Ann Thorac Surg 2000;70:S20-S32
© 2000 The Society of Thoracic Surgeons
Management approaches to platelet-related microvascular bleeding in cardiothoracic surgery
George J. Despotis, MDa,1,
Lawrence T. Goodnough, MDa,b
a Departments of Department of Anesthesiology, Pathology, Washington University School of Medicine, St. Louis, Missouri, USA
b Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
Address reprint requests to Dr Despotis, Department of Anesthesiology, Box 8054, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 63110
e-mail: despotig{at}notes.wustl.edu
Presented at the "Managing the Patient Receiving Platelet Inhibitors in Cardiac Surgery" Roundtable Discussion, San Antonio, TX, Jan 22–23, 1999.
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Abstract
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Patients undergoing cardiac surgery with cardiopulmonary bypass are at increased risk for microvascular bleeding that requires perioperative transfusion of blood components. Platelet-related defects have been shown to be the most important hemostatic abnormality in this setting. The exact association between preoperative use of potent platelet inhibitors and either bleeding or transfusion in patients undergoing cardiac surgical procedures is currently being defined. Laboratory evaluation of platelets and coagulation factors can facilitate the optimal administration of pharmacologic and transfusion-based therapy. However, their turnaround time makes laboratory-based methods impractical for concurrent management of surgical patients, which has led many investigators to study the role of point-of-care coagulation tests in this setting. Use of point-of-care tests of hemostatic function can optimize the management of excessive bleeding and reduce transfusion. Accordingly, point-of-care tests that assess platelet function may also identify patients at risk for acquired, platelet-related bleeding. The ability to reduce the unnecessary use of blood products and to decrease operative time or reexploration rates has important consequences for blood inventory, blood costs, and overall health care costs.
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Introduction
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Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk for microvascular bleeding (MVB). The frequency of excessive bleeding with CPB can vary based on the definition used. If it is defined as greater than 2 L blood loss within the first 24 postoperative hours, 5% to 7% of patients will have excessive bleeding [1]. In two large series, 3.6% [2] to 4.2% [3] had excessive bleeding, and were defined as those patients who required reexploration.
Excessive MVB can result in reexploration and prolonged hospitalization [3, 4]. Patients may require exploration either to correct a potential surgical source of excessive bleeding or to evacuate a hemodynamically compromising accumulation of blood (eg, pericardial tamponade). When patients undergo reoperation for excessive bleeding, more than 50% of patients bleed secondary to various acquired hemostatic defects [5, 6], whereas the remaining patients exhibit surgical sources for bleeding [2, 3]. Two large studies have demonstrated that reexploration can be associated with a variety of negative outcomes such as increased mortality, renal failure, sepsis, atrial arrhythmias, prolonged requirement for mechanical ventilatory support, and longer length of stay [2, 3]. Transfusion of allogeneic blood or blood components is potentially associated with a number of adverse events, such as blood-borne disease transmission, increased incidence of wound infections, hemolytic and nonhemolytic transfusion reactions with increased mortality [3, 4, 7–9], increased operative time [10], as well as increased cost. Based on a national annual frequency of 500,000 adult cardiac surgical procedures per year, an average cost of $250 per unit of blood, and an average transfusion rate of 4 units per patient (3.9 ± 5.9 U) [1], costs related to red cell and non-red cell transfusions approximate $500 million annually.
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Risk factors for microvascular bleeding
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Patients at risk for excessive blood loss who may benefit from various nonpharmacologic or pharmacologic blood conservation techniques (Table 1) can be identified. The risk of development of excessive, nonsurgical bleeding is influenced by the type of procedure (Fig 1) [10, 11] and the duration of CPB [1–3, 12]. Several other factors may also be associated with excessive bleeding and transfusion such as female gender, lower heparin doses, lower core body temperature, older age, a greater volume of salvaged red cells reinfused intraoperatively, and abnormal intraoperative laboratory coagulation test results [1]. In addition, the following perioperative risk factors for exploration have been identified in two large series: increasing patient age, preoperative renal insufficiency, noncoronary operation, and prolonged CPB time [2, 3].
