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PubMed1994

Selective heparinization of the extracorporeal membrane oxygenation circuit using continuous infusions of protamine and heparin in a short-term pig model.

Systemic heparinization is required for both neonatal and paediatric extracorporeal membrane oxygenation (ECMO). However, it places the patient at risk of serious haemorrhage. We report an alternative: 'selective' heparinization of the ECMO circuit using a continuous infusion of heparin near the venous catheter as blood enters the circuit, and a simultaneous protamine infusion near the arterial catheter as blood enters the patient. Theoretically, the circuit remains heparinized while the patient maintains near-normal clotting activity. Three healthy piglets were placed on venoarterial ECMO in standard fashion. When the animal and its extracorporeal circuit flow were stable, a protamine infusion was begun: 1 mg of protamine to neutralize each 100 units of infused heparin. No haemodynamic instability was noted during the five hours of each study. Mean activated clotting times (ACT) were significantly lower in all three piglets than in their respective circuits (p < 0.001). We conclude that 'selective' heparinization of the ECMO circuit is possible using continuous infusions of protamine and heparin in a short-term piglet model.

Animals↗

PubMed1997

Neurone-specific enolase and Sangtec 100 assays during cardiac surgery: Part I--The effects of heparin, protamine and propofol.

Neurone-specific enolase (NSE) and Sangtec 100 (S-100) (Sangtec Medical, Sweden) assays are designed for clotted samples, but when studying cerebral damage following cardiac surgery, perioperative samples will contain heparin and/or protamine. The lipid emulsion propofol is also frequently used during cardiac surgery and could affect the assays. We, therefore, studied the effects of heparin, protamine and propofol on the accuracy of NSE and S-100 assays in five healthy patients. Blood samples were taken and divided into four groups: normal saline was added to group A; heparin to group B; heparin followed by protamine to group C; and propofol to group D. NSE and S-100 concentrations were measured for all samples. Neither heparin, protamine nor propofol affected the accuracy of S-100 and NSE assays; therefore, samples can be taken throughout operations involving cardiopulmonary bypass without influencing the results.

Anesthetics, Intravenous↗

PubMed1988

Unpredictable anaphylactic reaction to protamine sulfate.

Anaphylactic reactions to protamine administration often can be predicted by the presence of patient risk factors. In the case described, an anaphylactic reaction to protamine occurred in a patient without identifiable risk factors. A history of prior protamine exposure, fish allergy, or vasectomy suggests patients may be at greater risk for anaphylactic response to protamine; however, patients can develop anaphylaxis in the absence of such factors.

Anaphylaxis↗

PubMed2007

Relative neutralization of the biological actions of sulfaminoheparosans (K5 derivatives) and heparins by protamine sulfate.

Biosynthetic, semisynthetic, and synthetic analogues of heparins are currently developed as substitute antithrombotic agents for heparin. Sulfaminoheparosan (SAH) represents a bacterial polysaccharide (K5)-derived antithrombotic polymer from which pharmacologically active products with varying molecular weights (5-25 kDa) can be derived. These agents have been shown to exhibit pharmacologic effects comparable to heparins. The objective of this investigation is to determine the relative neutralization profile of various SAH derivatives, also called as bioheparins, by protamine sulfate. Four SAH fractions with varying molecular weights (20, 9, 7, and 6 kDa), a low molecular weight heparin (LMWH), tinzaparin, and unfractionated heparin (UFH) were supplemented to normal human pool plasma over a concentration range of 6.2 to 100 microg/mL. A fixed amount of protamine sulfate at 25 microg/mL (final concentration) was supplemented to determine the neutralization profile by performing tests such as prothrombin time (PT), activated partial thromboplastin time (APTT), Heptest, prothrombin-induced clotting time (PiCT), and amidolytic anti-Xa and anti-IIa assays. Protamine sulfate produced varying degrees of neutralization of all bioheparin fractions in the clotting assays. In the amidolytic anti-IIa assay relatively stronger inhibition was noted for all agents than inhibition of FXa. On a cumulative basis the neutralization profile of SAHs was comparable with heparins. These results suggest that the anticoagulant activities of SAH derivatives can be antagonized by protamine sulfate. These studies warrant further in vivo investigation to validate the relative neutralization profile of sulfaminoheparosans.

Bacterial Capsules↗

PubMed1999

Protamine induces elevation of cytosolic free Ca2+ in cultured porcine aortic endothelial cells.

