REVIEW ARTICLE
Bleeding Complications Associated With Cardiopulmonary Bypass
By Richard C. Woodman and Laurence A. Harker
C ARDIOPULMONARY bypass (CPB) for open-heart
surgery (OHS) is commonly performed in hospitals
throughout the world. In the United States more than
250,000 OHS procedures are performed annually, primarily
for coronary artery bypass grafting (CABG).' With improve-
ments in surgical techniques and extracorporeal oxygen-
ation, the overall mortality for this procedure is low (1% to
4%)., However, excessive perioperative bleeding continues to
complicate CPB. Management of the abnormal bleeding
often requires reoperation and frequently is associated with
excessive, and sometimes inappropriate, blood product admin-
istration that occasionally exceeds the available blood sup-
ply. In some hospitals more than 25% of all blood products
are dedicated to OHS3A concerted multispecialty approach
between cardiac surgery, hematology, and transfusion medi-
cine is required to reduce the need for reoperation and its
increased and to minimize the possibility of transmit-
ting transfusion-related diseases.
The actual frequency of severe bleeding with CPB may
vary, depending on the criteria used and the patient profile
~tudied.~" An incidence of 3% to 5% is commonly reported
when abnormal bleeding is defined as comprising more than
10 U of blood transfused in the perioperative p e r i ~ dWhen
.~
these patients undergo reoperation for excessive bleeding,
more than half exhibit significant incomplete surgical hemo-
stasis that is, at least in part, corrected by exploration.
However, the remaining patients bleed because of various
acquired hemostatic defects, most commonly related to
acquired transient platelet dysfunction (Table l).7 An appre-
ciation for the various causes of bleeding following CPB and
their incidence is essential for optimal management.
PATHOGENESIS
Platelets
CPB adversely affects both platelet count and function.
Hemodilution causes platelet counts to decrease rapidly to
about 50%of preoperative levels soon after starting CPB, but
usually remain above 100,00O/pL throughout by pas^.^.^-" Of
greater significance, however, is the progressive loss of
platelet function. Within minutes after starting CPB, the
bleeding time (BT) is prolonged significantly and platelet
~
From the Department of Molecular and Experimental Medicine,
Research Institute of Scripps Clinic, La Jolla. CA; and Department
of Medicine, Emory University. Atlanta. GA.
Submitted April 16. 1990; accepted July 22. 1990.
Supported in part by Grants HL41619 and HL31950 from the
National Institutes of Health. R.C. W . is a recipient of a Research
Grant from the Department of Medicine. Division of Hematology,
University of Calgary, Alberta. Canada.
Address reprint requests to Richard C. Woodman, MD, Univer-
sity of Calgary, Foothills Hospital. 1403 29th S t NW, Calgary,
Alberta, Canada T2N 2T9.
0 I990 by The American Society of Hematology.
0006-4971/90/7609-000l%3.00/0
1680
aggregation to adenosine diphosphate (ADP) or collagen is
The changes in BT are independent of the
modest reduction in platelet count. These functional abnor-
malities worsen throughout CPB, and as the duration of CPB
approaches 2 hours the BT progressively increases to more
than 30 minute^.^,'^ Similar changes in platelet counts, BT,
platelet aggregation, and postoperative bleeding occur regard-
less of whether bubble or membrane oxygenators are used.I4
Usually 20 minutes after the discontinuation of CPB and the
administration of protamine, the BT shortens to approxi-
mately 15 minutes and normalizes by 2 to 4 h o ~ r s The .~
platelet count usually requires several days to correct.
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Platelet dysfunction appears to be dependent on contact of
platelets with the synthetic surfaces of the extracorporeal
oxygenator and the hypothermia associated with bypass.
Studies in primates clearly demonstrate that the prolonga-
tion of BT and platelet aggregation are produced by either
the oxygenator or by h y p ~ t h e r m i a .Recently
~ it has been
suggested that hypothermia induces reversible platelet dys-
function by impairing platelet thromboxane A, synthesis."
Although the exact mechanism(s) responsible for this
transient platelet dysfunction remains unknown, several lines
of evidence suggest that it is consequent to transient platelet
activation, similar to the "refractory state" induced in vitro
by ADP.9*'3s'6 First, CPB causes progressive increases in the
plasma and urine levels of several biochemical indicators of
platelet activation in vivo, including platelet factor 4 (PF4),
0-thromboglobulin (P-TG), and thromboxane B2.7.16-22 Plate-
let functional abnormalities have also been attributed to
a-granule d e p l e t i ~ n . ~Second,
.'~ after exposure to the extra-
corporeal oxygenator, platelets undergo transient morpho-
logic changes consistent with primary reversible aggregation
and platelet activation.'2.22Finally, several investigators have
demonstrated in both nonhuman primates and patients
undergoing CPB that prevention of platelet activation by
PGE, or prostacyclin (PGI,) infused into the bypass circuit
abolishes the development of platelet dysf~nction.'~.''-~'.~~-~~
Complete normalization of plasma PF4 and P-TG usually
occurs within the first 2 to 4 postoperative hours, although
the reduction in the number of platelet a-granules persists
despite the improvement in platelet function, thereby suggest-
ing that a-granule depletion and platelet dysfunction are
independent consequences of CPB. Additionally, changes in
the concentration of platelet adenine nucleotides, serotonin,
and the number of dense granules are unaffected by CPB.7
Therefore, it is unlikely that selective release of either
platelet a-granules or dense granules is responsible for the
transient platelet dysfunction associated with CPB.
Platelet dysfunction after CPB also has been attributed to
temporary depletion or modification of some functional
platelet membrane component(s), although there is consider-
able controversy about these findings. Several studies have
reported significant decreases in the amount of membrane
antigen for glycoproteins (GP) Ib, IIb, and IIIa on circulat-
ing platelets following CPB.26-29 Platelet a,-adrenergic recep-
Blood, Vol 76,No 9 (November l), 1990:pp 1680-1697
BLEEDING AFTER CARDIOPULMONARY BYPASS
Table 1. Various Causes of Bleeding After CPB
Common (95% to 99%)
Defective surgical hemostasis
Acquired transient platelet dysfunction
Uncommon ( 1 % to 5%)
Drug-induced platelet dysfunction (aspirin)
Thrombocytopenia (druginduced or heparin-induced antibod-
ies, sepsis, posttransfusionpurpura, fat emboli)
Vitamin K-dependent factor deficiencies (warfarin, liver dys-
function)
Consumptive coagulopathy (sepsis, cardiogenic shock)
Inherited clotting factor deficiencies or platelet dysfunction
Doubtful significance
Primary fibrinolysis
Heparin (inadequate neutralization, rebound)
Protamine excess
tors are also reduced by CPB.30The loss of platelet G P IIIa is
associated with a reduction in total fibrinogen binding sites, a
process that is prevented by prostanoids (PGE,).3' However,
CPB does not appear to alter the binding affinity for
fibrin~gen.~~
Several mechanisms, alone or in combination, may be
responsible for these membrane abnormalities. Mechanical
trauma due to shear stress, surface adherence, and turbu-
lence within the extracorporeal oxygenator may cause frag-
mentation of platelet membranes with a loss of surface
receptors.26 Plasma concentrations of platelet membrane
microparticles unrelated to a-granule secretion are increased
after CPB and suggest membrane damage.26Another consid-
eration is the proteolytic removal of platelet membrane G P
by plasmin. In vitro the incubation of platelets with plasmin
(and other proteases) causes the degradation of platelet
membrane G P Ib with associated loss of von Willebrand
factor (vWF)-dependent, ristocetin-mediated a g g l ~ t i n a t i o n . ~ ~ prolonged
Plasmin also impairs ADP-induced aggregation in vitro;
however, the exact mechanism has not been d e t e r m i ~ ~ e d . ~ ~suggested .~~
Evidence for plasmin-mediated alterations in platelet behav-
ior in vivo is not convincing, although the ability of the
protease inhibitor aprotinin to minimize GP Ib loss after
CPB does provide further evidence to implicate plasmin in
the development of platelet dysfunction.28 Despite these
observations, no correlation between bleeding and platelet
activation or platelet membrane abnormalities has been
established.
Coagulation Factors
Shortly after starting CPB, predictable reductions in the
plasma concentration of coagulation factors 11, V, VII, IX,
X, and XI11 occur, primarily due to h e m ~ d i l u t i o n . For
reasons that are unclear, only factor V levels decrease more
then can be predicted by dilution alone. Nonetheless, all
coagulation factors, including factor V, remain well above
levels normally considered to be adequate for hemostasis (ie,
2 15% for factor V and 230% for all other clotting factors),
even in patients with excessive bleeding following CPB.7 In
contrast to the other coagulation factors, plasma factor VI11
levels remain within normal limits during and after CPB
despite h e m o d i l u t i ~ n . ~Generally,
.'~ all coagulation factors
1681
(with the exception of fibrinogen) normalize by the first 12
hours after CPB.7 The prothrombin time (PT) and activated
partial thromboplastin time (APTT) are usually normal
following discontinuation of CPB and protamine administra-
tion. l o
A complex and poorly understood relationship exists
between CPB and the concentration and multimeric compo-
sition of vWF. During bypass, and unrelated to hemodilu-
tion, the plasma concentration of v W F generally decreases
but usually remains well above levels normally considered
adequate for h e m o ~ t a s i sIndeed,
.~~ increased functional activ-
ity by ristocetin cofactor measurements has been reported in
vitro.36 Despite the reduction in plasma v W F concentration
during CPB, some35but not all36investigators have demon-
strated an increase in the proportion of high-molecular-
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weight multimers (HMWM), suggesting the release of
stored vWF, possibly from platelet a - g r a n ~ l e s Although .~~
patients who had a preoperative v W F level of less than 1.8
U/mL and a postoperative level of less than 1.2 U / m L had a
tendency toward excessive postoperative bleeding,35 neither
the pre- nor the postoperative v W F levels or multimeric
patterns are clinically useful as predictors of bleeding. After
CPB there is an increase in the total plasma concentration of
vWF (characteristic of an acute-phase reactant) and the
proportion of lower-molecular-weight m ~ l t i m e r s . ~The ' post-
bypass concentration of v W F appears to be adequate for
hemostasis.
An acquired deficiency of H M W M has been described in
association with valvular heart disease and noncyanotic
congenital heart d i ~ e a s e . ~Although
'.~~ the mechanism respon-
sible for the loss of H M W M remains unknown, proteolysis or
turbulence may both be contributing factors.35 In children
with noncyanotic congenital heart disease, the reduced
H M W M are sometimes associated with bleeding symptoms,
BT, decreased vWF concentrations, and dimin-
ished ristocetin cofactor activity.37 In adults, it has been
that the reduced H M W M may contribute to the
increased incidence of gastrointestinal mucosal bleeding
reported in association with aortic stenosis.35 These patients
generally require no special management before OHS; sur-
gery is usually followed with correction of the v W F multi-
meric pattern and improvement in hemostasis.
Heparin Rebound and Protamine Excess
Heparin is administered during CPB to prevent clotting in
the extracorporeal oxygenator. Its administration is usually
adjusted to maintain an activated clotting time (ACT) of 350
to 500 seconds (normal 5130 second^).^^.^^ After returning
blood from the extracorporeal oxygenator to the patient a t
~ . ~ ~ the end of CPB, heparin is routinely neutralized by the
administration of protamine ~ u l f a t e . ~ ~Different . ~ ' . ~ ~ reversal
protocols are used, but usually about 1 mg of protamine is
given for every 100 U of heparin administered throughout
the operation. (Several investigators recommend protamine
dosages based on total milligrams of heparin given during the
intraoperative period, usually trying to achieve a protamine-
to-heparin ratio of z1:1.38.4i.42 This approach is not recom-
mended because [ 11 heparin is almost always administered in
terms of units; [2] there is an imprecise and variable
1682 WOODMAN AND HARKER

relationship between units and milligrams; and [3] present- suggested that pleural, pericardial, and periosteal surfaces
day purified heparin preparations contain variable amounts contain plasminogen activator-like substances that initiate
of low- and high-molecular-weight heparin form~.’’~) Ade- fibrin~lysis.~’ However, the findings implicating fibrinolysis,
quacy of protamine neutralization may be monitored by ie, a shortened euglobin lysis time, a prolonged PT and
whole blood clotting times, occassionally with protamine APTT, hypofibrinogemia, and elevated fibrin(ogen)-degrada-
t i t r a t i ~ n , ’ ”or
. ~ plasma
~ heparin levels.44 tion products (FDP) have probably reflected dilution by
Heparin rebound has been proposed as one cause of non-blood-priming solutions, inadequate heparinization, con-
bleeding after CPB.’ This diagnosis is based on the reappear- sumption of platelets and fibrinogen by surgically damaged
ance of a prolonged ACT, often performed in conjunction tissue, and secondary fibrinolysis. Nonetheless, hyperfibrino-
with protamine t i t r a t i ~ n . ~ ’However,
,~* its exact frequency, lysis emerged as a perceived cause of bleeding after CPB and
pathogenesis, and role in CPB-related bleeding remains prompted the common surgical practice of administering
poorly e ~ t a b l i s h e d . ~Obviously
’.~~ the ACT is prolonged by antifibrinolytic agents such as epsilon aminocaproic acid
other factors, including hypofibrinogenemia, coagulation (EACA) to patients undergoing OHS.
factor deficiencies, or the presence of acquired inhibitor^.^' Subsequent and more detailed studies of fibrinolysis dur-
Although excess protamine sulfate has been reported to ing and after CPB have shown that increased fibrinolysis is

