Blood product administration continues to be a leading health care expense in surgical patients.1–3 In addition, the deleterious effects of excessive blood transfusions are being reported with increasing frequency.4–7 For these reasons, there is an expanding focus on blood conservation in most surgical subspecialties.8,9
Achieving target levels of specific factors in the coagulation cascade represents an emerging concept aimed at avoiding excess transfusion. One particular coagulation factor of interest is factor I (fibrinogen). Normal plasma fibrinogen values range between 200 and 450 mg/dL, and studies have shown that a reduction of fibrinogen occurs first in major surgical bleeding.10–12 In fact, significantly lower fibrinogen levels have been demonstrated after major cardiac surgery, in obstetrical hemorrhage, and in trauma patients.13–16 Historical recommendations suggested that goal levels >100 mg/dL were ideal when treating either congenital or acquired fibrinogen deficiency.12 More recently, guidelines suggest that a minimum goal of 150 mg/dL is ideal.17 Repletion to adequate levels can be accomplished with fresh frozen plasma (FFP); however, the extent of repletion with FFP may be limited when compared with cryoprecipitate or fibrinogen concentrates.18–21 Fibrinogen concentrate is approved in 18 countries for the treatment of acquired fibrinogen deficiency, but in the United States, it is approved only for congenital fibrinogen deficiency and not for use in cardiac surgery.12,22
Ideally, targeted coagulation factor therapy is guided by testing for specific factors. Traditional laboratory fibrinogen assays (Clauss method) are not point-of-care tests, and they generally remain too time-consuming to utilize in the actively bleeding patient. Expanding the clinical use of viscoelastic testing, like thrombelastography (TEG; Haemonetics, Braintree, MA) and thromboelastometry (ROTEM; Tem International, Munich, Germany), has led to the development of novel clinical applications. One such application, the TEG-based functional fibrinogen level (FLEV), reports a fibrinogen level in significantly less time than laboratory assays, and moderate correlation has been observed between FLEV and Clauss fibrinogen values.23 However, this does not mean that the FLEV assay provides an accurate measurement of the plasma fibrinogen level. In fact, 1 small case series has suggested that FLEV values may be on average 100 mg/dL higher than the standard laboratory test.24 If these findings were validated in a larger case series with surgical patients at risk for bleeding, this could have significant implications on integrating FLEV into transfusion strategies. FLEV could be used for point-of-care fibrinogen analysis and targeted transfusion, but redefining hypofibrinogenemia with FLEV or utilizing the FLEV graph itself may be needed.
The use of viscoelastic clotting tests after cardiopulmonary bypass (CPB) to guide targeted therapy is an increasingly described strategy to predict and limit postoperative transfusion.21,25,26 This method, however, still requires time for blood product ordering, preparation, and delivery. The time from ordering to receipt of cryoprecipitate can often exceed 45 minutes. A short thawed shelf life, moderate cost and restricted availability, limits preemptive ordering practices. If FLEV values obtained immediately postbypass do not change by a clinically significant amount compared with values obtained before the discontinuation of CPB, then the earlier FLEVs could be used for product ordering in preparation for separation from bypass, especially in patients with high bleeding risk. This approach would promote prompt transfusion, reduce unnecessary exposure, and limit product wastage.
In this study, we aimed to assess fibrinogen levels in patients undergoing cardiac surgery with CPB using TEG-based FLEV assays (and Clauss assays) at 3 time points during surgery: prebypass (no heparin), on CPB during rewarming (heparinized), and postbypass after heparin reversal. Although previous investigations have looked at viscoelastic testing and standard laboratory assays in this setting, the value of these findings has not been consistent. Clauss assays during CPB have been reported previously as invalid; however, the device type and reagent may affect the results.27,28 Similarly, viscoelastic test results have been shown to be similar during rewarming on CPB and postprotamine; however, they too have been reported as not being immune to the effects of excess heparin.29 To add to the available data on point-of-care testing in cardiac surgery, and given the variable previous results, our primary goal was to test the hypothesis that fibrinogen levels obtained using the point-of-care FLEV assay on CPB during rewarming would not be statistically different from values obtained postbypass. We also aimed to examine the agreement and correlation between FLEV assays and standard laboratory assays by simultaneously measuring fibrinogen levels using the Clauss method at each of the 3 time points. Last, we aimed to assess the time advantage gained by determining fibrinogen values at rewarming versus after bypass separation.