To test the hypothesis that protamine influences calcium movement in endothelial cells, we measured the concentration of intracellular free calcium ([Ca2+]i) in cultured porcine aortic endothelial (PAE) cells in Krebs solution (2.5mM Ca2+, pH 7.4) at 37 degrees C, by fura-2 fluorimetry. The basal [Ca2+]i of PAE cells was 113+/-18 nM (n=6). Protamine increased [Ca2+]i in a concentration-dependent manner (EC50, the concentration having 50% of the maximum effect, 1.4+/-0.3 microg mL(-1), n=6). The response of PAE cells to 100 microg mL(-1) protamine (330+/-80 nM, n=6) was blocked by a Ca2+ chelator, 5 mM glycoletherdiaminetetraacetic acid (EGTA; 131+/-16 nM, n=6), and by a non-selective Ca2+ channel blocker, 3 mM Co2+ (134+/-14 nM, n=6). These results suggest that Ca2+ influx through cell-membrane Ca2+ channels is mainly responsible for the protamine-induced Ca2+ elevation.

Animals↗

PubMed1987

The major protamine from stallion sperm. Isolation and amino-acid sequence.

The major stallion protamine was isolated from sperm cell nuclei by extraction with 6M guanidine/5% mercaptoethanol, alkylation with 4-vinylpyridine and subsequent reversed-phase high-performance liquid chromatography. The primary structure of stallion protamine was determined by N-terminal sequencing of the intact protein and of the fragments obtained from thermolysin cleavage of the S-pyridylethylated and from endoproteinase Lys-C cleavage of the S-aminoethylated protein. Stallion protamine consists of 49 amino-acid residues and shows 49% identity with all other sequenced mammalian type 1 protamines.

Acetates↗

PubMed1987

Haploid expression of a protamine gene during bovine spermatogenesis.

A 500-base cDNA encoding the bovine protamine was used for hybridization experiments with total RNA prepared from testes of prepubertal and sexually mature bulls and from pachytene spermatocytes and spermatids isolated from mature testes. The mRNA for protamine was first detected in the 7-month old testis containing 10-15% of round spermatids but was absent in testes of younger animals containing only diploid spermatogenic cells. Hybridization of the protamine cDNA with the RNA of isolated spermatids of the mature testis resulted in a prominent hybridization signal, while the faint signal obtained with the RNA of pachytene spermatocytes was found to be due to contamination of the cell preparation by spermatids. As demonstrated by in situ hybridization on testis-sections the transcripts are confined to the central cell layers of the tubuli seminiferi corresponding to the spatial arrangement of postmeiotic spermatogenic cells. The results indicate that the protamine gene in the bull is postmeiotically expressed and the mRNA is synthesized as a 680 nucleotide long molecule.

Animals↗

PubMed1988

Immunocytochemical localization of protamine in the boar testis.

Protamine was specifically demonstrated in spermatids and spermatozoa of the boar by immunoelectron microscopy, using anti-boar or anti-ram protamine antisera, and three different direct or indirect labelling techniques. The two isomers of the protamine could not be labelled separately. The protamine is present in the cytoplasm of elongating spermatids and it enters the nuclei throughout the elongation process after possible storage in the cytoplasm or in the nuclear envelope of spermatids, or both. These findings differ from previous observations in other species.

Animals↗

PubMed1989

Potentiality of protamine sulfate as mutagen.

The mutagenicity of protamine sulfate has been clarified based on chromosomal aberration of cultured chinese hamster lung cells (cell line) in direct and metabolic activation methods and microbial mutagenesis (Ames test). In chromosomal aberration test, protamine sulfate caused cytotoxicity in the high doses (2500 and 5000 micrograms/ml) in the presence of rat liver homogenates (S-9). But very negligible or no cytotoxicity occurred in direct method at high dose (5000 micrograms/ml). Structural aberration of chromosome was not occurred in either of the methods. In microbial mutagenesis study, protamine sulfate did not show any cytotoxicity to microbes up to the dose of 5000 micrograms per plate. Furthermore, it did not have any effect in microbes like mutagens or like some toxic agent. The study reveals that protamine sulfate is not mutagen.

Animals↗

PubMed1989

Morphological study of the cytoskeleton of endothelial cells in vitro. Effects of heparin and protamine.

