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Platelet Dysfunction as Measured by a Point-of-Care Monitor is an Independent Predictor of High Blood Loss in Cardiac Surgery

Orlov, David MD*; McCluskey, Stuart A. MD, FRCPC, PhD*; Selby, Rita MD, FRCPC; Yip, Paul PhD, FCACB; Pendergrast, Jacob MD, FRCPC; Karkouti, Keyvan MD, FRCPC, MSc*§‖

doi: 10.1213/ANE.0000000000000054
Cardiovascular Anesthesiology: Research Report

BACKGROUND: Excessive bleeding carries a heavy burden of illness in cardiac surgery. Although platelet dysfunction is considered to be an important cause, it is not routinely measured. Our objective was to explore the relationship between platelet dysfunction and blood loss in cardiac surgery.

METHODS: In 100 consenting patients undergoing cardiac surgery requiring cardiopulmonary bypass, platelet function was measured before, during, and after bypass with a point-of-care device that compares platelet counts before and after exposure to an agonist. Clinicians were blinded to the results of testing. Patients whose calculated blood loss was part of the highest quartile for the cohort were classified as having had high blood loss. The independent relationship between platelet function and high blood loss was measured with the aid of multivariable Poisson regression modeling (with a robust error variance) that controlled for patients’ overall risk of high blood loss.

RESULTS: Calculated blood loss was negatively skewed with a median of 798 mL (25th and 75th percentiles of 380 and 1775 mL). Patients whose blood loss exceeded 1770 mL were classified as having had high blood loss, and 25 patients met this criterion. There was 1 death in the high blood loss group unrelated to hemorrhage. After adjusting for bleeding risk, each 10 × 109/L increase in collagen-activated functional platelet count during rewarming and postprotamine, respectively, was associated with a relative risk of 0.89 (95% confidence interval, 0.82–0.97; P = 0.006) and 0.87 (95% confidence interval, 0.78–0.98; P = 0.02) for high blood loss.

CONCLUSIONS: Platelet dysfunction, as measured by a point-of-care method during rewarming and postprotamine, is independently associated with high blood loss in cardiac surgery. Additional studies are needed to determine whether the incorporation of this assay into blood management algorithms might help rationalize blood transfusion therapy, potentially reducing blood loss and improving clinical outcomes.

From the Departments of *Anesthesia and Pain Management, Laboratory Medicine, Clinical Biochemistry, and §the Toronto General Research Institute, Toronto General Hospital, University Health Network, University of Toronto, and Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada.

Accepted for publication October 18, 2013.

Funding: Helena Laboratories (Beaumont, Texas) provided the material for PlateletWorks®. K. Karkouti is funded in part by a merit award from the Department of Anesthesia, University of Toronto.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Keyvan Karkouti, MSc, MD, FRCPC, Department of Anesthesia and Pain Management, Toronto General Hospital, University Health Network, 200 Elizabeth St., Toronto, Ontario, Canada, M5G 2C4. Address e-mail to

Excessive bleeding is a common and serious complication of cardiac surgery with cardiopulmonary bypass (CPB). It occurs in approximately 10% to 20% of patients and consumes 80% of all blood products used in this setting.1 More importantly, it is associated with significant morbidity and mortality.2–7 Rapid diagnosis and treatment of post-CPB bleeding, therefore, is important for avoiding excessive blood loss while optimizing blood product management.

The reason for bleeding after cardiac surgery is often the result of CPB-induced clotting defects. While these defects are often multifactorial, the main causes are depletion of clotting factors and dysfunction of platelets.8–13 Accordingly, correcting these defects often necessitates the transfusion of fresh frozen plasma (FFP) and platelets, respectively. To guide this therapy, physicians often rely on laboratory tests that have long turnaround times, are nonspecific, and cannot detect important defects such as platelet dysfunction. In essence, clinicians must either delay treatment and await the results of these tests or resort to empiric transfusion of blood products based on their clinical judgment in the hope of correcting the coagulopathy. Neither of these strategies is ideal, potentially leading to increased blood loss, increased transfusion rates, or both.10,14 Because of this shortcoming, the use of supplemental point-of-care testing has been recommended in the Society of Thoracic Surgeons/Society of Cardiovascular Anesthesiologists Blood Conservation Guidelines to help rationalize blood product transfusions.1 Although this recommendation is class IIa (in favor of treatment or procedure being useful/effective), it has been assigned a grade of C for level of evidence (based on very limited data). The objective of this prospective, observational study was to explore the relationship of platelet dysfunction, as measured by a point-of-care monitor, with blood loss in cardiac surgery.

