(Circulation. 1995;91:2188-2194.)
© 1995 American Heart Association, Inc.
Articles |
Reversal of Heparin Anticoagulation by Recombinant Platelet Factor 4 in Humans
From the C.V. Richardson Cardiac Catheterization Laboratory of the University of North Carolina Hospitals and the Cardiology Division of the University of North Carolina at Chapel Hill.
Correspondence to Gregory J. Dehmer, MD, Director, Cardiac Catheterization Laboratory, University of North Carolina Hospitals, 101 Manning Dr, Chapel Hill, NC 27514.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background Protamine is used to reverse the anticoagulant effects of heparin, but it can have important side effects. Platelet factor 4 (PF4) is a protein found in platelet alpha granules that binds to and thereby neutralizes heparin. We evaluated the safety and effectiveness of intravenous recombinant PF4 to neutralize heparin anticoagulation after cardiac catheterization in a phase 1, open-label trial.
Methods and Results The study group consisted of 18 patients having diagnostic cardiac catheterization. Heparin (5000 U) was given after vascular access was obtained. In the first 12 patients, additional heparin was given at the conclusion of the procedure so that all patients had activated coagulation times >300 seconds before rPF4 was given. Three patients each received 0.5, 1.0, 2.5, or 5.0 mg/kg rPF4 over a period of 3 minutes at the conclusion of the catheterization procedure. In 6 additional patients, extra heparin was not given at the conclusion of the procedure, and 1.0 mg/kg rPF4 was given. Hemodynamic measurements, cardiac output, and serial blood tests were performed 5, 10, 20, and 30 minutes after rPF4 and then into the next 24 hours. There were no serious side effects in any patient, despite transient rPF4 levels as high as 14 870 ng/mL in the patients receiving 5.0 mg/kg. One patient receiving 2.5 mg/kg had a slight transient rise in liver enzymes possibly related to the rPF4. There were no important hemodynamic effects of rPF4 administration at any dose used. Doses of 2.5 and 5.0 mg/kg were uniformly effective in reversing the anticoagulant effect of heparin. At lower doses, rPF4 neutralized the effects of heparin in most but not all patients. Pharmacokinetic analysis suggested a monophasic and one-compartment clearance of the PF4-heparin complex. No neutralizing factors to rPF4 were detected in the samples collected 7 days after dosing.
Conclusions rPF4, in doses ranging from 0.5 to 5.0 mg/kg over 3 minutes, had no serious side effects. Given in sufficient amounts, rPF4 can completely and rapidly reverse the anticoagulant effects of heparin.
Key Words: angiography • anticoagulants • heparin • cardiopulmonary bypass • platelet-derived factors
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Heparin sulfate is used extensively in clinical medicine as an anticoagulant. In addition to its use for deep venous thrombosis, for pulmonary embolism, and in patients after thrombolytic therapy for myocardial infarction, heparin is used during invasive angiographic procedures and cardiopulmonary bypass to prevent thrombus formation. Rapid reversal of anticoagulation is required after cardiopulmonary bypass and some invasive angiographic procedures. Protamine sulfate irreversibly binds to heparin, thereby neutralizing its anticoagulant effect, and is the only drug clinically available for this purpose. Used according to established guidelines, protamine is a relatively safe and effective drug, but serious adverse reactions may occur. The exact incidence of severe reactions, including respiratory compromise, hypotension, and shock, varies from 0.2% to 3% in a general population1 2 3 4 5 6 to as high as 27% in patients who are allergic to fish and those who have received therapy with neutral protamine Hagedorn (NPH) insulin.7 8 9
Platelet factor 4 (PF4) is a protein released from platelet alpha granules during activating events. Although its exact physiological role remains uncertain, several biological properties of the protein have been demonstrated. One of these is the ability of PF4 to neutralize the anticoagulant action of heparin. A recombinant PF4 has been synthesized and evaluated in animals for this potential application. These data suggest that rPF4 effectively reverses the anticoagulant effects of heparin and is free of the adverse hemodynamic and allergic problems associated with protamine.10 Therefore, the purpose of this study was to evaluate the safety and utility of rPF4 to reverse heparin anticoagulation in humans. Since this was the first use of intravenous rPF4 in humans, our primary goal was to evaluate its safety. A secondary goal was to determine preliminary information about the effective dose of rPF4 for heparin neutralization and the speed with which rPF4 could be administered.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Patients
The study population consisted of 18 patients referred for diagnostic cardiac catheterization, 9 men and 9 women, with a mean age of 58±10 years. All patients were studied because of known or suspected coronary artery disease. The catheterization procedure showed coronary artery stenoses >50% luminal diameter narrowing in one or more arteries in 14 patients, while the remaining 4 patients had coronary stenoses of lesser severity. The mean left ventricular ejection fraction was 0.61±0.12, and in 3 patients, it was <0.50. Five patients were receiving NPH insulin for the treatment of diabetes mellitus. The study was approved by the Human Studies Committee of the University of North Carolina, and all subjects gave informed consent.
