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Bleeding and coagulation have a multifactorial basis. Each of the contributing areas is discussed separately.
Hemodilution results in a decrease in the concentration of platelets and coagulation factors at the initiation of CPB because of the crystalloid used to prime the CPB circuit. Although the decrement in coagulation factor concentration can be profound (especially, e.g., factor V, which can decrease to approximately 15% of normal levels), a clinical coagulopathy problem does not necessarily ensue, probably because clinical coagulation can be effected even when the concentration of a specific coagulation factor is in the region of approximately 30% (and/or factor V is ≅15%) of normal, if all other factors are present at normal concentrations. However, such is not the case during CPB, when the concentration of all factors is decreased simultaneously. The use of crystalloid cardioplegia also contributes to hemodilution at the beginning of CPB. Hemodilution is exacerbated by two additional factors: (1) the addition of crystalloid to the pump to maintain safe reservoir volumes in the CPB circuit and safe target flows to the patient in the setting of the changing pathophysiologic conditions of CPB (i.e., alterations in vascular tone and changes in fluid flux between the intravascular and extravascular compartments and (2) cell salvage techniques, which by definition wash the salvaged blood with the objective of returning only red blood cells to the patient. Coagulation factors and platelets are lost in the process. Indeed, some authors have demonstrated that excessive use of such techniques can paradoxically lead to increased blood loss and transfusion of blood products.[265] [266]
Figure 50-41
Thrombin is generally accepted as a branching or amplification
step in coagulation. One can see from the various proteins stimulated by it that
it not only promotes coagulation but also stimulates fibrinolysis through tissue
plasminogen activator (TPA) and coagulation control through the protein S/C system.
In any given patient, it is not known which of these various reactions will predominate.
(Redrawn from Miller RD, Lichtor JL [eds]: Atlas of Anesthesia: III. Preoperative
Preparation and Intraoperative Monitoring. Philadelphia, Churchill Livingstone,
1997, p 15.5)
These complex areas are the focus of ongoing investigation. For a detailed discussion, the interested reader is referred to publications by Spiess [208] and Murray and Despotis.[267] However, it is now clear that coagulation—and the body's counteractive and balancing responses to coagulation fibrinolysis—should not be viewed as compromising independent cascade systems. In contrast, these systems should be viewed as having the capacity for crosstalk with each other and with inflammatory pathways that have multiple levels of intrapathway and interpathway negative and positive (amplification) feedback loops. Moreover, it is now clearly established that thrombin occupies a central role in the activation of coagulation ( Fig. 50-41 ).[268] AT-III binds thrombin, and its activity is potentiated 1000-to 10,000-fold by heparin. However, even in the presence of heparin, the capacity of AT-III to immediately bind every thrombin molecule produced in the circulation is incomplete. There are always finite amounts of thrombin to exert its deleterious effects. Moreover, the circulation has only a finite amount of AT-III to neutralize the ongoing thrombin generation that occurs during CPB. The coagulation cascade can be activated during CPB by several mechanisms, including contact activation with the CPB circuit (leading to activation of factor XIIa and kallikrein) and tissue factor activation (surgically induced tissue injury, cardiotomy-induced red blood cell hemolysis).
Fibrinolysis, an intrinsic response to coagulation, can also be activated by tissue plasminogen activator released
Heparin rebound can be responsible for bleeding after CPB, but with better monitoring of the ACT and heparin concentrations, this cause of bleeding should become less prevalent. The possible role of heparin-induced inhibition of platelet function is another potential mechanism underlying heparin-associated bleeding after CPB.[272] Protamine's systemic and pulmonary vascular effects, its immunologic effects, and its ability to inhibit thrombin at high concentrations are well recognized. However, its effects on platelet function (increasing the egress of large platelets from the circulation) may be a clinically more important phenomenon.[264] Moreover, complement release after heparin neutralization with protamine is associated with acute decreases in platelet number,[273] [274] possibly by pulmonary sequestration. The inhibitory effects of hypothermia on platelet function are well recognized.[275]
Platelet activation and aggregation are central features of in situ thrombus formation. Moreover, it is now clearly established that these mechanisms are pivotal in mediating acute coronary syndromes, myocardial infarction, thromboembolic cerebral vascular disease, post-stent coronary thrombosis, saphenous vein graft occlusion, and intermittent claudication. Platelets can be activated by (1) endothelial cell von Willebrand factor activation of 1b-1x platelet surface receptors; (2) collagen (exposed in the presence of endothelial cell denudation) activation of platelet surface 1a receptors; (3) thrombin activation of platelet surface thrombin receptors, and (4) ADP activation
Figure 50-42
Schematic diagram of an activated platelet. Normal platelets
in their resting state are discoid in appearance and very pliable; therefore, they
are able to roll and flow through the vasculature. When activated, they change their
shape to spiculated, and once adherent to a surface, they spread in an ameboid shape.
