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181
• Increased fi brinolysis activity by cardiopulmonary bypass
• Surgical damage to blood vessels
– Cannulation sites
– Internal mammary artery bed and anastomosis
– Vein graft branches
– Soft tissue suture lines
– Arterial anastomoses
– Sternal wiring site
Reoperation for postoperative bleeding is associated with increased morbidity
and mortality and is seen in 2–9 % of patients after cardiac surgery (Vivacqua et al.
2011 ; Charalambous et al. 2006 ; Choong et al. 2007 ; Moulton et al. 1996 ). In more
than half of the patients returning to operating room, the surgeon can locate an obvi-
ous bleeding site (Karthik et al. 2004 ). Studies have identifi ed the following factors
as some of the main predictors for postoperative bleeding leading to surgical reex-
ploration (Karthik et al. 2004 ; Biancari et al. 2012 ):
• Advanced age
• Left ventricular dysfunction
• Chronic renal failure
• Lower body mass index (BMI)
• Preoperative use of antiplatelet medication
• Prolonged CPB time
• Urgent/emergent operation
• Reoperations
The primary indications for returning to the operating room for bleeding include:
• Sudden massive bleeding at any time in postoperative period
• Continuous chest tube drainage according to the Kirklin criteria (Karthik et al.
2004 )
1. >500 ml in the fi rst hour postoperatively
2. >400 ml during each of the fi rst 2 h postoperatively
3. 300 ml during each of the fi rst 3 h postoperatively
4. 1,000 ml (total bleeding) during the fi rst 4 h postoperatively
• Evidence of excessive pleural or pericardial effusion by chest X-ray or
echocardiography
• Signs of tamponade on clinical exam (including, but not restricted to, increased
central venous pressure (CVP), decreased urinary output, hypotension, mediasti-
nal widening on chest X-ray accompanied with sudden reduction of chest tube
drainage)
The time interval between surgery and resternotomy is the main predictor of
outcome. A delay of > 12 h to reoperation is associated with additional compli-
cations such as prolonged mechanical ventilation, high blood transfusion rate,
stroke, need for intra-aortic balloon pump (IABP) placement, sternal wound
infections, and renal failure (Vivacqua et al. 2011 ; Karthik et al. 2004 ; Choong
et al. 2011).
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6.8 Appendix A Heparin-Induced Thrombocytopenia
Marzia Leacche, John G. Byrne, and Sary F. Aranki
6.8.1 Abstract
HIT is a potentially fatal side effect of heparin that is more common with Unfractionated
Heparin (UFH) than Low Molecular Weight Heparin (LMWH). HIT is a clinical-
pathologic syndrome: its diagnosis is based on compatible clinical features and pres-
ence of HIT antibodies. Antibodies against PF4/heparin are formed commonly during
heparin treatment; HIT occurs in the subset of patients with strong platelet-activating
IgG antibodies. Binding of HIT antibodies to PF4/heparin complexes on the platelet
surface results in platelet activation, thrombocytopenia, and increased risk of thrombo-
sis, mainly venous but also arterial. Platelet, monocyte, and endothelial cell activation
results in a hypercoagulable state and increased risk of venous thrombosis. HIT-
associated thrombosis occurs in some patients 1–2 days before platelet counts decrease.
Platelet count monitoring is important to diagnose isolated HIT and thus has the poten-
tial to prevent thrombosis. Recognizing a relative decrease of platelet count is impor-
tant since platelets do not always fall below 150 × 10
9
/L, especially in cardiac surgery
patients who have had exposure to unfractioned heparin. Platelet count monitoring is
recommended in most patients receiving UFH and in some patients receiving LMWH.
Heparin should be stopped immediately in all situations where HIT is strongly sus-
pected. Coumadin should also be stopped since it results in reduction of the levels of
protein C. Due to the high risk of thrombosis in patients with HIT, anticoagulation
with a non-heparin anticoagulant should be started even in the absence of overt throm-
bosis. A number of conditions should be considered in the differential diagnosis of
pseudo-HIT—conditions that closely mimic both the signs and symptoms of HIT and
occur in a clinical context that makes the diagnosis of HIT likely, heparin- associated
thrombocytopenia (HAT), cancer-associated DIC, pulmonary embolism, DIC/sepsis,
EDTA-induced pseudo-thrombocytopenia, and drug-induced thrombocytopenia.