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produce anticoagulant and antiplatelet these phe- usually not the principal cause of bleeding.7,66-68 Both plasma
nomena are probably in vitro artifacts without clinical fibrinogen and plasminogen levels decrease during CPB not
significance. Thus, a second dose of protamine sulfate for the due to consumption but primarily due to hem~dilution.~.”
management of excessive post-CPB bleeding is generally Generally, fibrinogen and plasminogen normalize by 12 and
safe, but indicated only when the first dose of protamine is 24 hours after CPB, re~pectively.~ a,-Antiplasmin and anti-
less than the ratio of 1 mg protamine per 100 U heparin. thrombin I11 undergo similar changes due to hemodilu-
However, protamine injections also have occasionally been t i ~ n . ~ ~Moreover,
.” total clottable fibrinogen levels do not
associated with mild transient thrombocytopenia, increases change detectably with CPB, thus excluding a significant
in the ACT and PTT,39 and a spectrum of allergic defect in fibrin polymerization due to FDP.7
reaction^.^'.^^ For example, skin rash, urticaria, broncho- Although consumption is generally not significant, there
spasm, increased pulmonary artery pressure, hypotension, are circumstances such as cardiogenic shock, sepsis, or crush
cardiogenic shock, and anaphylaxis have been reported to injury when consumptive coagulopathy may produce throm-
occur occasionally within 10 to 20 minutes of protamine bocytopenia and hypofibrinogenemia during or after CPB.
admini~tration.~~.” Mild hypotension has been attributed to
transient peripheral v a s ~ d i l a t i o n . ~ ’Patients
~’~ suggested to Aspirin-Related Bleeding
be at risk for the life-threatening allergic reactions include
vasectomized men, patients with fish allergies, diabetics with Patients taking aspirin before CABG have excessive and
prior exposure to preparations of protamine insulin, and prolonged mediastinal bleeding complicating CPB.7’,72To
patients who have received protamine p r e v i o ~ s l y . ~ ~illustrate, ~ ~ ~ ~ a~recent
~ ~ ~large
~ - ~prospective
~ multicenter randomized
These allergic reactions appear to be mediated by both IgG study reported that aspirin (325 mg) administration 12 hours
and IgE.49The incidence of protamine-mediated anaphylaxis before CABG was associated with significantly increased
is low, occurring in 0.6% to 2% of neutral protamine postoperative bleeding, transfusion requirements, and reoper-
Hagedorn insulin-dependent diabetics compared with 0.6% ation rates.73 Importantly, initiating aspirin therapy early
in the general OHS p o p ~ l a t i o n . ~ ~ , ’ ~ postoperatively (6 hours) obviates the bleeding complication
The usefulness of preoperative screening of patients at risk while preserving aspirin’s beneficial effects on increasing
for protamine-induced allergic reactions remains unveri- graft patency.74In view of these results, aspirin should not be
fied,49.55and at present these risk factors do not constitute administered preoperatively. When possible, aspirin should
contraindications to protamine administration. Other poten- be discontinued at least 5 days before CPB. The management
tial heparin antagonists include hexadimethrine b r ~ m i d e ~ ~ . ~aspirin-related
of ~ post-CPB bleeding is similar to that for
and methylene blue.” Unfortunately, the availability and other acquired platelet defects, consisting of monitoring the
clinical characterization of these agents is extremely limited. BT, administering desmopressin, and transfusing platelets.
Spontaneous reversal of heparin anticoagulation is another
alternative to protamine that has been used successfully in MANAGEMENT OF CPB-RELATED BLEEDING
However, in patients with excessive bleeding after The management of CPB-related bleeding begins with its
CPB, this approach may not be appropriate and more rapid recognition. Although most of the recent studies regarding
neutralization of heparin with protamine sulfate may be CPB and hemostasis have used blood loss or transfusion
required. requirements during the first 24 postoperative hours to define
excessive bleeding, these criteria may not be useful for
Consumptive Coagulopathy and Fibrinolysis immediate bedside evaluation and early intervention. A more
Historically, bleeding after CPB has been attributed to practical clinical definition may be postoperative chest tube
excessive fibrinolysis beginning after sternotomy, increasing drainage of E- 100 mL/h.7,”-38
throughout CPB, and persisting for up to 2 hours after A common cause of bleeding following CPB is a localized
CPB.6*’3.60-64 Hypothermia6’ and prolonged pump times63 defect in surgical hemostasis. However, it may be difficult to
were considered to aggravate hyperfibrinolysis. It has been distinguish bleeding due to an acquired systemic coagulopa-
BLEEDING AFTER CARDIOPULMONARY BYPASS
thy from a localized surgical problem unless the patient has
obvious evidence of a generalized bleeding tendency such as
epistaxis or oozing from catheter sites. In the absence of a
coagulopathy, bleeding that exceeds 10 mL/kg in the first
postoperative hour or an average of 2 5 mL/kg in the first 3
postoperative hours has been suggested as a guideline for
re~peration.~' Any sudden bleeding after chest tube drainage
has stopped is also considered an indication for re~peration.~'
Patients who undergo reoperation through a previous sterno-
tomy, regardless of the indication, often experience excessive
bleeding, particularly in the intraoperative p e r i ~ d . ' ~Aspi-
,~~
rin administration, infective endocarditis, and prolonged
pump times may be important risk factors. The need for
reoperation due to hemorrhagic complications has decreased
over the past decade and is currently reported to be approxi-
mately 5%.53",77378
LABORATORY EVALUATION
Patients undergoing CPB, without a prior bleeding his-
tory, are at moderate risk of surgical bleeding, and a patient
with a suspicious history for a bleeding disorder or a
documented bleeding disorder are at high risk of surgical
bleeding. A schema for preoperative hemostatic evaluation
has been proposed by Rapaport (Table 2).79To identify the
rare patient with a mild undiagnosed congenital bleeding
disorder and no prior bleeding history,8'X8' it recommends
preoperative evaluation for all patients undergoing CPB,
including a platelet count, template BT, PT, APTT, factor
XI11 screen (urea clot lysis), and a whole blood clot lysis.
Because this screening approach has a low yield of detecting
abnormalities compared with the number of tests performed
and the number of artifactually abnormal test results, many
centers have discontinued routine screening. However, the
proposed screening serves the following purposes: (1) safe-
guarding against an inadequate history or an unreliable
historian; (2) detecting coagulopathies that only present
postoperatively or that are mild and present only postopera-
tively; and (3) uncovering acquired hemostatic defects that
have developed since the last hemostatic challenge. In any
event, for patients with a bleeding history the screening
evaluation is indicated, and if the screening tests are negative
Table 2. Preoperative Hemostatic Evaluation
Level of Risk Screening History
Minimal Negative and
i Prior surgery
Low Negative and
Prior surgery
Moderate Possible bleeding disorder or
High Highly suspicious or and
documented bleeding
disorder
Modified with permi~sion.~'
1683
additional evaluation is required to identify abnormalities
not always detected by the initial elevation, including a
thrombin time (TT), plasma qantiplasmin activity, assays
for circulating inhibitors, factor VI11 and IX activity levels,
and platelet aggregation studies. The aspirin tolerance test,
vWF levels, and vWF multimers are not recommended as
preoperative tests in patients undergoing CPB.
BLOOD ADMINISTRATION
Although perioperative blood loss has decreased little over
the past 2 decades, transfusion practices associated with
CPB have changed dramatically. Since 1972 the total
average blood loss in adults after CPB has remained at about
1,000 mL, whereas total postoperative administration of
homologous red blood cells (RBC) has decreased from
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greater than 8 U to less than 3 U.6s*'2 The factors primarily
responsible for this trend have been an acceptance of lower
postoperative hematocrits and an awareness of the risks
associated with blood transfusion.
Homologous Blood Transfusion
Conventional practice after CPB in adults involves transfu-
sion of RBC to maintain hematocrits 230% (or hemoglobins
2 10.0 g/dL).3.68ss3*84 Although earlier data suggested that
decreased tissue oxygenation occurs in surgical patients with
hematocrits less than 30%,85 there is no other available
evidence to support this guideline.86For example, patients
without myocardial infarction, congestive heart failure, or
neurologic complications tolerate hematocrits of less than
28%.68,87 In general, blood products should be administered
for specific clinical indications and in the presence of
bleeding.
Transfusion-transmitted viral diseases have become the
most significant complication of CPB and underscore the
need for appropriate and judicious blood product administra-
tion. Cardiac surgery patients account for 27%of individuals
contracting transfusion-transmitted acquired immunodefi-
ciency syndrome (AIDS)," a risk that is directly related to
their exposure to homologous blood products.88Although the
use of human immunodeficiency virus (HIV) seronegative
Proposed Surgery RecommendedTests
Minor (eg, dental extraction) None
Major (eg, cholecystectomy) Platelet count
APlT
CNS As above plus
CPB BT
Prostatectomy PT
Urea clot lysis
Whole blood clot lysis
Major or As above plus, if negative,
minor FVIII-FIX levels
Thrombin time
a2antiplasmin
Platelet aggregation
1684
blood has reduced this complication, it has not been com-
pletely eliminated in patients undergoing CPB.89
The incidence of transfusion-related type C (non-A, non-B)
viral hepatitis after CPB occurs in 6% to 10% of patients
receiving a single unit of blood, and the risk increases with
the number of units administered or with the transfusion of
fresh frozen plasma (FFP).82.90These patients are also at risk
for developing chronic hepatitis and cirrhosis.82~88
In addition to the other well-recognized complications of
transfusion therapy:' transfusion-associated graft-versus-
host disease has recently been reported in patients undergo-
ing cardiac surgery with a mortality rate approaching
90%.9',92This complication appears to be related to the
administration of fresh, nonirradiated whole blood from a
blood donor homozygous for one of the recipient's HLA
haplotypes. In view of these findings, packed RBC are
probably preferable to fresh whole blood during CPB.
Autologous Blood Transfusionfor Elective CPB
The risk of alloimmunization and transfusion-transmitted
viral diseases may be avoided by transfusing previously
deposited autologous blood. Unfortunately, this service re-
mains an underutilized source of blood for patients undergo-
ing elective CPB.93.94Although initially there was concern
that donations could precipitate myocardial ischemia if
vasovagal reactions occurred, several studies have clearly
shown that preoperative phlebotomy is well tolerated by the
majority of patients with underlying cardiovascular di-
seases82.95-98 and rarely induces angina.82*95*96 Vasovagal reac-
tions occur in about 4% of autologous donations, equivalent
to that for homologous donations.97Patients with unstable
angina, left main coronary artery stenosis, and critical aortic
stenosis have generally been excluded from autologous blood
donation programs.96
Phlebotomies are frequently scheduled at 4- to 7-day
intervals, with the last donation occurring at least 72 hours
. ~ ' * ~ a hematocrit of 234% (or
before the o p e r a t i ~ n . ~ ~Usually
hemoglobin > 11 g/dL) is required before each donation.
About two thirds of the patients scheduled for elective OHS
have donations deferred because of anemia.97 Oral iron
supplementation, started before phlebotomy and continued
postoperatively, has been recommended to minimize the
development of anemia.97-99 Recombinant erythropoietin with
preoperative autologous blood collection is an alternative
that has not yet been reported in patients undergoing OHS.
The insertion or crossover of unused autologous blood into
the homologous blood pool remains controver~ial.~~ If autolo-
gous blood is crossed over, it must meet the standard donor
criteria, including testing for AB0 and Rh type, alanine
aminotransferase (ALT) level, crossmatching, antibodies,
syphilis, hepatitis B surface antigen, HIV, and human T-cell
leukemia virus (HTLV-III).97s99
In patients undergoing elective CPB who are capable of
donating more than 2 U of autologous blood, the administra-
tion of homologous blood can be completely avoided in 65%
of cases compared with 20% for patients unable to deposit
autologous blood?7 Furthermore, 100%of patients donating
only 1 U of blood and 71% of patients donating 2 U of
autologous blood subsequently required homologous blood
WOODMAN AND HARKER
products. A preoperative donation of 3 U is associated with
only a 4% reduction in h e m a t ~ c r i t . In
~ ~the
.~~complex OHS
cases (CABG plus valvular replacement) in which bypass
times often exceed 120 minutes, it has been recommended
that 4 U of autologous blood be collected
Therefore, it appears that a donation of at least 3 U is
preferable. Although the preoperative collection of autolo-
gous platelets and FFP by apheresis before CPB is under
investigation, the guidelines for patient selection are variable
and have not yet been standardized.
Reinfusion of Intraoperative and Postoperative Autologous
Blood
Other techniques to reduce the requirement for homolo-
gous blood transfusion following CPB, have included: (1)
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intraoperative phlebotomy followed by hemodilution and
autotransfusion; (2) intraoperative reinfusion of blood sal-
vaged from the surgical field using the cell separator; (3)
postoperative reinfusion of shed mediastinal blood (SMB);
and (4) more extensive use of bloodless volume ex-
p a n d e r ~ . 6 ~ *Intraoperative
'~*~~ salvage and reinfusion prac-
tices have had variable and uncertain benefits on homologous
blood requirements and obviously are not useful in patients
with excessive bleeding p o s t o p e r a t i ~ e l y . 6 ~ Although
.~~~'~'~~
the postoperative reinfusion of SMB can be given without
significant risks of infection, microemboli, or coagulopa-
thy,68,'01*'04*105 it has had variable success in reducing the need
for homologous RBC transfusions and obviously does not
affect platelet requirement^.^^.^^.'^'^'^^ The hematocrit of
unwashed SMB varies from 20% to 30%68,83,'0','05 but can be
increased with hemoconcentration after washing.68 Other
features of SMB include reduced clotting factors with the
exception of factor IX,6' and in vitro the platelets have
abnormal aggregation.68*106 Unwashed SMB also contains
high titers of FDP and infusion results in elevated plasma
FDP levels.68 Although elevated FDP theoretically may
cause platelet dysfunction and impair fibrin polymerization,
more importantly it may lead to an incorrect diagnosis of
consumptive coagulopathy or fibrinolysis with the institution
of inappropriate therapy, especially in patients with bleeding
complications.68Despite the safety of SMB, the benefits are
unproven and the postoperative reinfusion of SMB, particu-
larly unwashed, does not appear warranted.
Platelet Transfusions
Because CPB causes transient platelet dysfunction, some
centers have routinely provided random donor platelets for
CPB patients.Io7 To test the usefulness of administering
prophylactic platelet transfusions, two prospective random-
ized studies have been p e r f ~ r m e d . ' ~ In ' ~ ' studies 4 U of
~ ~both
random donor platelets were infused immediately after
discontinuation of the extracorporeal oxygenator and after
protamine injection. No clinically significant benefit with
respect to transfusion requirements, blood loss, platelet
counts, bleeding times, or postoperative hospital stay was
demonstrated by either study. Although beneficial effects of
transfusing more platelets was not excluded by these studies,
a recent National Institutes of Health consensus conferen~e'~'
BLEEDING AFTER CARDIOPULMONARY BYPASS 1685