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Table 1. A Summary of Current and Emerging Blood Conservation Strategies to Minimize Microvascular Bleeding or Transfusion After Cardiac Surgery
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Fig 1. Varying incidence of microvascular bleeding (MVB) corresponding to number of procedures or operative history. MVB defined as excessive pericardial bleeding after discontinuation of CPB and administration of protamine without an identifiable surgical source that requires administration of hemostatic transfusion therapy (ie, platelets, plasma). Single procedure = one operative procedure; combined = one or more operative procedures (ie, coronary revascularization and valve repair/replacement); primary operation = first cardiac surgical procedure; reoperation = repeat cardiac surgical procedure. Actual incidence of MVB is denoted by the fractions within the parentheses, whereas fractions within the brackets represent the calculated probability from logistic regression. (Reprinted with permission from Despotis GJ, Santuro SA, Spitznagel E, et al. Prospective evaluation and clinical utility of on-site monitoring of coagulation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1994;107:271–9.)
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Pharmacologic therapies may also increase the risk of bleeding. Thrombolytic therapy (eg, recombinant tissue plasminogen activator [tPA], streptokinase) within 48 hours of surgery was not associated with the need for exploration in these two studies [2, 3]. However, the development and use of inhibitors of thrombin (eg, hirudin, argatroban) and factor Xa (eg, low-molecular-weight heparin [LMWH]) as well as of platelets may be associated with increased perioperative bleeding. These new platelet inhibitors either bind to the platelet glycoprotein (GP) IIb/IIIa receptor complex (ie, fibrinogen receptor) on the platelet surface (eg, abciximab, eptifibatide) or inhibit adenosine diphoshate (ADP)-mediated platelet activation (eg, ticlopidine, clopidogrel). Either process may lead to increased bleeding depending on the timing of administration or reversibility of these agents. Accordingly, some reports have indicated that use of abciximab may increase transfusion requirements [13–17], especially if this agent is administered within 12 hours before surgery [15]. However, only one analysis actually assessed the impact of this agent on perioperative blood loss. Lincoff and associates found that patients requiring surgical intervention who were randomized to receive abciximab (n = 28) had blood loss similar to patients receiving placebo (n = 40) in the Evaluation of PTCA to Improve Long-term Outcome by c7E3 GP IIb/IIIa Receptor Blockage (EPILOG) and Evaluation of Platelet IIa/IIIb Inhibition for Stenting (EPISTENT) studies [18]. Similar blood loss and transfusion requirements were also observed in another study, the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II) trial [19], which compared patients requiring urgent surgery who received eptifibatide with patients who received placebo. Findings from another study indicate that new antiplatelet agents may actually preserve hemostasis if they are short-acting or readily reversible [20].
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Pathophysiology of hemostatic abnormalities with extracorporeal circulation
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Excessive bleeding may be related to one or more of several acquired hemostatic defects (Table 2) [5, 6]. Although preexisting hemostatic abnormalities occasionally cause excessive perioperative bleeding [6], more often, exposure of blood to the extracorporeal circuit leads to impairment of the hemostatic system and excessive bleeding [10, 12]. Significant hemodilution related to the administration of crystalloid or colloid solution (eg, CPB prime or cardioplegia), as well as to loss of platelets or coagulation factors via excessive use of cell-salvage systems [1], may in part account for the decline of coagulation factors and platelets that has been demonstrated with CPB [10, 21].
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Table 2. A Summary of Hemostatic Abnormalities Associated With Cardiac Surgery Involving Extracorporeal Circulation
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Additionally, activation results from stimulation of both intrinsic [22] and extrinsic [23, 24] pathways when blood interfaces with extracorporeal and pericardial surfaces, as well as from the negative pressure of cardiotomy suction. This activation results in generation of thrombin [23, 25–28] and excessive fibrinolysis [29–35], which can lead to consumption of platelets and labile coagulation factors [26, 27, 36] even in the presence of standard high-dose heparin-induced anticoagulation. Elastase release from polymorphonuclear leukocytes [37, 38], tumor necrosis factor [39, 40], complement activation [41–47], or white cell-platelet interactions [48–50] may impair hemostasis.
Although therapeutic heparin during bypass preserves the hemostatic system [36, 51], residual heparin after protamine reversal can inhibit coagulation (ie, predominantly Xa and IIa) [52] and platelet function [53, 54]. Heparin rebound can occur postoperatively and is secondary to release of heparin from one of several heparin-binding sites (eg, endothelial cells, histidine-rich glycoprotein, etc) and may be precipitated by transfusion of plasma. Similarly, excess protamine can inhibit coagulation [55] and affect platelet function [56–58]. In fact, several studies have demonstrated improved bleeding or transfusion outcomes when protamine doses were reduced by approximately 50% or greater and when the ratio of protamine to total heparin was reduced below one [59–62]. Finally, systemic hypothermia used for myocardial and central nervous system protection may also increase perioperative blood loss [1], possibly related to its effect on platelet function [12, 63, 64] or inhibition of temperature-dependent enzymatic steps within the coagulation cascade [5, 33, 65].