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Study Setting and Patient Population

After obtaining Research Ethics Board approval, adult patients (≥18 years) undergoing nonemergent cardiac surgery with CPB at Toronto General Hospital (Toronto, ON, Canada) between July 2011 and December 2012 were screened for inclusion in this prospective, observational study. Patients undergoing specialized procedures (e.g., heart transplantation, complex congenital repairs) or those with congenital hematological disorders (e.g., hemophilia, sickle cell disease) were excluded. Patients who were receiving antiplatelet (aspirin, thienopyridines, Gp IIb/IIIa inhibitors) or anticoagulant (heparin, warfarin) medications were not excluded, but the time course for their perioperative therapy was ascertained in detail. Eligible patients who provided informed written consent were included in the study. Recruitment was stratified to include at least 50% of patients undergoing high-risk surgeries, which included nonelective, redo, or combined aortocoronary bypass and valve surgeries, to obtain a sufficient number of patients with high blood loss. No formal sample size calculations were conducted. Based on previous experience, a sample size of 100 patients was deemed sufficient for exploring the relationships of interest.15

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Clinical Practice

Management of CPB was standardized for all patients as per our institutional practice. All patients received an antifibrinolytic drug prophylactically (tranexamic acid [Cyklokapron®, Pfizer Canada Inc., Kirkland, Canada]), 50 to 100 mg/kg, as an IV bolus with or without a continuous infusion. Anticoagulation for CPB was achieved with heparin to maintain an activated clotting time above 480 seconds. The CPB circuit was primed with 1.8 L Ringer’s lactate solution and 50 mL of 20% mannitol. Albumin (25%) was added to the circuit as needed. Management of CPB included systemic drift to 34°C, α-stat pH management, targeted mean perfusion pressure between 50 and 70 mm Hg, and pump flow rates of 2.0 to 2.4 L/min/m2. Myocardial protection was achieved with intermittent antegrade and, occasionally, retrograde blood cardioplegia. When necessary, deep hypothermic circulatory arrest was achieved by cooling to 25°C to 28°C with or without retrograde cerebral perfusion. During CPB, pericardial blood was salvaged into the cardiotomy suction reservoir and reinfused via the CPB circuit for as long as patients were anticoagulated. After CPB, heparin was neutralized with protamine sulfate (1:1 ratio with initial loading heparin dose) to a target activated clotting time of within 10% of baseline.

Allogeneic red blood cells (RBC) were transfused if the hematocrit decreased below 20% during CPB or below 24% after CPB. A single pool of platelets was transfused in the presence of bleeding and significant thrombocytopenia (platelet count <80 × 109/L) or empirically when platelet dysfunction was suspected clinically (caregivers were blinded to the platelet function results; see below). FFP (10–15 mL/kg) was administered for bleeding associated with an international normalized ratio greater than 1.5. Cryoprecipitate was administered to bleeding patients if their fibrinogen level was <1.0 g/L. Administration of all transfusion products was in keeping with our institutional and standard practice guidelines.1,16 Except for RBC transfusions when needed, no blood products were transfused before the completion of platelet function testing.

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Platelet Function Assay

PlateletWorks® (Helena Laboratories, Beaumont, TX), a point-of-care assay that measures platelet function rapidly (< 7 minutes) on low volumes (1 mL per agonist) of whole blood,17 was used to measure platelet function before, CPB, during CPB (at rearming), and immediately after protamine administration. The assay uses a cell counter and a 2-step technique to calculate platelet aggregation. After exposure to an agonist, activated platelets form aggregates that are no longer counted as individual platelets by the cell counter. Comparison of platelet count without an agonist with the platelet count after exposure to an agonist (collagen and adenosine diphosphate [ADP] were used in this study; arachidonic acid is also available but was not used because it is specific for detection of cyclooxygenase-1 inhibition) allows for calculation of the agonist-specific functional platelet count (nonagonist platelet count–agonist platelet count). Other hematologic results including the hemoglobin (Hb) concentration may be simultaneously obtained from the PlateletWorks assay.

