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BleedingWeb.com
- the Bleeding Information Source, is an internet site designed
for physicians and other health care personnel who want information
about bleeding, coagulation, and hemostasis, including therapeutic
approaches.
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| MANAGEMENT
OF ANTICOAGULATION AND PLATELET RECEPTOR INHIBITORS IN CARDIAC SURGICAL
PATIENTS Jerrold
H. Levy, MD
Professor of Anesthesiology
Emory University School of Medicine
Division of Cardiothoracic Anesthesiology and Critical Care
Emory Healthcare
Atlanta, Georgia |
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Introduction
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In the early era of angioplasty, when emergency coronary artery
bypass grafting was all too common, we would bring patients to the
operating room for acute closure or dissection of coronary vessels.
The need for emergency CABG has dwindled, and rushing a patient
in cardiogenic shock from the cardiac catheterization laboratory
is now a far less frequent occurrence due to the advent of intracoronary
stents, and newer pharmacologic agents such as the glycoprotein
(GP) IIb/IIIa receptor antagonists.
The glycoprotein (GP) IIb/IIIa receptor antagonists have assumed
a pivotal role in cardiology, and have had a major impact on the
cardiac surgeon as well. Patients who have been treated with GP
IIb/IIIa receptor antagonists pose a challenge, not only for the
cardiac surgical team, but also for all the physicians and other
health care personnel involved in their management. We are still
learning how to effectively manage these patients for cardiac surgery
and CPB. This presentation will review the non-aspirin antiplatelet
agents currently available, and review the management of patients
receiving GP IIb/IIIa receptor antagonists and requiring cardiac
surgery. |
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Glycoprotein
IIb/IIIa antagonists
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Because of the pivotal role of the platelet glycoprotein IIb/IIIa
complex in platelet-mediated thrombus formation, potent antagonists
of this "final common pathway" of platelet aggregation
have been developed as therapeutic strategies to treat acute coronary
thromboses. Three different GP IIb/IIIa antagonists are currently
available, they differ in antagonist affinity, reversibility, and
receptor specificity. Glycoprotein IIb/IIIa (IIbß3) is a receptor
on platelets that binds to key hemostatic proteins, including fibrinogen
and von Willebrand factor (vWF), thus allowing for cross linking
of activated platelets and platelet aggregation. By blocking this
final common pathway using GP IIb/IIIa antagonists, these drugs
function as inhibitors of platelet participation in acute thrombosis.
Various antagonists of GP IIb/IIIa receptor are available. The first
of these agents, the monoclonal antibody abciximab (ReoPro), has
been approved for use in percutaneous coronary intervention (PCI).
Tirofiban (Aggrastat), a nonpeptide, has been approved for treatment
of acute coronary syndromes (unstable angina or nonQ-wave myocardial
infarction) and eptifibatide (Integrelin), a peptide, for use both
in PCI and acute coronary syndromes. Nonpeptide oral antagonists
of GP IIb/IIIa intended for long-term use are also in various stages
of clinical development and may find application in a broad spectrum
of atherothrombotic disease. |
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Ticlopidine
and clopidogrel
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Antiplatelet agents are used primarily to treat and prevent arterial
thrombosis. Ticlopidine and clopidogrel are believed to inhibit
the binding of adenosine 5'-diphosphate (ADP) to its platelet receptor;
this ADP receptor blockade leads to direct inhibition of the binding
of fibrinogen to the glycoprotein IIb/IIIa complex. Ticlopidine
may also interfere with von Willebrand factor, resulting in less
binding of von Willebrand factor to platelet receptors. Ticlopidine
and its more recently developed analog, clopidogrel, are thienopyridine
derivatives. Ticlopidine and clopidogrel can both be administered
orally. Both agents are inactive in vitro, requiring breakdown to
an unidentified active metabolite or metabolites to achieve in vivo
activity. Activation seems to occur in the liver, and the active
metabolites are primarily excreted renally.
