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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3978_Библиотеки_им_академика_М_И_Перельмана
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161
A. Dabbagh et al. (eds.), Postoperative Critical Care for Cardiac Surgical Patients,
DOI 10.1007/978-3-642-40418-4_6, © Springer-Verlag Berlin Heidelberg 2014
S. Martin-Stone , PharmD, BCPS
Department of Pharmacy Services, Cedars-Sinai Medical Center,
8700 Beverly Blvd., Room A-903 , Los Angeles , CA 90048 , USA
e-mail: sylvia.martin@cshs.org
6
Postoperative Bleeding Disorders
after Cardiac Surgery
Sylvia Martin-Stone
Contents
6.1 Overview of Postoperative Bleeding ............................................................................. 162
6.2 Preoperative Medication-Related Risk Factors ............................................................. 162
6.2.1 Oral Anticoagulants .......................................................................................... 163
6.2.2 Parenteral Anticoagulants ................................................................................. 164
6.2.3 Antiplatelet Agents ........................................................................................... 169
6.3 Other Agents ................................................................................................................. 170
6.4 Monitoring Coagulation Status ..................................................................................... 170
6.5 Postoperative Considerations ........................................................................................ 175
6.5.1 Medications ....................................................................................................... 175
6.5.2 Coagulopathies .................................................................................................. 175
6.5.3 Drug-Induced Thrombocytopenias ................................................................... 176
6.6 Medical Management of Bleeding ................................................................................ 178
6.6.1 Antifi brinolytics ................................................................................................ 178
6.6.2 Desmopressin .................................................................................................... 179
6.6.3 Exogenous Blood Products and Factors ............................................................ 179
6.7 Surgical Bleeding .......................................................................................................... 179
6.8 Appendix A Heparin-Induced Thrombocytopenia ........................................................ 182
6.8.1 Abstract ............................................................................................................. 182
6.8.2 Introduction ....................................................................................................... 182
6.8.3 Pathophysiology ................................................................................................ 183
6.8.4 Incidence of HIT ............................................................................................... 184
6.8.5 Consequences of HIT ........................................................................................ 184
6.8.6 Agents Used in the Treatment of HIT ............................................................... 188
6.8.7 Discussion ......................................................................................................... 192
6.8.8 Future Directions .............................................................................................. 192
References ..................................................................................................................... 192
6.8.9 Appendix A.1 Agents Used for Treatment of HIT ........................................... 194
References ................................................................................................................................ 194
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162
Abstract
Maintaining the delicate balance of thrombostasis postoperatively requires
attention to preoperative, intraoperative, and postoperative effects on the coagu-
lation cascade. Identifying preoperative risk factors for bleeding including med-
ication history, comorbid conditions, and prior bleeding complications is an
integral part of preventing postoperative bleeding complications. Outpatient
anticoagulant therapies are rapidly evolving with the development of novel
medications targeting specifi c coagulation factors such as thrombin and factor
Xa. These agents require an understanding of their effects and limitations in the
perioperative period. Additionally, an understanding of the interplay between
the coagulation cascade and external factors affecting platelet quantity and
function can help direct management of postoperative bleeding complications.
Applying appropriate monitoring techniques and result interpretation can guide
therapy especially in coagulopathic disease states such as disseminated intra-
vascular coagulopathy (DIC) and thrombocytopenia due to a variety of medica-
tions and specifi cally heparin.
6.1 Overview of Postoperative Bleeding
Cardiac surgery is associated with particular acquired hemostatic derangements
due primarily to the interaction of blood components with the surfaces of the car-
diopulmonary bypass (CPB) circuit. The primary effects are due to hemodilution,
excessive fi brinolysis, and platelet dysfunction (Ozier and Bellamy 2010 ). During
CPB, anticoagulation with heparin is required to avoid clot formation, while post-
CPB, hemostasis must be reestablished. Hemodilution during the procedure results
in a 30–50 % decrease from baseline in platelets, coagulation factors, and packed
cell volume (Koh and Hunt 2003 ). Platelet dysfunction develops as a result of
CPB- related activation/degranulation, heparin exposure, and hypothermia (<36
°C). These abnormalities are likely the most important early postoperative hemo-
static defect (Despotis and Goodnough 2000 ). Additionally pH and plasma cal-
cium levels should be optimized to maintain >7.3 and 1 mmol/L, respectively
(Weber et al. 2013 ).
