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PubMed1991

Protamine-heparin-induced pulmonary hypertension in pigs: effects of treatment with a thromboxane receptor antagonist on hemodynamics and coagulation.

Adverse hemodynamic reactions after protamine neutralization of heparin are an infrequent but important clinical problem. Pre-treatment of swine with a thromboxane A2 receptor antagonist has been reported to prevent the pulmonary hypertensive response occasionally seen after protamine reversal of heparin anticoagulation. In the current study, a control group of pigs (n = 9) received intravenous heparin (300 IU/kg), followed after 10 min by a neutralizing dose of protamine (3 mg/kg). A treatment group of pigs (n = 11) was treated identically, except that the thromboxane A2 receptor antagonist L-670596 (2 mg/kg) was infused intravenously 2 min after the protamine infusion. Hemodynamic and coagulation profiles were monitored during these procedures. Pulmonary hypertension developed and reached a peak within 2 min of protamine administration, often at the same time that L-670596 was administered in the treatment group. There was no statistical difference between control and treatment groups' peak pulmonary arterial pressure and peak pulmonary vascular resistance. However, the interval for return of mean pulmonary artery pressure from peak to baseline values was 11.6 +/- 3.1 versus 5.5 +/- 1.9 min (mean +/- SD) for control and treatment groups, respectively (P less than 0.01). Thromboxane B2 plasma concentrations increased in both groups and were correlated with the pulmonary hypertensive response (r = 0.86, P less than 0.01). Platelet aggregation to collagen was inhibited by the thromboxane A2 receptor antagonist (P less than 0.05). Bleeding time was prolonged beyond normal range in 50% of L-670596-treated pigs. All other coagulation tests in both groups returned to baseline after reversal of heparin with protamine and were unaffected by L-670596.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Neutralization of enoxaparine-induced bleeding by protamine sulfate.

It has been suggested that protamine sulfate is a poor antidote for the bleeding side-effects of low molecular weight heparins (LMWHs) in vivo, since protamine sulfate does not completely neutralize the anti-factor Xa activity of LMWHs in vitro or ex vivo. Therefore, we performed experiments to compare directly the abilities of protamine sulfate to neutralize the anticoagulant activities of the LMWH, enoxaparine, and unfractionated heparin ex vivo, with its ability to neutralize the bleeding side-effects of both compounds in vivo. Bleeding was measured as the amount of blood lost from 5 cuts made in rabbits ears before and after treatment with enoxaparine or unfractionated heparin +/- protamine sulfate. Plasma anti-factor Xa and anti-thrombin activities ex vivo, were measured chromogenically. Doses of 400 and 1,500 anti-factor Xa U/kg of heparin and enoxaparine, respectively, were required to enhance blood loss to the same extent. Protamine sulfate completely neutralized blood loss induced by both compounds, but did not neutralize the anti-factor Xa nor antithrombin activities ex vivo. We conclude that protamine sulfate is an effective antidote for the bleeding side-effects of enoxaparine and unfractionated heparin, despite its inability to completely neutralize their anticoagulant activities.

Animals↗
PubMed1990

The role of protamine dose assay in reversal of heparin following extracorporeal circulation for open heart surgery.

The amount of protamine required for the neutralisation of heparin following cardiopulmonary bypass was determined by a Protamine Titration Assay using the principle of the dose--response curve and the patient's estimated blood volume. In 300 open heart surgery patients, infusion of the determined dose of protamine normalised the Activated Clotting Time (ACT) to baseline levels in 97% of these patients and produced adequate hemostasis. Our present study showed that the dose of protamine dropped to 75% of the dose calculated by conventional method of heparin to protamine ratio of 1:1. This had minimised the adverse effects of excessive protamine administration and optimised coagulation control after extracorporeal circulation.

Adolescent↗
PubMed1989

Electromechanical effects of protamine in isolated human atrial and canine ventricular tissues.