Study Outline
Before the cardiac catheterization procedure,
patients underwent
a baseline physical examination and series of blood tests including a
complete blood count, platelet count, blood chemistries, liver and
renal function tests, clotting assays, and arterial blood gas. Right
and left heart catheterization, left ventriculography, and coronary
arteriography were performed from the femoral approach in all patients
by standard techniques. Nonionic contrast (iohexol) was used in all
procedures. A balloon-flotation catheter with thermistor was used to
record the right-heart pressures and measure cardiac output by the
thermodilution method. Thermodilution cardiac output measurements were
performed in triplicate and averaged to obtain the measurement value at
a given time in the study protocol. Although intra-arterial blood
pressure measurements were available during the catheterization
procedure, auscultatory measurements of systemic arterial blood
pressure were used throughout the study so that the same method was
used before, during, and after the invasive portion of the study
protocol. Baseline measurements of the hemodynamic variables were
recorded during the catheterization procedure before administration of
radiographic contrast. At the conclusion of the routine catheterization
procedure, after angiography but before rPF4 administration, all
hemodynamic measurements were repeated. Hemodynamic measurements were
repeated 5, 10, 20, and 30 minutes after the rPF4 was given; then all
catheters were removed, and hemostasis was obtained by local pressure
over the puncture site. At the same time intervals, measurements of
clotting function were obtained. After completion of the invasive
monitoring, patients were observed for 24 hours, with serial
measurements of vital signs in addition to repeat blood tests. Patients
received treatment for their clinical conditions as necessary and
returned 7 days after rPF4 administration for a follow-up physical
examination and repeat series of blood tests for comparison.
rPF4 Administration
The study was divided into two parts with
regard to the schedule
used to administer rPF4. Previous studies of heparin anticoagulation
during cardiac catheterization have demonstrated that some patients are
not adequately anticoagulated at the conclusion of the
procedure.11 12 To ensure that rPF4 was being tested
in a
fully anticoagulated patient, an activated coagulation time (ACT) was
measured at the conclusion of the routine catheterization procedure.
Although activated partial thromboplastin times (aPTT) were obtained
simultaneously, the results were not available immediately. Thus, the
ACT measurements were used to monitor the effect of rPF4 in the
catheterization laboratory. In the first 12 consecutive patients
studied (part A), additional heparin was given, if necessary, at the
conclusion of the catheterization procedure until the ACT was >300
seconds. Cohorts of 3 patients then received 0.5, 1.0, 2.5, or 5.0
mg/kg rPF4 as a bolus over 3 minutes. The rPF4 (Repligen Corp) used for
this study was full-length human sequence PF4 and was not stabilized by
other proteins or detergents in solution. After completion of the drug
bolus, an ACT was measured again and, if it was not <200 seconds, an
additional bolus of rPF4 identical to the initial bolus was given.
In part B of the study, additional heparin was not administered, to more closely mimic the usual conditions of a catheterization procedure. In this part, 6 additional patients were given 1.0 mg/kg rPF4, and the speed of rPF4 administration was increased so that 3 patients received the bolus over 2 minutes and 3 received it over 1 minute.
PF4 Levels and Neutralizing Factors
Serum levels of PF4 were
obtained at baseline and at 5, 20, 60,
and 240 minutes after drug administration. Blood samples were obtained
carefully to minimize venous trauma and the potential for platelet
activation. The first 10 mL of blood was discarded before the actual
sample was obtained. Samples were collected into an evacuated tube
containing EDTA, mixed by gentle inversion, and immediately placed in
an ice bath for 30 minutes. Plasma was obtained by spinning the sample
tubes in a refrigerated centrifuge for 20 minutes. Plasma samples were
stored at -70°C until analysis with a commercially available
ELISA-based kit that does not discriminate between endogenous and
exogenous PF4 (Enzygnost; Behring). Neutralizing factors to PF4 were
determined at baseline and after 7 days by use of an antibody produced
in rabbits to human PF4.