6.2 Preoperative Medication-Related Risk Factors
An assessment of risk factors for postoperative bleeding begins preoperatively.
Factors to consider include medication history, surgical history, documented coagu-
lopathies, baseline coagulation values, and comorbid conditions. Among the most
preventable risks of postoperative bleeding is an accurate medication history and
discontinuation of any anticoagulant, antiplatelet, or other medications affecting the
S. Martin-Stone
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163
coagulation cascade or platelet function within the appropriate time frame. A risk/
benefi t assessment must be made with respect to patients at highest risk of thrombo-
sis (i.e., recent stent placement, history of recurrent venous thromboembolism,
mechanical valves). In some cases alternative anticoagulant therapy (i.e., unfrac-
tionated heparin) must be provided through the day of surgery due to the unaccept-
ably high risk of thrombosis following discontinuation of a longer acting
antithrombotic (Halasynski et al. 2004 ).
6.2.1 Oral Anticoagulants
Anticoagulants are a mainstay of cardiac medicine. Patients are prescribed with oral
antithrombotic agents for a variety of indications including prophylaxis/treatment
of venous thromboembolism (VTE), valve replacement, and atrial fi brillation. Over
the last 10 years, other oral agents with unique mechanisms of action have been
brought to market.
• Warfarin (Coumadin
®
) is perhaps the most well known of the oral anticoagu-
lants but is associated with many drug interactions (primarily involving the
cytochrome P450 enzyme system) and requires close monitoring. Its antico-
agulant effect involves inhibition of vitamin K dependent blood factors includ-
ing factors II, VII, IX, and X. In patients with VTE, therapy with warfarin
requires concurrent parenteral therapy for a period of 4–5 days and a therapeu-
tic international normalized ratio (INR) to allow for adequate inhibition of fac-
tor II, which has a half-life of approximately 60 h. Side effects include bleeding,
microvascular thrombosis, and, rarely, nonhemorrhagic cholesterol emboliza-
tion to the feet and toes. Risk factors for bleeding include age >65, history of
gastrointestinal (GI) bleeding or stroke, hematocrit <30 %, creatinine >1.5,
malignancy, hepatic disease, and diabetes (Ageno et al. 2012 ). In patients pre-
viously stable on warfarin who are unable to take medications enterally, the IV
formulation can be administered at the same dose. Lower doses of the IV for-
mulation may be required in the hospitalized patient due to decreased intake of
vitamin K, acute illness, and interacting medications. Higher doses may be
required in patients receiving vitamin K containing enteral nutritional supple-
ments (Dager 2011 ; Wittkowsky 2011 ).
• Dabigatran (Pradaxa
®
) is a direct thrombin ( factor IIa ) inhibitor that requires no
monitoring, has limited drug interactions [involving mainly the p-glycoprotein
(P-gp) effl ux transporter present in the GI tract versus the cytochrome P450
(CYP) system], and is dosed twice daily. Onset of anticoagulation occurs between
30 and 120 min post dose (Brighton 2010 ). Plasma levels of this agent are
affected by age and renal function. Age >65, female gender, and renal dysfunc-
tion are factors associated with higher plasma levels and bleeding risk. The pri-
mary drawback of this agent is the lack of a reversal agent or routinely available
monitoring parameters. The primary side effects are bleeding (particularly GI)
6 Postoperative Bleeding Disorders after Cardiac Surgery
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164
and dyspepsia. Signifi cant drug interactions involve induction or inhibition of
the P-gp transporter and include inhibitors such as amiodarone, dronedarone,
diltiazem, verapamil, ketoconazole, quinidine, and clarithromycin and inducers
such as rifampin. Absorption of dabigatran etexilate can be reduced postopera-
tively due to decreased GI motility and use of proton pump inhibitors such as
pantoprazole (Ageno et al. 2012 ).
• Rivaroxaban (Xarelto
®
) is a direct factor Xa inhibitor that has no monitoring
requirements, comparatively minimal drug interactions, and is dosed once
daily. The onset of action is between 2 and 4 h post dose (Brighton 2010 ).