Ticlopidine was first shown to decrease major events compared with
placebo or aspirin in patients with stroke or recent transient ischemic
attack. Randomized studies in patients undergoing coronary artery
stenting have shown that ticlopidine reduces the risk for subacute
stent thrombosis compared with warfarin-based regimens. Smaller
studies have also shown this drug to have benefit during follow-up
in patients with unstable angina, peripheral arterial disease, saphenous
vein coronary bypass grafts, and diabetic retinopathy. Clopidogrel
was approved by the FDA for the reduction of ischemic events in
patients with recent myocardial infarction, stroke, or peripheral
arterial disease with no added risk for neutropenia. The combination
of clopidogrel and aspirin, as well as the increasing use of clopidogrel
in coronary stenting, is rapidly growing. Many heart centers now
administer clopidogrel before anticipated stenting procedures. The
variability in bleeding in patients receiving these agents for cardiac
surgery may relate to the time and duration of therapy.
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Heparin
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Heparin represents the most commonly used anticoagulant to prevent
clotting during cardiac or vascular surgery. Heparin is isolated
from either porcine intestine or from beef lung where it is bound
to histamine and stored in the mast cell granules. When heparin
is isolated, the purification leads to a heterogeneous mixture of
molecules. Heparin is an acidic polysaccharide with side groups,
either sulfates or N-acetyl groups, attached to individual sugar
group. The sulfate groups are extremely important in the anticoagulant
activity of heparin. Heparin acts indirectly as an anticoagulant
by binding to antithrombin III (AT III) enhancing the rate of thrombin-AT
III complex formation by 1000 to 10,000 fold. Several other steps
in coagulation cascade, including clotting factor X are also inhibited
to a lesser degree by AT III. Anticoagulation thus depends on the
presence of adequate amounts of circulating AT III. The advantage
of this is that heparin anticoagulation can be re versed immediately
by removing heparin from AT III with protamine. Heparin also binds
to a number of other blood and endothelial proteins including high
molecular weight kininogen, von Willebrand factor, plasminogen,
fibronectin, lipoproteins and platelet and endothelial receptors.
Each of these may potentially influence the ability of heparin to
act as an anticoagulant, and may, along with AT III levels, affect
heparin dose responses in patients. Heparin can also produce platelet
dysfunction following acute and/or constant administration, especially
with high dose administration during cardiac surgery.
Despotis reported that the maintenance of higher than usual patient-specific
heparin concentrations during cardiopulmonary bypass (CPB) was associated
with more effective suppression of hemostatic activation. Maintenance
of higher patient-specific heparin concentrations during CPB more
effectively suppressed excessive hemostatic system activation than
did standard heparin doses chosen based on measurement of ACT. These
findings may explain, at least in part, the significant reduction
in perioperative blood loss and blood product use when higher heparin
concentrations are maintained. Further, Mochizuki has shown that
excess protamine can further alter coagulation and coagulation tests,
and the careful exact titrated reversal of heparin avoiding excess
protamine may be an important contribution of work by done Despotis. |
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New
Anticoagulants
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Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening,
adverse effect of heparin therapy produced by antibodies (IgG) to
the composite of heparin-platelet factor 4 (PF4) that leads to the
formation of immune complexes. These immune complexes bind to platelets
via platelet Fc-receptors (CD 32) producing intravascular platelet
activation, thrombocytopenia, and platelet activation with potential
thromboembolic complications that can result in limb loss or death.
When patients with HIT require CPB, the heparinoid danaparoid (Orgaran),
ancrod, and several other drugs have been used with various degrees
of success. Danaparoid is often used but it has limitations that
include cross-reactivity with HIT antibodies, a relatively long
half-life (t1/2 of antifactor Xa activity of 24 hours), and monitoring
that is complicated by the need to measure antifactor Xa activity.
Also, no antidote is available. Hirudin, an antithrombotic substance
produced in leech salivary is the most potent and specific thrombin
inhibitor currently known. It acts independently of cofactors such
as antithrombin, and unlike heparin, it is not inactivated by PF4.
Recombinant hirudin (Lepirudin) is currently available. Potch reported
on using Lepirudin during cardiopulmonary bypass in patients with
HIT using a 0.25-mg/kg bolus and then 5-mg boluses when hirudin
concentration was <2500 ng/mL as determined by ecarin clotting
time.