Statistical Analysis
Analysis of these data was performed
with a repeated-measures
ANOVA followed by a Newman-Keuls test when a significant difference was
detected. All results are expressed as the mean±SD, and
P<.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Reversal of Heparin Anticoagulation
The effect of rPF4 was monitored by changes in the ACT and aPTT (Fig 1
). Baseline ACT was normal in all patients. As
required by protocol for the 12 patients studied in part A, additional
heparin was given to elevate the ACT to >300 seconds before rPF4 was
administered. Eight of the 12 patients required additional heparin,
ranging from 2500 to 7500 U. Recombinant PF4 was then administered
until the ACT was lowered to <200 seconds. Doses of 2.5 or 5.0 mg/kg
were uniformly effective in reducing the ACT to <200 seconds by 5
minutes after administration. Each of the smaller doses (1.0 and 0.5
mg/kg) reduced the ACT to <200 seconds in 2 of 3 patients tested by 5
minutes.
|
The aPTT values were normal at baseline in all patients. The aPTT was >150 seconds in 11 of the 12 patients studied in part A immediately before rPF4 was given. For the statistical analysis, aPTT values >150 seconds were entered as equal to 150 seconds. Like the ACT, the aPTT was lowered to the baseline value within 5 minutes in all patients who received doses of 2.5 or 5.0 mg/kg. At the lower doses of 0.5 and 1.0 mg/kg, the aPTT was reduced to normal or near normal in 5 of 6 patients. In the 1 remaining patient, the ACT was lowered to <200 seconds by 0.5 mg/kg rPF4, but the aPTT remained at >150 seconds.
In
part B of the study, 6 patients received 1.0 mg/kg rPF4 without
additional heparin at the conclusion of the procedure. The mean ACT was
reduced from 302±99 seconds before rPF4 to 150±33 seconds by 5
minutes after rPF4. In these same patients, the aPTT was >150 seconds
in 5 patients before rPF4 and was reduced to 31.4±7.5 seconds within 5
minutes after rPF4. Subsequent measurements of the ACT and aPTT values
at 10, 20, 30, and 60 minutes after rPF4 are shown in Fig 1
.
Examination of the individual responses up to 24 hours did not show a
rebound of the ACT or aPTT back into an elevated range after 2.5 or 5.0
mg/kg rPF4. One of the 3 patients who received 0.5 mg/kg (part A) and 2
of the 9 patients (parts A and B combined) who received 1 mg/kg had a
slight increase in aPTT after the rPF4 was given. On the basis of the
dose and number of doses required, the 0.5- and 1.0-mg/kg doses were
indistinguishable in terms of changes in aPTT or ACT. However, as shown
in Fig 1, those treated with 0.5 mg/kg rPF4 demonstrated a
persistent
slight elevation of the ACT and aPTT up to 4 hours in comparison with
all the other doses.
For all 18 patients in the study, the mean prothrombin time at baseline was 11.2±0.4 seconds and was prolonged by the heparin administration to 17.9±4.6 seconds at the conclusion of the catheterization procedure before rPF4 was given. The prothrombin time was lowered to baseline within 5 minutes after rPF4 and did not change significantly over the next 60 minutes. Mean serum fibrinogen did not vary from the baseline value as measured serially during the first 60 minutes after rPF4. After catheter removal, there was no difficulty obtaining hemostasis by compression of the puncture site in any patient, and no patient developed a significant hematoma.
Hemodynamic Effects
The hemodynamic measurements obtained at
baseline and for the
first 30 minutes after the rPF4 infusion in all 18 patients are
summarized in the Table. Neither systolic nor diastolic
arterial blood pressure varied significantly from the baseline values
after rPF4. The pulse rate was slightly lower 30 minutes after the rPF4
infusion (68±15 beats per minute) compared with the pulse rates at
baseline (75±17 beats per minute) and at the completion of the
angiography (74±13 beats per minute). Cardiac output was higher at the
conclusion of the catheterization procedure immediately after
angiography (6.0±1.6 L/min) compared with the baseline value
(5.4±1.4
L/min, P<.01). After rPF4, the cardiac outputs declined by
9% to 15% (P<.01) in comparison with the value at the
conclusion of the procedure, but none of the cardiac output
measurements after rPF4 were different from the baseline value. Mean
pulmonary capillary wedge pressure and the pulmonary artery systolic
and diastolic pressures were all slightly higher at the conclusion of
the catheterization procedure after contrast administration before rPF4
was given. These changes are consistent with the effects of
radiographic contrast and fluid administration during routine
catheterization. After the administration of rPF4, all of these
pressures gradually decreased to their baseline values over the next 30
minutes. The hemodynamic changes were examined separately in the 6
patients who received the highest two doses of rPF4 and were similar to
those described for the whole group.