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Specific defects in the hemostatic system
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Excluding those with incomplete surgical hemostasis [3], patients bleed excessively because of various acquired hemostatic defects, such as reductions in platelet number, size, and mass; acquired platelet dysfunction and reduction in plasma clotting factors; increased fibrinolytic activity; and inadequate heparin neutralization or excessive protamine (see Table 1). Platelet-related abnormalities are now considered to be the most important defect in hemostasis in the early postoperative period after the use of extracorporeal circulation [6, 12, 66–69]. Adherence of platelets to the CPB surfaces and platelet activation/degranulation/desensitization, as well as the effects of heparin and/or hypothermia, may induce platelet dysfunction. This explains why routine coagulation tests (prothrombin time [PT], activated partial thromboplastin time [aPTT], and platelet count) have not been consistent in their ability to identify patients with excessive blood loss after cardiac surgery [70–75]. The use of new platelet inhibitors for acute coronary syndromes may be associated with hemorrhagic complications in patients who subsequently undergo cardiac surgical procedures [13–17]. These agents may be beneficial, however, if they reduce the incidence of urgent revascularization procedures and myocardial infarction [16, 17], or if they are short-acting and preserve platelets during CPB [20].
Plasma coagulation factors have been observed to decrease during and after CPB [10, 21, 29, 74, 76–78], with factors V and VIII being reduced to the greatest extent [10, 21, 74, 77, 79, 80]. During CPB, von Willebrand’s factor levels generally decrease, whereas after CPB, the plasma concentration may increase, characteristic of the acute-phase reactant nature of this molecule [6]. A recent study indicates that reductions in factor XIII during cardiac surgery may be more important than once thought owing to an inverse relationship between blood loss and factor XIII levels [76]. Decreases in fibrinogen levels during CPB generally remain within the normal range during CPB [10, 74, 79, 81, 82]. However, they can occasionally decrease substantially [36, 80] secondary to either hemodilution [6], disseminated intravascular coagulation, or excessive fibrinolysis. Increased fibrinolytic activity accompanying CPB [29, 66] may be due either to increased activation of plasminogen via tPA or to a decreased level of plasmin inhibitors such as plasminogin activator inhibitor (PAI) [83], related in part to hemodilution. Excessive fibrinolysis may occur in certain patients [84], which can lead to both fibrinogen depletion and elevated fibrinogen/fibrin split products (FSP) that may interfere with platelet function [12, 53]. Finally, excessive mediastinal fibrinolytic activity may result in excessive bleeding [85]. This is supported by two studies that have demonstrated reduced chest-tube drainage when aprotinin has been topically applied to the heart, mediastinum, and pericardium [86, 87].
Limitations of laboratory-based tests
Blood component administration in patients with excessive bleeding after CPB and heparin neutralization is generally empiric. Thus, transfusion of red blood cells (RBCs), platelets, and fresh-frozen plasma (FFP) to cardiac surgical patients requiring CPB varies considerably among institutions, in part due to prophylactic administration of FFP and platelets [88–91], despite evidence that this practice is unwarranted [81, 92]. This variability has been attributed to the empiric use of blood components such as FFP and platelets, which are administered in an attempt to distinguish between excessive MVB due either to hemostatic system impairment or to surgical bleeding [93, 94]. Neither approach appears to be an appropriate patient management strategy. Laboratory coagulation tests can provide a rational basis for diagnosis and treatment of MVB after cardiac surgery. Although a panel of laboratory-based screening tests may be useful in the differential diagnosis of intraoperative disorders of hemostasis [95], the clinical utility of laboratory tests is often limited by long turnaround time [96]. Waiting for laboratory coagulation results can prolong operative time and potentially increase blood loss. This has led many investigators to study the role of point-of-care coagulation tests in this setting as a means of optimizing management of the bleeding patient.