Effects of protamine sulfate (1-100 mg%) on the electrical and mechanical activities of isolated dog ventricular tissues and human atrial fibers were studied. In dog Purkinje fibers, 10 mg% protamine reduced markedly the maximum diastolic potential and the rate of phase 0 depolarization. Eventually, slow response action potential developed at a depolarized level and the twitch force declined abruptly. The depolarization and the negative inotropy were reversed by increasing [Ca])o or [K]o but not by tetrodotoxin. When Purkinje fibers were depolarized in 27 mM [K]o Tyrode solution plus 0.5 microM epinephrine, higher concentrations of protamine (30 mg% or above) were required to depress the slow response action potentials and twitch, in contrast to the action of verapamil and diltiazem (1-30 microM). Dog ventricular and human atrial muscle fibers were more resistant to the depressant effects of protamine. In human atrial fibers, however, 10 mg% protamine was able to depress significantly the oscillatory afterpotentials and aftercontractions induced by epinephrine and theophylline. The present findings suggest that the depolarization and decline in force of cardiac tissues induced by protamine, at a concentration about twice of the maximum clinically relevant dose, may be explained by the development of slow response action potentials as a result of decrease in membrane K+ and Na+ conductances.

Action Potentials↗
PubMed1989

Purification and properties of a distinct protamine kinase from the cytosol of bovine kidney cortex.

A protamine kinase has been purified to apparent homogeneity from extracts of the cytosol of bovine kidney cortex. This protamine kinase exhibited an apparent Mr = 43,000 as estimated by gel permeation chromatography on Sephacryl S-200 and an apparent Mr = 45,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The purified protamine kinase exhibited about 5% activity with casein, 8% with histone H2B, and less than 0.1% with histone H1, histone H4, glycogen synthase a from rabbit skeletal muscle, ovalbumin, bovine serum albumin, and phosvitin. The activity of the highly purified protamine kinase was unaffected by cyclic AMP (up to 0.1 mM), cyclic GMP (up to 0.1 mM), the heat-stable protein inhibitor of cyclic AMP-dependent protein kinase (up to 100 micrograms/ml), heparin (up to 100 micrograms/ml), EGTA (up to 1 mM), Ca2+ (up to 1 mM), calmodulin (up to 0.5 microM) in the absence or presence of Ca2+ (0.05 mM), and phosphatidylserine (up to 40 micrograms/ml) and/or diolein (up to 1 microgram/ml) in the absence or presence of Ca2+ (up to 0.5 mM). Experiments in which extracts of kidney cytosol were incubated with [gamma-32P]ATP and MgCl2 revealed that the phosphorylation of numerous polypeptides was markedly increased in the presence of the purified protamine kinase. The results indicate that this protamine kinase of kidney cytosol is a novel protein kinase.

Animals↗
PubMed1988

Beneficial effect of cyclooxygenase inhibition on adverse hemodynamic responses after protamine.

The hypothesis that adverse effects observed when heparin is antagonized by protamine are mediated by metabolites of the arachidonic acid cascade was tested during general anesthesia (enflurane, fentanyl) in 16 pigs classified into two groups. In the first group (n = 9), effects of intravenously administered protamine on systemic hemodynamics, blood/gas tensions, and arterial and mixed-venous prostanoid levels were studied. The second group (n = 7) was pretreated with indomethacin 10 mg/kg, and the same measurements were made. All pigs received heparin 150 units/kg. When protamine 1.1 +/- 0.1 mg/kg was administered over 3 minutes, marked hemodynamic alterations were observed in group 1: pulmonary artery pressure and pulmonary vascular resistance increased, and left ventricular end-diastolic and systemic arterial pressures decreased. Arterial and mixed-venous PO2 values deteriorated in all pigs in group 1 at the end of protamine infusion. These alterations were accompanied by significantly elevated prostanoid levels in arterial and mixed-venous plasma samples: Thromboxane A2, prostaglandin F2 alpha, KH2-PGF2 alpha (a metabolite of prostaglandin F2 alpha), and prostacyclin were maximally elevated at completion of protamine and remained significantly above control values at 5 minutes but were not significantly different from control after 10 minutes. Blocking the cyclooxygenase cascade by pretreatment of the pigs with indomethacin (group 2) prevented hemodynamic and blood gas alterations. It is concluded that in pigs the detrimental side effects associated with the use of protamine to reverse heparin are mediated by metabolites of the cyclooxygenase cascade.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, General↗
PubMed1978

Differentiation between antibodies to protamines and somatic nuclear antigens by means of a comparative fluorescence study on swollen nuclei of spermatozoa and somatic cells.