|
Laboratory Measurements
There were no changes in the mean
values for hemoglobin,
hematocrit, platelet count, liver enzymes (aspartate aminotransferase,
alanine aminotransferase, lactate dehydrogenase, and alkaline
phosphatase), total bilirubin, and creatinine at baseline, 4 hours, 24
hours, and 7 days after rPF4 administration. Examination of the
laboratory changes in each patient showed no clinically important
alterations in hemoglobin, hematocrit, platelet count, creatinine, or
total bilirubin. One patient, who received 2.5 mg/kg rPF4, did have a
transient elevation in aspartate aminotransferase to 52% and lactate
dehydrogenase to 16% above their respective normal ranges within the
first 24 hours after rPF4. These enzyme values returned to normal at 7
days. No other patients who received 2.5 mg/kg and none of the patients
who received 5.0 mg/kg rPF4 had elevations in their liver enzymes.
Finally, there were no changes in pH,
PCO2, or PO2
compared with the baseline values at 5 and 30 minutes after rPF4
administration.
Possible Clinical Side Effects
Possible clinical side effects
occurred in 4 patients. One patient
had chills lasting 20 minutes beginning 45 minutes after the rPF4 was
given but did not develop fever. Three patients developed a headache
during the 24 hours after rPF4 was given. In 1 of these patients, it
was described as an occipital pain that occurred 5 minutes after the
patient received rPF4 and lasted 5 minutes. In the other 2, it occurred
several hours later and was relieved by acetaminophen. One patient
experienced transient back and abdominal pain during rPF4
administration, but the infusion was completed nevertheless. These
symptoms were thought to be musculoskeletal in origin, since they
responded to slight changes in position. This latter patient is 1 of
the 3 who later developed a headache. All of these clinical reactions
were classified as possibly related to the rPF4, but similar symptoms
can occur during and after cardiac catheterization alone.
PF4 Levels, Pharmacokinetics, and Neutralizing Assays
PF4
serum levels were determined at 5, 20, 60, and 240 minutes
after completion of the dosing. Elimination of the PF4/heparin complex
followed a monophasic pattern (Fig 2). The half-life was
determined to be 25.5±13.5 minutes and was independent of the dose
administered. The Cmax increased in an approximately linear
manner as the dose increased, and the plasma clearance of rPF4 was
constant regardless of the dose above 1.0 mg/kg. Serum samples were
tested before and 7 days after the rPF4 in 17 of the patients. There
was no indication that rPF4 elicited an immunologic response.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
This study reports the first use of intravenous rPF4 to reverse the anticoagulant effects of heparin in humans. The main goals of this investigation were to establish the safety of intravenous rPF4 administration over a wide range of concentrations and to develop preliminary data about the dosage necessary to neutralize heparin anticoagulation. Accordingly, rPF4 was administered over a 10-fold range of concentrations from 0.5 to 5.0 mg/kg. At these doses, there were no adverse hemodynamic effects or serious laboratory abnormalities clearly related to rPF4. Cardiac output, mean pulmonary capillary wedge pressure, pulmonary artery systolic and diastolic pressures, and mean right atrial pressure were all elevated at the conclusion of the routine catheterization procedure compared with the baseline values. These changes are consistent with the effects of radiographic contrast and fluid administration during cardiac catheterization.13 14 15 No acute adverse hemodynamic effects were detected in the first 5 minutes after rPF4. By 30 minutes after rPF4 administration, cardiac output, mean pulmonary capillary wedge pressure, and pulmonary artery diastolic pressure had all returned to their baseline values, whereas the mean right atrial and pulmonary artery systolic pressures remained minimally elevated. Systemic arterial pressure did not change after the catheterization procedure or during the first 30 minutes after rPF4 administration. Of importance, the hemodynamic changes in the 6 patients who received the highest two doses of rPF4 were not different from those seen in the entire study group. With the exception of one patient who exhibited a slight transient increase in liver enzymes, there were no important laboratory alterations associated with rPF4 administration, and the drug was well tolerated clinically. One patient had transient chills without fever after rPF4, but similar events occur after routine catheterization and thus may not necessarily be related to the rPF4.16 17 Likewise, the occurrence of back and abdominal pain in one patient was probably from muscle spasms, since they were relieved by a change of position on the catheterization table. The occurrence of headache in 3 patients is unexplained, but this was transient and there were no sequelae. Overall, rPF4 appeared to have a satisfactory safety profile and was effective when administered to reverse heparin anticoagulation after cardiac catheterization.