The relation between the cytoskeleton and multiplication of cultured endothelial cells was observed immunocytochemically and electron microscopically. Heparin and protamine were used to control the multiplication of the cells. Cytochalasin D, a microfilament synthesis inhibitor, was also used, and its effect on cytoskeletal morphology was compared with the effect of heparin or protamine. In order to quantify changes in microfilaments, the ratio of the length of microfilaments to that of intermediate filaments (M/I ratio) was measured by transmission electron microscopy of the whole mounted cells. The addition of heparin to the culture medium not only enhanced multiplication of the endothelial cells, but also induced the outgrowth of many pseudopodia. In association with these changes, microfilaments became sparse, and stress fibers became short. The addition of protamine to the culture medium suppressed multiplication of endothelial cells and made them spherical. The thickening of the cytoplasmic layer increased the apparent density of the cytoskeleton, but the M/I ratio remained unchanged. Cytochalasin D made the endothelial cells spherical, and at the same time stress fibers disappeared, and microfilaments became sparse. The M/I ratio was smaller than that of the others. Protamine may inactivate protein which forms bridges to connect microfilaments or which binds microfilaments and the cell membrane.

Actin Cytoskeleton↗

PubMed1980

Cross-reactions between protamines of different species: the role of arginine clusters.

Human and monkey sera containing autoantibodies to protamines reveal often strong cross-reactions with protamines of other species including salmon protamine. These cross-reactions can be readily detected both in the immunofluorescence test and th micro-complement fixation test. These sera react to a much lesser extent with poly-L-arginine. The results indicate that the cross-reactions of these protamines are not primarily due to clusters of arginine.

Animals↗

PubMed1981

Use of the activated coagulation time in cardiac surgery. Effects on heparin-protamine dosages and bleeding.

A standard heparin-protamine protocol was used for a series of 44 patients. In a second series of 82 patients. Activated Clotting Time (ACT) by the Hemochron method was used to control heparinization and its reversal with protamine. The two groups was similar in regard to surgical procedures, pump-times and perfusion technique. Patients in group II controlled by Hemochron received in average 13% less heparin and 48% less protamine than patients in group 1 (p less than 0.001 Student's t-test). The intra-operative blood loss was on an average 50% less in group II than in group I (p less than 0.001). There was, however, no significant difference in regard to postoperative bleeding. The introduction of the ACT test thus resulted in reduced dosages of heparin and protamine and in a reduction of intra-operative bleeding, while surgical technique seems to be the main factor in the control of postoperative bleeding.

Adult↗

PubMed1992

Hemodynamic effects of intraaortic versus intravenous protamine administration after cardiopulmonary bypass in man.

A hemodynamic study of men undergoing elective coronary artery bypass surgery was undertaken to elucidate the side effects of protamine given into the ascending aorta (group A, n = 16) or into the central venous line (group V, n = 16). After termination of extracorporeal circulation, protamine was infused over 120 seconds, and the hemodynamic profile was continuously recorded. During the first minute, the systemic arterial pressure fell to about 60% of the preprotamine level in both groups, but the hemodynamic changes occurred more rapidly (p < 0.05) in group V than in group A, with maximal pressure drop at 61.7 +/- 2.7 vs 74.4 +/- 4.9 seconds. Following spontaneous restoration of the systemic blood pressure, the pulmonary artery pressure rose considerably in both groups, as did the pulmonary capillary wedge and central venous pressures, reaching higher levels in the intravenous group. The cardiovascular responses were again more rapid in group V than in group A (p = 0.004). The degree of systemic hypotension thus did not benefit from use of the intraaortic rather than the intravenous route for administering protamine. The more pronounced and more rapid pulmonary circulatory changes in the intravenous group suggest that the hemodynamic effects of protamine are initiated in the lungs.

Aorta↗

PubMed1999

Different effects of protamine on canine coronary microvessel and conductance arteries: evidence of hyperpolarizing factor release.