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Hemostatic testing

Routine indwelling arterial catheters were used for blood sampling: (1) before induction of anesthesia (baseline time point), (2) during CPB on rewarming (when temperature reached 36°C), and (3) immediately after protamine administration (postprotamine time point). Standard laboratory tests including Hb, platelet count, international normalized ratio, and activated partial thromboplastin time were performed at our hospital core laboratory at the above time points as per routine practice. For the PlateletWorks assay, 5 mL whole blood was collected at each of the above time points and analyzed within 10 minutes of collection. This entailed adding 1 mL blood to each of the following test tubes: (a) no agonist (EDTA containing 0.024 mL of 7.5% K3EDTA solution), (b) ADP agonist (containing a final concentration of 20 μM citrated ADP after reconstitution), and (c) Collagen agonist (containing 10 μg citrated liquid collagen-equine tendon). Samples were analyzed with the cell counter in accordance with the manufacturer’s instructions. Functional platelet counts with both ADP and collagen agonists were calculated. All samples were analyzed without knowledge of clinical data or patient outcomes. Caregivers were blinded to the platelet function results to ensure that standard-of-care transfusion practice was not modified.

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Dependent Variable

The primary outcome measure was estimated blood loss after heparin reversal to 24 hours after surgery, with the top quartile of the cohort categorized into the high blood loss group. Estimated blood loss was calculated by adding the estimated amount of post-CPB blood loss (from heparin reversal until admission to the intensive care unit [ICU]) to the amount of chest tube (CT) drainage during the first 24 hours after surgery (or until CT removal if this occurred earlier than 24 hours) using the following formula:15

Post-CPB blood loss (L) = (BV × ΔHbOR/HbPost-CPB Aver.) + (RBC units × RBC vol. × RBC Hb/HbPost-CPB Aver.) + (CS vol × CS Hb/HbPost-CPB Aver.) + CT drainage,

where Hb = hemoglobin (g/dL); BV = blood volume (L), calculated using Nadler’s formula;18 ΔHbOR = (Hbpost-CPB − HbICU-arrival); HbPost-CPB Aver. = (Hbpost-CPB + HbICU-arrival)/2; RBC units = number of units of stored RBCs transfused from termination of CPB until arrival to the ICU; RBC vol. = each unit of stored RBCs provided by the Canadian Blood Services is assumed to have a volume of 0.29 L; RBC Hb = stored RBCs are assumed to have a hematocrit of 0.6, which is the average hematocrit of units supplied by the Canadian Blood Services multiplied by 33.3 to convert to Hb; CS vol. = volume of cell-saved blood returned to the patient (L); CS Hb = CS blood is assumed to have a hematocrit of 0.5, which is the average hematocrit of units after processing multiplied by 33.3 to convert to Hb; CT drainage = measured hourly up to 24 hours after ICU admission or until removal if removed within 24 hours (L).

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Independent Variables

Known important patient-related, surgical, and laboratory variables associated with blood loss as well as the predicted probability of excessive blood loss based on an existing, validated prediction rule for large-volume RBC transfusion (Appendix 1) were explored in relation to the dependent variable.3,20 The associations of high blood loss with platelet function measures, as assessed with collagen and ADP agonists, were the principal relationships of interest.

Appendix 1

Appendix 1

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Statistical Analysis

Descriptive statistics were used to summarize study demographics. Continuous data were presented as medians and 25th and 75th percentiles. Categorical variables were presented as frequencies or percentages. The unadjusted relationships between the independent and dependent variables were assessed with t tests or Wilcoxon ranked sum tests for continuous variables and χ2 or Fisher exact tests for categorical variables. Bivariate associations of total platelet count and Hb measured by PlateletWorks with standard laboratory-measured total platelet count and Hb were analyzed with the Pearson correlation coefficient (r) to assess the accuracy of the PlateletWorks system for these 2 measures.