Use of Protamine to Reverse Heparin Anticoagulation
Intravenous rPF4 could provide an alternative to
protamine for the reversal of heparin anticoagulation.
Protamine is a low-molecular-weight protein derived from the
genital tissue of certain fish. Because it is high in arginine
and is cationic, protamine binds tightly to heparin, which
is highly anionic, thereby neutralizing the anticoagulant effect of
both substances.9 Protamine is used to neutralize heparin
after invasive vascular procedures such as cardiac catheterization and
is required in most cardiac surgeries at the conclusion of
cardiopulmonary bypass. Although the majority of patients who receive
protamine have no difficulties, serious and unpredictable side effects
occur. Intravenous protamine causes peripheral vasodilation, pulmonary
hypertension, and bradycardia and may have a direct negative inotropic
effect.18 19 20 The mechanism by which
protamine causes
systemic vasodilation and myocardial depression is uncertain, both from
laboratory and clinical
studies.1 2 3 4 5 6 7 8 9 18 19 20
Protamine/heparin complexes activate the classic complement pathway
leading to the formation of C5a, which causes aggregation and
activation of leukocytes, release of free oxygen radicals, lipid
peroxidation, platelet aggregation, and the formation of thromboxane
A2 in lung tissue.10 21 Several of these
actions could mediate the increase in pulmonary artery resistance that
is occasionally seen.5 6 While the hemodynamic
effects of
protamine are generally thought to occur if the drug is administered
too rapidly, one study examined this carefully and did not demonstrate
such a relation.19 Although the association between
adverse events and the speed of protamine administration is unproven,
most physicians elect to infuse protamine slowly. It has been
speculated that protamine induces an allergic response mediated by
histamine, which may cause some of the hemodynamic effects. However,
histamine depletion before protamine administration does not modify the
hypotensive effect.22 Allergic reactions to protamine have
been divided into two types: immediate and delayed.1
Anaphylactic reactions usually occur in individuals with a prior
exposure to protamine or NPH insulin or those allergic to
fish.7 8 9 23 Such
anaphylactic reactions may be mediated by
a complement-dependent IgG antibody that appears after prior exposure
to protamine.24 Delayed and severe reactions attributed to
protamine have been described after cardiac
surgery.1 4 5 6
The onset of these reactions occurs from 30 minutes to several hours
after protamine. They are characterized by catastrophic pulmonary
vasoconstriction with noncardiogenic pulmonary edema and total vascular
collapse. Mortality in this type of reaction exceeds 30%, and
survivors have significant morbidity.1 Some evidence
suggests that these latter reactions are not
antibody-mediated.1
Use of PF4 to Reverse Heparin Anticoagulation
In this study,
all patients received a 5000-U bolus of heparin for
anticoagulation during the cardiac catheterization procedure. Prior
studies, however, have shown that not all patients remain adequately
anticoagulated for the duration of their catheterization procedure
after a 5000-U bolus.11 12 Since we wanted to make
certain
that all patients were adequately anticoagulated before they received
rPF4, the protocol was designed to test the level of anticoagulation
with an ACT test before rPF4 was administered. As a result, all
patients studied in part A had ACTs >300 seconds, and 11 of the 12
patients had aPTT values >150 seconds before rPF4 administration. Even
without extra heparin administered at the conclusion of the procedure
(part B), 5 of the 6 patients tested had aPTT values >150 seconds.
Thus, in 17 of the 18 patients, the aPTT was above the standard
therapeutic range before rPF4 administration. The ability of rPF4 to
restore the aPTT to the normal range was clearly related to the amount
given. All patients receiving 2.5 or 5.0 mg/kg PF4 had a normal aPTT 5
minutes after the dose. Although aPTT promptly returned to normal in
most of the patients who received smaller doses, it remained slightly
elevated in some. On the basis of the response at higher doses, it is
likely that failure of the aPTT to normalize at lower doses merely
represents the administration of an insufficient amount of rPF4
rather than a failure of the drug to neutralize heparin. Just as
heparin therapy is monitored by a test of clotting status with
subsequent dosage adjustments, the exact dose of rPF4 to reverse
anticoagulation in individual patients could be monitored by serial
testing.