The indirect immunofluorescence test on swollen nuclei of rat thymocytes, chicken red blood cells and human and salmon spermatozoa was found to be an easy and satisfactory method for the discrimination between antibodies to sperm-specific nuclear antigens and somatic nuclear antigens. This study shows that nuclear antibodies present in the sera of vasectomized men and in rabbit antisera to human protamines are directed against the human sperm-specific nuclear antigens (protamines), and that they may cross-react with salmon protamine. These sera do not react with somatic nuclear antigens. This comparative fluorescence study and a complement fixation study, performed with sera from diabetic patients, proved that the administration of insulin retard (protamine-zinc-insulin) may lead to the formation of antibodies to the fish protamine. These antibodies may reveal a weak cross reaction with human protamines. The results obtained in this study also prove that the nuclei of chicken red blood cells and human sperm do not contain, or contain very small amounts of, histone fraction H1, and that salmon sperm nuclei do not contain any of the histone fractions, and suggest that the nuclei of mature human spermatozoa contain smaller amounts of histones in comparison to somatic cell nuclei.

Animals↗
PubMed1987

High-performance liquid chromatographic separation and partial characterization of human protamines 1, 2, and 3.

A method for separating the three human protamines by HPLC of underivatized, total protamine extracts on a Nucleosil RP-C18 column is described. The identities of the three proteins have been confirmed by a combination of disc gel electrophoresis, amino acid composition, and primary sequence analysis. The results show that human protamine 3 elutes first, closely followed by protamine 2. Protamine 1 elutes later. The amino acid compositions and partial amino terminal sequences of human protamines 2 and 3 indicate that these two proteins are very closely related and suggest that they differ only by three amino-terminal amino acids.

Amino Acids↗
PubMed1985

Heparin, protamine, and ionized calcium in vitro and in vivo.

The possibility that hypotension associated with protamine or heparin might be related to changes in levels of serum ionized calcium values was determined by in vitro and in vivo studies in dogs. In vitro protamine did not decrease serum calcium levels, but heparin did in a dose-dependent fashion. The reduction ranged from 7% with 10 units/ml of heparin to 20% with 100 units/ml of heparin. Ionized calcium concentrations initially decreased by heparin were restored toward control levels by our increasing the dose of protamine, indicating that the electrostatic attraction between protamine and heparin molecules is stronger than that between heparin and ionized calcium. Despite significant reductions in blood pressure and heart rate, clinical doses of protamine did not decrease ionized calcium in vivo. Although the results of the in vitro study suggested that heparin-induced hypocalcemia might occur in vivo, in vivo heparin caused neither a decrease in ionized calcium nor hypotension. The reduction of ionized calcium by heparin might have been rapidly compensated for in vivo. The results indicate that hypotension due to protamine or heparin is unlikely to be related to changes in serum ionized calcium levels.

Animals↗
PubMed1986

Rate of protamine administration: its effect on heparin reversal and antithrombin recovery after coronary artery surgery.

Patients received a calculated dose of protamine at two different rates (5 min and 30 min) after coronary artery surgery to determine the relationship of the rate of protamine administration with the adequacy of heparin reversal and the rate of return of antithrombin III (AT III) activity. Plasma heparin concentrations and AT III activities were measured at specific times both during and for 3 days after cardiac surgery. Both rates of protamine administration resulted in clinically acceptable clotting, return of the activated coagulation time to normal, and zero heparin concentration after 24 hr. Two hours after protamine administration, patients who received rapidly administered protamine had prolonged coagulation compared to the other group. Normal AT III activity returned the second postoperative day. These results imply that normal postoperative coagulation occurs when protamine is administered over 30 min without a bolus, and that blood is potentially hypercoagulable immediately after heparin reversal because of depressed AT III activity.

Aged↗
PubMedDate not supplied

[Protamine sulfate-induced resistance to the hypoglycemic effect of insulin].

Administration of protamine sulfate in a dose (0.9-1.1 mg/200 g) sufficient for binding reactive circulatory heparin provokes in rats the status of temporary resistance to the hypoglycemic action of both exogenous and endogenous insulin. This effect occurs after protamine sulfate administration 5-30 minutes prior to insulin in doses of 0.2-2.4 Units/200 g, respectively, or release of endogenous heparin stimulated by sugar load. As the time interval between administration of protamine sulfate and administration (release) of insulin is prolonged or shortened, the status of resistance does not develop. Protamine sulfate does not produce any effect on the blood concentration of immunoreactive insulin. Similarly to protamine sulfate, the resistance to the hypoglycemic action of insulin may be also provoked by the synthetic heparin antagonist, 2,5-ionene that binds heparin, forming a stable polyelectrolyte complex ionene-heparin. Administration of a sufficient heparin dose (10 Units/200 g) may interrupt the protamine sulfate-induced resistance, which manifests in the recurrence of the hypoglycemic action of insulin. There are reasons to assume that the presence of reactive heparin in the circulation is necessary for insulin reception by target tissues.