Combined strong inhibitors of CYP3A4 and P-gp, including ketoconazole,
itraconazole, voriconazole, posaconazole, and HIV protease inhibitors may
increase systemic levels of rivaroxaban and potential risk of bleeding.
Combined strong CYP3A4 and P-gp inducers can reduce rivaroxaban levels
and include rifampin, phenytoin, carbamazapine, phenobarbital, and St. John’s
wort (Ageno et al. 2012 ).
• Apixaban (Eliquis
®
) is the newest direct factor Xa inhibitor approved by the
FDA and, as with rivaroxaban, has no monitoring requirements and has limited
drug interactions. Coadministration of apixaban with strong dual inhibitors of
CYP3A4 and P-gp, including but not limited to ketoconazole, itraconazole, rito-
navir, and clarithromycin can result in increased levels of apixaban. Similarly,
coadministration of this agent with strong dual inducers of CYP3A4 and P-gp
(i.e., rifampin, carbamazepine, phenytoin, St. John’s wort) can result in subthera-
peutic levels of apixaban. This agent is dosed twice daily and has an onset of
action between 3 and 4 h post dose (Table 6.1 ).
6.2.2 Parenteral Anticoagulants
Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), direct
thrombin inhibitors, and indirect factor Xa inhibitors are parenteral agents with
varying dosing schedules and clinical uses. Heparin and LMWH are used for the
treatment of acute coronary syndromes (ACS), VTE, and for prophylaxis of throm-
botic events. Both UFH and LMWH indirectly inhibit factor IIa and Xa, with
LMWH having a higher affi nity for factor Xa. Fondaparinux is an indirect factor Xa
inhibitor used for treatment and prophylaxis of VTE. Direct thrombin inhibitors
(DTIs) are used in the treatment of heparin-induced thrombocytopenia (HIT) and
include argatroban and bivalirudin (Angiomax
®
). Of the available DTIs, bivalirudin
has been used in patients with a history of HIT requiring cardiac surgery. Of the
agents listed in Table 6.2 , heparin and the DTIs are the primary parenteral antico-
agulants in the cardiac surgery setting and will therefore be the focus in this
section.
• Heparin is the anticoagulant of choice in the cardiac surgery setting due to its
fast onset/offset, reversibility with protamine, and point of care (POC) moni-
toring option. Benefi ts during CPB include inactivation of thrombin and factor
Xa thereby reducing the risk of clot formation in the circuit. Typical doses
S. Martin-Stone
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165
Table 6.1 Oral anticoagulant dosing, monitoring, and preoperative discontinuation
Anticoagulant Half-life (t
1/2
)/dose Monitoring
Discontinue prior to surgery (days)/reversal
agent
Dabigatran
(Pradaxa
®
).
https://www.
pradaxa.com/ .
Accessed 17
July 2012
12–17 h in healthy subjects No readily available method CrCl ≥50 mL/min: 1–2 days
CrCl >30 mL/min: 150 mg BID Activated partial thromboplastin time
(aPTT) demonstrates presence but not
degree of anticoagulation
CrCl 30–50 mL/min: 2–4 days
CrCl 30–50 mL/min + dronedarone or ketoconazole:
75 mg BID
Prothrombin time (PT) insensitive CrCl <30 mL/min: ≥5 days
CrCl 15–30 mL/min: 75 mg BID Thrombin time (TT)—normal value
rules out presence of dabigatran
No reversal agent available; dialysis may
remove up to 62 % within 2 h (Ageno et al.
2012 ; van Ryn et al. 2010 )
Ecarin clotting time (ECT)—linear dose
relationship; not routinely available
Rivaroxaban
(Xarelto
®
).
http://www.
xareltohcp.com/ .
Accessed 17
July 2012
5–9 h in healthy subjects No readily available method At least 1 day (24 h)
Atrial fi brillation Prolongs aPTT, PT/INR No reversal agent available and unlikely to
be dialyzable due to high protein binding
(Ageno et al.