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Point-of-care test systems
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Coagulation- and anticoagulation-related problems
Some studies have shown that PT and aPTT coagulation measurements can identify patients with excessive bleeding [97–99]; however, other studies have not supported these findings [70–74, 100, 101]. The inability of these tests to identify patients at risk for increased bleeding may be related to the substantial variability that can be observed between various reagents and test methods [75]. Nevertheless, whole blood PT and aPTT tests can be used to identify patients with bleeding related to factor deficiency when results are directly compared with coagulation factor levels (ie, r2 approximately 0.8) [102].
Persistent levels of circulating heparin caused by inadequate neutralization [103] or heparin rebound [104–108] can contribute to excessive post-CPB bleeding. The empiric administration of additional doses of protamine may result in higher perioperative blood losses [60, 62, 109–111]. Therefore, patient-specific, point-of-care methods that are sensitive to lower circulating heparin levels can facilitate assessment of unneutralized heparin or heparin rebound. Activated coagulation time (ACT) measurements may be misleading because values are insensitive to lower heparin concentrations (ie, < 0.6 U/mL) [111] and can be prolonged by several other factors (eg, platelet count and function, coagulation factor levels, etc) [112]. Point-of-care (POC) tests (eg, thromboelastogram [TEG], thrombolytic assesment system [TAS], simple RED test) may also identify patients with significant bleeding related to excessive fibrinolysis that may benefit from antifibrinolytic agents. This approach is supported by the successful use of aprotinin to minimize streptokinase-related bleeding [113] and excessive fibrinolysis during the (an-hepatic) stage of liver transplantation [114] and cardiac surgery [115]. Tests that may be helpful in identifying patients with coagulation factor depletion, unneutralized heparin/heparin rebound, or excessive fibrinolysis are summarized in Table 3.
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Table 3. A Summary of Point-of-Care Tests/Instruments That Can Be Used to Assess Nonplatelet Hemostatic Abnormalities Associated With Cardiac Surgery
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Platelet-related abnormalities
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Platelet concentration
Platelet count [73] has not been shown to identify patients at risk for excessive bleeding [70–74, 100, 101]. Although a platelet count of less than 100,000/µL has been suggested [116] and used [8, 10, 117] as a trigger for platelet transfusion, the most appropriate platelet concentration threshold for platelet transfusion cannot be defined. The minimum concentration for normal hemostasis can therefore vary from 50,000 to 200,000/µL, depending on the functional state of the circulating platelets. Nevertheless, one can calculate the normal circulating platelet pool by using the platelet concentration, blood volume, and an estimate for splenic stores (eg, 200,000/µL x 5 L = 10 x 1011 x 120% = 12 x 1011). The normal content of allogeneic platelets (6 concentrates or 1 apheresis unit) contains approximately 4 x 1011 platelets and generally increases the count by 30,000 to 60,000/µL.
Smaller, compact, automated instruments that provide accurate, timely CBC results using whole-blood specimens can potentially be used as POC tests to measure platelet number. These include the following: Coulter T540, MD 16, and AcT8 (Coulter Electronics, Hialeah, FL); Cell-Dyne 1400 and 1700 (Abbott, Abbott Park, IL); K-800, K-1000, or SF-3000 (Sysmix Corp, Long Grove, IL); QBC (Becton Dickenson, Sparks, MD); 9100 series (Biochem Immunosystems Inc, Allentown, PA); and the ICHOR (Array Medical, West Ridgewater, NJ) [118]. The T540 and MD 16 Coulter instruments, which provide precise and accurate cell counts and hemoglobin values [102, 119] have been incorporated into treatment algorithms [10, 110].
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Platelet function
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Several laboratory-based platelet-function assays (eg, aggregation, glass-bead retention test, activation/receptor expression via flow cytometry, etc) are often used to identify specific abnormalities of platelet function initially identified by abnormal bleeding time. Platelet activation can also be assessed using plasma markers of platelet release [36, 120]. Although several studies have demonstrated a functional abnormality using aggregometry [29, 68, 78, 120–126], these findings have not been universal [127]. Some investigations have demonstrated a relationship between excessive post-CPB bleeding and impaired platelet aggregation [29, 124] or activation [123]. Despite their potential usefulness, laboratory-based platelet function studies require considerable technical expertise, are expensive, and involve long turnaround times in both performance and interpretation, all of which limits their clinical utility.