PF4 Levels in Humans
A small amount of PF4, ranging from 1.7
to 20.9 ng/mL, is found in
plasma from normal individuals.25 26 27
Elevated plasma
levels of PF4 have been shown in diabetics and after exercise in some
patients with coronary artery
disease.25 28 29 30 Heparin
administration both to normal volunteers and to patients with coronary
artery disease will cause a 10- to 30-fold increase in plasma PF4
levels.25 30 31 32 It has
been postulated that PF4 released
from circulating platelets immediately attaches to heparan sulfate
molecules on the endothelial cell
surface.25 30 32 The
increase in plasma PF4 after heparin injection may be due to the
detachment of PF4 bound to the endothelial cell surface.25
The peak plasma levels of PF4 measured after our infusions were as high
as 14 870 ng/mL after doses of 5 mg/kg, but these levels were
transient because of the avid binding of heparin by rPF4.
Pharmacokinetic analysis suggested a monophasic one-compartment
clearance of the PF4/heparin complex, and this is similar to animal
studies performed previously.33 Despite these very high
levels of rPF4, there were no obvious hematologic or hemodynamic
abnormalities.
Potential Side Effects of PF4
Although we did not demonstrate
any serious adverse effects
related to the rPF4 administration, several possibilities should be
considered. The rPF4 administered in this study was made by recombinant
DNA methods using Escherichia coli as the source of the
recombinant protein. The amino acid structure of this rPF4 is identical
to the naturally occurring PF4 found in platelet alpha granules, but
proteins made in bacteria are not glycosylated and may have altered
secondary structures leading to neoantigen formation. Neutralizing
antibodies to rPF4 were not detected after 7 days but could have
developed beyond the surveillance period of this study. Two recent
studies have implicated PF4 as a possible cofactor in the syndrome of
heparin-induced thrombocytopenia.34 35 Complexes of
heparin and PF4 circulate after heparin injection in most patients
without any clinical significance. However, some patients have IgG
specific for these complexes and, when treated with heparin, form
immune complexes in close proximity to the platelet surface. These
immune complexes activate platelets, releasing more PF4, which promotes
more platelet activation, and ultimately thrombocytopenia develops.
These complexes also may cause endothelial injury and thus predispose
to thrombosis. If this proposed mechanism is correct, administration of
rPF4 to a patient predisposed to heparin-induced thrombocytopenia could
aggravate the syndrome. However, since heparin therapy is
contraindicated in patients known to have developed this syndrome in
the past, it is unlikely that there would be an indication to
administer rPF4 to reverse heparin anticoagulation.
Conclusions
Although our experience with rPF4 to reverse
heparin
anticoagulation was favorable, the small number of patients tested in
this initial phase 1 trial is a limitation. Before the possibility of
important side effects can be excluded, more patients must be evaluated
in different clinical circumstances, such as cardiac surgery. However,
if the lack of important side effects and effectiveness demonstrated in
this initial trial is confirmed, rPF4 would be a alternative to
protamine for the reversal of heparin anticoagulation.
|
Acknowledgments |
|---|
This work was funded, in part, by the Repligen Corp, Cambridge, Mass. The authors acknowledge the expert assistance of the technical staff of the C.V. Richardson Cardiac Catheterization Laboratory at the University of North Carolina Hospitals. In addition, the help of the cardiology fellows and nurses who assisted in various aspects of this study is appreciated.
|
Footnotes |
|---|
Dr Bonnem is Medical Director of Clinical Research for Repligen Corp, manufacturer of the platelet factor 4 used in this study. Dr Teo is employed by Repligen in the Division of Pharmacology and Toxicology.
Received August 24, 1994; revision received November 7, 1994; accepted November 14, 1994.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Holland CL, Singh AK, McMaster PRB, Fang W. Adverse reactions to protamine sulfate following cardiac surgery. Clin Cardiol. 1984;7:157-162. [Medline] [Order article via Infotrieve]
2.
Moorthy SS, Pond W, Rowland RG. Severe circulatory shock
following protamine (an anaphylactic reaction). Anesth
Analg. 1980;59:77-78.