The independent relationship of platelet function measures with blood loss was determined with multivariable Poisson regression modeling with a robust error variance,19 using blood loss (>75th percentile of the sample population classified as high blood loss) as the dependent variable, platelet function as the independent variable, and the risk index for excessive blood loss (as calculated from the preexisting prediction rule shown in Appendix 1) as a covariate to adjust for bleeding risk. The linearity assumption of Poisson regression was assessed by restricted cubic spline function plots of the independent variables against the logarithm of the dependent variable. All analyses were performed with SAS™ version 9.3 (SAS Institute, Cary, NC), and a P <0.05 was used to indicate statistical significance.

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One hundred fourteen eligible patients were approached for the study, 100 of whom agreed to participate. Three patients were subsequently excluded due to missing data that precluded the calculation of blood loss. Blood loss was negatively skewed with a median of 798 mL (25th and 75th percentiles of 380 and 1775 mL) and a mean and standard deviation (SD) of 1454 ± 1820 mL. Patients whose blood loss exceeded 1700 mL were classified as having had high blood loss, and 25 patients met this criterion. There was 1 death in the high blood loss group unrelated to hemorrhage.

Patients with high blood loss differed from those without high blood loss on several baseline characteristics and outcome measures (Table 1). Patients with high blood loss were on average older, had higher baseline creatinine values, had longer CPB durations, more often had surgery with a rate of high blood loss more than the median for the cohort, and overall were at substantially higher risk for large-volume RBC transfusion (as per the risk score outlined in Appendix 1). They also received a larger proportion of blood products (including RBCs, FFP, platelet concentrates, and cryoprecipitate), underwent more postoperative reexplorations, and had longer stays in the ICU and hospital.

Table 1

Table 1

Patients with missing laboratory data were excluded from the relevant analyses (Table 2). Laboratory- and PlateletWorks-derived Hb and total platelet counts obtained at the same time points showed strong positive correlations (r = 0.95, P < 0.0001 and r = 0.91, P < 0.0001, respectively). There was a substantial decrease in platelet function from rewarming to postprotamine (Table 2; P < 0.001), but its magnitude was similar for patients with high and low blood loss (median 28% decrease in collagen-induced functional platelet count in low blood loss versus 33% in high blood loss groups; P = 0.7).

Table 2

Table 2

Collagen-induced functional platelet counts were significantly and inversely related to high blood loss when measured at rewarming and postprotamine time points. The spline function plots of collagen-induced functional platelet count and excessive bleeding risk index against the log of high blood loss were congruent with the linearity assumption of Poisson regression. After adjusting for bleeding risk, each 10 × 109/L increase in functional platelet count during rewarming and postprotamine, respectively, was associated with a relative risk of 0.89 (95% confidence interval [CI], 0.82–0.97; P = 0.006) and 0.87 (95% CI, 0.78–0.98; P = 0.02) for high blood loss. Each unit increase in bleeding risk was associated with a relative risk of 1.42 (95% CI, 1.09 – 1.85; P = 0.01) and 1.5 (95% CI, 1.18 – 1.9; P = 0.001) in the 2 models, respectively.

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In this prospective, exploratory observational study, collagen-induced functional platelet counts at rewarming during CPB and postprotamine were independent predictors of high blood loss. After adjusting for bleeding risk, each 10 × 109/L increase in functional platelet count during rewarming and postprotamine, respectively, was associated with a relative risk of 0.89 (95% CI, 0.82–0.97; P = 0.006) 0.87 (95%CI, 0.78–0.98; P = 0.02) for high blood loss. Since the turnaround time for this point-of-care measure is short, our findings suggest that it may be useful for early identification of patients at risk for high blood loss and for guiding transfusion therapy in bleeding patients.

