Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
Emerging constructs to maintain safety among patients with acute coronary syndromes requiring surgical coronary revascularization
Richard C. Becker*
Cardiovascular Thrombosis Center, Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27715, USA
* Corresponding author. Tel: +1 919 688 8926; fax: +1 919 668 7056. E-mail address: becker021{at}mc.duke.edu
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Abstract
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Pharmacotherapies directed towards well-defined biochemical
processes underlying coronary atherothrombosis have favourably
influenced the natural history of disease; however, coronary
revascularization is still required in 0–15 percent of
patients admitted to the hospital with acute coronary syndromes.
Because surgical coronary revascularization has a profound impact
on haemostasis, especially when cardiopulmonary bypass (CPB)
is employed, antithrombotic and antiplatelet therapies must
be chosen carefully during the peri-operative period. Though
the potential benefit of platelet P2Y
12-receptor inhibition
in this particular patient population is recognized widely,
the available evidence show that adenosine-diphosphate-mediated
platelet activation is an absolute prerequisite for post-operative
haemostasis. Pharmacotherapies in development that have rapid
onset and offset of P2Y
12 inhibition may allow much-needed flexibility
in the perioperative setting. Alternative anticoagulants to
unfractionated heparin that attenuate thrombin-mediated haemostatic
derangements may add further to the optimal pharmacological
management of patients undergoing coronary revascularization.
Key Words: Cardiopulmonary bypass • Coronary artery bypass grafting • Haemostasis • Thrombosis
Coronary heart disease is responsible for nearly 500 000 deaths yearly in the United States and represents the leading cause of death for both women and men worldwide.1 There are an estimated 15 million Americans with coronary artery disease, which affects people of all races, cultures, and ethnicities. Current projections indicate that 1.2 million Americans will experience an acute coronary syndrome (ACS) in the coming year.2 Although pharmacotherapies directed specifically towards individual cellular components and well-defined biochemical processes underlying coronary atherothrombosis have favourably influenced the natural history of disease, percutaneous and surgical coronary revascularization is performed on upward of 50 and 15% of patients admitted to the hospital with ACS, respectively.3 In the United States and in other countries, invasive procedures are frequently performed prior to hospital discharge or within the ensuing weeks. Because surgical coronary revascularization exerts a profound effect on haemostasis, particularly when cardiopulmonary bypass (CPB) is employed, antithrombotic therapy—and platelet-directed therapies in particular—must be chosen carefully during the peri-operative period to maximize patient benefit and minimize risk.
This review focuses on haemostatic alterations during surgical coronary revascularization, the mechanistic basis for these observed anomalies, and the potential impact of peri-operative platelet-directed therapy on overall patient outcomes.
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A brief history of cardiopulmonary bypass
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In the late 19th and early 20th centuries, several scientists
demonstrated that venous blood could be ‘arterialized’
by adding oxygen, and as a result attempts were made to investigate
oxygenators for
in vitro organ culture studies.
4 In 1885, von
Frey and Gruber
5 devised a rotating cylinder filled with oxygen;
however, the pioneering work of John Gibbon in 1934 was the
first to consider a means of ‘bypassing’ the heart
and lungs for the purpose of ‘open heart surgery’.
Gibbon and his wife Mary, working in the laboratory of Dr Edward
Churchill in Boston, built the first heart–lung machine
from glass, rubber, homemade valves, a rotating cylinder, and
assorted laboratory air pumps (
Figure 1).
6 On 16 May 1953,
an 18-year-old patient successfully underwent closure of an
atrial–septal defect using CPB.
7
The modern-day components of a CPB circuit are shown in
Figure 2.