After approval by the Institutional Review Board at the University of Pennsylvania (Philadelphia, PA), a prospective nonrandomized study was performed in accordance with the submitted protocol. The study was registered with ClinicalTrials.gov (NCT01992757) before patient enrollment. Written informed consent was obtained from every participant before surgery, with copies of the study protocol and consent provided to each participant.
Fifty-one patients over the age of 18 years undergoing cardiac surgery requiring CPB were recruited between November 2013 and February 2014 for enrollment into the study during the preoperative period. Exclusion criteria included emergency surgery, reoperative cardiac surgery, a history of coagulation disorders, and inability to sign consent. Patients who received plasma transfusions intraoperatively before the discontinuation of bypass were also excluded because of the fibrinogen contribution from FFP.
Two samples were obtained from participants at each of the 3 time points: baseline, rewarming (on CPB), and postbypass for a total of 6 samples from each subject. Each sample was collected into standard citrated blood collection tubes. One sample from each time point was sent to the central laboratory for analysis by institutional standard fibrinogen assay using the Clauss method (TriniCLOT Fibrinogen Kit with Destiny Max Coagulation Analyzer; Tcoag, Bray, Ireland). Results are reported to be unaffected by heparin levels up to 3.0 USP U/mL. The second sample from each time point was analyzed by 1 of the research investigators using the TEG 5000 Thrombelastograph Hemostasis Analyzer System to report an FLEV. Fibrinogen levels are determined from the maximum amplitude (MA) part of the graph, reported in millimeters, using proprietary reference values not published by Haemonetics. All FLEV assays were done in accordance with Haemonetics protocol utilizing the provided functional fibrinogen reagent vials.
Baseline samples were obtained immediately after induction of anesthesia and before surgical incision. Rewarming samples were obtained from the perfusionist during the rewarming phase of bypass immediately after the patient’s venous intake temperature exceeded 34°C. The final postbypass samples were obtained approximately 3 minutes after protamine administration with the discontinuation of CPB. All blood samples at each time point were requested and obtained bedside by 1 of the research investigators. The exact time that each sample was drawn, and subsequently tested, was also recorded. All samples were tested within 1 hour of being acquired, with the majority tested immediately after collection.
The primary aim of this investigation was to examine the magnitude of change in fibrinogen values obtained by the FLEV assay between rewarming and postbypass periods. Power analysis determined that our sample size had an 80% power to detect a 50 mg/dL difference in FLEV values, assuming a standard deviation of 90 mg/dL an α–level of 0.05, and a correlation between measures of 0.2. This analysis was conservative because the observed correlation in the sample among repeated measures was substantially higher (>0.5) across all time points. We used multiple separate statistical methods to ensure that our conclusions were robust to distributional assumptions. In our primary analysis, we fit a mixed-effects linear regression model that included random intercept and random slope terms.30 In addition, we examined the difference in values across time points using repeated measures analysis of variance followed by pairwise comparisons using paired t tests. Last, we used nonparametric tests: the Friedman test, followed by pairwise Wilcoxon signed rank tests. The Bonferroni correction was used for all pairwise comparisons. Thus, α-level for the overall test was set at 0.05 and was corrected to 0.016 for the post hoc pairwise comparisons. In addition, 95% confidence intervals (CIs) were corrected using the Bonferroni method. Our results were similar across statistical analysis methods, and thus, we present P values from the mixed-effects model, our primary analysis (Supplemental Digital Content,.
A secondary aim of this study was to examine correlation and agreement between fibrinogen values obtained by FLEV and standard laboratory Clauss assays. Agreement between the tests was investigated by using Bland-Altman plots at each time point.31 Using the plots, mean differences with CIs were calculated. In addition, upper and lower limits of agreement were analyzed. We also examined the correlation between the 2 measures using the Pearson correlation coefficient, with r > 0.7 used to signify strong correlation. Last, to determine whether the bias was constant at each time point, correlation between the difference between tests and mean of both tests was calculated using the Spearman rank correlation test, which does rely on distributional or linearity assumptions. A strong correlation is evidence that the difference between tests is a function of the magnitude of the average test result, with the difference either increasing or decreasing as the average test results increases.