We found that collagen-induced but not ADP-induced measures of platelet dysfunction were predictive for high blood loss. In the absence of recent use of thienopyridine therapy (none of the study patients used thienopyridines within 5 days of surgery), this finding is not surprising, given collagen’s critical role in facilitating both platelet activation and adhesion to the vascular endothelium via effects on at least 3 different platelet surface receptors.21–23 In fact, receptor polymorphisms in the platelet collagen receptor (glycoprotein Ia/IIa) have been shown to be independent predictors of blood loss after cardiac surgery when added to a multivariable model consisting of clinical variables alone.24 In contrast, ADP is a weaker agonist for platelet activation, exerting its effects primarily on P2Y1 and P2Y12 platelet receptors after its release from dense granules in activated platelets.25 During CPB, the administration of tranexamic acid is thought to attenuate activation of the ADP pathway26 and may have partially preserved the perioperative in vitro response to this agonist during exposure to extracorporeal circulation for all of our study patients. At least 1 other study has also observed the inferiority of the ADP agonist to the collagen agonist for yielding an association with postoperative blood loss after cardiac surgery.27 We also found that the functioning platelet count deteriorates from rewarming to postprotamine. This is not surprising and can be explained by the additional time that blood is exposed to the CPB circuit, resulting in more consumption of platelets, and possibly due to excessive protamine administration.10,28

Of the several platelet function assays currently available, the PlateletWorks system has not been as well studied as some of the others.29 It has, however, been successfully used for monitoring the response to thienopyridines (e.g., clopidogrel) and GpIIb/IIIa inhibitors (e.g., abciximab, tirofiban) in several observational studies.30–35 Consistent with our findings, some studies have found that functional platelet counts measured by PlateletWorks are inversely associated with postoperative blood loss in cardiac surgery, and others have found that incorporating this test into standard-of-care practice results in substantial reduction in blood product administration,27,36 although these findings have not been entirely consistent.37

This study had several limitations that warrant careful interpretation of the results. First, this was a single institution observational study, which precludes determination of causation and renders the results less generalizable to other settings and populations. Second, the sample size was relatively small, and our results may therefore have been unduly influenced by outliers, potentially biasing our findings. It also hindered the identification of thresholds for platelet transfusion and a more thorough analysis of the added predictive value of platelet function monitoring in the multivariable modeling via net reclassification and integrated discrimination improvement values, for example.38,39 Moreover, it precluded us from analyzing the effects of platelet and plasma transfusion on the observed relationships. Third, given that measuring perioperative blood loss is inherently difficult,40,41 we relied on a calculated measure of blood loss that required the rigorous collection of 9 variables. Fourth, some patients had to be excluded from some of the analyses due to missing laboratory tests. Finally, we did not measure specific coagulation factor levels and therefore are unable to draw conclusions regarding the interaction between platelet plug formation, secondary hemostasis, and fibrinolysis in the context of high blood loss.

In summary, this prospective observational study found that collagen-induced functional platelet counts on rewarming during CPB and postprotamine were independently associated with high blood loss after cardiac surgery. These findings need to be confirmed in larger multicenter studies. If valid and reproducible, the incorporation of this assay into blood management algorithms might serve to rationalize transfusions of blood products while reducing blood loss and inappropriate transfusions in cardiac surgery. All these would be important achievements, because they would reduce the burden of excessive blood loss in cardiac surgery, improve clinical outcomes, and provide cost containment in the context of a diminishing supply of blood products.

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Name: David Orlov, MD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: David Orlov has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Stuart McCluskey, MD, FRCPC, PhD.

Contribution: This author helped to design the study, analyze the data, and write the manuscript.

Attestation: Stuart McCluskey has seen the original study data, reviewed the analyses of the data, and approved the final manuscript.

Name: Rita Selby, MD, FRCPC.

Contribution: This author helped to design and conduct the study and write the manuscript.

Attestation: Rita Selby has seen the original study data, reviewed the analyses of the data, and approved the final manuscript.

Name: Paul Yip, PhD, FCACB.

Contribution: This author helped to design and conduct the study and write the manuscript.

Attestation: Paul Yip has seen the original study data, reviewed the analyses of the data, and approved the final manuscript.

Name: Jacob Pendergrast, MD, FRCPC.

Contribution: This author helped to design and conduct the study and write the manuscript.

Attestation: Jacob Pendergrast has seen the original study data, reviewed the analyses of the data, and approved the final manuscript.

Name: Keyvan Karkouti, MD, FRCPC, MSc.

Contribution: This author helped to design and conduct the study, analyze the data, and write the manuscript.

Attestation: Keyvan Karkouti has seen the original study data, reviewed the analyses of the data, approved the final manuscript, and is the author responsible for archiving study files.

This manuscript was handled by: Jerrold H. Levy, MD, FAHA, FCCM.

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