8 The circuit can be summarized as follows: venous blood drains
by means of gravity from a cannulated right atrium through a
half-inch polyvinyl chloride tube that extends into the venous
reservoir. The reservoir filters blood and also acts as a capacitance
chamber to manage acute volume changes due to heart manipulation,
drugs, shunts, or hypothermia. Filtration is achieved when the
blood passes through porous plastic foam and a woven polypropylene
sheet. The foam provides a tortuous fluid path removing particulate
matter and small blood clots, and the sheet removes gaseous
micro-emboli. The filtered venous blood is then drawn from the
reservoir and pumped towards a heat exchanger and oxygenator
block. The two types of arterial pumps currently include a partially
occlusive peristaltic roller pump and a non-occlusive, constrained-vortex
centrifugal pump. The arterial pump serves the role of ‘ventricles’
in providing the blood with momentum. The overall cardiac output
generated by the pump is calculated using the surface area of
the patient multiplied by the cardiac index, taking patient
temperature into consideration. The blood then passes through
a heat exchanger, passing over plastic-coated aluminium or polypropylene
membranes. The membrane itself separates blood from temperature-controlled
water, enabling control of blood temperature. Subsequently,
the blood then passes through the oxygenator or a gas-exchange
device, which consists of a porous polypropylene membrane arranged
in hollow fibres. There, the small holes in the membrane create
a blood–gas interface but do not allow the passage of
fluid. This phenomenon, combined with the large surface area,
ensures the efficient addition of oxygen and removal of carbon
dioxide. The final component of a standard CPB circuit is a
40 µm arterial-line screen filter designed to further
remove micro-emboli and serve as an air-bubble trap.
8
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Figure 2 Cardiopulmonary bypass circuit. Venous blood drains through a half-inch polyvinyl chloride tube extending into a venous reservoir (1, 1a), where it is filtered through porous plastic foam and a woven polypropylene sheet (1b). Filtered blood is drawn from the reservoir (1c) and passes through either a partially occlusive peristaltic roller pump (2a) or a non-occlusive constrained vortex centrifugal pump (2b). Blood then passes over a plastic-coated or polypropylene membrane that separates it from temperature-controlled water on the other side (3a) on to the heat exchanger (3), which consists of a porous polypropylene membrane arranged in hollow fibres (3b). The final component is a 40 µm arterial-line screen filter (4). Reprinted from Surgery (Oxford), 25, Mulholland JW, Cardiopulmonary bypass, 217–219, 2007, with permission from Elsevier.8
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Haemostasis in cardiopulmonary bypass
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Cardiac surgery with concomitant CPB can profoundly alter normal
haemostasis, predisposing patients to both major haemorrhagic
complications and early thrombotic events.
9,10 The incidence
of severe bleeding in cardiac surgery exceeds 10%, and 5–7%
of these patients experience blood loss in excess of 2 L within
the initial 24 h after surgery.
11
Surgical re-exploration for bleeding, which occurs in 2–6% of patients undergoing isolated coronary artery bypass grafting (CABG) procedures, has been associated with case-fatality rates approaching 30% in some series; however, a specific site of bleeding is identified in fewer than 50% of those undergoing emergent re-operation.11–15 In most cases, an acquired haemostatic defect that causes diffuse mediastinal haemorrhage is uncovered.
The activation of coagulation proteases following contact between circulating blood and the extracorporeal CPB circuit represents an initiating event of pathobiological significance and in essence is the provocative ‘root cause’ of haemostatic derangements observed in CABG surgery. During CPB, blood is pumped continuously over 1.5–2 m2 of non-biological surfaces.12,16 The most profound activation of circulating coagulation proteases occurs within the oxygenator, where flow is non-laminar by design in order to maximize O2 transport.17 The venous reservoir and arterial line filter also offer large blood contact areas and are associated with non-laminar flow.16
There are many points of interface within an extracorporeal circuit that exert shear stress on circulating blood cells—a potential source of tissue factor (TF). Blood is driven under a propulsive force through a variety of conduits of differing and changing diameters.16 Moreover, the exposed myocardium and pericardium, a rich source of TF-expressing microparticles, are bathed in a mixture of blood and cardioplegia solution, which is subsequently drained into the cardiotomy reservoir and often reinfused directly via the extracorporeal circuit.12 CPB circuits provide an opportunity to investigate both contact and TF-activated models of coagulation. Biologically, the contact and TF-activated coagulation pathways represent an integrated system designed to generate thrombin. Factor Xa, when complexed with fVa, calcium, and phospholipid substrate, forms the prothrombinase complex on activated platelets, cleaving prothrombin into thrombin.18,19 The pivotal event in the development of haemostatic abnormalities during CPB is thrombin generation.20 Thrombin is a pluripotent protease that activates platelets and coagulation factors V, VIII, and IX.21 Thrombin-mediated platelet activation leads to their rapid clearance and consumption and contributes directly to fibrin(ogen)olysis, coagulation protease bioamplification (with further thrombin generation), and profound haemostatic abnormalities (Table 1, Figure 3).21–23
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Figure 3 Cardiopulmonary bypass, combined with cardiothoracic surgery, invokes a profound haemostatic response mediated by blood-non-biological surface interface, tissue injury, and inflammation. Contact- and tissue factor-initiated thrombin generation represents a pivotal step in platelet activation (followed by functional exhaustion, hyperfibrinolysis, and coagulation protease consumption).