recommended that prophylactic platelet transfusions not be
routinely administered following CPB."o."l
Obviously, platelet transfusions are indicated for patients
with excessive bleeding caused by thrombocytopenia who are
receiving blood replacement after CPB.7 In this setting both
platelet dysfunction, as measured by a prolonged BT, and
platelet count should determine the need for platelet transfu-
sions. Normally in patients without bleeding complications
the BT shortens significantly ( 5 1 5 minutes) 20 minutes after
CPB and has returned almost to normal (t9 minutes) 2
hours after CPB.7 In patients with excessive bleeding the BT
remains prolonged (>22 minutes) for several hours after
CPB, and the bleeding is controlled and the BT shortened
(t15 minutes) by platelet transfusions. Transfusion of 1 U of
random-donor platelets per 10 kg body weight has been
effective alternative for treatment of acquired deficiencies of
factors 11, VII, IX, and X.Il3
Cryoprecipitate administration may be needed for the rare
patient with von Willebrand's disease (vWD) who is undergo-
ing ~ p ~ . 8 0 , 8 l , l l 7 - 1 2 0Factor replacement with concentrates
may be preferable for other factor deficiencies. Cryoprecipi-
tate may also be indicated for patients who have had
unsuccessful thrombolytic therapy and develop excessive
bleeding after emergency CABG (see below).
Fibrin Glues
In cardiac surgery, local hemostasis may be improved by
topical fibrin g l ~ e s . ~The
~ ~fibrin
- ' ~ ~is formed by the local
application of reconstituted topical thrombin with fibrinogen
and factor XI11 obtained from cryoprecipitate or autologous

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recommended."' Clinical response, platelet counts, and pos-
sibly BT measurements should be used to monitor the
efficacy of platelet transfusions. The BT measurement gener-
ally provides useful diagnostic information but may be
variably affected by the complexities of bypass. Single-donor
HLA-compatible plateletapheresis units may be required for
patients in whom alloantibodies have previously formed to
random donor platelets.
Transfusion of FFP and Cryoprecipitate
The indications for the administration of FFP or cryopre-
cipitate in CPB are specific and limited. There is no evidence
to support the prophylactic transfusion of either FFP or
cryoprecipitate during or after CPB."8."1-114Particularly,
FFP administration is not indicated for volume expansion,
nutritional support, wound healing, or factor replacement in
patients receiving massive transfusions, because in general
none of the coagulation factors decrease to levels sufficient to
cause abnormal bleeding or require replacement.
Administration of FFP during CPB should generally be
reserved for patients with acquired deficiencies of vitamin
K-dependent coagulation factors caused by warfarin or
congestive hepatomegaly. FFP may rarely be required for
patients with inherited deficiencies of factor V, VII, X, or XI
who are undergoing cardiac s ~ r g e r y . ~ ~ . "The
~ . " ~recom-
mended dose of FFP is 10 mL/kg followed by 5 mL/kg every
12 hours. Single-donor plasma has been proposed as an
plasma.'21*123*'24
If a high concentration of fibrinogen (90
mg/mL) is used, local hemostasis may be successfully
achieved in more then 95% of patients despite the presence of
systemic heparinization.12' The fibrin glue has been claimed
to be particularly useful in OHS associated with internal
mammary grafts,I2' reoperations for bleeding,'24and vascu-
lar prostheses.I2'Although intravascular coagulation has not
been reported by the use of the fibrin glue, infusion of the
thrombin and cryoprecipitate directly into the vascular space
or bypass pump must be avoided."' Other potential complica-
tions of this material include tamponade due to adhesionsI2'
and transfusion-transmitted viral infections, although the
risk does not exceed that associated with plasma
transf~sion.'~'.'~~
DRUG THERAPY
Aprotinin
Infusion of the protease inhibitor aprotinin (Trasylol;
Bayer AG, Leverkusen, West Germany) during OHS greatly
decreases blood loss and normalizes bleeding time (Table
3).125-'27 This naturally occurring polypeptide inhibits serine
proteases, including trypsin, kallikreins, plasmin, and plasmin-
streptokinase by reversibly complexing the active site
s e r i ~ ~ e . ' ~Whereas
~,''~ aprotinin given as a bolus injection
after CPB produced no obvious benefit,61*63*64s'29 continuously
infused aprotinin therapy, initiated before and maintained

Table 3. Usual Dosage of Hemostatic Agents Used in CPB

Drug Dosage Reference

Routine
Heparin IV bolus 300 IU/kg followed by CII to maintain intraoperative ACT be- 38
tween 350 and 500 s or P l T 1.5-2.0 times normal
Protamine Administered after CPB at -1 mg/100 U of total perioperative heparin 38,41,42
Aprotinin Preoperative IV loading dose of 280 mg followed by CII of 7 0 mg/h dur- 84, 126, 127
ing CPB. Just before termination of CPB, a second loading dose of
280 mg is added to the blood in the pump.

Therapeutic
Desmopressin 0.3 pg/kg IV (maximum 21 pg) over 15-30 min for excessive postoper- 11,36, 132, 133, 135
ative bleeding
EACA Preoperative IV loading dose of 5- 10 g followed by CII of 1 g/h until 3, 125, 139
comDletion of surQerv
Abbreviations: IV, intravenous; CII, continuous IV infusion.
1686
throughout OHS, produced substantial reductions in BT,
perioperative bleeding, and transfusion requirements for
patients undergoing first-time elective CABG (20% of the
aprotinin-treated patients required homologous blood trans-
fusion compared with 95% of the control patients).843127 been associated with a shortening of the bleeding time.
Patients undergoing repeat CABG also showed considerable
reduction in postoperative blood loss (approximately 1,500
mL) and transfusion requirements (8 of 35 aprotinin-treated
patients required a total of 10 homologous U of blood
compared with a total of 41 U for the 11 untreated patients)
after prophylactic aprotinin therapy.84,i26Additionally, in an
uncontrolled study of 15 patients undergoing O H S for
bacterial endocarditis, similar reductions in perioperative
blood loss and transfusion requirements were achieved with
prophylactic aprotinin therapy.84+130 The results of these
studies are summarized in Table 4.
In all of these studies a dosage of aprotinin was used that
maintained a constant intraoperative plasma aprotinin con-
centration of approximately 4 pmol/L. This concentration
has been reported to inhibit plasmin in vitro, and has been
reported to prevent platelet activation and a g g r e g a t i ~ n ~ ~ * ' 'ture
and to block the loss of platelet membrane GPJb during
CPB." However, it is not clear how these effects of aprotinin
on normalizing hemostatic function might be related to
inhibition of plasmin or coagulation cascade serine pros-
teases. Unraveling the mechanism whereby aprotinin acts
may provide some important clues regarding the acquired
platelet defect associated with CPB.
Aprotinin clearly represents a promising prophylactic
agent in the management of CPB-related bleeding. It may be
particularly beneficial for patients a t high risk for CPB-
related bleeding (bacterial endocarditis and reoperations) or
those patients who will not accept blood t r a n s f ~ s i o n s At
present, a past history of known or suspected pancreatitis,
allergic reactions, or previous exposure to aprotinin consti-
tute contraindications to aprotinin therapy.84
Desmopressin
The hemostatic properties of the synthetic vasopressin
analogue desmopressin acetate (desmopressin; 1-deamino-8-
D-argine vasopressin) were first demonstrated in patients
undergoing dental extractions with mild or moderate hemo-
Table 4. Aorotinin-Induced Reductions in Blood Loss and Transfusion Requirements After CPB
~
Average Postoperetive
N Blood Loss (mL)
Primary elective CABG
Placebo 37
Aprotinin 40
Complex CABG (reoperation)
Placebo 11
Aprotinin 11
Aprotinin 24
Infective endocarditis
Aprotinin 15
" P > .01.
t P > .001.
WOODMAN AND HARKER
philia and vWD.I3' Over the past decade desmopressin has
proven to be useful as a relatively nonspecific hemostatic
agent for a variety of surgical and clinical bleeding problems,
including CPB.I3' The reductions in blood loss often have
In a randomized double-blind trial of patients undergoing
CPB for valvular heart disease alone or in conjunction with
CABG, a significant reduction in perioperative blood loss
(900 mL over 24 hours) was achieved when desmopressin
was administered immediately after protamine i n f ~ s i 0 n . l ~ ~
In a second prospective study, desmopressin reduced bleed-
ing and RBC and platelet transfusion requirements in
patients experiencing excessive postoperative CPB bleeding."
In these patients a significant improvement in bleeding time,
vWF, factor VIII, and PTT followed desmopressin adminis-
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tration. Detailed analyses of perioperative v W F levels and
vWF multimers, particularly HMWM, demonstrated that
the hemostatic benefits of desmopressin in CPB were not
explained by increases in H M W M or v W F levels.35Although
it has been suggested that desmopressin may cause prema-
~ saphenous vein graft o c c l ~ s i o n , ' ~three ~ - ' ~ prospective
~
studies reported no increase in the frequency of graft
occlusion.' i - 3 6 ~ 1 3 3In general, desmopressin administration has
been well tolerated without episodes of perioperative hypoten-
sion or acute myocardial infarctions.'1,36.'33
In a recent randomized double-blind study of 150 consecu-
tive patients undergoing elective CPB, Hackmann et a1 found
no significant difference in blood loss or postoperative trans-
fusion requirements in the patients receiving desmopressin at
the end of CPB.36They also failed to detect any difference in
ristocetin cofactor activity or vWF multimeric patterns with
desmopressin administration. Similarly, in another random-
. ~ ~ ized study of 100 patients undergoing O H S for atrial septal
defects or valvular heart disease, Rocha et a1 reported no
significant reduction in postoperative blood transfusion re-
quirements by prophylactic desm~pressin,'~' although a mar-
ginal reduction in blood loss (60 mL/m') was found in
treated patients. On the basis of these trials, it appears that
desmopressin should not be given routinely, but reserved for
postoperative administration in those patients experiencing
excessive post-CPB-related bleeding. The results of the
above studies are summarized in Table 5.
Postoperative Homologous
Transfusion Requirements
Patients (%) Units Reference
573 35 (95) 75 84
309" 8 (20) 13
1,509 1 1 (100) 41 126
286t 4 (36) 5
245 4 (16) 5 84
388 6 (40) 11 130
BLEEDING AFTER CARDIOPULMONARY BYPASS 1687

Table 5. Controlled Trials Using Desmopressin With CPB

study Patient
Desmopressin-AssociatedReductions
Design Pwulation N Blood Loss124 h BT Transfusion124 ho Reference
Randomized Repeat CABG 70 900 mL NS NS 133
Double-blind Valvular
Prophylactic

Nonrandomized CABG 39 1,700mL >4.0min 7 U platelets/patient 11

TheraDeutic ( P < .5) ( P = .004)
3 U RBC/patient
(P = .015)
Randomized Valvular 100 NS r4.0min NS 135
Double-blind ASD ( P < .001)
Prophylactic

Randomized CABG 150 NS ND NS 36

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Double-blind Valvular
Prophylactic

0.3 pg/kg desmopressin given IV over 15-30 minutes after CPB and protamine.
Abbreviations: NS, not significant; ND, not done; ASD, atrial septal defect.
*Transfusion requirements in first 24 postoperative hours.