6.8.2 Introduction
Heparin-induced thrombocytopenia (HIT) is caused by heparin-induced antibodies
that activate platelets and monocytes through the Fcγ IIa receptor. Thrombotic com-
plications can occur in half of the untreated patients mostly in the venous system
(Kelton et al. 2013). Thrombocytopenia occurs only after exposure of heparin, typi-
cally 5–10 days after the initial exposure. Many cardiac surgery patients, however,
have been previously exposed to heparin and may have developed IgG antibodies
against the complex platelet factor 4 (PF4)-heparin; thus, a sudden new onset, after
hours from reexposure of heparin, is possible with different degree of thrombocyto-
penia, sometimes with sudden decrease of more than 50 % in the platelet count. The
third manifestation of HIT is a delayed manifestation which occurs weeks after
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heparin exposure. Because in cardiac patients there might be alternative causes of
thrombocytopenia and because the tests available are sensitive but not specifi c, HIT
may be undertreated or underdiagnosed.
6.8.3 Pathophysiology
The process is initiated when the patient receives heparin. Low-molecular-weight
heparin is much less likely to be associated with HIT than unfractionated heparin.
Less frequently 2 non-heparin polyanions, pentosan polysulfate (used in interstitial
cystitis) and polysulfated chondroitin sulfate (used in arthritis), may be associated
with the condition. Antibodies develop against a multimolecular complex of hepa-
rin and PF4 which become accessible after it binds heparin (Greinacher et al. 1992;
Goad et al. 1994). PF4 is a small cytokine released by activated platelets which
binds heparin. Although IgG, IgM, and IgA antibodies have been described in HIT,
it appears likely that most patients with the HIT syndrome have IgG antibodies
(Amiral et al. 1992; Visentin et al. 1994).
The newly formed complex (IgG-PF4-heparin) binds to Fcϒ receptor IIa located
on platelets, monocytes, and other cell surfaces which results in intense platelet activa-
tion and release of procoagulant microparticles from platelets and monocytes. Platelet
microparticles provide a negatively charged phospholipid surface that promotes pro-
coagulant activity and thrombin generation (Warkentin et al. 1996; Giles et al. 1982).
Increased levels of thrombin- antithrombin (TAT) complexes and D-dimer levels
refl ect the hypercoagulable state. The induction of further release of PF4 further com-
promises the situation by neutralizing heparin’s anticoagulant activity (Fig. A.1 ).
H PF4
H / PF4
HIT – Ig G
Platelets
Activated
More platelet activation
PF4
released
Thrombosis
FC
Positive feedback
ADP Thromboxane A2
HS/PF4/IgG
HS/PF4/IgG
HS/PF4/IgG
HS/PF4/IgG
Procoagulant
Rich microparticles
EC injury
Monocyte activation
+
+
Fig. A.1 Mechanism of thrombin formation in HIT
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There is evidence that binding of PF4/HIT-IgG complexes to the endothelium
occurs and results in endothelial cell injury (Visentin et al. 1994; Kwaan et al. 1999).
Binding of PF4/HIT-IgG to monocytes results in monocyte activation and release of
tissue factor which supports additional thrombin generation refl ected by further
increase in TAT and D-dimer levels (Arepally et al. 2001; Pouplard et al. 1999).
Platelet and monocyte microparticles activate the coagulation cascade by releasing
tissue factor which binds factor VIIa leading to activation of factors IX and X.