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Quantitative and qualitative platelet abnormalities during cardiopulmonary bypass
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There is an immediate decline in the number of circulating platelets
following initiation of CPB. Although haemodilution is thought
to represent a major contributor, heparin-induced (type 1) reticulo-endothelial
system clearance and activation (followed by clearance) participate
as well. In addition to a quantitative platelet abnormality,
CPB initiates a profound qualitative abnormality (
Table 2).
24–28
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A unifying theme for haemodynamic derangements during cardiopulmonary bypass
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The well-described changes in haemostatic potential during CPB
reflect the cumulative effects of decreased coagulation protease
levels, hyperfibrinolysis, and both quantitative and qualitative
platelet abnormalities. While the operative environment is complex,
heightened thrombin generation may well represent a unifying
theme. The thrombin–platelet interface is particularly
important in the genesis of both intra-operative and post-operative
bleeding complications and could provide important clues towards
understanding the incremental and seemingly disproportional
impact of even modest drug-induced platelet inhibition on bleeding-related
surgical end points.
Thrombin is a potent platelet agonist and provokes a particularly robust procoagulant response in the presence of collagen (thrombin and collagen costimulation, also referred to as COAT platelets). Thrombin-induced platelet activation is an important event during CPB for several reasons. First, cleavage of platelet surface protease-activated receptors (PARs), specifically PAR-1 and PAR-4, establishes a highly supportive surface for prothrombinase assembly and further thrombin generation. Secondly, concomitant thrombin and platelet-induced PAR cleavage threatens platelet preservation29–31 and clot stability.32 Lastly, thrombin generation on platelet surfaces augments profibrinolytic and inflammatory responses, with cleavage of adhesive (GPIb/IX) and platelet aggregate stabilizing (GPIIb/IIIa) receptors.
An ability of aprotinin to reduce surgical bleeding is based on several mechanisms that reach beyond its capacity to attenuate the inflammatory cascade and limit fibrinolysis. Indeed, aprotinin is a platelet PAR-1 receptor antagonist that ‘spares’ its cleavage during CPB, minimizing thrombin-induced platelet activation33 and thereby permitting platelets to participate in surgical-wound haemostasis.
While one might anticipate that a platelet PAR-1 receptor antagonist would increase the risk of bleeding, fully intact platelet responses to other agonists, such as adenosine diphosphate (ADP) and collagen, may preserve haemostatic capacity in surgical wounds.34
The importance of ADP-induced platelet aggregation in maintaining haemostatic potential during surgery is supported by several lines of evidence. Adenosine triphosphate (ATP), released by exocytosis from damaged erythrocytes, leukocytes, and platelets, is converted to ADP by ecto-ATPases. In turn, ADP interacts with P2Y1 and P2Y12 receptors to induce platelet aggregation.35 The platelet P2Y1 receptor is responsible for an initial aggregatory response to ADP, while activation of P2Y12, through G protein-coupled signalling, is required for achieving and maintaining stability of platelet aggregates (Figure 4).36 It also participates in platelet adhesion and activation in response to epinephrine—a prevalent biochemical in surgical settings and trauma (Figure 5).36
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Figure 4 Platelet activation at the apex of arterial thrombi. Thrombi formed after a 2.5 min perfusion period of wild-type (A, C, E) and P2Y12 –/– (B, D, F) blood at 840/s over collagen. Fixed (but not permeabilized) thrombi were stained for P-selectin (A, B), Gas6 (C, D), and with Alexa 488-fibrinogen (E, F). Reprinted from J Clin Invest, 112, Andre P, et al., P2Y12 regulates platelet adhesion/activation, thrombus growth, and stability in injured arteries, 398–406, 2003, with permission from Elsevier.36
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Figure 5 Platelet P2Y12 contributes to platelet activation in response to epinephrine. (A) In vivo arterial thrombotic profile of wild-type (+/+), P2Y12 +/–, and P2Y12 –/– mice. (B) Modulation of the thrombotic profile upon epinephrine treatment. B, bleaching; Epi, epinephrine. Vertical arrows indicate time when filter paper was removed from the artery. Reprinted from J Clin Invest, 112, Andre P, et al. P2Y12 regulates platelet adhesion/activation, thrombus growth, and stability in injured arteries, 398–406, 2003, with permission from Elsevier.36
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Coagulant substrate, conditions, and clot stability: fundamental determinants of haemostatic potential
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Haemostasis, particularly when initiated in complex environments
as typified by surgical trauma and CPB, is highly dependent
on coagulant substrate concentration and coexisting conditions
(temperature, acid–base balance, circulatory flow).