Antifibrinolytic Agents reported in a subset analysis of children with cyanotic

The synthetic lysine analogue EACA (Amicar, Lederle
Laboratories, Wayne, NJ) has been used frequently as an
antifibrinolytic agent during CPB. Although EACA is effec-
tive in reducing bleeding in a variety of clinical circum-
stances,'*' its use in CPB has been contr~versial."~Despite
its widespread administration in CPB over the past 20 to 30
years, most of the published reports claiming benefits have
been uncontrolled and r e t r o s p e c t i ~ e . ~ ~ ~ ~ ~ ' ~ ~
Three prospective randomized double-blind studies have
evaluated the effects of prophylactic EACA administration
in CPB3.'38*'39 (Table 6). The first prospective study was
performed in children undergoing OHS for the correction of
congenital heart defects.13' Although there was no overall
benefit, a significant reduction in postoperative blood loss was
congenital heart defects and in those with pump times
greater than 60 minutes, with the greatest difference in blood
loss occurring between the time when bypass was discontin-
ued and surgery was completed. Two subsequent studies
have examined EACA in adults undergoing elective
CABG.3.'39Although both studies reported statistically signif-
icant differences, the reduction in postoperative blood loss
was not clinically important (60 mL and 166 mL, respec-
tively). Moreover, both arterial and venous thrombosis have
complicated EACA therapy in a number of studies, (eg,
arterial occlusion causing stroke,".14' gangrene,I4' and acute
renal f a i l ~ r e . ' ~In~the
, ' ~above
~ studies, no thrombotic events
were observed after CPB except for the possibility of EACA-
related perioperativemyocardial infarctions in two patients.'3g

Table 6. Controlled Trials Using Prophylactic EACA in CPB

Blood Loss
Patient
Reference Condition N Placebo EACA Comments
Children with congenital heart disease
138 Cyanotic 30 62* 35+t Significant reduction in bleeding greatest immediately
Acyanotic 26 29. 26+ after CPB and for patients with bypass times >60 min