BACKGROUND: Protamine administration may lead to systemic hypotension, perhaps because of vasodilatation produced by endothelial nitric oxide. This study compared release of vasoactive substances from canine coronary microvessels with that from paired conductance arteries. METHODS: Microvessels were mounted in a videoscopic no-flow system, and circumflex arteries were studied in organ chambers; both were induced to contract by endothelin-1. RESULTS: Protamine (10 to 160 micrograms/mL) produced concentration-dependent relaxation in both microvessel and conductance arteries (46% +/- 14% maximal relaxations in microvessel and 82% +/- 15% in conductance arteries, n = 10 each). Removal of the endothelium abolished this relaxation (P < .05, n = 6). Indomethacin (10(-5) mol/L) did not alter the relaxation in either group (51% +/- 10% in microvessel and 103% +/- 7% in conductance arteries, n = 6 each). NG-monomethyl-L-arginine (L-NMMA, 10(-4) mol/L) attenuated relaxation in conductance arteries (38% +/- 12%, P = .04, n = 6) but had no effect on microvessel arteries (58% +/- 10%, n = 6). Tetraethylammonium chloride (10(-3) mol/L), an inhibitor of voltage-dependent potassium channels, had no effect on conductance arteries (103% +/- 9%, n = 6) but abolished relaxation in microvessels (-25% +/- 11%, P = .03, n = 6). CONCLUSIONS: Protamine sulfate causes endothelium-dependent relaxation in microvessel and conductance arteries in the heart by different mechanisms--that is, by nitric oxide release in conductance arteries and by endothelium-derived hyperpolarizing factor (EDHF) release in microvessels. This is the first description of the release of EDHF in response to protamine administration.

Animals↗

PubMed1999

The heparin-protamine interaction. A review.

The heparin-protamine interaction is a topic of intense scrutiny due to its mandatory use during cardiopulmonary bypass. It can be estimated that over 2,000,000 patients are exposed to the heparin-protamine interaction each year. From clinical and experimental observation it is known that protamine neutralization of heparin causes increased pulmonary artery pressures and decreased systolic and diastolic blood pressure, myocardial oxygen consumption, cardiac output, heart rate, and systemic vascular resistance. These multiple cardiovascular effects are mediated via complement activation, histamine release, thromboxane and nitric oxide production, and antibody formation. This article reviews the current understanding of the heparin-protamine interaction from the world's literature.

Animals↗

PubMed2000

Monitoring unfractionated heparin therapy: relationship between eight anti-Xa assays and a protamine titration assay.

Several studies have demonstrated that heparin assays, such as anti-activated factor X (anti-Xa) assays, can be successfully substituted for activated partial thromboplastin time for heparin dosage monitoring. A number of different assays are available and the relationship between results with different techniques is largely unknown. The aim of the present study was to assess the relationship between heparin assays by protamine titration and anti-Xa assays. Samples were collected from 43 patients receiving unfractionated heparin (UFH). In each sample, the heparin level was determined using a protamine titration assay and eight commercially available anti-Xa assays. The mean heparin level by protamine titration was 0.31 U/ml. Mean anti-Xa activity results ranged from 0.40 to 0.42 IU/ml for the three clotting-based assays, and from 0.32 to 0.40 IU/ml for five chromogenic assays. Thus mean results of different anti-Xa assays varied by up to 30%. The range of anti-Xa activity equivalent, on average, to 0.2-0.4 U/ml by protamine titration, considered to be the therapeutic range, was approximately 0.25-0.5 IU/ml, depending on the assay. The relationship between results of clotting and chromogenic methods was similar irrespective of whether or not warfarin-induced prolongation of international normalized ratios was present.

Antibodies↗

PubMed2000

Fatal anaphylactic reaction to protamine after femoropopliteal by-pass surgery.

BACKGROUND AND AIMS: Administration of protamine might cause serious complications especially in patients treated preoperatively with NPH insulin. MATERIAL AND METHODS: A case report. RESULTS AND CONCLUSION: Administration of protamine sulphate caused fatal anaphylactic reaction to a diabetic patient undergoing femoropopliteal by-pass surgery. Care should be taken when administering protamine to a patient treated preoperatively with NPH insulin and the possibility of an anaphylactid reaction to protamine have to be kept in mind.

Anaphylaxis↗

PubMed2000

Fatal anaphylactoid shock associated with protamine for heparin reversal during anesthesia.

A 19-year-old female was scheduled for elective surgery of repair of ventricular septal defect (VSD). She had no known previous food or drug allergy history. She was not previously exposed to protamine and did not have any of the risk factors pointing to protamine hypersensitivity reaction. Unfortunately there were two anaphylactoid shocks occurring during this surgery. One was caused by intravenous (i.v.) administration of antibiotics, and the other happened following i.v. drip of protamine sulfate for reversal of systemic heparinization. She had none of the risk factors suggestive of hypersensitivity to drugs and was therefore considered not at risk for such severe adverse reactions which happened. This article was to discuss the anaphylactoid shock induced by antibiotics and protamine during anesthesia, and the prevention and management of such a reaction.

Adult↗