37 The dynamic nature of thrombin generation during CABG and extracorporeal
circulation (ECC) with concomitant and rapid fluctuation of
cellular, fibrinolytic, and intrinsic thromboresistant protein
activity, produces clots with altered fibrin structure and decreased
stability.
38 A change in fibrin architecture also influences
both lysability and thrombin binding. Thus, the composition
and strength of a clot is specific to the conditions under which
it is formed.
An example illustrating the importance of substrate and conditions for haemostasis is haemophilia (A-factor VIII deficiency or B-factor IX deficiency). Skin biopsies procured from patients with haemophilia show a thin peripheral layer of fibrin deposition surrounding a central region with relatively few fibrin strands. Decreased and delayed thrombin generation, in turn, delays fibrin polymerization and yields abnormally thick fibrin strands with increased porosity and susceptibility to lysis (Figure 6).38–40
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Figure 6 Factor IX deficiency (haemophilia B) produces clots that contain abnormally thick fibrin strands. Fibrin clots were formed in a cell-based model of haemostasis and imaged using electron scanning microscopy (scale bar = 8 µm). Reprinted from Blood Rev, 21, Wolberg A, Thrombin generation and fibrin clot structure, 131–142, 2007, with permission from Elsevier.40
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Platelet antagonists and clinical outcome following coronary artery bypass grafting
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The impact of CPB on platelets, both quantitatively and qualitatively,
has been summarized in previous sections. Intuitively, one would
anticipate an ability of platelet antagonists to further impair
haemostasis and increase post-operative haemorrhagic risk. The
point that must be emphasized once more is the fundamental contribution
of thrombin-mediated platelet activation in CPB-associated haemostatic
abnormalities and of platelet P2Y
12 activation in achieving
platelet aggregate stability. Thus, attenuating thrombin-induced
platelet activation (to be discussed in a subsequent section)
and preserving P2Y
12-induced signal transduction may represent
an ideal strategy.
Aspirin
A meta-analysis of 10 randomized and non-randomized studies including a total of 1748 patients undergoing elective, isolated CABG41 reported increased post-operative chest-tube drainage and transfusion of red blood cells and fresh frozen plasma among those receiving aspirin up to the time of surgery. Re-exploration rates were not influenced by aspirin administration. Using prospectively collected data from 1636 consecutive patients undergoing first-time, isolated CABG at the Mayo Clinic, Bybee et al.42 found that patients receiving aspirin pre-operatively had significantly lower post-operative in-hospital mortality compared with those not receiving aspirin [1.7 vs. 4.4%; adjusted odds ratio (OR), 0.34; 95% confidence interval, 0.15–0.75, P = 0.02] (Figure 7). Pre-operative aspirin therapy was not associated with an increased risk of re-operation for bleeding or requirement for post-operative blood transfusions.