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Other
Anticoagulation Strategies
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One promising therapy currently under investigation is the use
of purified antithrombin III (AT III). Despite high dose heparin
for patients undergoing cardiac surgery, thrombin generation and
activity continues during cardiopulmonary bypass (CPB). Antithrombin
III (ATIII) levels, which are lower in patients receiving IV heparin
prior to the procedure, and decrease further by 40 to 50% following
initiation of CPB, may be critical in determining the extent of
thrombin inhibition. Better anticoagulation during CPB may be associated
with less bleeding post procedure, presumably related to preservation
of critical coagulation components. Supplemental AT III, through
improved heparin sensitivity and enhanced anticoagulation, may preserve
hemostasis during CPB and thereby decrease the microvascular bleeding
and complications during cardiac surgery. Adequate anticoagulation
depends on the interaction between AT and heparin, however patients
receiving intravenous heparin prior to surgery have significantly
lower AT III levels and these levels further decrease following
initiation of cardiopulmonary bypass (CPB). A potentially significant
contributing factor that prevents the inhibition of thrombin generation
and activity while on CPB is a low concentration of ATIII. Further,
the use of heparin preoperatively is associated with a diminished
anticoagulation response as measured by ACT and this is presumably
due to the lower AT III levels. The importance of augmenting ATIII
levels is also suggested by data from patients who have received
warfarin preoperatively and who had higher AT III levels at the
start of procedures, a greater prolongation of the anticoagulation
response to heparin and less thrombin generation while on CPB with
greater preservation of platelet function.
Because maintaining normal or elevated plasma AT III levels during
cardiopulmonary bypass could potentially improve thrombin inhibition,
we have investigated the role of increasing doses of AT III from
transgenic recombinant sources as a potential source of AT III.
The development of microvascular bleeding requiring transfusions
of allogenic blood products, which is a significant complication
of CPB, can be potentially minimized through better anticoagulation
and thrombin inhibition during the period when the patient is on
CPB. The advantage of use of transgenically produced recombinant
proteins include safety when compared to plasma derived proteins
as well as an unlimited supply thus potentially allowing applications
of even supraphysiologic doses of the AT III. |
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Heparin
Reversal
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Unfractionated heparin has a relatively short half-life. Protamine
can immediately reverse the anticoagulation effect of unfractionated
heparin by non-specific polyionic-polycationic (acid-base) interactions.
There are different methods to determine the amount of protamine
to be administered, but using a ratio of 1.0-1.3 mg protamine: 100
units of unfractionated heparin administered are effective. Although
protamine has the potential to function as an anticoagulant, this
effect is only seen when large excessive doses have been administered.
More importantly, protamine, a polypeptide isolated from fish sperm,
does have the potential to produce anaphylactic reactions, and therefore
must be administered slowly.
Fractionated heparin sulfate enjoys wide use in clinical practice
as an anticoagulant to facilitate extracorporeal circulation, to
prevent prosthetic graft thrombosis during vascular surgery, and
to prevent thrombus formation during invasive angiographic procedures.
Heparin's advantage as an anticoagulant consists of its rapid offset
of action upon administration of a neutralizing agent. Protamine,
the mainstay neutralizing agent, is a basic polypeptide isolated
from salmon sperm. Comprised mostly of arginine, protamine reverses
heparin by a non-specific acid-base interaction (polyanionic-polycationic).
Neutralization by protamine is immediate; it is the only drug widely
available for clinical use. The literature documents a variety of
adverse reactions to protamine ranging from minimal cardiovascular
effects to life threatening cardiovascular collapse. Life threatening
reactions to protamine probably represent true anaphylactic or allergic
manifestations, mediated by immunospecific antibodies. Stewart reported
a 27% incidence of reactions following cardiac catheterization in
insulin dependent diabetics who were also receiving neutral protamine
Hagedorn insulin preparations. Other reports do not corroborate
the extreme results of Stewart. Levy reported the incidence of life
threatening reactions in cardiac surgical patients ranges from 0.6%
to 2% in patients at risk. Life threatening reactions to protamine
represent true allergic reactions.
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Managing
patients receiving abciximab for cardiac surgery
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The management of emergency coronary revascularization afterabciximab
treatment is still evolving. Lemmer recently reported on 12 patients
over a 29-month period who required emergencycoronary artery bypass
grafting within 12 hours (mean, 1.9 hours)of abciximab therapy.