Adults with coronary artery disease

139 Elective CABG 60 332$ 272t$ 2 EACA-related acute MI
Controls lower preoperative plasma fibrinogen levels
Postoperative platelet counts slightly higher with EACA
3 Elective CABG 350 8835 6 17511 Reduction in transfusion requirements exceeded blood
loss
No increase in postoperative thrombotic complications
with EACA
Abbreviation: MI, myocardial infarction.
*mL/kg body weight.
tP < .02.
SmL for the first 12 postoperative hours.
5mL for the first 24 postoperative hours.
1[P < .05.
1688
The minimal benefit of EACA with respect to bleeding and
the uncertainty regarding risk for increasing thrombotic
events have generally discouraged its clinical use.
The effect of other lysine analogues such as the longer
acting tranexamic acid (AMCA; Cyclokapron Kabivitrum,
Alameda, CA) on CPB-related bleeding has recently been
evaluated in a randomized double-blind trial with results
similar to that described previously with EACA.I4’
Prostaglandins
The capacity of PGI, and its analogues to protect platelets
from activation and subsequent destruction during CPB have
been studied extensively. PGI, inhibits platelet activation by
stimulating adenyl cyclase to increase intracellular cyclic
adenosine monophosphate levels.’46Its immediate potent but
reversible inhibition of platelet activation, together with its
rapid clearance in vivo (-3 minutes), characterize PGI, as an
attractive agent for protecting platelets during CPB without
affecting coagulation proces~es.’~ Initial studies in experimen-
tal animals undergoing CPB demonstrated that PGI, pre-
served circulating platelets and decreased blood I o s s . ~ ~ , ’ ~ ’ may be influenced in vitro by such factors as the molecular
Using a baboon model, Malpass et al also demonstrated that
PGI, prevented prolongation of the bleeding time when
administered within the therapeutic window of 40 to 80
ng/kg/min.16 However, experimental animal studies also
demonstrated that CPB performed with PGI, alone without
heparin anticoagulation produced depletion of the consum-
able clotting factors and excessive thrombosis within the
extracorporeal
Randomized double-blind trials of prophylactic PGI, ad-
ministration in humans undergoing CPB have been per-
formed without conclusive evidence for benefit.’9-21,23.25,148,149
Although there were differences in (1) PGI, dosages (rang-
ing from 10 to 100 ng/kg/min); (2) site of administration;
(3) initiation of therapy; and (4) duration of the PGI,
infusion, the most consistent finding among all studies was
the dose-dependent production of vasodilation and hypoten-
sion requiring aggressive management. Despite a modest
improvement in perioperative platelet counts by PGI, in
some studies, there was no significant associated reduction in
postoperative blood loss or transfusion requirement^.'^.^^,'^^
Thus, there are no demonstrated clinical indications for using
PGI, in CPB. Iloprost (Berlex Laboratories Inc, Cedar
Knolls, NJ), a stable potent PGI, analogue, has similarly
been reported to preserve platelet counts and produce hypoten-
sion during extracorporeal circulation.22 At present there is
no clinical evidence to support the routine use of Iloprost
during CPB. However, of some clinical relevance, Iloprost
therapy may protect the platelet count in patients with
heparin-induced thrombocytopenia (HIT) who receive hep-
arin during CPB despite the presence of heparin-associated
platelet antibodies.
SPECIFIC HEMOSTATIC COMPLICATIONS DURING CPB
HIT
Patients undergoing CPB necessarily require heparin anti-
coagulation during CPB. Thrombocytopenia complicates
heparin therapy in about 2% to 5% of these patient^."^ The
WOODMAN AND HARKER
onset and severity of HIT is variable, usually occurring
within 6 to 12 days of heparin administration but occasion-
ally beginning earlier in patients who have had previous
e x p o s ~ r e HIT . ~ ~occurs
~ ~ ~ independent
~~ of dose or route of
heparin administration, but does not always recur with
heparin rechallenge and may even resolve during heparin
therapy. In most patients the thrombocytopenia is mild and
not associated with bleeding; however, occasionally it may be
complicated by life-threatening bleeding and acute arterial
thrombosis, including myocardial infarction, stroke, and
limb i ~ c h e m i a . l ~Unfortunately,
*-~~~ at present there is no
reliable method for predicting which patients develop
HIT. I50,15I , 154- I56
It recently has been shown that a specific antiheparin IgG
antibody binds to repeating antigenic determinants in hep-
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arin, which in turn bind to the surface of the platelet through
an unidentified 82-Kd platelet membrane protein.”’ Immune
platelet destruction results. It has also been determined that
platelet membrane G P Ib, IIb, IIIa, or IX are not involved in
the pathogenesis of HIT.IS6The heparin-platelet interaction
weight and sulfation of heparin, antithrombin I11 binding,
and the presence of the platelet a-granule proteins thrombo-
spondin and histidine-rich GP.IS4 When the heparin-
antibody complex forms, the IgG binds to the platelet Fc
receptor and initiates platelet activation with serotonin
release and subsequent platelet a g g r e g a t i ~ n . ~ This ’~~~~~.~~~
activation process is independent of complement fixation,
occurs in vitro at therapeutic heparin concentrations (but not
at higher concentrations), and forms the basis for the
serotonin platelet-release a ~ s a y . ’Unbound
~ ~ . ~ ~ immune
~ com-
plexes in the plasma of patients with HIT have not been
detected and it is unclear why the heparin-IgG complexes
preferentially bind to platelet Fc receptors as opposed to
granulocyte/monocyte high-affinity Fc receptors. The rela-
tionship between heparin-IgG complexes and thrombotic
complications also remains unexplained. Assays of heparin-
dependent platelet aggregation or the presence of platelet-
associated IgG are of limited diagnostic value because of
their lack of specificity and s e n s i t i ~ i t y . ~ ~ However,~-’~@~~~
improved sensitivity and specificity for detecting HIT has
been achieved by measuring platelet serotonin released by
heparin at high (100 U/mL) and therapeutic (0.1 U/mL)
concentrati~ns.’~~J~~
In the postoperative period HIT is often a diagnosis of
exclusion and must be distinguished from other potential
causes of postoperative thrombocytopenia such as sepsis,
disseminated intravascular coagulation, posttransfusion pur-
pura, hemodilution, fat emboli, use of an intra-aortic balloon
pump, or medications other than heparin. In this context a
diagnosis of HIT necessitates immediate discontinuation of
any heparin administration. Platelet transfusions should not
be given prophylactically and are only indicated for bleeding
complications. Acute arterial thrombosis occasionally has
been precipitated by platelet t r a n s f ~ s i o n s . l ’ ~ J ~ ~
The management of patients with HIT associated with
CPB is influenced by whether they present pre-operatively or
postoperatively (Fig 1). It has been recommended that
patients with known or suspected HIT may safely undergo a
BLEEDING AFTER CARDIOPULMONARY BYPASS
Detected immediately prior
to CPB or a past history of HIT
I
I I
Elective or
Heparin re-challenge
Fig 1. Management ap-
proach for patients developing
I
If possible delay
HIT during or after CPB. Cur- surgery until
rently Iloprost, ancrod, and he- disappearance of
parinoid (ORG 10172) are inves- heparin antibody
tigational in the United States.
heparin rechallenge during CPB, provided pre-operative and
postoperative heparin administration is completely avoided
and there is no in vitro evidence for heparin-dependent IgG
(using the serotonin release a ~ s a y ) . " ~ *The ' ~ ~ heparin-
dependent IgG activity usually disappears within 4 to 8
weeks after discontinuation of h e ~ a r i n . ' ~Some ~ . ' ~ observers
~ preoperatively and to titrate intraoperatively.
have reported that HIT may also be reduced by substituting
porcine heparin preparations for bovine heparin prepara-
tions, although this claim is controversial.'50~'5'
The appropriate management of patients with HIT who
must undergo emergency CPB remains uncertain, but sev-
eral alternatives to standard heparin anticoagulation have
been suggested. Warfarin,16' low-molecular-weight
dextran^,'^' low-molecular-weight heparins (LMWH),'54*'65
h e p a r i n ~ i d s , ' ~ ~profound
* ' ~ ~ - ' ~ hemodilution
~ with deep
h y p ~ t h e r m i a ,ancrod
' ~ ~ (Arvin; Knoll AG Pharmaceuticals,
Whippany, NJ),165*'7'.172 and recombinant hirudin have all
been considered as possible anticoagulant regimens to hep-
arin anticoagulation during CPB. The prostacyclin analogue
Iloprost has also been reported to protect platelets during
heparin anticoagulation for CPB.'6s*'73"75 Clearly no optimal
alternative to heparin during CPB has been demonstrated.
Some success has been reported with heparinoid when
prescreening with the heparinoid by in vitro tests for heparin-
antibody are negative. At present Iloprost, ancrod, or hirudin
are investigational agents. When possible it may be more
prudent to postpone surgery until the heparin-specific IgG
has disappeared. One approach reported to be successful
involves a continuous intraoperative infusion of Iloprost
administered concurrently with a porcine heparin
preparati~n.'~~*"~-''~ The perioperative bleeding, transfusion
1689
TT
Detected ,fter CPB
Emergency CPB
Iloprost plus heparin
or Ancrod
or Heparinoid
Platelet Serotonin Zelease Assay
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1
Negitive Positive
Exclude other - Discontinue heparin
causes of - Avoid platelet
thrombocytopenia transfusions
If surgery cnhnot be delayed
- Iloprost plus heparin
or Ancrod
or Heparinoid
- Avoid platelet transfusions
requirements, BT, and platelet counts were comparable with
historical controls and the hypotension often associated with
the prostacyclins was adequately managed by intraoperative
phenylepinephrine infusions. The dose of Iloprost varied
between 3 and 36 ng/min/kg and is difficult to determine
The defibrinating agent ancrod (Arvin) has also been
reported to be successful during CPB,'70*'76,'77 although
others have recommended that surgery is contraindicated
with ancrod therapy.17' Preoperative fibrinogen levels of 0.4
to 0.8 g/L are required for successful anticoagulation during
CPB'76*'77;reduced levels will persist for several days.'78
Ancrod also has been proposed as an alternative to heparin
during CPB for patients with protamine-induced allergic
reactions or antithrombin I11 d e f i ~ i e n c y . ' ~ ' . ' ~Currently
~.'~~
ancrod is under investigation in the United States for stroke
and HIT.
Heparinoid (ORG 10172), composed of heterogeneous
porcine polysulfated heparin and nonheparin glycosaminogly-
cans, has been used in a limited number of cases of HIT,'66-'69
including CABG.'68Although heparinoid provided adequate
anticoagulation and stabilized or improved platelet counts,
significant postoperative bleeding requiring discontinuation
of the drug and administration of FFP occurred in some
patients.'68LMWH have also been used in HIT154.179~'80 when
the assay for heparin-dependent platelet aggregation was
negative to LMWH. In the presence of a positive assay for
platelet aggregation, 4 of 11 patients had an unfavorable
clinical o~tcome."~
Hirudin, a specific potent polypeptide inhibitor of throm-
bin, has recently been cloned and sequenced.'" Recombinant
1690
hirudin is a theoretically attractive but untested alternative
to heparin anticoagulation during CPB.
Inherited Disorders of Coagulation Factors
CPB and OHS for congenital heart disease, acquired
valvular heart disease, and coronary artery disease have been
performed successfully in patients with hemophilia A,120*182-185implanted heart valves without using oral anticoagulation,
hemophilia B,12O,I86-188 vWD,80.81,117-1 19.189 f actor VI1 defic-
iency,II5 and factor XI deficiency1I6(Table 7). The manage-
ment of these patients is similar to the standard recommenda-
tions given for patients with inherited coagulopathies
undergoing other kinds of major surgery. Complete replace-
ment of the missing clotting factor and maintenance a t
therapeutic levels throughout surgery and 2 weeks postopera-
tively using appropriate concentrates is r e q ~ i r e d . ’ ~ & It Iis
~ ~ velop either coronary reocclusion or cardiogenic shock and
important to appreciate that replacement therapy for pa-
tients with mild deficiencies undergoing CPB must be as
vigorous as for severely deficient patients. The presence of
inhibitors to factor VI11 or factor IX is presently considered
to be an absolute contraindication to elective OHS,120,183.187greatly compounds the hemostatic problems in these patients
although the availability of activated factor VI1 concentrates
may influence this guideline. During CPB, heparin anticoag-
ulation followed by protamine neutralization is required in
the conventional dosages, and EACA therapy is generally
not used.
There are a number of special considerations in OHS.
First, at the completion of CPB, additional factor may need
to be administered to achieve appropriate therapeutic levels.
Second, desmopressin administration in patients with hemo-
philia A and vWD undergoing OHS has not been empha-
sized, although the usual recommendations regarding a test
dose, tachyphylaxis, contraindications (type IIb and pseudo-
vWD) and its use for the treatment of excessive CPB-related
bleeding still apply. Obviously, desmopressin alone will not
provide adequate hemostasis during CPB in any patient with
hemophilia A or vWD regardless of their underlying factor
VI11 levels. Third, the use of either activated or unactivated
prothrombin complex concentrates (PCC) in OHS for factor
IX r e p l a ~ e m e n t ’ ~ ~have
* ’ ~ ’been associated with thrombotic
complications, including acute myocardial infarction and
pulmonary embolism.’95Liver disease, prolonged administra-
tion, and excessive doses of PCC appear to increase the risk
of developing thrombotic complications. The addition of
Table 7. Patients W i t h Inherited Deficiencies of Hemostasis Undergoing CPB
No. of
Disorder Cases Factor Replacement
vWD 6 Cryoprecipitate
FFP
Hemophilia A 4 Cryoprecipitate
FVlll concentrate
1 Megadoses of FVlll concentrate pre-
operatively then CII of FVlll intraop-
eratively
Hemophilia B 4 FIX concentrate
Factor XI deficiency 1 FFP
Factor VI1 deficiency 1 FFP
WOODMAN AND HARKER
heparin to the PCC (60 U per vial) has been recommended to
cover the period immediately after administration while
activated species of clotting factors are being ~ 1 e a r e d . l ~ ~
Fourth, nonsteroidal anti-inflammatory drugs are avoided
after OHS in patients with hereditary bleeding disorders.