Animals↗
PubMed1983

Effect of increased glomerular permeability on the localization of immune aggregates and protamine-heparin aggregates in the rat.

The effect of adriamycin (doxorubicin)-induced proteinuria, which is characterized by a defect in the glomerular size selective filter with intact charge barrier function, was studied on the glomerular localization of immune aggregates and protamine-heparin aggregates. For that purpose, passive Heymann's nephritis and protamine-heparin aggregates were induced in rats with adriamycin nephrosis (mean proteinuria 311 mg/24 hours at 4 weeks after intravenous administration of adriamycin, 6.5 mg/kg). The distribution of immune aggregates and protamine-heparin aggregates in the proteinuric rats was studied by immunofluorescence and electron microscopy and compared with glomerular aggregate localization in untreated control rats. The amount of glomerular aggregates was measured by semiquantative immunofluorescence. The results showed that glomerular localization of immune aggregates in nephrotic rats was similar to that in control rats. The aggregates were present in a granular distribution along the epithelial side of the glomerular basement membrane and also in areas of widespread foot process obliteration, in a slightly lesser amount than in controls. The localization of protamine-heparin aggregates in the glomerular capillary wall of nephrotic rats was identical with that in controls. No mesangial accumulation of immune or protamine-heparin aggregates was found. The results indicate that increased permeability per se has no effect on the glomerular distribution of macromolecular aggregates. In addition, this study shows that in adriamycin-induced nephrosis--in contrast to what has been reported in aminonucleoside nephrosis--(a) the glomerular capillary wall has maintained the antigens that take part in in situ immune complex formation in passive Heymann's nephritis, (b) the intact glomerular charge barrier is capable of binding protamine-heparin aggregates, and (c) no mesangial accumulation of aggregates occurs, suggesting a normal mesangial function in this model.

Animals↗
PubMed1984

[Protaminase activity of plasma and serum in vitro. II.- Electrophoretic study of serum albumin-protamine soluble complexes].

Cellulose acetate electrophoresis (pH 8,6 ionic strength 0,05) puts in evidence the soluble complexes "albumin-protamine" which are easily distinguished from albumin being more positively charged. The albumin-protamine complexes formed in serum or plasma, after addition of protamine, undergo in vitro a dissociation progressing with time to the complete restitution of albumin. This dissociation is slowed down by the inhibitors of the carboxypeptidase B (SCPB), an enzyme present in plasma and serum, but is not influenced by the inhibitor phenylmethyl-sulfonyl fluoride (PMSF). A protamine which had lost its four C-terminal arginines by the action of a DFP-treated carboxypeptidase B (CPB) still formed complexes with albumin (and, besides, remained able to neutralize heparin). On the contrary protamine degraded first by CPB, and afterwards by the DFP-treated carboxypeptidase A (CPA) lost these two properties. These results suggest that the dissociation of albumin-protamine complex in plasma and serum requires a protaminase action additional to the action of SCPB.

Animals↗
PubMed1981

Cardiovascular effects of protamine sulfate in man.

The effect of protamine sulfate on several cardiovascular and biochemical variables was studied in man under clinical conditions. This study was performed to quantitate these effects in 15 adult patients who had undergone cardiopulmonary bypass for coronary artery bypass grafting. Protamine was administered in typical clinical doses (3 mg/kg) at typical clinical rates (total dose infused over 5 minutes). This infusion rate is greatly in excess of the 50 mg/10 min suggested in the protamine package insert. No statistically significant changes in mean arterial blood pressure, cardiac output, central venous pressure, total or ionized calcium, PaO2, PaCO2, pH, Na+, or K+ were found during or after administration of protamine sulfate. Hypotension was observed after administration of protamine to one patient, but no etiologic mechanism was apparent. Previous reports suggest cardiovascular depression by protamine in the dog, a species highly susceptible to these effects. Data obtained in man in this study do not corroborate the canine studies.

Adult↗
PubMed1997

[A case of twice catastrophic pulmonary vasoconstriction-type shock induced with protamine sulfate].