Citrated (3.2%) blood collection tubes were used for all samples. FLEV assays were determined by TEG 5000 Thrombelastograph Hemostasis Analyzers in accordance with Haemonetics protocol. First, 0.5 mL blood from the citrated tubes was added to the manufactured functional fibrinogen vials, which contain a glycoprotein IIb/IIIa receptor inhibitor. Next, 340 μL blood from the vial was added to standard TEG cups (heparinase cups were used for all bypass samples), and the analyzer calculated the MA of the reported thromboelastograph. This amplitude is then used to extrapolate a fibrinogen value (FLEV).
Clauss laboratory assays were performed by the laboratory at the University of Pennsylvania in accordance with laboratory protocol. According to the protocol, plasma from citrated samples is collected by centrifuge and then diluted to a standard ratio. High concentration thrombin is then added to diluted plasma samples, and clotting times are observed and compared with standard reference values for the determination of fibrinogen levels.
Of the 51 patients enrolled, 2 patients were excluded after receiving FFP during bypass, which would alter postoperative fibrinogen levels. Data from the remaining 49 patients were included for analysis. The age of enrolled patients ranged from 22 to 84 years. Other patient demographics and range of surgical cases are detailed in Table 1. Durations for each surgical time variable are listed in Table 2. Valve surgery was the most common operation. Surgeries in the “other” category included adult congenital operations, ventricular assist device insertion, root operations, or mass removal. Six of the 49 patients required deep hypothermic circulatory arrest for aortic surgery. On average, 47 minutes (95% CI, 41.3 to 53.9) elapsed between rewarming and postbypass sampling.
Mean fibrinogen values determined at each time point by both laboratory and FLEV assays are listed in Table 3. Fibrinogen levels measured by both methods changed significantly over time (P < .0001). Specifically, values of both tests decreased significantly from baseline to rewarming but were unchanged from rewarming to postbypass (Table 4). Box plots for change over time with FLEV assay and laboratory assay can be seen in Figures 1 and 2, respectively. An estimated change of −1.1 mg/dL for FLEV from rewarming to postbypass is noted with a CI that crosses zero (95% CI, −25.8 to 23.6; P = .917), demonstrating no statistical difference between the FLEV at the 2 time points of interest. A similar pattern is seen with fibrinogen values measured using the Clauss method.
Next, correlation between baseline FLEV and standard laboratory assay was investigated using a simple linear regression (scatter plot in Figure 3). Analysis demonstrated a strong correlation between tests at baseline, with a Pearson correlation coefficient of r = 0.76 (P < .0001). This strong correlation between tests persisted at all 3 time points.
Despite strong correlation, we additionally analyzed our findings for agreement between tests using Bland-Altman analysis of agreement. Bland-Altman plots of FLEV and laboratory assay differences compared with the means at each time point are presented in Figures 4 to 6. These plots include lines for upper and lower limits of agreement. The results demonstrate a systematic bias with FLEV values being consistently higher than standard laboratory assay. Table 3 includes the Bland-Altman data analysis that demonstrates a mean difference at baseline of 92.5 (71.1 to 114.9), which increases to 120.0 (104.1 to 137.1) and 119 (101.7 to 137.4) with rewarming and postbypass, respectively. These findings represent, despite strong correlation, a clinically significant disagreement between tests, which increases after the initiation of CPB.
Last, based on Figures 4 to 6, an analysis for correlation between the differences and the means of the FLEV and laboratory assay was performed. No correlation exists with baseline values (r = −0.07; P = .633). This lack of correlation between difference and mean suggests the presence of a constant bias at that time point. For rewarming and postbypass samples, correlation increases, and for postbypass specifically the correlation is statistically significant (r = 0.434; P = .002), which implies a less predictable bias. In this instance, the difference between tests tended to increase as the average value of the tests increased. This was particularly evident in the range of 150 to 250 mg/dL.