The bleeding time, most commonly performed with the Ivy method, measures the interaction between platelets and the vessel wall. Although it is the most commonly used screening test to evaluate in vivo platelet function [128], results are unpredictably elevated when platelet counts are less than 100,000/µL and can be influenced by many diseases, physiologic factors, test conditions, and therapeutic actions, which may or may not reflect abnormalities in platelet function [129]. Several studies have measured and documented prolonged bleeding time results after cardiac surgery [12, 73, 77, 78, 122, 127, 130]. In a recent review of the literature, bleeding time measurements were not shown to predict excessive blood loss or bleeding complications [129]. Two recent studies, however, indicate that bleeding time values performed in the postoperative interval may be useful in predicting postsurgical blood loss [12, 73].
Several tests have been developed that assess the response of platelets to various platelet agonists within whole blood. Two of these POC test systems (Ultegra, Chrono-log aggregometer) evaluate platelet function in a similar fashion to platelet-rich plasma (PRP)-based turbidometric aggregometry and have recently been investigated. The Rapid Platelet Function Test (RPFA; Accumetrics, San Diego, CA) is based on the ability of platelets in whole blood to rapidly agglutinate fibrinogen-coated beads when stimulated with an agonist peptide [131]. Because measurements obtained with this instrument were shown to correlate with increased GP IIb/IIIa receptor blockade using c7E3 Fab and platelet aggregometry [132], it may be useful in identifying patients with qualitative platelet abnormalities. Measurements from another whole-blood test (modified whole-blood aggregometer; Chrono-log Corp., Havertown, PA) have recently been shown to correspond to changes in turbidometric measurements during GP IIb/IIIa receptor blockade with abciximab [133]. However, clinical evaluations of these instruments in cardiac surgical patients are needed.
Three additional tests that utilize platelet agonists to assess platelet function include the PFA-100, ICHOR, and hemoSTATUS test systems. A point-of-care method, the in vitro bleeding or PFA-100 tests, was developed to overcome the limitations of the standard bleeding time [134]. The dual-channel Thrombostat 4000 (VDG-von der Goltz, Seeon, Germany) instrument allows automated measurement of in vitro bleeding time using either citrate-anticoagulated platelet-rich plasma or whole blood [135]. A significant (p = 0.04) but weak (r2 = 0.07) relationship between in vitro bleeding volume measured at the end of surgery and blood loss in the first 24 postoperative hours was demonstrated in 54 patients undergoing cardiac surgery [135]. In contrast, the ICHOR system (Array Medical, West Ridgewater, NJ), which has been recently validated for measurement of CBC parameters [118], facilitates assessment of platelet function by comparing platelet counts before and after in vitro addition of platelet agonists.
The hemoSTATUS (Medtronic Blood Management, Parker, CO) assay evaluates the effects of platelet-activating factor (PAF) on acceleration of coagulation using the kaolin-activated ACT [73, 98, 136]. Although a strong correlation between clot ratio values and postoperative blood loss was observed in one study [73], a weaker relationship was observed in another study [98]. Significant increases in clot ratio values after administration of desmopressin or platelets, however, indicates that these values reflect platelet function [73]. The notion that this POC test can detect platelet dysfunction is supported by two additional studies that demonstrated a dose-dependent reduction in clot ratios by abciximab (c7E3) [137] and parallel changes in platelet function during CPB when compared with flow cytometry [138].
Three methods that assess the viscoelastic properties of blood include the thromboelastogram (TEG), the Sonoclot, and the clot retractometer. The TEG was shown to be a significantly better predictor of postoperative hemorrhage and need for transfusion than were either ACT or routine coagulation profile in two studies [100, 139]. However, others have failed to confirm a definitive relationship between TEG parameters and either intraoperative [97] or postoperative bleeding [140]. Integration of multiple celite-activated TEG measurements may provide a more accurate estimate of bleeding risk [141]. The heparinase-modified TEG assay enables the test to be used in clinical scenarios involving systemic heparinization [142], whereas addition of 
-amino caproic acid to the specimen may enhance the ability of the TEG to identify patients who have excessive post-CPB fibrinolysis [114]. Although both platelet count and fibrinogen concentration were significantly correlated with TEG maximum amplitude (MA) values using a multivariate statistical model [143], the nonspecific nature of the MA does not support its use to detect platelet dysfunction until refinements in the test system are made. In addition, use of tissue factor may improve the precision or reproducibility of TEG measurements, reduce the time required for obtaining a trace, and enhance sensitivity of this assay in detecting specific platelet defects [144].
