formation.
CONCLUSIONS
We report important results toward innovative personalized, targeted treatment options via electrostatic nanocarrier therapy in AML.
Topics: Humans; Mice; Animals; Protamines; Static Electricity; RNA, Small Interfering; Leukemia, Myeloid, Acute; Methyltransferases; DNA
PubMed: 36457063
DOI: 10.1186/s13045-022-01390-5 -
Translational Cancer Research Nov 2021Protamine 1 (PRM1) is specific in sperm and plays essential roles in fertilization, also a member of cancer testis antigen (CTA) family. This study aims to summarize the... (Review)
Review
OBJECTIVE
Protamine 1 (PRM1) is specific in sperm and plays essential roles in fertilization, also a member of cancer testis antigen (CTA) family. This study aims to summarize the expression and function of PRM1 in spermatogenesis, and to broaden the current knowledge and inspire future development of PRM1-based therapeutic strategies in cancer treatment and nanomedicine.
BACKGROUND
The protamine proteins, are characterized by an arginine-rich core and cysteine residues. Humans express two types of protamine: PRM1 and PRM2. The abnormal expression or proportion of PRM1 and PRM2 is known to be associated with subfertility and infertility, especially for PRM1 which is highly evolutionary conserved in mammalians and expressed in all vertebrates. Biological functions of PRM1 have been unveiled in diverse cellular processes, such as tumorigenesis, somatic cell nucleus transfer, and drug delivery systems. Moreover, PRM1 is identified as a CTA in chronic leukemia (CLL) and colorectal cancer (CRC).
METHODS
Literature was obtained using PubMed and the keywords protamine 1, PRM1, or P1, from January 1, 1980, through July 20, 2021. We also collect the additional evidence through screening references of articles identified through the PubMed searches.
CONCLUSIONS
PRM1 is well-studied in male infertility, and further researches and attempts to develop PRM1 as novel tumor marker, as well as drug delivery vector, will be of important clinical significance.
PubMed: 35116345
DOI: 10.21037/tcr-21-1582 -
Polymers Feb 2022Biomolecules are attractive building blocks with self-assembly ability, structural diversity, and excellent functionality for creating artificial materials. Heparin and... (Review)
Review
Biomolecules are attractive building blocks with self-assembly ability, structural diversity, and excellent functionality for creating artificial materials. Heparin and protamine, a clinically relevant pair of biomolecules used in cardiac and vascular surgery, have been shown to coassemble into particulate polyelectrolyte complexes in vitro. The resulting heparin-protamine particles exhibit adhesive properties that enable advantageous interactions with proteins, cells, and various other substances and have been employed as functional materials for biomedical applications. In this review article, we summarize recent progress in research on the use of heparin-protamine particles as drug carriers, cell adhesives, and cell labels. Studies have demonstrated that heparin-protamine particles are potentially versatile in biomedical fields from drug delivery and regenerative medicine to plastic surgery.
PubMed: 35267754
DOI: 10.3390/polym14050932 -
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 -
Nature Communications May 2023Genetic studies elucidate a link between testis-specific serine/threonine kinases (TSSKs) and male infertility in mammals, but the underlying mechanisms are unclear....
Genetic studies elucidate a link between testis-specific serine/threonine kinases (TSSKs) and male infertility in mammals, but the underlying mechanisms are unclear. Here, we identify a TSSK homolog in Drosophila, CG14305 (termed dTSSK), whose mutation impairs the histone-to-protamine transition during spermiogenesis and causes multiple phenotypic defects in nuclear shaping, DNA condensation, and flagellar organization in spermatids. Genetic analysis demonstrates that kinase catalytic activity of dTSSK, which is functionally conserved with human TSSKs, is essential for male fertility. Phosphoproteomics identify 828 phosphopeptides/449 proteins as potential substrates of dTSSK enriched primarily in microtubule-based processes, flagellar organization and mobility, and spermatid differentiation and development, suggesting that dTSSK phosphorylates various proteins to orchestrate postmeiotic spermiogenesis. Among them, the two substrates, protamine-like protein Mst77F/Ser and transition protein Mst33A/Ser, are biochemically validated to be phosphorylated by dTSSK in vitro, and are genetically demonstrated to be involved in spermiogenesis in vivo. Collectively, our findings demonstrate that broad phosphorylation mediated by TSSKs plays an indispensable role in spermiogenesis.
Topics: Animals; Male; Humans; Protein Serine-Threonine Kinases; Testis; Phosphorylation; Spermatogenesis; Histones; Drosophila; Protamines; Fertility; Serine; Threonine; Mammals
PubMed: 37149634
DOI: 10.1038/s41467-023-38357-0