These study results are consistent with our hypothesis that fibrinogen levels obtained during the rewarming phase of CPB accurately reflect postbypass fibrinogen levels when determined by FLEV assay. This is an important question to answer because the value of replenishing low fibrinogen values in cardiac surgery is well documented.16,32 Implementing this evidence into practice would ideally use real-time plasma fibrinogen levels to guide therapy. Standard laboratory assays (Clauss method) involve plasma dilution and thrombin concentrate titration, which traditionally precludes use of this assay in a point-of-care fashion unless the testing facility has access to rapid Clauss assays. In addition, thawing cryoprecipitate is time consuming. For both these reasons, efficient preemptive ordering practices are impossible without predictive point-of-care tests. Prophylactic cryoprecipitate ordering and transfusion serve as alternative strategies but are potentially wasteful and may unnecessarily expose patients to blood products. Accurate point-of-care fibrinogen determination before the discontinuation of bypass using FLEV could alleviate these concerns and promote efficient fibrinogen replacement and may reduce overall transfusion rates.
In addition to time considerations, Clauss methods are impacted by CPB in a variety of ways. Decreasing fibrinogen levels seen after CPB initiation, as demonstrated in both the FLEV and the Clauss methods in Table 2, are often attributed to hemodilution. Hemodilution alone, however, does not explain the increasing difference seen between tests at baseline versus rewarming. Evidence demonstrating the effect of anticoagulants on Clauss assays may best explain this finding, although most Clauss assays are reportedly heparin insensitive.29 This insensitivity is related mostly to plasma dilution (commonly 1:10) performed on the testing sample. Next, concentrated thrombin is added to initiate clot, and clotting times are used to determine fibrinogen levels using standard reference values.33 Despite dilution, heparin in high concentrations (>0.6 U/mL), direct thrombin inhibitors, and other low-molecular-weight heparins have been shown to falsely lower fibrinogen values through their effects on thrombin.29,34,35 This effect represents another limit to using the Clauss assay during CPB. Investigators have attempted to determine the clinical significance of these Clauss assay confounders with mixed results. A small study of 30 patients by Solomon et al28 suggested that fibrinogen values determined by Clauss method shortly before CPB weaning were not different than values determined after protamine reversal. Ortmann et al27 report a similar study with 50 patients using both Clauss and viscoelastic testing methods. They demonstrate significant difference in Clauss assay at similar time points. The results of the Ortmann study further support the use of viscoelastic testing during CPB for determining fibrinogen values.
In our study, the increased difference between tests persists into the postbypass period after reversal of systemic heparinization. This is in contrast to the Ortmann trial that showed recovery of fibrinogen via Clauss after protamine reversal. Possible explanations for our findings include residual heparin effects or an independent protamine effect. If dilution alone explained these findings, that would imply at minimum that FLEV is impacted to a lesser degree by dilution than the standard laboratory assay, again offering an advantage. Further studies would need to be performed to determine why Clauss assays are impacted to a greater degree than FLEV and why different investigators have mixed results when looking at Clauss fibrinogen levels on CPB. These mixed results may in part be due to different reagents used for Clauss. The clinical significance of this finding is difficult to determine; however, the more important finding is that FLEV assays report fibrinogen values in significantly less time and are apparently impacted to a lesser degree by CPB as evidenced by our findings and other cited investigators. It should be noted that newer, more rapid Clauss assays are available and its clinical application in this context is yet to be determined.