Finally, to avoid the risk of systemic emboli arising from
bioprostheses are preferable in patients with underlying
inherited bleeding disorders.
Emergency CABG After Unsuccessful Thrombolytic
Therapy and Angioplasty
Between 5% and 15% of patients receiving thrombolytic
therapy for evolving acute myocardial infarction may de-
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require emergency coronary angioplasty or CABG.’96-199
Because streptokinase, urokinase, and to a lesser extent
tissue-type plasminogen activator (tPA) destroy fibrinogen
and coagulation factors V and VIII, thrombolytic therapy
during CPB. In one retrospective study, about 19% of
patients who had emergency CABG after receiving throm-
bolytic therapy and angioplasty developed perioperative
bleeding complication^.^^' In addition to hypofibrinogenemia
and the depletion of factors V and VIII, defective fibrin
polymerization and platelet dysfunction are produced by
high levels of FDP during thrombolytic therapy.48 Although
there is no in vivo evidence for direct plasmin-induced
platelet dysfunction, platelet aggregation in vitro has been
inhibited by: (1) plasmin-mediated proteolysis of platelet GP
Ib and IIb/IIIa, (2) plasmin-mediated FDP elevation, (3)
plasmin-mediated degradation of platelet-bound fibrinogen,
and (4) plasmin-mediated inhibition of thromboxane A,
synthesis.48
In one series of 24 patients undergoing emergency CABG
after unsuccessful streptokinase therapy and angioplasty, an
average perioperative blood loss of more than 1,400 mL was
observed and all 24 patients required substantial postopera-
tive transfusion with RBC, FFP, and platelet^.'^^ Surpris-
ingly, only 11 of the 24 patients had abnormal postoperative
coagulation parameters (PT, PTT, platelet count, fibrinogen
level, and FDP; BT not obtained), which were often attrib-
uted to inadequate heparin neutralization. A reptilase time
% Factor Level
Pre- Post- Duration of Replacement
operative operative Therapy (postoperatived) References
>80 40-200 4-10 80.81. 117-119, 185
22-190 30-100 7-42 120, 182-184
600 >40 8 185
23-90 12-90 7-14 120, 186-188
22 20-25 8 116
ND 50-100 2 115
BLEEDING AFTER CARDIOPULMONARY BYPASS
may be helpful in distinguishing fibrinolysis from inadequate
protamine administration. Based on various thrombolytic
trials, it appears unlikely that FDP or fibrinogen would be
useful as predictors of perioperative bleeding due to throm-
bolytic therapy.48 Significant perioperative bleeding and
increased transfusion requirements were reported in 2 of 24
patients (8%) undergoing emergency CABG after unsuccess-
ful thrombolysis with recombinant tPA ( F ~ P A ) . Although
’~~
no randomized study has directly compared hemorrhagic
complications after thrombolytic therapy with either strep-
tokinase or r-tPA, the transfusion requirements and the
fibrin-specific effects of r-tPA suggest that r-tPA might
result in less bleeding after emergency CABG.48*’98
Thus, emergency CABG may be safely performed after
thrombolytic therapy, although the exact management of
postoperative hemostasis has not been established. Prophylac-
tic aprotinin is most likely to be beneficial in this setting,
although it has not yet been formally tested in this subset of
patients undergoing CABG. The indications for the use of
intraoperative and postoperative EACA therapy remains
u n ~ e r t a i n ? ~and
. ’ ~ ~the routine preoperative administration
of replacement blood products such as cryoprecipitate or
FFP has not been studied and currently cannot be recom-
mended.
Total Artificial Hearts and Ventricular Assist Devices
Bleeding is a common cause of morbidity and mortality in
patients with ventricular assist devices (VAD) and total
artificial hearts (TAH).136~’w’0’In one report, 22 of 30
patients on VAD required a total of 24 reoperations for
hemorrhagic complications.’” An acquired platelet defect
appears to be the most frequent cause of bleeding.’36It has
yet to be determined whether this defect is the same as that
associated with CPB. Effective management usually re-
quires: (1) prolonged systemic anticoagulation with heparin
or warfarin; (2) platelet inhibition with dextran, aspirin, and
dipyridamole; and (3) liberal administration of platelets and
FFP. In at least one center, aprotinin also has been routinely
used during TAH implantation.’m Desmopressin has been
used empirically to control bleeding in patients with VAD;
however, the effectiveness of this approach remains to be
e~tab1ished.l~~
Cryoglobulinemia
Because moderate systemic hypothermia (25 to 28OC) is
routinely used during OHS, it may present special risks for
patients with cryoglobulinemia and cold agglutinin disease if
the thermal amplitude of the cryoprotein falls within the
REFERENCES
1 . Rimm A: Trends in cardiac surgery in the United States. N
Engl J Med 312:119, 1985 (letter)
2. Allen CM: Cabbages and CABG. Br Med J 297:1485,1988
3. DelRossi AJ, Cernaianu AC, Botros S,Lemole GM, Moore R:
Prophylactic treatment of postperfusion bleeding using EACA.
Chest 96:27, 1989
4. Serry C, Bleck PC, Javid H, Hunter JA, Goldin MD, DeLaria
1691
range of the anticipated surgical temperatures. Thus, it
becomes important to determine the thermal amplitude in
patients with established disease, because preoperative
plasmapheresiszo3and regional pericardial-myocardial hypo-
thermia’03*’04
have been reported to provide effective manage-
ment in a limited number of instances.
SUMMARY
Bleeding after CPB has been difficult to characterize and
its treatment equally difficult to standardize. The complexity
of this problem is related to the hemostatic process, the
technical variations in the operative procedures, and the
many uncontrolled variables associated with CPB, including
the effects of anesthetic or pharmacologic agents, the nature
of the priming solution, hemodilution, hypothermia, the type
Downloaded from https://ashpublications.org/blood/article-pdf/76/9/1680/604685/1680.pdf by guest on 09 April 2020
of oxygenator, and the use of transfused blood products.
Although there are multiple and generally predictable com-
plex changes in the hemostatic mechanism during CPB, the
temporary loss of platelet function is the most common and
clinically relevant. This transient platelet dysfunction occurs
in all patients undergoing CPB; however, it only causes
excessive bleeding in a small percentage of patients. Unfortu-
nately, it has not yet been possible to predict which patients
will develop hemorrhagic complications, although prolonged
pump times are a contributing risk factor.
Over the past decade there has been extensive investiga-
tion into the management of bleeding associated with CPB,
provoked primarily by the increased awareness of transfusion-
transmitted viral diseases and the inappropriately excessive
use of homologous blood products. Several approaches to
autotransfusion of shed blood and autologus blood donation
have been developed to minimize perioperative homologous
blood transfusion. Pharmacologic agents such as desmo-
pressin, aprotinin, and topical fibrin glues have also been
introduced to improve hemostasis during CPB. The protease
inhibitor aprotinin is particularly promising in the reduction
of bleeding associated with CPB when given prophylacti-
cally. Aprotinin may provide new insights into the mecha-
nism of CPB-induced platelet dysfunction. Desmopressin is
indicated only for the treatment of bleeding after CPB. The
management of bleeding associated with CPB will undoubt-
edly continue to improve.
ACKNOWLEDGMENT
We are indebted to Carol Fedoryszyn for her invaluable assistance
in the preparation of this manuscript. We also thank Drs J. Kelton,
T. Warkentin, and M. Glynn for their assistance.
GA, Najafi H: Sternal wound complications. J Thorac Cardiovasc
Surg 80861,1980
5. Bachmann F, McKenna R, Cole ER, Najafi H: The hemostatic
mechanism after open-heart surgery. J Thorac Cardiovasc Surg
(Part I) 7@76, 1975
6. Lambert CJ, Marengo-Rowe AJ, Leveson JE, Green RH,
Thiele JP, Geisler GF, Adam M, Mitchel BF: The treatment of
postperfusion bleeding using e-aminocaproic acid, cryoprecipitate,
1692
fresh-frozen plasma, and protamine sulfate. Ann Thorac Surg
28:440, 1979
7. Harker L, Malpass TW, Branson HE, Hessel I1 EA, Siichter
S A Mechanism of abnormal bleeding in patients undergoing cardio-
pulmonary bypass: Acquired transient platelet dysfunction associ-
ated with selective a-granule release. Blood 56:824,1980
8. CIagett GP: Artificial devices in clinical practice, in Coleman
RW, Hirsh J, Marder VJ, Salzman EW (eds): Hemostasis and
Thrombosis (ed 2). Philadelphia, PA, Lippincott, 1987, p 1348
9. McKenna R, Bachmann F, Whittaker B, Gilson JR, Weinberg
M Jr: The hemostatic mechanism after open-heart surgery. 11.
Frequency of abnormal platelet functions during and after extracor-
poreal circulation. J Thorac Cardiovasc Surg 70298, 1975
10. Milam JD, Austin SF, Martin RF, Keats AS, Cooley D A
Alteration of coagulation and selected clinical chemistry parameters
in patients undergoing open heart surgery without transfusions. Am
J Clin Pathol76:155, 1981
11. Czer LSC, Bateman TM, Gray RJ, Raymond M, Stewart
ME, Lee S, Goldfinger D, Chaux A, Matloff JM: Treatment of
severe platelet dysfunction and hemorrhage after cardiopulmonary
bypass: Reduction in blood product usage with desmopression. J Am
Coll Cardiol9:1139, 1987
12. Zilla P,Fasol R, Groscurth P, Klepetko W, Reichenspurner
H, Wolner E Blood platelets in cardiopulmonary bypass operations.
Recovery occurs after initial stimulation, rather than continual
activation. J Thorac Cardiovasc Surg 97:379,1989
13. Moriau M, Masure R, Hurlet A, Dekeys C, Chalant C,
Ponlet R, Iaumain P, Suraze-Kestens Y, Ravaux A, Lewis A,
Goener M: Haemostasis disorders in open heart surgery with
extracorporeal circulation. Vox Sang 32:41, 1977
14. Edmunds LH, Ellison N, Colman RW, Niewiarowski S, Rao
AK, Addonizio TP, Stephenson LW, Edie RN: Platelet function
during cardiac operation. Comparison of membrane and bubble
oxygenators. J Thorac Cardiovasc Surg 83:805,1982
15. Valeri CR, Cassidy G, Khuri S, Feingold H, Ragno G,
Altschule MD: Hypothermia-induced reversible platelet dysfunc-
tion. Ann Surg 205:175, 1987
16. Malpass TW, Hanson SR, Savage B, Hessel I1 EA, Harker
LA: Prevention of acquired transient defect in platelet plug forma-
tion by infused prostacyclin. Blood 57:736,1981
17. Addonizio VP Jr, Strauss J F 111, Colman RW, Edmunds LH
Jr: Effects of prostaglandin E, on platelet loss during in vivo and in
vitro extracorporeal circulation with a bubble oxygenator. J Thorac
Cardiovasc Surg 77:119, 1979
18. Addonizio VP Jr, Smith JB, Strauss J F 111, Colman RW,
Edmunds LH Jr: Thromboxane synthesis and platelet secretion
during cardiopulmonary bypass with bubble oxygenator. J Thorac
Cardiovasc Surg 79:91, 1980
19. Walker ID, Davidson JF, Faichney A, Wheatley DJ, David-
son KG: A double blind study of prostacyclin in cardiopulmonary
bypass surgery. Br J Hematol49:415, 198 1
20. Aren C, Feddersen K, Radegran K Effects of prostacyclin
infusion on platelet activation and postoperative blood loss in
coronary bypass. Ann Thorac Surg 36:49,1983
21. Malpass TW, Amory DW, Harker LA, Ivey TD, Williams
DB: The effect of prostacyclin infusion on platelet hemostatic
function in patients undergoing cardiopulmonary bypass. J Thorac
Cardiovasc Surg 87550, 1984
22. Addonizio VP Jr, Fisher CA, Jenkin BK, Strauss J F 111,
Musial JF, Edmunds LH Jr: Iloprost (ZK36374), a stable analogue
of prostacyclin, preserves platelets during stimulated extracorporeal
circulation. J Thorac Cardiovasc Surg 89:926,1985
23. Longmore DB, Hoyle PM, Gregory A, Bennett JG, Smith
MA, Osivand T, Jones WA: Prostacyclin administration during
cardiopulmonary bypass in man. Lancet 1:800,1981
WOODMAN AND HARKER
24. Coppe D, Sobel M, Seamans L, Levine F, Salzman E
Preservation of platelet function and number by prostacyclin during
cardiopulmonary bypass. J Thorac Cardiovasc Surg 81:274,1981
25. Radegran K, Egberg N, Papaconstantinou C: Effects of
prostacyclin during cardiopulmonary bypass in man. S a n d J Thorac
Cardiovasc Surg 15:263,1981
26. George JN, Pickett EB, Saucerman S, McEver RP, Kunicki
TJ, Kieffer N, Newman PJ: Platelet surface glycoproteins. Studies
on resting and activated platelets and platelet membrane microparti-
cles in normal subjects, and observations in patients during adult
respiratory distress syndrome and cardiac surgery. J Clin Invest
78:340,1986
27. Dechavanne M, Ffrench M, Pages J, Ffrench P, Boukerche
H, Byron PA, McGregor J L Significant reduction in the binding of
a monoclonal antibody (LYP 18) directed against the IIb/IIIa
glycoprotein complex to platelets of patients having undergone
extracorporeal circulation. Thromb Haemost 57:106, 1987
Downloaded from https://ashpublications.org/blood/article-pdf/76/9/1680/604685/1680.pdf by guest on 09 April 2020
28. van Oeveren W, Eijsman L, Roozendaal KJ, Wildevuur
CRH: Platelet preservation by aprotinin during cardiopulmonary
bypass. Lancet 1:644, 1988 (letter)
29. Wenger RK, Lukasiewicz H, Mikuta BS, Niewiarowski S,
Edmunds LH Jr: Loss of platelet fibrinogen receptors during clinical
cardiopulmonary bypass. J Thorac Cardiovasc Surg 97:235,1989
30. Wachtfogel YT, Musial J, Jenkin B, Niewiarowski S, Ed-
munds LH Jr, Colman RW: Loss of platelet qadrenergic receptors
during simulated extracoporeal circulation: Prevention with pros-
taglandin E,. J Lab Clin Med 105:601, 1985
31. Musial J, Niewiarowski S, Hershock D, Morinelli TA,
Colman RW, Edmunds LH Jr: Loss of fibrinogen receptors from the
platelet surface during simulated extracorporeal circulation. J Lab
Clin Med 105:514, 1985
32. Adelman B, Michelson AD, Loscalzo J, Greenberg J, Handin
RI: Plasmin effect on platelet glycoprotein IEvon Willebrand factor
interactions. Blood 65:32, 1985
33. Niewiarowski S, Senyi AF, Gillies P Plasmin-induced plate-
let aggregation and platelet release reaction. J Clin Invest 51:1647,
1973
34. Brody JI, Pickering NJ, Fink GB: Concentrations of factor
VIII-related antigen and factor XI11 during open heart surgery.
Transfusion 26:478, 1986
35. Weinstein M, Ware JA, Troll J, Salzman E Changes in von
Willebrand factor during cardiac surgery: Effect of desmopressin
acetate. Blood 71:1648, 1988
36. Hackmann T, Gascoyne RD, Naiman SC, Growe GH,
Burchill LD, Jamieson WRE, Sheps SB, Schechter MT, Townsend
G E A trial of desmopressin (I-desamino-8-d-arginine vasopressin)
to reduce blood loss in uncomplicated cardiac surgery. N Engl J Med
321:1437,1989
37. Gill JC, Wilson AD, Endres-Brooks J, Montgomery RJ: Loss
of the largest von Willebrand factor multimers from the plasma of
patients with congenital cardiac defects. Blood 67:758, 1986
38. Edmunds LH Jr, and Addonizio VP Jr: Extracorporeal