Once activated, they release the contents of their granules and express a number
of glycoprotein binding sites, of which GPIIB/IIA is an example. GPIIB/IIIA is the
binding site for fibrinogen and fibrin and is the most prolific cellular ligand known.
vWF, von Willebrand factor. (Redrawn from Miller RD, Lichtor JL [eds]:
Atlas of Anesthesia, vol III, Preoperative Preparation and Intraoperative Monitoring.
Philadelphia, Churchill Livingstone, 1997, page 15.4.)
Exposure of blood to the CPB circuitry and oxygenator is a potent mechanism of platelet activation. Although platelet numbers are usually decreased after CPB as a result of hemodilution, platelet dysfunction secondary to platelet activation and degranulation is a more important contributor to platelet-associated disturbances in coagulation after CPB. Even though laboratory evidence of
The intraoperative management of cardiac patients and the threshold for platelet transfusion are often influenced by the patient's use of antiplatelet agents. Aspirin, ticlopidine, and clopidogrel are administered to patients with chronic vascular insufficiency. Glycoprotein IIb/IIIa inhibitors are usually administered in an acute setting. As previously indicated, the evidence that these agents are efficacious is well established. However, their perioperative use and their influence on surgical hemostasis pose at least two practical management questions: (1) should these drugs be discontinued before surgery and, if so, when? and (2) what influence should the use of these agents have on the threshold for platelet transfusion after CPB?
The influence of aspirin on perioperative morbidity and mortality illustrates our evolving understanding of the relative risks and benefits of these agents. Aspirin is a well-established, primary preventive measure. It has been and, for many physicians, is still customary to discontinue aspirin use 7 to 10 days before surgery (the approximate duration of the life of platelets). However, some evidence now suggests that outcome is actually improved in patients who continue aspirin versus those who discontinue aspirin before cardiac surgery[38] and in patients who start aspirin therapy immediately postoperatively.[39] Even if one accepts the criticism that aspirin was not given to patients who were bleeding and thus were potentially less stable, the latter study demonstrates, at a minimum, that aspirin was not harmful when given in these circumstances. Numerous studies have attempted to determine whether preoperative aspirin increases post-CPB bleeding. The results are far from clear-cut in that some studies have demonstrated an association[276] [277] [278] whereas several have not.[266] [279] [280] [281]
Because the benefits of aspirin have clearly been demonstrated, it is reasonable to continue aspirin preoperatively. Moreover, because preoperative aspirin is not necessarily associated with post-CPB bleeding, automatic platelet transfusion in this setting cannot be justified. Rather, platelet transfusion should be reserved for patients with clinical indications of bleeding. Although the data are far less extensive, a similar approach to patients taking ticlopidine and clopidogrel seems reasonable. However, in patients receiving a combination of aspirin and either of these two agents, prophylactic platelet transfusion post-CPB may be justified. [282] The glycoprotein IIb/IIIa inhibitors are potent platelet inhibitors. If possible, surgery should be deferred until the platelet inhibitory effects of these agents abate. In practice, such deferral is not always possible. However, the half-life of eptifibatide with return of aggregation parameters to 50% of normal in 4 to 6 hours renders it a more desirable antiplatelet agent. Its elimination half-life is 50% dependent on renal excretion and may be prolonged in the presence of preexisting renal impairment and during the decreased renal blood flow that occurs with CPB.
In the absence of surgical bleeding, the approach to patients with post-CPB coagulopathy and microvascular bleeding remains highly variable across institutions. These practices have even included the prophylactic administration of platelets and fresh frozen plasma.[283] This variability reflects the CPB-induced, interrelated complex changes in the coagulation and inflammatory cascades, our incomplete understanding of these cascades, and the lack of efficient and affordable tests to identify specific defects in coagulation. Even so, tremendous progress has been made in recent years in the areas of prophylaxis with antifibrinolytics (see earlier) and in the logical treatment of post-CPB coagulopathy. The latter is likely to advance further. Despotis and associates have made tremendous contributions to this area, and one algorithm for post-CPB coagulopathy from their work is illustrated in Figure 50-43 . [269] One recognizes that several of the point-of-care tests on which this algorithm is dependent are not yet in wide-spread use, but with blood and blood product safety and availability becoming even more important issues, the approach outlined by these workers, or some modification thereof, is probably the way of the future.
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