3. Jackson DR. Sustained hypotension secondary to protamine sulfate. Angiology. 1970;21:295-298.
4. Olinger GN, Becker RM, Bonchek LI. Noncardiogenic pulmonary edema and peripheral vascular collapse following cardiopulmonary bypass: rare protamine reaction? Ann Thorac Surg. 1980;29:20-25. [Abstract]
5. Nordstrom L, Fletcher R, Pavek K. Shock of anaphylactoid type induced by protamine: a continuous cardiorespiratory record. Acta Anaesthesiol Scand. 1978;22:195-201. [Medline] [Order article via Infotrieve]
6. Lowenstein E, Johnston WE, Lappas DG, D'Ambra MN, Schneider RC, Daggett WM, Akins CW, Philbin DM. Catastrophic pulmonary vasoconstriction associated with protamine reversal of heparin. Anesthesiology. 1983;59:470-473. [Medline] [Order article via Infotrieve]
7. Knape JTA, Schuller JL, DeHaan P, DeJong AP, Bovill JG. An anaphylactic reaction to protamine in a patient allergic to fish. Anesthesiology. 1981;55:324-325. [Medline] [Order article via Infotrieve]
8. Cobb CA, Fung DL. Shock due to protamine hypersensitivity. Surg Neurol. 1982;17:245-246. [Medline] [Order article via Infotrieve]
9.
Stewart WJ, McSweeney SM, Kellett MR, Faxon DP, Ryan TJ.
Increased risk of severe protamine reactions in NPH
insulin-dependent diabetics undergoing cardiac catheterization.
Circulation. 1984;70:788-792.
10.
Cook JJ, Niewiarowski S, Yan Z, Schaffer L, Lu W, Stewart GJ,
Mosser DM, Myers JA, Maione TE. Platelet factor 4 efficiently reverses
heparin anticoagulation in the rat without adverse effects of
heparin-protamine complexes. Circulation. 1992;85:1102-1109.
11. Vacek JL, Bellinger RL, Phelix J. Heparin bolus therapy during cardiac catheterization. Am J Cardiol. 1988;62:1314-1317. [Medline] [Order article via Infotrieve]
12. Dehmer GJ, Haagen D, Malloy CR, Schmitz JM. Anticoagulation with heparin during cardiac catheterization and its reversal by protamine. Cathet Cardiovasc Diagn. 1987;13:16-21. [Medline] [Order article via Infotrieve]
13. Mancini GBJ, Bloomquist JN, Bhargava V, Stein JB, Lew W, Slutsky RA, Shabetai R, Higgins CB. Hemodynamic and electrocardiographic effects in man of a new nonionic contrast agent (iohexol): advantages over standard ionic agents. Am J Cardiol. 1983;51:1218-1222. [Medline] [Order article via Infotrieve]
14.
Higgins CB, Gerber KH, Mattrey RF, Slutsky RA. Evaluation of
hemodynamic effects of intravenous administration of ionic and nonionic
contrast materials. Radiology. 1982;142:681-686.
15. Hanley PC, Holmes DR Jr, Julsrud PR, Smith HC. Use of conventional and newer radiographic contrast agents in cardiac angiography. Prog Cardiovasc Dis. 1986;28:435-448.[Medline] [Order article via Infotrieve]
16. Grossman W. Complications of cardiac catheterization: incidence, causes, and prevention. In: Grossman W, Baim DS, eds. Cardiac Catheterization, Angiography and Intervention. 4th ed. Philadelphia, Pa: Lea & Febiger; 1991:37-38.
17. Hildner FJ. Risks of cardiac catheterization. In: Hill JA, Lambert CR, Pepine CJ, eds. Diagnostic and Therapeutic Cardiac Catheterization. Baltimore, Md: Williams & Wilkins; 1989:26-28.
18. Green CE, Higgins CB, Kelley MJ, Schmidt WS, Haigler FH, Newell JD. Cardiovascular effects of protamine sulfate. Invest Radiol. 1981;16:324-329. [Medline] [Order article via Infotrieve]
19. Shapira N, Schaff HV, Piehler JM, White RD, Sill JC, Pluth JR. Cardiovascular effects of protamine sulfate in man. J Thorac Cardiovasc Surg. 1982;84:505-514. [Abstract]
20. Goldman BS, Joison J, Austen WG. Cardiovascular effects of protamine sulfate. Ann Thorac Surg. 1969;7:459-471.[Medline] [Order article via Infotrieve]
21.
Morel DR, Lowenstein E, Nguyenduy T, Robinson DR, Repine JE,
Chenoweth DE, Zapol WN. Acute pulmonary vasoconstriction and
thromboxane release during protamine reversal of heparin
anticoagulation in awake sheep: evidence for the role of reactive
oxygen metabolites following nonimmunological complement activation.
Circ Res. 1988;62:905-915.