A 71-year-old female was scheduled for the re-replacement of a mechanical mitral valve. After the cardiopulmonary bypass (CPB) she was administered protamine sulfate. Subsequently mean systemic blood pressure went down below 20 mmHg and central venous pressure and mean pulmonary blood pressure were above 50 mmHg, and immediately CPB was restarted as an assist device for circulation. After the second CPB, she was administered protamine sulfate again, and the same shock occurred. At last the third CPB was restarted and the third protamine administration was not undertaken after the third CPB. Although her postoperative drainage may have been relatively much more compared with cases of neutralization of heparin, postoperative course was uneventful in this patient. Administered protamine to neutralize the anticoagulat effects of heparin may often cause temporary treatable hypotension. Although protamine may rarely cause severe pulmonary vasocontriction and anaphylactoid reactions, clinical pictures become critical once these reactions occur. It is important in these cases to identify protamine as the cause of shock and avoid repeating the shocks.

Aged↗
PubMed1998

[Effect of protamine on the microbicidal efficacy of formaldehyde].

Testing the ability of commercial compounds to provide an effective disinfection of instruments requires test conditions that are close to reality which includes the proper selection of the material used to contaminate the test objects. The adhesion of the material must be strong enough to keep it attached to the test object during and after insertion into the disinfectant solution. Its characteristics should come as close as possible to those of the contaminations encountered in practice. The guideline for instrument disinfectants published by the Robert Koch-Institute recommends the use of coagulated blood. Accordingly, heparinized sheep blood is mixed with the test germs, and protamin is added to initiate coagulation. In the present investigation we compared this contamination procedure with a second one, in which coagulation was achieved by adding a CaCl2 solution to citrate blood. We also included agarose as an almost inert contaminant in our experiments. The results showed that protamine is able to increase the microbicidal efficacy of formaldehyde on staphylococci significantly. When these test germs were embedded either in citrat blood or in agarose, it took about twice the disinfectant concentrations to achieve the same microbicidal effects as with protamine blood (Fig. 1). Remarkably, the results obtained with citrate blood were the same as those with agarose, regardless of the differences in material between the two contaminants. It should also be noted that the microbicidal effect of the formaldehyde proved to be almost independent from the amount of contaminant per test area, hence, from the thickness of the layer. When M. terrae was employed as test germ, the results obtained with protamine blood and citrate blood, respectively, as contaminants were identical (Fig. 2). The same was true for the other test germs investigated, except for E. faecium (Fig. 3). The addition of even very small amounts of protamine to the embedding compound, agarose led to a substantially increased efficacy of the formaldehyde against staphylococci (Fig. 4). This effect was especially distinct in suspension (Fig. 5). Whenever the efficacy of formaldehyde-containing disinfectants is to be tested and evaluated, one should be aware of this synergism between protamine and formaldehyde. In these cases, it is advised to employ other contaminating agents, such as coagulated blood prepared by addition of CaCl2 to citrate blood.

Animals↗
PubMed1983

Interaction of protamine sulfate with thrombin.

Protamine sulfate (salmine), a basic protein with a molecular weight of 4,626 +/- 109, is a known antiheparin agent which in the absence of heparin demonstrates an anticoagulant activity. To date, much work has been done to elucidate the interaction of heparin with thrombin and its physiologic inhibitor, Antithrombin III (ATIII). Little is known, however, about the mechanism of anticoagulant action of protamine sulfate and its mode of thrombin inactivation. We provide information about the interaction of protamine sulfate with purified, labeled thrombin and ATIII through binding experiments in which protamine is shown to inhibit the inactivation of thrombin by ATIII. Furthermore, we show in clotting assays that protamine sulfate has an inhibitory effect on thrombin in the conversion of fibrinogen to fibrin, and that this inhibition is concentration dependent, partial, and reversible.

Antithrombin III↗
PubMed1992

Protamine-induced permeability changes in the neutrophil plasma membrane as the basis of activation of exocytosis.

Protamine induces a gradual change in plasma membrane permeability in rabbit neutrophils, which is evident from the increase of indol fluorescence, and the leakage of quin2 from quin2-loaded neutrophils. The influx of extracellular Ca2+ into the neutrophil provides an explanation for exocytosis which occurs in the presence of Ca2+ and protamine. The dependence of exocytosis on Ca2+ concentration follows the same pattern as is observed in neutrophils permeabilized by other means. In the absence of Ca2+, and in the presence of protamine, La3+ has an activating effect on exocytosis. At higher concentrations La3+ inhibits exocytosis that occurs in the presence of Ca2+ and protamine, as do some other metal ions. The resemblance between the membrane effects of a number of toxins, as reported in literature, and protamine-induced membrane damage suggests that they occur via the same mechanism.

Aminoquinolines↗