A standard heparin dose regimenwas used (500 units/kg, mean heparin
dose, 53,000 U per patient). Each patientreceived a single platelet
transfusion after protamineadministration, and further blood products
were transfused asnecessary depending on the bleeding. No patients
died and none were returned to the operatingroom for coagulopathy-related
bleeding. Per-patient transfusionrequirements were: red blood cells,
3.6 units; apheresisplatelets, 1.4 units; and fresh frozen plasma,
1.5 units. Ascompared with predicted values, there was no excessive
incidenceof mortality, stroke, or red blood cell transfusion requirements.
Lemmer suggests coronary artery bypass graft operationsusing full-dose
heparin can be performed successfully in acutelyischemic abciximab-treated
patients. He suggests that prophylactic transfusionof platelets
after protamine administration appears to be useful.
Boehrer described32 patients who required urgent CABG after abciximab
treatmentin a large, multicenter trial (EPIC) comparing abciximab
versusplacebo in 2,099 patients. A total of 5 of the 32 abciximab-treatedpatients
requiring surgery died within 30 days (16% mortality),although 4
of the deaths were not due to bleeding. Red blood cell transfusions
were administered to 88% of thepatients, and 76% required platelet
transfusions, higher levelsthan in the placebo group, although not
to a statistically significantdegree. Thespecific numbers of blood
product units required per patientwere not reported. In the EPIC
trial the medianduration from abciximab treatment to CABG was more
than 24 hours,at which time significant normalization of platelet
functionwould be expected.
Booth reported results in patients requiringurgent CABG in two large
trials of abciximab administrationwith percutaneous intervention.
Twenty patients randomized toreceive abciximab required CABG within
7 days of percutaneousintervention, versus 22 in the placebo group.
The investigatorsreport similar transfusion and bleeding complication
rates forthe two groups, with the exception of higher platelet transfusionrates
(75% versus 46%) for abciximab-treated patients versuscontrols.
In this abstract the time interval between abciximabtreatment and
CABG was not specified. Thespecific numbers of blood product units
required per patientwere also not reported.
Gammie reported the records of 11 consecutive patients who required
emergency cardiac operations after administration of abciximab and
failed angioplasty or stent placement. The interval from the cessation
of abciximab administration to operation was critical in determining
the degree of coagulopathy after cardiopulmonary bypass. The median
values for postoperative chest drainage (1,300 versus 400 mL; p
< 0.01), packed red blood cells transfused (6 versus 0 U; p =
0.02), platelets transfused (20 versus 0 packs; p = 0.02), and maximum
activated clotting time (800 versus 528 seconds; p = 0.01) all were
significantly greater in the early group (cardiac operation <
12 hours after abciximab administration; n = 6) compared with the
late (cardiac operation >12 hours after abciximab administration;
n = 5) group. This report suggests that the antiplatelet agent abciximab
is associated with substantial bleeding when it is administered
within 12 hours of operation.
Alvarez reported on 3 patients who underwent emergency CABGfor failed
stent implantation shortly after receiving abciximab.All 3 patients
were described as having a profound bleeding diathesis,and the transfusion
requirements were large (mean, 28 unitsplatelets, 4.7 units RBCs,
and 8.3 units plasma); 1 patientdied, although not of bleeding-related
causes.
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Managing
patients receiving other antiplatelet agents for cardiac surgery
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There is little published data regarding the effects of other
platelet inhibitors in cardiac surgery. Most of the information
available is regarding abciximab, since it was the first on market,
and has the longest half life of the IIb/IIIa inhibitors. Kleiman
reviewed the pharmacokinetics and dynamics of these drugs. The elimination
of abciximab from the body is the slowest of the agents: the catabolic
beta half-life is approximately 7 hours. Although no studies investigating
the route of elimination have been reported, renal clearance of
the ReoPro fragments is generally more rapid than that of whole
antibodies, and catabolism is likely to resemble that of other natural
proteins. In comparison, the plasma half-life of tirofiban is approximately
2 hours and the primary route of plasma clearance is renal. Approximately
65% of the administered dose is excreted in urine, and an additional
25% is eliminated through feces. Plasma clearance of tirofiban is
significantly lower (>50%) in patients with severely impaired
renal function (creatinine clearance <30 mL/min), whereas moderate
reduction was apparent in elderly patients (age >65 years). In
patients with mild to moderate hepatic dysfunction, the rate of
plasma clearance was not significantly different from that observed
in healthy subjects. Plasma clearance of eptifibatide occurs with
a half-life of 2.5 hours, and the majority of the drug is eliminated
through renal mechanisms.