Sonoclot measurements (eg, R2 or R3 slope), which reflect the viscokinetic changes of blood, have been shown to be related to changes in platelet count and activity [145]. As with the TEG, however, decreases in coagulation factors and the presence of heparin will affect the Sonoclot signature. In a study involving 69 cardiac surgical patients, excessive postoperative hemorrhage occurred in 25 patients whose laboratory coagulation test results were normal, yet 84% of them had abnormal Sonoclot impedance test results [145]. Tuman and associates also demonstrated that Sonoclot parameters could identify 9 patients with excessive bleeding [139]. Although both the Sonoclot and the TEG facilitate evaluation of overall hemostatic function, addition of specific agents (eg, heparinase, tartrate-resistant [leukocyte] acid phosphatase [TRAP], GP IIa/IIIb blockers, and fibrinogen) should help enhance their ability to assess individual components of the hemostatic system.
The clot retractometer (Hemodyne) [146] measures the mechanical force generated by platelets within a clot. Therefore, this POC method can detect qualitative platelet abnormalities via assessment of clot retraction [147, 148]. Platelet force development uses thrombin-mediated platelet activation and can be affected by platelet concentration and function. In a recent study involving a series of 8 patients, the percentage recovery of platelet force development was found to be inversely related to postoperative chest-tube drainage (r = -0.71, p = 0.048) [149].
Three additional techniques, which are summarized under the "Miscellaneous" category in Table 4, include the pressure normalization (ie, clot signature analyzer [CSA] test), glass-bead retention, and flow cytometry. Hemostatometry utilizes native blood obtained from routine venipuncture to assess platelet response to shear forces within 20 minutes by measuring the normalization of pressure within a tubular system. Because this method has been shown to identify patients at risk for excessive blood loss after cardiac surgery [150] and patients with heparin-related bleeding [54], a POC modification of this system may be useful. Finally, two other techniques that may be useful in the identification of platelet abnormalities involve the assessment of platelet activation using POC flow cytometry or glass-bead platelet retention [151, 152].
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Table 4. A Summary of Point-of-Care Tests/Instruments That Can Be Used to Assess Platelet-Related Abnormalities Associated With Cardiac Surgery
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Use of POC tests to optimize management
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POC tests may help physicians establish more appropriate management of excessive bleeding, first, by targeting blood-component therapy according to identified abnormalities in the coagulation system. Second, rapid test results may identify patients who could benefit from pharmacologic interventions. Third, identification of patients who have a surgical source of bleeding can be expedited if coagulation tests reveal relatively normal results in the setting of excessive bleeding. An ideal POC test system should provide real-time, accurate, and reproducible results. Additionally, it must be user-friendly, compact, and inexpensive; it should require minimal blood specimen volumes; and it should allow for easy or automatic performance of quality control. Finally, such a system should automatically record data so that review of written records can be performed to verify both assay and quality control results along with corresponding normal range values. The interface between laboratory medicine and other clinical services is important. Good working relationships will facilitate tracking of patient and quality control results, billing or cost accounting needs, as well as compliance with regulatory requirements (ie, Clinical Laboratory Improvement [CLIA], College of American Pathologists [CAP] guidelines).
Another critical requirement is to couple POC test results with transfusion algorithms. A step-wise approach based on laboratory coagulation results (PT, aPTT, platelet count, and possibly fibrinogen or FSP) for intraoperative treatment of the actively bleeding cardiac surgical patient has been suggested by Traber and Jobes [152]. Similarly, Horrow recommended a strategy for diagnosis and treatment of postoperative bleeding using PT/aPTT, FSP, fibrinogen, platelet count, and bleeding time values [153]. Although these approaches have been suggested, their clinical usefulness has not been formally evaluated in randomized, prospective, controlled trials.
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Use of algorithms with POC tests
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Several studies have demonstrated that use of POC and laboratory-based coagulation results (ie, platelet count, PT, aPTT, and fibrinogen) can result in reduced transfusion requirements, shorter operation times, and reduced blood loss. Recently, a prospective, randomized trial comparing empiric treatment of microvascular bleeding in cardiac surgical patients with therapy administered according to a transfusion algorithm linked to a rapid, POC whole-blood PT, aPTT, and platelet results was reported [10]. The transfusion algorithm was based on previously published guidelines for transfusion based on coagulation assays [116, 154–156]. The algorithm-treated patients (n = 30) received fewer blood products (Fig 2), had shorter operative times, and had less blood loss after treatment of excessive MVB when compared with standard, empiric therapy (n = 36) [10]. In this trial, reduced transfusion requirements and blood loss may have occurred as a consequence of prompt, optimal management of bleeding, identification of patients with a surgical source of bleeding, or a change in the transfusion trigger [157]. These findings indicate that physician transfusion behavior can be altered significantly when a transfusion algorithm is coupled with on-site coagulation data.