circulation, in Coleman RW, Hirsh J, Marder VJ, Salzman EW
(eds): Hemostasis and Thrombosis (ed 2). Philadelphia, PA, Lippin-
cott, 1987, p 901
39. Ellison N, Ominsky AJ, Wollman H: Is protamine a clinically
important anticoagulant? A negative answer. Anesthesiology 35:
621,1971
40. Gravlee GP, Haddon WS, Rothberger HK, Mills SA, Rogers
AT, Bean VE, Buss DH, Prough DS, Cordell A R Heparin dosing
and monitoring for cardiopulmonary bypass. J Thorac Cardiovasc
Surg 99:518,1990
41. Ellison N, Beatty CP, Blake DR, Wurzel HA, MacVaugh H
I11 Heparin rebound. Studies in patients and volunteers. J Thorac
Cardiovasc Surg 67:723, 1974
BLEEDING AFTER CARDIOPULMONARY BYPASS
42. Pifarre R, Babka R, Sullivan HJ, Montoya A, Bakhos M,
El-Etr A Management of postoperative heparin rebound following
cardiopulmonary bypass. J Thorac Cardiovasc Surg 81:378, 1981
43. Ratnoff OD: Some therapeutic agents influencing hemostasis,
in Coleman RW, Hirsh J, Marder VJ, Salzman EW (eds): Hemosta-
sis and Thrombosis (ed 2). Philadelphia, PA, Lippincott, 1987, p
1026
44. Umlas J, Gauvin G, Taff R: Heparin monitoring and neutral-
ization during cardiopulmonary bypass using a rapid plasma separa-
tor and a fluorometric assay. Ann Thorac Sur 37:301,1984
45. Jobes DR, Schwartz AJ, Ellison N: Heparin rebound. J
Thorac Cardiovasc Surg 82:940, 198 1
46. Weiler JM, Freiman P, Sharath MD, Metzger WJ, Smith
JM, Richerson HB, Ballas ZK, Halverson PC, Shulan DJ, Matsuo
S,Wilson RL: Serious adverse reactions to protamine: Are alterna-
tives needed? J Allergy Clin Immunol75:297, 1985
47. Lowenstein E, Lynch K, Robinson DR, Fitzgibbon CM,
Zapol W: Incidence, severity and causation of adverse cardiopulmo-
nary response to protamine reversal of heparin anticoagulation in
man. Am Rev Respir Dis 137:245a, 1988 (abstr)
48. Sane DC, Califf RM, Topol EJ, Stump DC, Mark DB,
Greenberg CS: Bleeding during thrombolytic therapy for acute
myocardial infarction: Mechanisms and management. Ann Intern
Med 111:1010,1989
49. Weiss ME, Nyhan D, Peng Z, Horrow JC, Lowenstein E,
Hirshman C, Adkinson N F Jr: Association of protamine IgE and
IgG antibodies with life-threatening reactions to intravenous prota-
mine. N Engl J Med 320886,1989
50. Levy JH, Schwieger IM, Zaidan JR, Faraj BA, Weintraub
WS: Evaluation of patients at risk for protamine reactions. J Thorac
Cardiovasc Surg 98:200,1989
51. Stefaniszyn HJ, Novick RJ, Salerno T A Toward a better
understanding of the hemodynamic effects of protamine and heparin
interaction. J Thorac Cardiovasc Surg 87:678,1984
52. Frater RWM, Oka Y, Hong Y, Tsubo T, Loubser PG,
Masone R: Protamine-induced circulatory changes. J Thorac Cardio-
vasc Surg 87:687, 1984
53. Levy JH, Zaidan JR, Camp VM: Effects of protamine on
histamine release from human lung. Agents Actions 23:70, 1989
54. Levy JH, Zaidan JR, Faraj B: Prospective evaluation of risk
of protamine reactions in NPH insulin-dependent diabetes. Anesth
Analg 65:739, 1986
55. Stewart WJ, McSweency SM, Kellett MA, Faxon DP, Ryan
TJ: Increased risk of severe protamine reactions in NPH insulin-
dependent diabetics undergoing cardiac catherization. Circulation
709:788, 1984
56. Levy JH: Life-threatening reactions to intravenous prota-
mine. N Engl J Med 321:1684, 1989 (letter)
57. Gottschlich GM, Gravlee GP, Georgitis JW: Adverse reac-
tions to protamine sulfate during cardiac surgery in diabetic and
non-diabetic patients. Ann Allergy 61:277, 1988
58. Sloand EM, Kessler CM, McIntosh CL, Klein HG: Methyl-
ene blue for neutralization of heparin. Thromb Res 54:677, 1989
59. Castaneda A R Must heparin be neutralized following open-
heart operations? J Thorac Cardiovasc Surg 52:716, 1966
60. Gans H, Krivit W, Runyeon A, McAuley M, Cans M A
Problems in hemostasis during open-heart surgery. 111. Epsilon
aminocaproic acid as an inhibitor of plasminogen activator activity.
Ann Surgery 155:268,1962
61. Tice DA, Reed GE, Clauss RH, Worth MH: Hemorrhage
due to fibrinolysis occurring with open-heart operations. J Thorac
Cardiovas Surg 46:673,1963
62. Kevy SV, Glickman RM, Bernhard WF, Diamond LK, Gross
R E The pathogenesis and control of the hemorrhagic defect in open
heart surgery. Surg Gynecol Obstet 123:313,1966
1693
63. Cans H, Castaneda AR, Subramanian V, John S, Lillehei
CW: Problems in hemostasis during open heart surgery: IX. Changes
observed in the plasminogen-plasmin system and their significance
for therapy. Ann Surg 166:980, 1967
64. Mammen E F Natural proteinase inhibitors in extracorporeal
circulation. Ann NY Acad Sci 146:754, 1968
65. Rhodes GR, Silver D: Periepicardial fibrinolytic activity:
Relation to cardiac bleeding. Surgery 78:23, 1975
66. Bentall HH, Allwork SP Fibrinolysis and bleeding in open-
heart surgery. Lancet 1:4, 1968
67. Umlas J Fibrinolysis and disseminated intravascular coagula-
tion in open heart surgery. Transfusion 16:460, 1976
68. Griffith LD, Billman GF, Daily PO, Lane T A Apparent
coagulopathy caused by infusion of shed mediastinal blood and its
prevention by washing of the infusate. Ann Thorac Surg 47:400,
1989
69. Mammen EF, Kaerts MH, Washington BC, Walk LW,
Downloaded from https://ashpublications.org/blood/article-pdf/76/9/1680/604685/1680.pdf by guest on 09 April 2020
Brown JM, Burdick M, Selik NR, Wilson R F Hemostasis changes
during cardiopulmonary bypass surgery. Semin Thromb Hemostas
11:281,1985
70. Stibbe J, Kluft C, Brommer EJP, Comes M, De Jong DS,
Nauta J: Enhanced fibrinolytic activity during cardiopulmonary
bypass in open-heart surgery in man is caused by extrinsic (tissue-
type) plasminogen activator. Eur J Clin Invest 14375,1984
71. Torosian M, Michelson EL, Morganroth J, MacVaugh H 111:
Aspirin- and coumadin-related bleeding after coronary-artery by-
pass graft surgery. Ann Intern Med 89:325, 1978
72. Michelson EL, Morganroth J, Torosian M, MacVaugh H 111:
Relation of preoperative use of aspirin to increased mediastinal blood
loss after coronary artery bypass graft surgery. J Thorac Cardiovasc
Surg 78:694,1978
73. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K,
Ovitt MAT, Doherty J, Read R, Chesler E, Sako Y, Lancaster L,
Emery R, Sharma GVRK, Josa M, Pacold I, Montoya A, Parikh D,
Sethi G, Holt J, Kirklin J, Shabetai R, Moores W, Aldridge J,
Masud Z, DeMots H, Floten S , Haakenson C, Harker LA: Improve-
ment in early saphenous vein graft patency after coronary artery
bypass surgery with antiplatelet therapy: Results of a Veterans
Administration cooperative study. Circulation 77:1324, 1988
74. Goldman S, Copeland T, Moritz T, Henderson W, Harker
L A Improvement in graft patency without bleeding complications
by postoperative initiation of aspirin therapy after coronary artery
bypass grafting. Thromb Haemostas 62:33a, 1989 (abstr)
75. Giordano GF, Rivers SL, Chung GKT, Mammana RB,
Marco JD, Raczkowski AR, Sabbagh A, Sanderson RG, Strug BS:
Autologous platelet-rich plasma in cardiac surgery: Effect on intra-
operative and postoperative transfusion requirements. Ann Thorac
Surg46:416,1988
76. Giordano GF, Giordano G F Jr, Rivers SL, Chung GKT,
Mammana RB, Marco JD, Raczkowski AR, Sabbagh A, Sanderson
RG, Strug BS: Determinants of homologous blood usage utilizing
autologous platelet-rich plasma in cardiac operations. Ann Thorac
Surg 47:897,1989
77. Wasser MNJM, Houbiers JGA, DAmaro J, Hermans J,
Huysmans HA, van Konijnenburg GC, Brand A: The effect of fresh
versus stored blood on postoperative bleeding after coronary bypass
surgery: A prospective randomized study. Br J Haematol 72:s 1,
1989
78. Cosgrove DM, Loop FD, Lytle BW, Gill CC, Golding LR,
Taylor PC, Forsythe SB: Determinants of blood utilization during
myocardial revascularization. Ann Thorac Surg 40380,1985
79. Rapaport SI: Preoperative hemostatic evaluation: Which
tests, if any? Blood 61:229, 1983
80. deLeval MR, Taswell HF, Bowie EJW, Danielson G K Open
1694
heart surgery in patients with inherited hemoglobinopathies, red cell
dyscrasias, and coagulopathies. Arch Surg 109:618, 1974
81. Ma DDF, Chang VP, Concannon AJ, Lau J: Aortic valve
replacement in a patient with von Willebrand’s disease. Aust N Z J
Surg 49:247,1979
82. Love TR, Hendren WG, OKeefe DD, Daggett WM: Transfu-
sion of predonated autologous blood in elective cardiac surgery. Ann
Thorac Surg 43508.1987
83. Thurer RL, Lytle BW, Cosgrove DM, Loop FD: Autotransfu-
sion following cardiac operations: A randomized, prospective study.
Ann Thorac Surg 27500,1979
84. Bidstrup BP, Royston D, Sapsford RN, Taylor KM: Reduc-
tion in blood loss and blood use after cardiopulmonary bypass with
high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 97:364,
1989
85. Czer LSC, Shoemaker WC: Optimal hematocrit value in
critically ill postoperative patients. Surg Gynecol Obstet 147:363,
1978
86. Office of Medical Applications of Research. National Insti-
tutes of Health: Perioperative red cell transfusion. JAMA 260:2700,
1988
87. McCarthy PM, Popovsky MA, Schaff HV, Orszulak TA,
Williamson KR, Taswell HF, Ilstrup DM: Effect of blood conserva-
tion efforts in cardiac operations at the Mayo Clinic. Mayo Clin Proc
63:225, 1988
88. Walker RH: Special report: Transfusion risks. Am J Clin
Pathol88:374,1987
89. Cohen ND, Munoz A, Reitz BA, Ness PK, Frazier OH,
Yawn DH, Lee H, Blattner W, Donohue JG, Nelson KE, Polk F
Transmission of retroviruses by transfusion of screened blood in
patients undergoing cardiac surgery. N Engl J Med 320:1172, 1989
90. Aymard JP, Janot C, Gayet S, Guillemin C, Canton P,
Gaucher P, Streiff F: Posttransfusion non-A, non-B hepatitis after
cardiac surgery. Vox Sang 51:236, 1986
91. Thaler M, Shamiss A, Orgad S, Huszar M, Nussinovitch N,
Meisel S, Gazit E, Lavee J, Smolinsky A: The role of blood from
HLA-homozygous donors in fatal transfusion-associated graft-versus-
host disease after open-heart surgery. N Engl J Med 321:25,1989
92. Juji T, Takahashi K, Shibata Y, Ide H, Sakakibara T, Ino T,
Mori S: Posttransfusion graft-versus-host disease in immunocompe-
tent patients after cardiac surgery in Japan. N Engl J Med 32156,
1989
93. Toy PTCY, Strauss RG, Stehling LC, Sears R, Price TH,
Rossi EC, Collins ML, Crowley JP, Eisenstaedt RS, Goodnough LT,
Greenwalt TJ, Johnston MFM, Kennedy MS, Lenes BA, Lusher
JM, Mintz PD, Patten ED, Simon TL, Westphal RG: Predeposited
autologous blood for electivesurgery. N Engl J Med 316517.1987
94. Goodnough LT, Kruskall M, Stehling L, Johnston M, Kennedy
M, Mintz P, Schwartz K, Whitsett C: A multi-center audit of
transfusion practice in coronary artery bypass (CABG) surgery.
Blood 72:1020a, 1988 (suppl 1 ) (abstr)
95. Silver H: Banked and fresh autologous blood in cardiopulmo-
nary bypass surgery. Transfusion 15:600, 1975
96. Cove H, Matloff J, Sacks HJ, Sherbecoe R, Goldfinger D:
Autologous blood transfusion in coronary artery bypass surgery.
Transfusion 16:245, 1976
97. Kruskall MS, Glazer EE, Leonard SS, Willson SC, Pacini
DG, Donovan LM, R a n d BJ: Utilization and effectiveness of a
hospital autologous preoperative blood donor program. Transfusion
26:335, 1986
98. Council on Scientific Affairs: Autologous Blood Transfusions.
JAMA 256:2378,1986
99. American Association of Blood Banks. Autologous transfu-
sion, in Technical Manual. Arlington, VA, 1990, p 433
WOODMAN AND HARKER
100. Cosgrove DM, Thurer RL, Lytle BW, Gill CG, Peter M,
Loop FD: Blood conservation during myocardial revascularization.
Ann Thorac Surg 28:184,1979
101. Schaff HV, Hauer J, Gardner TJ, Donahoo JS, Watkins L
Jr, Gott VL, Brawley RK: Routine use of autotransfusion following
cardiac surgery: Experience in 700 patients. Ann Thorac Surg
27:493, 1979
102. Winton TL, Charrette EJP, Salerno TA: The cell saver
during cardiac surgery: Does it save? Ann Thorac Surg 33:379,1982
103. Mayer ED, Welsch M, Tanzeem A, Saggau W, Spath J,
Hummels R, Schmitz W: Reduction of postoperative donor blood
requirement by use of the cell separator. Scand J Thorac Cardiovasc
Surg 19:165, 1985
104. Litwak RS, Jurado RA, Lukban SB, Mitchell BA, Kahn M,
Berger S, Estioko MR, Aledort L: Perfusion without donor blood. J
Thorac Cardiovasc Surg 64:714,1972
105. Schaff HV, Hauer JM, Bell WR, Gardner TJ, Donahoo JS,
Downloaded from https://ashpublications.org/blood/article-pdf/76/9/1680/604685/1680.pdf by guest on 09 April 2020
Gott VL, Brawley R K Autotransfusion of shed mediastinal blood
after cardiac surgery: A prospective study. J Thorac Cardiovasc
Surg 75:632,1978
106. Raines J, Buth J, Brewster DC, Darling RC: Intraoperative
autotransfusion: Equipment, protocols, and guidelines. J Trauma
16:616,1976
107. Harding SA, Shakoor MA, Grindon AJ: Platelet support for
cardiopulmonary bypass surgery. J Thorac Cardiovasc Surg 70:350,
1975
108. Simon TL, Akl BF, Murphy W P Controlled trial of routine
administration of platelet concentrates in cardiopulmonary bypass
surgery. Ann Thorac Surg 37:359, 1984
109. Office of Medical Applications of Research. National Insti-
tutes of Health: Platelet transfusion therapy. JAMA 257:1777, 1987
1 10. National Blood Resource Education Program. Indications
for the use of red blood cells, platelets, and fresh frozen plasma, in:
Transfusion Alert. Publication no. 9-2974a (abstr). Bethesda, MD,
National Institutes of Health, 1989
11 1. Use of blood components. FDA Drug Bull 19:14, 1989
112. Office of Medical Applications of Research. National Insti-
tutes of Health: Fresh frozen plasma indications and risks. JAMA
353551, 1985
113. Oberman HA: Inappropriate use of fresh-frozen plasma.
JAMA 2 5 3 3 6 , 1 9 8 5
114. Collins JA: Recent developments in the area of massive
transfusion. World J Surg 11:75, 1987
1 15. Cartmill TB, Castaldi PA, Halliday EJ: Cardiac-valve
surgery in factor-VI1 deficiency. Lancet 1:752, 1968 (letter)
116. Brunken R, Follette D, Wittig J: Coronary artery bypass in
hereditary factor XI deficiency. Ann Thorac Surg 38:406,1984
117. Komp DM, Nolan SP, Carpenter MA: Open-heart surgery
in a patient with von Willebrand’s disease. J Thorac Cardiovasc Surg
29:225, 1970
118. Aris A, Pisciotta AV, Hussey CV, Gale H, Lepley D:
Open-heart surgery in von Willebrand’s disease. J Thorac Cardio-
vasc Surg 69:183, 1975
119. Young PH, Bouhasin JD, Barner HB: Aortic valve replace-
ment in von Willebrand’s disease. J Thorac Cardiovasc Surg 76:218,
1978
120. Roskos RR, Gilchrist GS, Kazmier FJ, Feldt RH, Danielson
GK: Management of hemophilia A and B during surgical correction
of transposition of the great arteries. Mayo Clin Proc 58:182, 1983
121. Lupinetti FM, Stoney WS, Alford WC Jr, Burrus GR,
Glassford Jr DM, Petracek MR, Thomas CS: Cryoprecipitate-
topical thrombin glue. Initial experience in patients undergoing
cardiac operations. J Thorac Cardiovasc Surg 90502, 1985
BLEEDING AFTER CARDIOPULMONARY BYPASS
122. Jessen C, Sharma P Use of fibrin glue in thoracic surgery.
Ann Thorac Surg 39521,1985