2012 )
CrCl >50 mL/min: 20 mg daily with evening meal No direct effect on platelet aggregation
CrCl 15–50 mL/min: 15 mg daily with evening meal
VTE prophylaxis: 10 mg daily ± food
VTE treatment: 15 mg PO twice daily × 21 days, then
20 mg daily
Apixaban
(Eliquis
®
). http://
packageinserts.
bms.com/pi/
pi_eliquis.pdf .
Accessed 27
February 2013
~12 h following repeated dosing No readily available method 24–48 h prior to surgery depending on risk,
location, and ability to control bleeding
Atrial fi brillation Prolongs aPTT, PT/INR No reversal agent and unlikely to be
dialyzable due to high protein binding
5 mg twice daily No direct effect on platelet aggregation Activated charcoal may be useful in
overdose situations
2.5 mg twice daily in patients with any two of the
following characteristics: ≥80 years of age, weight
≤60 kg, serum Cr ≥1.5 mg/dL
2.5 mg twice daily in patients taking strong dual
inhibitors of CYP3A4 and P-gp (ketoconazole,
itraconazole, ritonavir and clarithromycin)
No data in patient with CrCl <15 mL/min
(continued)
6 Postoperative Bleeding Disorders after Cardiac Surgery
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166
Warfarin
(Coumadin
®
).
http://
packageinserts.
bms.com/pi/
pi_coumadin.
pdf . Accessed
17 July 2012
20–60 h PT/INR Minimum of 5 days without reversal agents
Individualized dosing Reversal agents
Vitamin K
10 mg PO/IVPB for emergent
normalization of PT/INR; IVPB initial
effect at 2 h and full correction within
24 h
5 mg PO and 1 mg IVPB produce
similar effects on INR at 24 h
0.5–1 mg orally for reducing PT/INR
into therapeutic range (for <2.5 mg use
IV form administered orally)
Ineffective in hepatic disease due to
inability to produce factors
Oral route not effective in biliary
disease
SQ not recommended due to
unpredictable absorption and reversal
characteristics
Prothrombin complex concentrate (PCC,
Factor IX complex, Profi lnine
®
)
25–50 units/kg with vitamin K to
prevent rebound increase in INR
(Ageno et al.
2012 ; Schulman and
Bijsterveld 2007 )
Recombinant activated factor VII
For intracranial hemorrhage—doses
vary; 20–40 μg/kg have been used;
available as 1, 2, 5, and 8 mg vial
sizes; use lowest dose rounded to
nearest vial size and repeat if needed
due to risk of arterial and venous
thrombotic and thromboembolic events
Anticoagulant Half-life (t
1/2
)/dose Monitoring
Discontinue prior to surgery (days)/
reversal agent
Table 6.1 (continued)
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167
Table 6.2 Parenteral anticoagulants and monitoring (Douketis 2010 ; Douketis et al. 2012 ; Bojar 2011 )
Anticoagulant
Half-life (t
1/2
)/dose Monitoring
Discontinue prior to surgery (hours)/
reversal agent
Unfractionated heparin
(UFH)
60–90 min aPTT 4–6 h
VTE: 80 unit/kg bolus, then 18 units/
kg/h
Anti-factor Xa activity level (UFH levels) Protamine 1 mg/100 units of heparin
(max 50 mg at a rate not to exceed
5 min)
ACS: 60 unit/kg bolus, then 12 units/
kg/h
Activated clotting time (ACT;
intraoperatively)
Dose adjust based on time since
heparin held: >60 min 0.5 mg/100
units; >2 h 0.25 mg/100 units
Prophylaxis: 5,000 units SQ BID or TID
Low-molecular-weight
heparin
4.5–7 h Anti-factor Xa activity level (LMWH
level)
24 h
Dalteparin (Fragmin
®
).
www.pfi zer.com/fi les/
products/uspi_fragmin.pdf
.