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Fig 2. Blood product utilization between standard therapy versus algorithm therapy cohorts during the intraoperative (INTRAOP) and postoperative (POSTOP = first 24 hours) intervals. T-bars represent standard deviation. CRYO = cryoprecipitate units; FFP = fresh-frozen plasma; RBC = red blood cells; PLT = platelet concentrates. (Reprinted with permission from Despotis GJ, Santoro SA, Spitznagel E, et al. Prospective evaluation and clinical utility of on-site monitoring of coagulation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1994;107:271–9 [10].)
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The usefulness of preset criteria for transfusion was confirmed in two other recent studies, which demonstrated that preset transfusion triggers, based on either laboratory or POC methods, can dramatically affect transfusion requirements of patients undergoing cardiac surgery [8, 117]. The first study compared transfusion rates between 314 consecutive patients managed with preset transfusion criteria with a retrospective group of 947 consecutive patients [8]. A significant decrease in the percentage of patients receiving red cells (26% vs 41%) and plasma (13% vs 24%) was observed in the treatment versus the control patients. In addition, the percentage of patients not receiving allogeneic blood products was significantly greater in the treatment group (69%) compared with historical controls (48%). Other algorithms that consists of laboratory-based platelet counts fibrinogen levels and TEG-based measurements have been developed and used [159]. Both retrospective [158] and prospective [159] analyses revealed that using this approach can reduce transfusion requirements.
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Pharmacologic interventions to manage platelet-related bleeding
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Desmopressin is an arginine vasopressin analogue (antidiuretic hormone [ADH]) that results in shortened bleeding-time results [160] most likely owing to a marked increase in plasma levels of large-molecular weight multimers of von Willebrand’s factor [161] that are released by endothelial cells in response to secretion of PAF by monocytes [162]. In an early randomized, prospective, double-blind study, desmopressin (0.3 µg/kg intravenous infusion) administered immediately after protamine significantly reduced mean intra- and early postoperative blood loss, without any untoward effects [163]. In several subsequent studies, however, a consistent beneficial effect of prophylactic administration of desmopressin could not be shown, as positive studies [164–169] were slightly outnumbered by negative studies [170–175].
More recently, studies have revealed that certain patient subsets may benefit from desmopressin, including those requiring prolonged use of cardiopulmonary bypass [163], those with excessive postoperative bleeding (ie, 1,180 mL/24 h) [176], those on platelet-inhibiting drugs [164, 166, 167, 177], or those at high risk for excessive bleeding as identified by tests of hemostatic function [169, 178, 179]. The first study, by Czer and associates, demonstrated that desmopressin is beneficial when administered to patients with excessive bleeding and prolonged bleeding times [169].
Mongan and Hosking [178] studied the use of TEG for risk stratification of patients when evaluating post-CPB coagulation status. Hematocrit (Hct), platelet counts, PT, aPTT, and fibrinogen measurements were obtained in addition to TEG measurements after neutralization of heparin and discontinuation of bypass. Patients were also randomly assigned to receive either normal saline (placebo) or 0.3 µg/kg of desmopression. A post hoc analysis divided the patients into normal or abnormal TEG groups based on TEG MA measurements. The mediastinal chest tube drainage in the placebo-treated, abnormal MA (< 50 mm) patients was substantially greater compared with normal MA (> 50 mm) patients, indicating that TEG could identify patients at risk for excessive bleeding. Of interest, the blood loss was similar in both desmopressin-treated patients with abnormal TEG values and placebo-treated patients who had normal TEG values. These findings indicate that desmopressin can improve hemostasis in patients who have abnormal TEG and who are at risk for increased blood loss. Desmopressin also seemed to be effective in reducing blood loss and blood component administration in the early postoperative period in patients at risk for increased blood loss (TEG/UMA < 50) [178].