123. Dresdale A, Bowman FO Jr, Malm JR, Reemtsma K, Smith
CR, Spotritz HM, Rose EA: Hemostatic effectivenessof fibrin glue
derived from single-donor fresh frozen plasma. Ann Thorac Surg
40:385, 1985
124. Garcia-Rinaldi R, Simmons P, Salcedo V, Howland C: A
technique for spot application of fibrin glue during open heart
operations. Ann Thorac Surg 47:59, 1989
125. Verstraete M: Clinical application of inhibitors of fibrinoly-
sis. Drugs 29:236, 1985
126. Royston D, Taylor KM, Bidstrup BP, Sapsford RN: Effect
of aprotinin on need for blood transfusion after repeat open-heart
surgery. Lancet 2:1289, 1987
127. van Oeveren W, Jansen NJG, Bidstrup BP, Royston D,
Westaby S, Neuhof H, Wildevuur CRH: Effects of aprotinin on
hemostatic mechanisms during cardiopulmonary bypass. Ann Tho-
rac Surg 44:640,1987
128. Marder VJ, Butler FO, Barlow GH: Antifibrinolytic ther-
apy, in Coleman RW, Hirsh J, Marder VJ, Salzman EW (eds):
Hemostasis and Thrombosis (ed 2). Philadelphia, PA, Lippincott,
1987, p 380
129. Ambrus JL, Schimert G, Lajos TZ, Ambrus CM, Mink JB,
Lassmann HB, Moore RH, Melzer J: Effect of antifibrinolytic
agents and estrogens on blood loss and blood coagulation factors
during open heart surgery. J Med Exp Clin 2:65,1971
130. Bidstrup BP, Royston D, Taylor KM, Sapsford RN: Effect
of aprotinin on need for blood transfusion in patients with septic
endocarditis having open-heart surgery. Lancet 1:366, 1988 (letter)
131. Mannucci PM: Desmopressin (DDAVP) for treatment of
disorders of hemostasis. Prog Hemost Thromb 8:19, 1986
132. Mannucci PM: Desmopressin: A nontransfusional form of
treatment for congenital and acquired bleeding disorders. Blood
72:1449, 1988
133. Salzman EW, Weinstein MJ, Weintraub RM, Ware JA,
Thurer RL,Robertson L, Donovan A, Gaffney T, Bertele V, Troll J,
Smith M, Chute L E Treatment with desmopressin acetate to reduce
blood loss after cardiac surgery. N Engl J Med 314:1402, 1986
134. Bond L, Bevan D: Myocardial infarction in a patient with
hemophilia treated with DDAVP. N Engl J Med 318:121, 1988
(letter)
135. Rocha E, Llorens R, Paramo JA, Arcas R, Cuesta B, Trenor
AM: Does desmopressin acetate reduce blood loss after surgery in
patients on cardiopulmonary bypass? Circulation 77:13 19,1988
136. Copeland JG 111, Harker LA, Joist JH, DeVries WC:
Bleeding and anticoagulation. Ann Thorac Surg 47:88, 1989
137. Sterns LP, Lillehei CW: Effect of epsilon aminocaproic acid
upon blood loss following open-heart surgery: An analysis of 340
patients. Can J Surg 10304, 1967
138. McClure PD, Izsak J: The use of epsilon-aminocaproic acid
to reduce bleeding during cardiac bypass in children with congenital
heart disease. Anesthesiology 40604, 1974
139. Vander Salm TJ, Ansell JE, Okike ON, Marsicano TH, Lew
R, Stephenson WP, Rooney K: The role of epsilon-aminocaproic
acid in reducing bleeding after cardiac operation: A double-blind
randomized study. J Thorac Cardiovasc Surg 95:538, 1988
140. Sonntag VKH, Stein BM: Arteriopathic complication dur-
ing treatment of subarachnoid haemorrhage with epsilon aminocap-
roic acid. J Neurosurg 40480, 1976
141. Hoffman EP, Koo AH: Cerebral thrombosis associated with
amicar therapy. Radiology 131:667, 1979
142. Naeye RL: Thrombotic state after a hemorrhagic diathesis,
a possible complication of therapy with epsilon-aminocaproic acid.
Blood 19:694,1962
1695
143. Gralnick HR, Greipp P Thrombosis with epsilon aminocap-
roic acid therapy. Am J Clin Pathol56:151, 1971
144. Biswas CK, Milligan DAR, Agte SD, Kenward DH, Tilley
PJB: Acute renal failure and myopathy after treatment with
aminocaproic acid. Br Med J 12:115,1980
145. Horrow JC, Hlavacek J, Strong MD, Collier W, Brodsky I,
Goldman SM, Goel IP: Prophylactic tranexamic acid decreases
bleeding after cardiac operations. J Thorac Cardiovasc Surg 99:70,
1990
146. Weksler BB: Platelet interactions with the blood vessel wall,
in Coleman RW, Hirsh J, Marder VJ, Salzman EW (eds): Hemosta-
sis and Thrombosis (ed 2). Philadelphia, PA, Lippincott, 1987, p 793
147. Longmore DB, Gueirrara D, Bennett G, Smith M, Bunting
S, Reed P, Moncada S, Read NG, Vane JR: Prostacyclin: A solution
to some problems of extracorporeal circulation: Experiments in
greyhounds. Lancet 1:1002, 1979
148. DiSesa VJ, Huval W, Lelcuk S, Jonas R, Maddi R, Lee-Son
Downloaded from https://ashpublications.org/blood/article-pdf/76/9/1680/604685/1680.pdf by guest on 09 April 2020
S, Shemin RJ, Collins JJ Jr, Hechtman HB, Cohn LH: Disadvan-
tages of prostacyclin infusion during cardiopulmonary bypass: A
double-blind study of 50 patients having coronary revascularization.
Ann Thorac Surg 38:514,1984
149. Fish KJ, Sarnquist FH, van Steennis C, Mitchell RS,
Hilberman M, Jamieson SW, Linet 01, Miller D C A prospective,
randomized study of the effects of prostacyclin on platelets and blood
loss during coronary bypass operations. J Thorac Cardiovasc Surg
91:436, 1986
150. King DJ, Kelton JG: Heparin-associated thrombocytopenia.
Ann Intern Med 100:535, 1984
151. Levine MN, Hirsh J, Kelton JG: Hemorrhagic complica-
tions of antithrombotic therapy, in Coleman RW, Hirsh J, Marder
VJ, Salzman EW (eds): Hemostasis and Thrombosis (ed 2). Philadel-
phia, PA, Lippincott, 1987, p 873
152. Cimo PL, Moake JL, Weinger RS, Ben-Menachem Y,
Khalil KG: Heparin-induced thrombocytopenia: Association with a
platelet aggregating factor and arterial thromboses. Am J Hematol
6:125, 1979
153. Rhodes GR, Dixon RH, Silver D: Heparin-induced throm-
bocytopenia with thrombotic and hemorrhagic manifestations. Surg
Gynecol Obstet 136:409, 1973
154. Warkentin TE, Kelton JG: Heparin and platelets. Hematol
Oncol Clin North Am 4:243, 1990
155. Sheridan D, Carter C, Kelton JGK: A diagnostic test for
heparin-induced thrombocytopenia. Blood 67:27,1986
156. Kelton JG, Sheridan D, Santos A, Smith J, Steeves K, Smith
C, Brown C, Murphy WG: Heparin-induced thrombocytopenia:
Laboratory studies. Blood 72:925, 1988
157. Lynch DM, Howe SE: Heparin-associated thrombocyto-
penia: Antibody binding specificity to platelet antigens. Blood
66:1176, 1985
158. Pfueller SL, Weber S, Luscher EF: Studies of the mecha-
nism of the human platelet release reaction induced by immunologic
stimuli. 111. Relationship between the binding of soluble IgG
aggregates to the Fc receptor and cell response in the presence and
absence of plasma. J Immunol 1 18:514, 1977
159. Chong BH, Castaldi PA, Berndt MC: Heparin-induced
thrombocytopenia: Effects of rabbit IgG, and its Fab and Fc
fragments on antibody-heparin-platelet interaction. Thromb Res
55:291, 1989
160. Kelton JG, Powers PJ, Carter CJ: A prospective study of the
usefulness of the measurement of platelet-associated IgG for the
diagnosis of idiopathic thrombocytopenic purpura. Blood 6 0 1050,
1982
161. Kelton JG, Sheridan D, Brain H, Powers PJ, Turpie AG,
Carter CJ: Clinical usefulness of testing for a heparin-dependent
1696
platelet-aggregating factor in patients with suspected heparin-
associated thrombocytopenia. J Lab Clin Med 103:606, 1984
162. Malik M, Collins J, Ludorf M, Taylor R, Anderson J, Aster
RH, McFarland J: Laboratory confirmation of heparin associated
thrombocytopenia (HAT). Blood 7 4 l l a , 1989 (suppl 1) (abstr)
163. Babcock RB, Dumper CW, Scharfman WB: Heparin-
induced immune thrombocytopenia. N Engl J Med 295:237, 1976
164. Oligner GN, Hussey CV, Olive JA, Malik MI: Cardiopulmo-
nary bypass for patients with previously documented heparin-
induced platelet aggregation. J Thorac Cardiovasc Surg 87:673,
1984
165. Schwartz AJ, Howie MB: Case conference. J Cardiothorac
Anesth 1:577,1987
166. Harenberg J, Zimmermann R, Schwarz R, Kubler W:
Treatment of heparin-induced thrombocytopenia with thrombosis by
new heparinoid. Lancet 1:986, 1983
167. Chong BH, Ismail F, Cade J, Callus AS, Gordon S,
Chesterman CN: Heparin-induced thrombocytopenia: Studies with
a new low molecular weight heparinoid, Org 10172. Blood 73:1592,
1989
168. Ortel TL, Gockerman JP, Califf RM, McCann RL, Green-
berg CS: Anticoagulant therapy with heparinoid (ORG 10172) in
patients with heparin associated thrombocytopenia (HAT) and
thrombosis (HATT). Blood 74:136a, 1989 (abstr, suppl)
169. Kiers L, Grigg LE, Cade JF, Street PR, Chong BH: Use of
Org 10172 in the treatment of heparin-induced thrombocytopenia
and thrombosis. Aust N Z J Med 16:719, 1986
170. Palmer Smith J, Walls JT, Muscat0 MS, McCord ES,
Worth ER, Curtis JJ, Silver D: Extracorporeal circulation in a
patient with heparin-induced thrombocytopenia. Anesthesiology
62~363,1985
171. Cole CW, Bormanis J: Ancrod: A practical alternative to
heparin. J Vasc Surg 8:59, 1988
172. Hyers TM, Hull RD, Weg JG: Antithrombotic therapy for
venous thromboembolic disease. Chest 95:37S, 1989
173. Kappa JR, Horn D, McIntosh CL, Fisher CA, Ellison N,
Addonizio P Jr: Iloprost (ZK36374), a new prostacyclin analogue,
permits open cardiac operation in patients with heparin-induced
thrombocytopenia. Surg Forum 36:285, 1985
174. Addonizio VP Jr, Fisher CA, Kappa JR, Ellison N: Preven-
tion of heparin-induced thrombocytopenia during open heart surgery
with iloprost (ZK36374). Surgery 102:796,1987
175. Kraenzler EJ, Starr NJ: Heparin-associated thrombocytope-
nia: Management of patients for open heart surgery. Case reports
describing the use of iloprost. Anesthesiology 69:964, 1988
176. Zulys V, Teasdale S, Michel E, Skala R, Glynn M F X
Ancrod anticoagulation for cardiopulmonary bypass. Clin Invest
Med 10:C44a, 1987 (abstr)
177. Teasdale SJ, Zulys VJ, Mycyk T, Baird RJ, Glynn MFX:
Ancrod anticoagulation for cardiopulmonary bypass in heparin-
induced thrombocytopenia and thrombosis. Ann Thorac Surg 48:
712,1989
178. Bell WR: Defibrinogenating enzymes, in Coleman RW,
Hirsh J, Marder VJ, Salzman EW (eds): Hemostasis and Thrombo-
sis (ed 2). Philadelphia, PA, Lippincott, 1987, p 886
179. Leroy J, Leclerc MH, Delahousse B, Guerois C, Foloppe P,
Gruel Y, Toulemonde F Treatment of heparin-associated thrombo-
cytopenia and thrombosis with low molecular weight heparin (CY
216). Semin Thromb Hemost 11:326,1985
180. Vitoux J-F, Mathieu J-F, Roncato M, Fiessinger J-N, Aiach
M: Heparin-associated thrombocytopenia treatment with low molec-
ular weight heparin. Thromb Haemost 55:37, 1986
181. Harvey RP, Degryse E, Stefani L, Schamber F, Cazenave
J-P, Courtney M, Tolstoshev P,Lecocq J - P Cloning and expression
WOODMAN AND HARKER
of a cDNA coding for the anticoagulant hirudin from the bloodsuck-
ing leech, Hirudo medicinalis. Proc Natl Acad Sci USA 83:1084,
1986
182. Brockman SK, April1 SN, Rabiner FS: Aortic valve replace-
ment in hemophilia. JAMA 222:660, 1972
183. Lusher JM, Ravindranath Y, Arciniegas E, Green E: Open
heart surgery in a hemophiliac patient. Am J Dis Child 127:708,
1974
184. Holub DA, Norman JC, Cooley D A Successful aortocoro-
nary bypass surgery in a patient with classical hemophilia A.
Cardiovasc Dis Bull, Texas Heart Inst 5:229, 1978
185. Leggett PL, Doyle D, Smith WB, Culpepper W 111, Cooper
S, Ochsner JL: Elective cardiac operation in a patient with severe
hemophilia and acquired factor VI11 antibodies. J Thorac Cardio-
vasc Surg 87:556, 1984
186. Lawson R, Rullman D, Broderu M, Starr A: Tricuspid
atresia with Christmas disease (hemophilia B). J Thorac Cardiovasc
Downloaded from https://ashpublications.org/blood/article-pdf/76/9/1680/604685/1680.pdf by guest on 09 April 2020
Surg 69:585, 1975
187. Tourbaf KD, Bettigole RE, Zizzi JA, Subramanian S,
Andersen MN: Coronary bypass in a patient with hemophilia B or
Christmas disease. J Thorac Cardiovasc Surg 77:562, 1979
188. Raish RJ, Witte DL, Goldsmith JC: Successful cardiac
surgery following plasmapheresis in a patient with hemophilia B.
Transfusion 25:128,1985
189. Goodnough LT, Saito H, Ratnoff OD: Thrombosis or
myocardial infarction in congenital clotting factor abnormalities and
chronic thrombocytopenias: A report of 21 patients and a review of
50 previously reported cases. Medicine 62248, 1983
190. Rizza CR: Clinical management of haemophilia. Br Med
Bull 33:225,1977
191. Coller BS: von Willebrand Disease, in Coleman RW, Hirsh
J, Marder VJ, Salzman EW (eds): Hemostasis and Thrombosis (ed
2). Philadelphia, PA, Lippincott, 1987, p 60
192. Levine PH: Clinical manifestations and therapy of hemophil-
ias A and B, in Coleman RW, Hirsh J, Marder VJ, Salzman EW
(eds): Hemostasis and Thrombosis (ed 2). Philadelphia, PA, Lippin-
cott, 1987, p 97
193. Brown B, Steed DL, Webster MW, Makaroun MS, Spero
JA, Bontempo FA, Ragni MV, Lewis JH: General surgery in adult
hemophiliacs. Surgery 90:154, 1986
194. Rudowski WJ, Scharf R, Ziemski JM: Is major surgery in
hemophiliac patients safe? World J Surg 11:378, 1987
195. Chavin SI, Siege1 DM, Rocco TA Jr, Olson J P Acute
myocardial infarction during treatment with an activated prothrom-
bin complex concentrate in a patient with factor VI11 deficiency and
a factor VI11 inhibitor. Am J Med 85:245, 1988
196. Skinner JR, Phillips SJ, Zeff RH, Kongtahworn C: Immedi-
ate coronary bypass following failed streptokinase infusion in evolv-
ing myocardial infarction. J Thorac Cardiovasc Surg 87:567, 1984
197. Ferguson TB Jr, Muhlbaier LH, Salai DL, Wechsler AS:
Coronary bypass grafting after failed elective and failed emergent
percutaneous angioplasty. J Thorac Cardiovasc Surg 95:761, 1988
198. Kereiakes DJ, Topol EJ, George BS, Abbottsmith CW,
Stack RS, Candela RJ, ONeill WW, Martin LH, Califf RM:
Emergency coronary artery bypass surgery preserves global and
regional left ventricular function after intravenous tissue plasmino-
gen activator therapy for acute myocardial infarction. J Am Coll
Cardiol 11:899, 1988
199. Collen D: Coronary thrombolysis: Streptokinase or recombi-
nant tissue-type plasminogen activator? Ann Intern Med 112:529,
1990
200. Muneretto C, Solis E, Pavie A, Leger P, Gandjbakhch I,
Szefner J, Bors V, Piazza C, Cabrol A, Cabrol C: Total artificial
heart: Survival and complications. Ann Thorac Surg 47:151, 1989
BLEEDING AFTER CARDIOPULMONARY BYPASS
201. Pennington DG, McBride LR, Swartz MT, Kanter KK,
Kaiser GC, Barner HB, Miller LW, Naunheim KS, Fiore AC,
Willman VL: Use of the Pierce-Donachy ventricular assist device in
patients with cardiogenic shock after cardiac operations. Ann
Thorac Surg 47:130,1989
202. Portner PM, Oyer PE, Pennington DG, Baumgartner WA,
Griffith BP, Frist WR, Magilligan DJ, Noon GP, Ramasamy N,
1697
Miller PJ, Jassawalla JS: Implantable electrical left ventricular
assist system: Bridge to transplantation and the future. Ann Thorac
Surg 47:142, 1989
203. Milam JD: Blood transfusions in heart surgery. Clin Lab
Med 2:65, 1982
204. Liotta D: Myocardial protection during cardiopulmonary
bypass. Cardiovasc Dis Bull, Texas Heart Inst 430,1977
Downloaded from https://ashpublications.org/blood/article-pdf/76/9/1680/604685/1680.pdf by guest on 09 April 2020