6.8.4 Incidence of HIT
The risk of heparin-induced thrombocytopenia is higher in patients receiving unfrac-
tionated heparin because the formation of the complex PF4-heparin depends on the
concentration of both, but also the length of the heparin chain and the degree of sulfat-
ing. UFH forms larger complex with PF4 than low-molecular- weight heparin. Thus, the
risk of HIT in patients receiving UFH is 5 %, while is 1 % in patients receiving low-
molecular-weight heparin. Fondaparinux (which has a lower molecular weight) is
unlikely to bind to form complex large enough to activate platelets (Gruel et al. 2003).
There are several factors infl uencing the frequency of HIT.
Patient Variables
• Medical disorder/treatment—it is more frequent in surgical than medical patients
and uncommon in obstetric patients.
• Gender—it is more common in females than males (Warkentin et al. 2002).
Product Variables
• Source of heparin—it is more frequently associated with the use of heparin
derived from bovine lung than porcine intestine (Francis et al. 2003).
• Type of heparin—it is more frequently associated with the use of unfractionated
than low-molecular-weight heparin.
Management Variables
• Duration of heparin therapy—platelet count falls within 5–10 days and thrombo-
cytopenia develops within 7–14 days.
• Dose of heparin—increase from low- to full-dose heparin.
Although various factors have been associated with a high risk for the develop-
ment of HIT, HIT has occurred with the following: all types of heparin, all routes of
heparin administration, and all heparin dose levels (Fig. A.2 ).
6.8.5 Consequences of HIT
While almost all patients develop PF4-heparin antibodies, the incidence of clinical
manifestation of HIT varies. In coronary artery bypass surgery, almost 20–50 % of
patients at some point will develop antibodies, but only about 1 % of them will
manifest the clinical feature of heparin-induced thrombocytopenia. The variation
between patients may depend on antibody titers but also on the size of PF4-
complexes. The treatment of HIT is heparin cessation, thrombotic complications
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still however can develop, including deep venous thrombosis (DVT), pulmonary
embolism (PE), stroke, or myocardial infarction (MI). Since thrombotic events
have been observed even after cessation of heparin exposure, early recognition and
initiation of appropriate therapy are essential steps in management (Levine et al.
2004). About half of patients who present with HIT have DVT. Patients presenting
with PE while on heparin should be evaluated for HIT—pulmonary emboli are the
presenting complication in 25 % of cases.
Between 10 and 20 % of patients may present with erythematous plaques or skin
necrosis at the site of heparin injection. About 25% of patients can develop a sys-
temic reaction to injection of heparin. In this clinical scenario, the patient had
already been exposed to heparin within the past 5–100 days and already developed
IgG antibodies. This reaction can include fever or chills and tachycardia, hyperten-
sion, dyspnea, and, very rarely, cardiopulmonary arrest (Warkentin et al. 2004).
HIT patients who are treated prematurely with warfarin may also develop
warfarin- induced venous limb gangrene about 5–10 % of the time.
In addition to the classic presentation of HIT, there are several less-common
ways that HIT may present.
Acute limb ischemia due to aortic or iliofemoral thrombosis can developed in 5–10 %
of the patients; in rare cases (<3 %), an adrenal hemorrhagic infarction may develop.
In a small percentage of patients (3–5 %), HIT presents as an acute thrombotic
stroke or myocardial infarction (MI) following the development of an arterial thrombus.
In HIT, arterial thrombi most commonly present as acute limb ischemia, stroke, or MI
(Warkentin et al. 1996; Hirsh et al. 2004).
Factors influencing frequency of HIT
Factor Influence
Type of heparin
Patient population
Duration of heparin
Dose of heparin
Gender
Definition of thrombocytopenia
5 or more days heparin use > 1–4 days
Change from low to full dose can lead abrupt
platelet ↓ in immunized patient
Female > male
Proportional platelet count fall (e.g. >50 %)
more sensitive than absolute platelet ↓
Bovine UFH > porcine UFH > LMWH
Post-surgery > medical > obstetrical
Fig. A.2 Factors infl uencing frequency of HIT
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The mortality rate due to thrombi associated with HIT ranges from about 30 %
to 50 %. Limb amputation or disability occurs in about 20 %. While venous thrombi
outnumber arterial thrombi in most patients, either one or both may occur. If HIT is
left untreated, the overall risk of thrombosis is 38–76 % in HIT patients (Warkentin
et al. 2004; Hirsh et al. 2004; Warkentin et al. 1998).