These findings were confirmed in another recent trial that used the hemoSTATUS method. Enrolled in this prospective, double-blind, placebo-controlled trial were 203 patients scheduled for elective cardiac surgical procedures [179]. After exclusion of 30 patients who required intraoperative management of microvascular bleeding with hemostatic blood products and 72 patients with normal clot ratio values, 101 patients with abnormal clot ratio values (ie, % maximal < 60 in channel 5) after administration of protamine were randomly assigned to either placebo (n = 51) or desmopressin (n = 50) treatment arms. Desmopressin-treated patients had a 50% reduction in red cells (1.1 vs 2.2 U), 95% reduction in platelets (0.1 vs 1.9 U), and 87% reduction in FFP (0.1 vs 0.8 U) transfused with an overall 69% reduction in total donor exposures (1.6 vs 5.2 U) compared with placebo patients. When compared with placebo-treated patients, patients who received desmopressin also had a 39% (182 vs 297 mL), 42% (299 vs 513 mL), and 39% (624 vs 1,028 mL) reduction in blood loss in the first 4, 8, and 24 postoperative hours, respectively [179]. These findings indicate that POC platelet function test systems may be useful in the identification of patients at risk for excessive bleeding who may benefit from administration of pharmacologic agents (eg, desmopressin) or in directing administration of hemostatic blood products.
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Conclusion
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Management of microvascular bleeding after CPB represents a unique opportunity. Real-time coagulation results enable physicians to rapidly diagnose bleeding abnormalities and, therefore, administer specific hemostatic therapy promptly. Recent data indicate that prompt availability of coagulation results from an on-site laboratory system and use of transfusion algorithms reduce blood product use, operative time, and postoperative blood loss. Rapid acquisition of coagulation data can also allow physicians to better differentiate between microvascular bleeding and surgical bleeding.
In addition, POC platelet function tests can facilitate identification of patients at risk for platelet-related bleeding who may benefit from pharmacologic agents. Although the association between preoperative use of potent platelet inhibitors and perioperative blood loss is currently being evaluated, POC tests that measure platelet function should be helpful in identifying patients who require transfusion or pharmacologic therapy. With new technological developments, an optimal approach would involve utilization of several new methods that can identify patients at risk for excessive blood loss and facilitate appropriate treatment by identifying specific hemostatic defects in a timely fashion (Fig 3). The ability to reduce the unnecessary use of blood products in this setting and to decrease operation time along with exploration rates has important implications for emerging issues in blood inventory and health care costs in an increasingly managed health care environment. [180]
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Fig 3. Treatment algorithm for patients with excessive post-CPB microvascular bleeding (MVB). [TT/HNTT = whole blood thrombin time/heparin neutralized thrombin time test (Hemochron instrument); heparinase ACT = heparinase kaolin-activated clotting time test (ACT instrument); heparinase aPTT = heparinase activated partial thromboplastin time test (Coagucheck Plus); WB HC = whole blood heparin concentration cartridge (Hepcon instrument); d-dimers = whole blood d-dimer assay (SimpleRED test); MA = maximum amplitude (thromboelastograph); MA/A60 ratio = maximum amplitude/amplitude at 60 minutes (thromboelastograph); CR = clot ratio values (hemoSTATUS cartridge, Hepcon instrument); PF = platelet force measurements (Hemodyne Instrument); R2/R3 = R2 and R3 slope values (Sonoclot instrument); WB FIB = whole blood fibrinogen test (Hemochron instrument); platelets = platelet transfusion (6 units of random donor or apheresis unit equivalent); DDAVP = desmopressin acetate; antifibrinolytic Rx = antifibrinolytic therapy (eg, -amino caproic acid, tranexamic acid, aprotinin); FFP = plasma therapy (2 units of fresh frozen plasma), [+] MVB = continued microvascular bleeding; PT:aPTT = prothrombin time and activated partial thromboplastin time control values (values/mean values from a normal reference population); PLAT Count = platelet count (1,000/µL).] (Reprinted with permission from Despotis GJ, Levine V, Saleem R, Joist JH, Spitznagel E. DDAVP reduces blood loss and transfusion in cardiac surgical patients with impaired platelet function identified using a point-of-care test: a double-blind, placebo controlled trial. Lancet 1999;354:106–10 [179].)
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Footnotes
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1 Doctor George Despotis is a medical consultant to Eli Lilly and Company, Indianapolis, IN. 
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Abstract
Introduction