22. Jaques LB. A study of the toxicity of protamine (Salmine). Br J Pharmacol. 1949;4:135-144. [Medline] [Order article via Infotrieve]
23. Caplan SN, Berkman EM. Protamine sulfate and fish allergy. N Engl J Med. 1976;295:172. Letter. [Medline] [Order article via Infotrieve]
24. Lakin JD, Blocker TJ, Strong DM, Yocum MW. Anaphylaxis to protamine sulfate mediated by a complement-dependent IgG antibody. J Allergy Clin Immunol. 1978;61:102-107. [Medline] [Order article via Infotrieve]
25. O'Brien JR, Etherington MD, Pashley M. Intra-platelet platelet factor 4 (IP.PF4) and the heparin-mobilisable pool of PF4 in health and atherosclerosis. Thromb Haemost. 1984;51:354-357. [Medline] [Order article via Infotrieve]
26. Dawes J, Smith RC, Pepper DS. The release, distribution, and clearance of human ß-thromboglobulin and platelet factor 4. Thromb Res. 1978;12:851-861. [Medline] [Order article via Infotrieve]
27.
Kaplan KL, Owen J. Plasma levels of ß-thromboglobulin and
platelet factor 4 as indices of platelet activation in vivo.
Blood. 1981;57:199-202.
28.
Nichols AB, Owen J, Kaplan KL, Sciacca RR, Cannon PJ, Nossel
HL. Fibrinopeptide A, platelet factor 4, and ß-thromboglobulin levels
in coronary heart disease. Blood. 1982;60:650-654.
29. Levine SP, Suarez AJ, Sorenson RR, Raymond NM, Knieriem LK. Platelet factor 4 release during exercise in patients with coronary artery disease. Am J Hematol. 1984;17:117-127. [Medline] [Order article via Infotrieve]
30. Sadayasu T, Nakashima Y, Yashiro A, Kawashima T, Kuroiwa A. Heparin-releasable platelet factor 4 in patients with coronary artery disease. Clin Cardiol. 1991;14:725-729. [Medline] [Order article via Infotrieve]
31. Cella G, Menardo A, Girolami A. Effect of heparin on in vivo platelet factor 4 (PF4) release and platelet aggregation after aspirin administration. Clin Lab Haematol. 1980;2:333-338.
32. Cella G, Colby SI, Taylor AD, McCracken L, Parisi AF, Sasahara AA. Platelet factor 4 (PF4) and heparin-released platelet factor 4 (HR-PF4) in patients with cardiovascular disorders. Thromb Res. 1983;29:499-509. [Medline] [Order article via Infotrieve]
33. Rveinski B, Knight LC, Niewiarowski S. Clearance of human platelet factor 4 by liver and kidney: its alteration by heparin. Am J Physiol. 1988;256:H800-H807.
34.
Kelton JG, Smith JW, Warkentin TE, Hayward CPM, Denomme GA,
Horsewood P. Immunoglobulin G from patients with heparin-induced
thrombocytopenia binds to a complex of heparin and platelet factor 4.
Blood. 1994;83:3232-3239.
35. Visentin GP, Ford SE, Scott JP, Aster RH. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexes with heparin or bound to endothelial cells. J Clin Invest. 1994;93:81-88.
This article has been cited by other articles:
 |
|
 |
|
  J. Hirsh, K. A. Bauer, M. B. Donati, M. Gould, M. M. Samama, and J. I. Weitz Parenteral Anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 141S - 159S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Eslin, C. Zhang, K. J. Samuels, L. Rauova, L. Zhai, S. Niewiarowski, D. B. Cines, M. Poncz, and M. A. Kowalska Transgenic mice studies demonstrate a role for platelet factor 4 in thrombosis: dissociation between anticoagulant and antithrombotic effect of heparin Blood, November 15, 2004; 104(10): 3173 - 3180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hirsh and R. Raschke Heparin and Low-Molecular-Weight Heparin: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 188S - 203S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Slungaard, J. A. Fernandez, J. H. Griffin, N. S. Key, J. R. Long, D. J. Piegors, and S. R. Lentz Platelet factor 4 enhances generation of activated protein C in vitro and in vivo Blood, July 1, 2003; 102(1): 146 - 151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hirsh, T. E. Warkentin, S. G. Shaughnessy, S. S. Anand, J. L. Halperin, R. Raschke, C. Granger, E. M. Ohman, and J. E. Dalen Heparin and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety Chest, January 1, 2001; 119 (2009): 64S - 94S. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||