This evidence supports that heparin cessation alone is inadequate due to high-
risk morbidity and mortality. Alternative therapy with a rapidly acting anticoagulant
should be initiated when heparin therapy is discontinued.
6.8.5.1 Diagnosis
The recognition of HIT is important to optimal management, yet diagnosis of HIT
is complicated. Several clinical clues suggest HIT in patients receiving heparin
therapy. Timing of onset of HIT and degree of thrombocytopenia are the two most
important clinical clues to exclude/include HIT (Warkentin et al. 1998).
Timing
In most patients, HIT develops between 5 and 14 days after heparin treatment is started.
However, it is important to remember that HIT can develop quickly in patients reexposed
to heparin. Thus, a patient’s history of heparin exposure is crucial. Delayed onset HIT
has been reported to occur 9–45 days after heparin discontinuation (Rice et al. 2002).
Degree of Thrombocytopenia
The actual platelet counts in patients with HIT are rarely <15,000/mol; more impor-
tant is the occurrence of a sudden drop in platelet count of 30–50 % from the
patient’s baseline. Drops >50 % seem particularly relevant to HIT diagnosis. Other
causes of thrombocytopenia such as sepsis, DIC, and drug therapy (such as Glib/IIIa
inhibitors, antibiotics) should be also ruled out.
Two general types of assays are used to make the diagnosis of HIT: functional
assay which detect platelet activation and quantitative direct binding assay to detect
antibodies.
14
C-Serotonin Release Assay (SRA) (Sheridan et al. 1986; Warkentin et al. 1992)
• The basis of the SRA is that antibodies from patients with HIT will cause platelet
activation and release of 14C-serotonin from platelet-dense granules when HIT serum
is incubated with normal donor platelets at therapeutic concentrations of heparin.
• Disadvantages of this test are the use of radioactive substances and it is techni-
cally demanding.
• The assay can be used to determine cross-reactivity with other anticoagulant
polysaccharides.
The Heparin-Induced Platelet Aggregation Assay (HIPAA) (Greinacher et al. 1992)
• The HIPAA, like the SRA, employs washed platelets from normal donor’s plate-
let aggregation in the presence of heparin rather than serotonin release is used as
an indicator of the presence of HIT antibodies.
• The assay is rapid, does not use a radioactive isotope, and is less technically
demanding than SRA.
• The assay can be used to determine cross-reactivity with other anticoagulant
polysaccharides.
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Platelet-Rich Plasma (PRP) Aggregation (Greinacher et al. 1991; Greinacher
et al. 1994; Favaloro et al. 1992)
• Platelet-rich plasma (PRP) aggregation is simple, rapid, and widely performed to
test for HIT.
PF4 Antigen Assays (Amiral et al. 1992; Arepally et al. 1995; Warkentin et al. 2004)
• The discovery that the major antigen of HIT was the platelet factor 4 (PF4)/heparin
complex led to development of an enzyme-linked immunosorbent assay to detect
HIT-specifi c antibodies.
• This assay can detect IgG, IgM, and IgA antibodies.
• These assays cannot be used to investigate cross-reactivity of HIT sera for other
anticoagulant polysaccharides.
• Has high sensitivity but low specifi city.
The antigen assays correlate much less with clinical HIT than the functional
assays does.
• The SRA, HIPAA, and PF4 antigen assays:
(a) Have high negative predictive value (negative test usually rules out HIT *)
applies to solid-phase EIAs and washed platelet activation assays
(b) Have moderate positive predictive value (stronger test result = higher chance
of HIT)
(c) Are not recommended for routine antibody testing in the absence of:
• Thrombocytopenia or >50 % ↓ in platelet count
• Thrombosis
• Heparin-induced skin necrosis
• Other sequelae of HIT
[Recommendation Grade 1C] (Warkentin et al. 2004; Guyatt et al. 2001)
A commonly used score to predict the likelihood of HIT is the “4 Ts” score intro-
duced in 2003 by Warkentin et al. A score of 0–8 points is generated; if the score is
0–3, HIT is unlikely. If the score is 4–5 a minority will have HIT (10–30 %), while
with a score 6–8 (20–80 % will have HIT).