The apparent advantage of FLEV assay during bypass likely relates to the method in which the assay calculates fibrinogen levels. Plasma levels are calculated from the MA portion of the TEG graph, again using proprietary reference values. The 2 main components of clot strength include an approximately 80% platelet and a 20% fibrinogen contribution. Mixing a pretest blood sample with a platelet inhibitor, like abciximab, theoretically makes fibrinogen the sole contributor to MA. Using previously created proprietary graphs with known fibrinogen concentrations, the FLEV assay reports a fibrinogen level. These values are free from impact by systemic heparinization, when specific heparinase cups are used. However, fibrinogen results using this approach have to be interpreted with caution, given the concern for incomplete inhibition of platelet contribution, as well as other blood constituents such as factor XIII or hematocrit levels that may affect the result.36,37 Similarly, as mentioned previously, many current Clauss assays are insensitive to therapeutic heparin levels.29
Despite proving our initial hypothesis that rewarming FLEV values are not different from postbypass FLEV values, additional considerations must be made for findings in our data before implementing FLEV values into transfusion strategies. Our Bland-Altman plots demonstrated a definite disagreement between the 2 tests. Bland and Altman31 proposed in 1986 that when comparing a new test with a standard test, the difference in each sample compared with the mean of both tests is the best assessment of agreement between the 2 tests. This is different than the correlation between assays shown in previous publications, which has numerous limitations.14,23,38 In particular, a change in the scale of measurement does not affect correlation but has a major effect on agreement.31 This is demonstrated in our data, where correlation is present but FLEV values are systematically higher than Clauss values. These findings are consistent with a recent study, published by Agren et al,24 which also found an overestimation of fibrinogen levels using the FLEV assay. Our findings, in conjunction with the Agren results, have major implications on using fibrinogen values determined by FLEV for ordering of fibrinogen replacement therapy when using FLEV.
Using rewarming FLEV values for transfusion practices would ideally follow current guidelines and recommendations for normalizing fibrinogen levels, which is largely based on observational and retrospective analyses using standard laboratory assays.17,39 Of the 49 patients included in this study, only 1 patient had an FLEV value <200 mg/dL (194 mg/dL) likely because of the systematic bias just discussed. This highlights the limitation of using rewarming FLEV values as a transfusion guide; however, identifying no statistical change between rewarming and postbypass FLEV values still has clinical merit. The consistency of the bias implies a fundamental issue with determining fibrinogen values from the reported MA. The source of error may relate to confounding contributors to FLEV MA demonstrated in studies of viscoelastic fibrinogen testing, including residual platelet effect, factor XIII, and even hematocrit influence on MA.36,40
Previous investigators have navigated this dilemma of confounding effects by restoring MA (or maximum clot firmness) to normal with fibrinogen products as opposed to using the reported FLEV fibrinogen value.25,26,41 This approach may represent the best way to implement our findings into clinical practice, or alternatively, a correction factor would need to be determined. In our analysis of correlation between difference and mean using the Bland-Altman plots, a predictable bias at baseline was identified. CPB appears to disrupt this relationship between the 2 tests, meaning a simple conversion factor is unlikely to overcome this limitation. Further investigations would be needed before using absolute rewarming values or FLEV MA as a transfusion guide.
One final important finding in our study was the average time of 47 minutes between the venous intake temperature reaching 34°C and protamine reversal. Ordering, preparation, and delivery of cryoprecipitate can be performed easily within this time constraint if accurate predictive point-of-care fibrinogen analysis is available. Of course, this additional time may not be as valuable and advantageous to institutions where fibrinogen concentrates are readily available for acquired fibrinogen deficiency. Currently, in the United States, fibrinogen concentrates are only approved for congenital fibrinogen deficiency.22
In summary, demonstrating no statistical difference between rewarming and postbypass FLEV values has the potential to allow preemptive ordering of appropriate product therapy, to reduce excessive or unnecessary transfusion, and to decrease wastage of blood products. Our findings warrant further investigations of efficient preemptive transfusion strategies as opposed to reactive, less efficient, and potentially harmful prophylactic approaches. These efficient strategies should use point-of-care coagulation analysis like FLEV assay to guide therapy as we better understand how to incorporate these tests into practice.
Name: Michael Fabbro II, DO.
Contribution: This author helped design and conduct the study, analyze the data, and prepare the manuscript.
Name: Jacob T. Gutsche, MD.
Contribution: This author helped prepare the manuscript.
Name: Todd A. Miano, PharmD, MSCE.
Contribution: This author helped design the study, analyze the statistic and data, and prepare the manuscript
Name: John G. Augoustides, MD.
Contribution: This author helped prepare the manuscript.
Name: Prakash A. Patel, MD.
Contribution: This author helped design and conduct the study, analyze the data, and prepare the manuscript.
This manuscript was handled by: Roman Sniecinski, MD.
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