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Figure 7 Adjusted odds ratios with 95% confidence intervals of primary and secondary outcome measures for those who received pre-operative aspirin and those who did not receive pre-operative aspirin within 5 days prior to CABG. Event rates are unadjusted results with corresponding relative risk reductions. Bybee KA, et al. Preoperative aspirin is associated with improved post-operative outcomes in patients undergoing coronary artery bypass grafting. Circulation 2005:112(Suppl I):I286–I289. Reproduced with permission from Lippincott, Williams and Wilkins.42
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Clopidogrel
Much like aspirin, thienopyridine P2Y
12 receptor antagonists
are frequently administered to patients with ACS and among those
undergoing PCI with stenting. A structured review of 23 studies,
including a total of 3505 patients exposed and 9970 patients
not exposed to clopidogrel within 7 days of CABG
43 identified
an increased incidence of chest-tube output, blood product transfusion,
and surgical re-exploration for bleeding among those exposed
to clopidogrel (
Figures 8 and
9). The risk of peri-operative
haemorrhagic complications appears to be particularly high among
patients exposed to clopidogrel within 2–3 days of CABG.
44,59 This observation supports the relative importance of ADP-mediated
platelet activation and P2Y
12-associated platelet aggregate
stabilization in maintaining haemostatic potential following
CPB and major surgery.
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Figure 8 Mean difference (95% confidence interval) in chest-tube output units in patient receiving clopidogrel within 7 days prior to undergoing CABG vs. patients not exposed to clopidogrel. Reproduced with permission from Pickard AS, et al. Clopidogrel associated bleeding and related complications among patients undergoing coronary artery bypass graft surgery. A structured review of the literature. Pharmacotherapy 2008;28:376–392.43–49
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Figure 9 Coronary artery bypass surgery and risk (95% confidence interval) of re-operation for bleeding in patients receiving clopidogrel within 7 days prior to operation vs. patients not exposed to clopidogrel. Reproduced with permission from Pickard AS, et al. Clopidogrel associated bleeding and related complications among patients undergoing coronary artery bypass graft surgery. A structured review of the literature. Pharmacotherapy 2008;28:376–392.43,44,47,49,50–58
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Peri-operative bleeding, blood product transfusion, and clinical outcomes
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The biological response to major surgery alone is highly complex,
with markedly heightened pro-inflammatory and pro-thrombotic
states. While the added or synergistic impact of major bleeding
on outcomes is an area of ongoing investigation, the available
data suggest that ‘thrombotic preparedness’ may
represent an early molecular response of biological value. Data
collected on 8004 patients undergoing isolated CABG in Northern
New England between 1996 and 2004 showed that having a lower
risk-adjusted haematocrit was associated with an increased risk
of developing low-output heart failure, and that the risk was
increased further when patients received red blood cell transfusions.
60 In a separate investigation, risk-adjusted probability of in-hospital
mortality and morbidity was modelled as a function of red blood
cell and collective blood product transfusion using a logistic
regression analysis.
61 From a total of 11 963 patients who underwent
isolated CABG, 5814 were given red blood cell transfusions (48.6%).
Transfusion of red blood cells was associated with a risk-adjusted
increase in post-operative events, including mortality (OR,
1.77; 95% CI, 1.67–1.87), renal failure (OR, 2.06; 98%
CI, 1.87–2.27), prolonged requirement for ventilator support
(OR, 1.79; 95% CI, 1.72–1.86), serious infection (OR,
1.76; 95% CI, 1.68–1.84), and neurological events (OR
1.37, 95% CI, 1.30–1.44), correlating directly with the
total number of units transfused. The investigators concluded
that peri-operative red blood cell transfusion was the most
powerful independent predictor of post-operative morbid events
following isolated CABG surgery.
Koch et al.62 subsequently evaluated the association between peri-operative red blood cell transfusion and long-term survival. The United States Social Security Death Index was used to ascertain survival status for 10 289 patients who underwent isolated CABG from 1 January 1995 through 28 June 2002. Survival among transfused patients was significantly reduced compared with non-transfused patients. The instantaneous risk of death displayed a biphasic pattern, with a declining hazard from the time of operation (early hazard) up until 6 months post-operatively, followed by a late hazard that continued out for 10 years. When the data were considered collectively, red blood cell transfusion was associated with risk-adjusted reductions in survival for both the early and late phases following CABG.
A similar observation of an early hazard was reported by Kuduvalli et al.63 who analysed outcomes for 3024 consecutive patients who underwent CABG. Patient records were linked to the National Strategic Tracing Service, which records all mortality in the UK. After adjusting for a propensity score, re-operation for bleeding, peri-operative blood loss, and post-operative complications, the adjusted 30-day mortality for patients transfused with red blood cells was 1.9% compared with 1.1% in patients not transfused. The adjusted hazard ratio for 1-year mortality was significantly increased at 1.88.