6.8.5.2 Management
If HIT is suspected the use of heparin, including fl ushing of arterial and venous lines,
should be discontinued immediately—( Recommendation Grade 1C+ ) (Greinacher
et al. 2004; Warkentin et al. 2004; Guyatt et al. 2001). There are numerous case reports
of progressive, new, or recurrent thromboembolic events if heparin is continued or
restarted. The thrombocytopenia is also likely to persist if heparin is not stopped:
• HIT is a strong independent risk factor for venous and arterial thrombosis (Girolami
et al. 2003), and a substantial number of HIT patients will develop a thrombotic
event some time after the cessation of heparin therapy (Girolami et al. 2000).
Moreover, many patients will be receiving heparin to either prevent or treat a throm-
botic disorder—usually venous thromboembolic disease (VTE). Consequently, con-
tinuation of antithrombotic therapy with an alternative non- heparin anticoagulant is
recommended— Recommendation Grades 1B (danaparoid), 1C+ (lepirudin), 1C
(argatroban), and 2C (bivalirudin ) (Warkentin et al. 2004; Guyatt et al. 2001).
• Specifi c serological tests should be performed to confi rm or reject the diagnosis
of HIT. It should be emphasized that, due to the signifi cant morbidity and mortal-
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ity associated with HIT, the previously outlined treatment decisions of stopping
heparin and initiating alternative antithrombotic therapy should not be delayed
pending the results of confi rmatory tests (Greinacher et al. 2004).
• If appropriate confi rmatory tests are negative, heparin may be restarted but regu-
lar monitoring of platelet counts should be reinstituted— Recommendation
Grade 2C . Alternatively, where a non-heparin antithrombotic has been substi-
tuted, this may be continued at full or low dose depending on the presence or
absence of a primary thrombotic disorder (Greinacher et al. 2004; Warkentin
et al. 2004; Guyatt et al. 2001).
Patients should not be converted from heparin therapy to VKA therapy— Recom-
mendation Grade 1C (Warkentin et al. 2004; Guyatt et al. 2001):
• It is ineffective.
• This may precipitate venous gangrene due to a precipitous fall in the levels of
protein C (Warkentin et al. 1997; Warkentin et al. 1991).
• If started prior to diagnosis of HIT it should be reversed by vitamin K (5–10 mg) PO
or IV— Recommendation Grade 2C (Warkentin et al. 2004; Guyatt et al. 2001).
• Low-molecular-weight heparin should not be substituted for unfractionated hepa-
rin due to the high risk of in vivo cross-reactivity despite its low frequency of caus-
ing this syndrome— Recommendation Grade 1C+ (Gruel et al. 2003; Warkentin
et al. 2004; Guyatt et al. 2001; Warkentin et al. 1996; Warkentin et al. 1997).
• Platelet transfusions are relatively contraindicated unless absolutely required to
manage life-threatening bleeding— Recommendation Grade 2C (Gruel et al.
2003; Warkentin et al. 2004; Guyatt et al. 2001; Warkentin et al. 1991; Warkentin
et al. 2003).
6.8.6 Agents Used in the Treatment of HIT
A number of non-heparin antithrombotic agents may be considered for substitution
therapy in suspected or confi rmed HIT. The recommendations for their use have
been graded at the most recent Consensus Meeting on Antithrombotic Therapy of
the American College of Clinical Pharmacy— Recommendation Grades 1B (dan-
aparoid), 1C+ (lepirudin), 1C (argatroban), 2C (bivalirudin) (Warkentin and
Greinacher 2004; Guyatt et al. 2001). Only danaparoid has been evaluated in a
randomized clinical trial in HIT:
• Danaparoid—Xa/IIa inhibitor (anti-factor Xa >> anti-IIa).