Accessed 18 July
VTE treatment
Dalteparin treatment doses should not be
used in patients with CrCl ≤30 mL/min
Protamine
Dalteparin : 200 units/kg SQ daily
Enoxaparin 1 mg/kg SQ daily may be
considered in patients with chronic stable
kidney disease and CrCl ≤30 mL/min
who are not dialysis dependent;
anti-factor Xa and serum creatinine
monitoring is highly recommended
<8 h after last dose: 1 mg/1 mg
enoxaparin or per 100 units of
dalteparin
Enoxaparin : 1 mg/kg SQ BID or
1.5 mg/kg SQ daily
8–12 h after last dose or if repeat is
necessary: 0.5 mg/1 mg enoxaparin
or per 100 units of dalteparin
Enoxaparin (Lovenox
®
).
http://products.sanofi .us/
lovenox/lovenox.
html#section-14.1
. Accessed
18 July
VTE prophylaxis
>12 h after last dose: administration
of protamine may not be necessary
Dalteparin 5,000 units SQ daily
The anti-factor Xa activity is never
completely reversed (typically 60 % is
reversed)
Enoxaparin 30 mg SQ BID or 40 mg
SQ daily
ACS
Dalteparin 120 units/kg SQ every 12 h
Enoxaparin 1 mg/kg SQ every 12 h
(continued)
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168
Table 6.2 (continued)
Anticoagulant
Half-life (t
1/2
)/dose Monitoring
Discontinue prior to surgery (hours)/
reversal agent
Direct thrombin inhibitors Argatroban 50 mins
aPTT 2 h
Argatroban
®
. http://us.gsk.
com/products/assets/us_
argatroban.pdf
. Accessed 31
July 2012
Treatment of HIT : 2 mcg/kg/min initial
dose; adjust for hepatic insuffi ciency
and critically ill patients with
multisystem organ failure
Bivalirudin (Angiomax
®
).
www.angiomax.com/
Downloads/Angiomax_
PI_2010_PN1601- 12.pdf
.
Accessed 18 July 2012
Bivalirudin 25 mins
No reversal agent
CPB dosing in setting of HIT
On pump :1 mg/kg bolus, 50 mg for
pump then 2.5 mg/kg/h; goal ACT
>2.5x baseline
Case reports suggest that
recombinant factor VIIa 90 μg/
kg × 1 may reverse the anticoagulant
effect (Schulman and Bijsterveld)
Off pump : 0.75 mg/kg bolus, 1.75 mg/
kg/h: goal ACT >300 s
Factor Xa inhibitor
Fondaparinux (Arixtra
®
).
http://us.gsk.com/products/
assets/us_arixtra.pdf
.
Accessed 31 July 2012
17–21 h Not routinely available. International
standards for anti-factor Xa activity for
UFH/LMWH do not apply
48 h
VTE No reversal agent
Prophylaxis : 2.5 mg SQ daily
Case reports suggest that
recombinant factor VIIa 90 μg/
kg × 1 reverse the anticoagulant
effect (Schulman and Bijsterveld)
Treatment:
<50 kg: 5 mg SQ daily
50–100 kg: 7.5 mg SQ daily
>100 kg: 10 mg SQ daily
S. Martin-Stone
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169
include 20,000–30,000 units to achieve a target ACT of 300–350 s, although
this varies widely among cardiac surgery centers. Rarely, patients may require
doses of heparin exceeding 500 units/kg without achieving the target ACT.
These patients may have a reduced response to heparin due to low levels of
antithrombin (AT), excessive factor VIII, or excessive fi brinogen (Dager 2011 ).
Antithrombin is a required cofactor for the anticoagulant effect of heparin.
Risk factors for antithrombin defi ciency include preoperative heparin, place-
ment of an intra-aortic balloon pump (IAPB), elevated platelet counts, and
infective endocarditis (Ranucci et al. 1999 ). Repletion of AT and subsequent
goal ACT can be achieved with administration of fresh frozen plasma (FFP) or
commercially available concentrates (i.e., Thrombate
®
) (Lemmer and Despotis
2002 ).
• Argatroban and bivalirudin are DTIs and are the primary agents used in the treat-
ment of HIT. Bivalirudin has been used as the intraoperative anticoagulant in
patients with a history of HIT or those who require surgical intervention in the
presence of active HIT.
6.2.3 Antiplatelet Agents
Antiplatelet therapy is a cornerstone of primary and secondary prevention of cardio-
vascular disease in patients with a history of myocardial infarction, ACS, and some
valvulopathies. Thienopyridines (clopidogrel and prasugrel) are hepatically or
enzymatically metabolized to active metabolites which bind to the platelet P2Y
12
receptor causing irreversible platelet inhibition. Antiplatelet therapy should be eval-
uated perioperatively with respect to dose, duration, last dose administered, and
hemorrhagic side effects.