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Does the choice of anticoagulant during cardiopulmonary bypass influence post-operative bleeding?
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The environment accompanying cardiac surgery and CPB is both
highly thrombotic and pro-inflammatory. In addition to preventing
ECC clot formation, anticoagulation may be a pivotal determinant
of haemorrhagic potential. Using an animal model of CPB, Welsby
et al.
64 showed that the direct thrombin inhibitor bivalirudin
reduced thrombin generation and markers of inflammation compared
with unfractionated heparin (UFH). Bivalirudin has been administered
to patients undergoing both on-pump and off-pump CABG.
65,66 An ability to reduce haemostatic activation via thrombin inhibition
was supported, with maintained fXIIa, prothrombin activation
fragment 1.2, fibrinopeptide A, thrombin–antithrombin
complexes, and D-dimer concentrations during CPB.
67 The clinical
trial data, derived from studies including 50–100 patients,
showed that bivalirudin was an effective anticoagulant during
CPB with similar rate of post-operative blood loss to UFH (and
protamine).
68–70
One may conclude from the collective evidence that anticoagulation with a direct thrombin inhibitor can reduce haemostatic activation, yet, at least based on the results of small-scale clinical trials, does not reduce haemorrhagic complications. This observation does not necessarily challenge thrombin as a mediator of both thrombosis and haemostatic derangements during CPB but does highlight the importance of regulating the intensity of anticoagulation both during CPB and in the immediate post-operative period. The development of RNA aptamers as anticoagulants and their complementary oligonucleotide antidotes may address the unmet need (Figure 10),71 but clinical trials will be required to determine their effective use and ability to attenuate thrombin-mediated haemorrhagic abnormalities.
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Figure 10 Top: The FIXa aptamer 9.3tC can support cardiopulmonary bypass. (A) The coagulation cascade showing specific inhibition of FIXa by aptamer 9.3tC (blue) vs. thrombin and FXa by heparin (red). TF, tissue factor; roman numerals, respective coagulation factors; a, activated factor. (B) Predicted secondary structure of anti-FXa aptamer 9.3tC and its interaction with antidote 5-2C to control aptamer function. (C) Porcine cardiopulmonary bypass timeline with drug and antidote administration (black arrows) and blood sampling (red arrows). (D) Aptamer maintained the patency of a cardiopulmonary bypass circuit and antidote prevented haemorrhage post-cardiopulmonary bypass. Bottom: FIXa aptamer–antidote-treated animals generate less thrombin and have a reduced inflammatory response during and after cardiopulmonary bypass. (A) Fragment f1+2 levels generated in swine undergoing cardiopulmonary bypass (quantified by ELISA). (B) Interleukin 1β (IL-1β) and (C) interleukin-6 (IL-6) levels generated in swine undergoing cardiopulmonary bypass (quantified by ELISA); no bar=below detection. Reprinted from Ann Thorac Surg, 78, Chu MW, et al. Does clopidogrel increase blood loss following coronary artery bypass surgery?, 1536–1541, 2004, with permission from Elsevier.57
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Summary
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Surgical revascularization is an important option in the management
of patients with atherothrombotic coronary artery disease and
ACS. Though the potential benefit of platelet P2Y
12 receptor
inhibition in this particular patient population is incontrovertible,
the available data show that ADP-mediated platelet activation
is an absolute prerequisite for post-operative haemostasis.
Accordingly, pharmacotherapies with rapid onset and offset of
P2Y
12 inhibition may permit much-needed flexibility in the peri-operative
setting. Alternative anticoagulants to UFH during CPB and CABG
that attenuate thrombin-mediated haemostatic derangements may
add further to the overall pharmacological management of this
high-risk patient population.
Conflict of interest: Dr. Becker received modest financial support from AstraZeneca, The Medicines Company, Bristol Meyers Squibb, Regado Biosciences, and Eli Lilly.
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Funding
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Dr. Becker is funded by the National Institute of Health (NIH)
and NIH Roadmap for Medical Research to study oligonucleotides.
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Abstract
A brief history of...