• Danaparoid provides an option for anticoagulation in either prophylactic or ther-
apeutic doses.
• Danaparoid has been used in at least 100,000 treatment episodes in patients with
HIT.
• Clinical studies in HIT suggest a 94 % success rate (investigator reported).
• It can be given by both IV and SQ routes with 100 % bioavailability.
• Direct thrombin inhibitor (DTI):
• Lepirudin
Indicated for anticoagulation in patients with HIT and associated thromboem-
bolic disease to prevent further thromboembolic complications
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• Argatroban
Indicated as an anticoagulant for prophylaxis or treatment of thrombosis in
patients with HIT
Indicated as an anticoagulant in patients with or
At risk for HIT undergoing PCI
Bivalirudin*
Indicated as an anticoagulant in patients undergoing percutaneous transluminal
coronary angioplasty (PTCA)
Recently approved for patients with or at risk HIT patients undergoing PCI
(December 2005):
• Angiomax
®
(bivalirudin) for injection [package insert]. Parsippany, NJ: The
Medicines Company; 2005; Argatroban Injection [package insert]. Research
Triangle Park, NC: GlaxoSmithKline; 2005.
Given the high risk category of HIT for thromboembolism, alternative non-
heparin anticoagulant therapy should be continued even when not initially compli-
cated thrombosis (Kelton et al. 2013). This should be continued until the platelet
count shows recovery to >100 × 10
9
. Venous thromboembolism VTE develops early
in HIT and may not be detected clinically. Consequently, lower limb ultrasonogra-
phy should be performed to detect occult DVT and monitor antithrombotic treat-
ment response — Recommendation Grade 1C (Fig. A.3 ) (Warkentin et al. 2004;
Guyatt et al. 2001).
Mechanisms of thrombin inhibition
Fibrin
• No cofactor
• No heparin interaction
• No antibodies
• Free + clot–bound
Thrombin
+
Danaparoid
Fondaparinux
AT III
Argatroban
Bivalarudin
Lepirudin
Platelet
activation
Fibrinogen
Thrombin
(IIa)
Xa
Prothrombin II
Fig. A.3 Argatroban and hirudin-related agents inhibits thrombin, while fondaparinux and dana-
proid inhibit factor Xa
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Case Study Number 1
A 64-year-old female with severe aortic stenosis and coronary artery disease
underwent uneventful aortic valve replacement with 23 mm pericardial valve
and saphenous vein graft to the right coronary artery. The patient was trans-
ferred to the step-down on POD 1.
On postoperative day 6, the patient had paroxysmal atrial fi brillation and
unfractionated heparin infusion was started. The same day, also warfarin was
started. On postoperative day 9, the patient suffered from delirium and was
transfer back to the intensive care unit. The platelet count was 20,000× 10
3
per
mm
3,
while the INR was 9 and she developed right upper anterior chest wall
necrosis. Heparin and Coumadin were discontinued, and PF4/IgG assay was
sent. Bivalirudin was started. PF4/IgG was elevated but borderline (0.4 anti-
platelet factor 4 (PF4)/heparin antibody OD value). When the platelet count
was >100,000 × 10
3
per mm
3
, Coumadin was restarted.
The patient was discharged day 35 and continued Coumadin for 6 months
(Fig. A.4 ).
Figure A.4 summarizes the relationship of platelet count and days of
hospitalization.
Day of hospialization
Platelet count (1,000/mcL)
1st ICU
POD 1
POD 2
POD 3
POD 4
POD 5
POD 6
POD 7
POD 8
POD 9
POD 10
POD 11
POD 12
POD 13
POD 14
POD 15
POD 16
POD 21
POD 26
POD 31
260
240
220
200
180
160
140
120
100
80
60
40
20
0
Case Study #1
Adm. plt.ct
380
IV
Heparin
Bival started
DC Bival @ disch. POD 33
DC coumadin
Borderline PF4
DC Heparin
Fig. A.4 Relationship of platelet count and days of hospitalization
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