There is little data regarding the use ticlopidine and clopidogrel
and bleeding in cardiac surgical patients. Mossinger reported in
their series of 96/1166 CABG patients who were receiving ticlopidine,
83% of which were also on ASA. A total of 28% of the ticlopidine
patients were urgent vs 9% of the other patients. Blood loss >1500
ml/24 hour period was more frequent in ticlopidine treated patients,
(14% vs 5%). The ticlopidine patients received allogeneic blood
more frequently 62%vs 45%, and required more packed red blood cell
transfusions (2 units vs 0). The post operative chest drainage was
also 30% greater in the ticlopidine treated patients. |
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Antiplatelet
agents and ACT
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Abciximab and other antiplatelet agents are associated with prolongation
of the ACT of 35-85 seconds. This effect was also observed in vitro
by Ammar and Gammie, and has contributedto the suggestion that a
smaller heparin dose should be usedfor abciximab-treated patients
who require emergency operation.A similar suggestion was also made
by Kereiakes and byFerguson. As previously reported for aprotinin
treated patients, the use of reduced heparindoses for cardiopulmonary
bypass in antiplatelet treated patients is problematic. Although
antiplatelet agents inhibit arterial thrombus formation andprolong
the ACT, the stimulus to thrombin generation is quite different
during extracorporeal ciruclation because the blood is exposed to
a large non-endothelized bypass circuit. Further, the effectiveness
of using smaller heparindoses in reducing transfusion requirements
in the setting ofcardiopulmonary bypass has not been demonstrated.
The ACT is a complicated test and can be affected by a varieyt of
factors including fibrinogen, platelets (which provide the phospholipid
surface for clotting as a whole blood clotting test), heparin levels,
temperature, plateletcount, and contact activation inhibitors (ie,
aprotinin). Although abciximab does prolongthe ACT to some degree,
it has not yet been demonstrated tobe a "heparin-sparing"
agent allowing for safe extracorporealperfusion with lower-than-standard
serum heparin levels. Finally, at the end of cardiopulmoanry bypass,
the heparin is completely reversed with protamine.
Although suggestions have been made that platelet transfusion be
performed beforethe operation, even en route to the operating room,
platelet transfusions pose the potential risk of hypersensitivity
reactions in a critically unstable patient. Further, platelets will
be subsequently impaired due to cardiopulmonary bypass, and reversal
of a therapeutic antiplatelet effect before surgical revascularization
couldprecipitate abrupt closure of a stenotic coronaryartery whose
patency is dependent on inhibiting platelet function. |
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Recommendations
for managing patients receiving antiplatelet agents and requiring
cardiac surgery:
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The following is a summary of recommendations for managing patients
receiving antiplatelet agents and requiring cardiac surgery. |
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SUMMARY
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Safety: Based on the data in press and published, urgent cardiac
surgery can be safely performed on patients who have received abciximab
or one of the other GPIIb/IIIa receptor inhibitors
Bleeding: Although the relative risk of abciximab -related bleeding
may be increased within twelve hours, this should not preclude urgent
revascularization. Platelets may be needed and should be available
when operating on abciximab -treated patients.
Heparin dosing: There are no data supporting reductions in heparin
dosing during cardiopulmonary bypass and for cardiac surgery. Therefore,
standard-loading doses should be considered and additional heparin
doses, based on time and duration of bypass or on actual heparin
levels, should be maintained.
Platelets. Platelets can be transfused to correct the bleeding defects
associated with abciximab use. However, patients should not receive
routine platelet transfusion prior to surgery and cardiopulmonary
bypass. Rather, platelets should be administered after heparin reversal
by protamine and after extracorporeal circulation.
Anticoagulation. When blood is activated during bypass, a pathological
prothrombic stimulus is initiated. Anticoagulation is achieved by
unfractionated heparin administration, which binds to antithrombin
and heparin cofactor II to inhibit thrombin. Despite the use of
high dose heparin, thrombin generation and activity continues during
extracorporeal circulation. New approaches with old and novel agents
for anticoagulation will be considered. Protamine reactions and
novel agents to reverse heparin will be also reviewed.
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