• Aspirin irreversibly inhibits platelet cyclooxygenase-1 (COX-1) which pre-
vents production of thromboxane A2. This results in inhibition of platelet acti-
vation and aggregation. At any given point, the age of circulating platelets
ranges from 1 to 10 days. New platelets with functioning COX-1 are continu-
ally being produced and replace 10–15 % of inhibited platelets daily allowing
overall platelet function to return gradually over a period of 7 days (Gibbs et al.
2001 ).
• Clopidogrel is a prodrug hepatically metabolized in two-step process to an active
form which inhibits ADP binding to the platelet P2Y
12
receptor. This results in
inhibition of ADP-mediated activation of the glycoprotein IIb/IIIa (GP IIb/IIIa)
complex and resultant platelet aggregation. The amount of the active form in
circulation varies due to genetic variation in hepatic metabolism (CYP2C19) and
drug interactions affecting CYP2C19 (i.e., proton pump inhibitors). These fac-
tors may contribute to the variable response associated with this agent. Data
evaluating the concurrent administration of omeprazole demonstrated no clini-
cally relevant interaction; however, the manufacturer recommends the use of
pantoprazole due to less inhibitory effect on CYP2C19 (Wallentin 2009 ;
Wallentin et al. 2009 ; Patrono et al. 2011 ).
6 Postoperative Bleeding Disorders after Cardiac Surgery
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170
• Prasugrel is a prodrug similar to clopidogrel and exhibits antiplatelet effects by
the same mechanism. However, it is unaffected by polymorphisms in CYP2C19
or interactions with proton pump inhibitors. Additionally, the active component
is produced following a one-step hepatic conversion resulting in a greater amount
of metabolite formed following a loading dose. Prasugrel is 10x more potent than
clopidogrel with a more rapid onset (30 min vs 1 h with 600 mg loading dose of
clopidogrel) and less variation in response (Eikelboom et al. 2012 ; Patrono et al.
2011 ).
• Ticagrelor undergoes enzymatic degradation to an active metabolite. Onset of
action is approximately 30 min post loading dose of 180 mg (Weitz et al.
2012 ).
• Intravenous antiplatelet agents administered primarily during percutaneous cor-
onary intervention (PCI) include abciximab, eptifi batide, and tirofi ban . These
agents block the binding of fi brinogen to the GP IIb/IIIa receptor and subsequent
platelet aggregation. Abciximab is a monoclonal antibody which acts as a non-
competitive inhibitor while eptifi batide and tirofi ban are competitive inhibitors
and therefore require high plasma levels for adequate antiplatelet effect (Patrono
et al. 2011 ; Bojar 2011 ) (Table 6.3 ).
6.3 Other Agents
Supplements such as fi sh oil, vitamin E (>400 units/day) and herbal supplements
can signifi cantly impact coagulation and platelet function and should be discontin-
ued at least 5 days prior to surgery. Examples of herbal supplements with anticoagu-
lant or antiplatelet activity include chamomile, garlic, chondroitin, evening primrose
oil, ginger, feverfew, ginseng, kava, mate, and goldenseal (Halasynski et al. 2004 ).
6.4 Monitoring Coagulation Status
The fi nal product of a functioning coagulation cascade is the dynamic harmony
between clot formation and dissolution known as hemostasis. Achieving hemostasis
involves not only blood factors and platelets but also proteins (i.e., cytokines) and
non-platelet cells (i.e., endothelial cells). Instability in the coagulation system due
to interaction between these factors, often released in situations of vascular injury
(i.e., surgery) or various illnesses (i.e., malignancy), increases the risk of hemor-
rhage or thrombosis. Within the coagulation system are two pathways known as the
extrinsic pathway and the intrinsic pathway. Pathway function can be assessed by
common laboratory tests (Table 6.4 ).
Thromboelastography, via either inpatient laboratory or point-of-care
reporting, is becoming more widely available. This type of monitoring pro-
vides a graphic representation of a patient’s complete coagulation status.
Tracings demonstrating hemorrhagic and thrombotic states are shown in
Figs. 6.1 and 6.2
S. Martin-Stone
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