International Journal of Laboratory Hematology The Official journal of the International Society for Laboratory Hematology
LETTER TO THE EDITOR
INTERNAT IONAL JOURNAL OF LABORATO RY HEMATO LOGY
Letter to the Editor
Can we predict excessive bleeding using point-of-care assays? Sir, We read with great interest the recently published review article by Chandler [1]. We agree with author that emergency assessment of hemostasis requires short turnaround time as slow testing may be of no clinical benefit [1]. Our working group has experience with the use of viscoelastic global hemostasis assay such as rotational thromboelastometry (TEM) [2] as well as with use of multiple electrode aggregometry (MEA) [3]. In contrast to Chandler [1], our recently published results suggest the evidence that platelet function testing might be useful for preoperative bleeding risk assessment and/or diagnosing the cause of acquire bleeding syndromes [2,3]. Herein, we will provide some recent literature evidence confirming our hypothesis. Ranucci et co-workers performed a retrospective analysis of prospectively collected data on cardiosurgical patients who were preoperatively exposed to thienopyridine treatment [4]. The authors concluded that the adenosine diphosphate (ADP) test value was associated with postoperative bleeding and platelet transfusion and provided an accurate preoperative prediction of postoperative bleeding [4]. Recently, we conducted prospective observational study with aim to elucidate the possibility of bleeding prediction in patients undergoing coronary artery surgery (CAS) [3]. Aspirin sensitive (ASPI test, P = 0.014) and thienopyridines sensitive (ADP test, P = 0.003) platelet function test values significantly correlated with the extent of chest tube output [3]. Using the receiver operating curve analysis [5], we defined both ASPI and ADP test cutoff values that delineated bleeding tendency [3]. Such a prospective observational trial allowed us to preoperatively stratify patients according to bleeding risk [3]. In addition, Mahla and co-workers [6] reported that a strategy based on preoperative platelet function testing to determine the timing of CAS in clopidogrel-treated patients was associated with the same amount of bleeding observed in clopidogrel-naive patients and 50% shorter waiting time than recommended in the current
496
guidelines [7]. Therefore, recommendations on empiric preoperative antiplatelet medication adjustments, not based on laboratory assessment of platelet function, might be obsolete and could probably be changed as there is growing recent evidence supporting the fact that platelet function testing is useful in predicting bleeding outcomes [2–4,8]. However, further research in this field is required as not all studies investigating this issue reported positive findings, thus lacking strong evidence and clear recommendations with precise cutoffs that would be reliably used in everyday practice. Furthermore, different study settings, and different assays used, as well as different definitions of excessive bleeding and transfusion outcomes hamper definitive conclusions on relationship between point-of-care testing findings and bleeding extent. Noteworthy, disturbances of coagulation consequent to cardiopulmonary bypass (CPB) in cardiosurgical patients have multifactorial etiology, such as loss of platelet reactivity, coagulation factor consumption, hemodilution due to CPB priming procedure, etc. [2]. Therefore, intraoperative use of point-of-care devices to predict excessive bleeding deems reasonable, providing even more accurate assessment of hemostatic disorder by accounting the role of preoperative platelet inhibitors intake, the role of CPB as well as surgical stress on blood hemostatic properties. Intra-operative assessment of hemostatic properties and platelet dysfunction may further enhance positive predictive value, which was found to be weak in some studies although simultaneously have had a high negative predictive value. With aim to evaluate if intra-operative assessment of hemostatic properties using point-of-care devices provides bleeding prediction, we conducted prospective trial in which we showed that both MEA and TEM were accurate in predicting excessive bleeding [2]. Put briefly our study showed that pre – and intra-operative MEA and TEM findings were useful for prediction of excessive bleeding after cardiosurgical procedures [2]. The best predictors were the tests performed after completion of surgical procedure [2]. The reason for higher accuracy of intra-operatively performed testing is probably in the fact that intra-operative
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 496–498
LETTER TO THE EDITOR
testing evaluated effects of preoperatively administered antithrombotic drugs as well as the effects of CPB and surgery trauma itself on blood hemostatic properties. Our experience [2, 3] together with evidence published by other authors [4, 6] is not in line with statement provided by Chandler that platelet function testing is useless for preoperative bleeding assessment. However, the data indicating an association between platelet function testing and extent of bleeding are still controversial, and the fact is that literature evidence provides both pro’s and con’s regarding this issue. Different study designs and data analysis methodologies certainly affect the reported results, thus making respective results to be the only preliminary thus requiring further research, but such discussion is beyond the scope of this letter. We will briefly discuss it through our experience [2, 3]. In our recent study, aspirin sensitive platelet function test value that delineated bleeding tendency was below the normal range values as provided by manufacturer (ASPI test 22 AUC, normal range 51–109 AUC) [3]. Thus, it is possible that certain patients may have values that are lower than normal range values, but still will not be considered to be at high risk of excessive bleeding. On the other hand, adenosine diphosphate receptor blockers sensitive platelet function test value (ADP test) that delineated bleeding tendency was within normal range values as provided by the manufacturer [3] (ADP test 70 AUC, normal range 56–96 AUC). Therefore, despite the fact that patient has platelet function test value within normal range, still may be at increased risk of bleeding if observed value is below 70 AUC [3]. When considering the possibility for excessive bleeding prediction using point-of-care tests, we suggest cutoff values to be defined through prospective observational study. Such a research setting allows for correlations between platelet function and observed bleeding outcome, and if significantly positive correlations exist, ROC analysis may delineate the cutoff value that has the best sensitivity/ specificity ratio. Use of predefined normal range of platelet function as provided by the manufacturer may hinder the optimal sensitivity and/or specificity as we observed in our study [3]. Thus, investigations based on the assessment of bleeding risk through predefined ‘normal range’ of platelet reactivity may reveal diminished accuracy of platelet function testing. Predefined normal range values are suitable for the assessment of platelet inhibitory response to antiplatelet drug, but still they are not validated for the assessment and prediction of particular clinical outcomes. Thus, validation of point-of-care device through specific cohort and specific outcomes in prospective observational study may elucidate more accurately the possibility for bleeding risk prediction. It is apparent
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 496–498
497
that platelet function tests should be firstly evaluated in particular group of patients (i.e., cardiac surgery patients) and obtained values should be correlated with observed bleeding outcomes through prospective observational study. In cases of significant correlations, receiver operating curve analysis [5] should be performed to provide cutoff values that have best sensitivity and specificity in predicting particular outcome such as excessive bleeding. Such an approach allows for bleeding risk prediction and stratification. Furthermore, according to cutoff values, it is possible to direct transfusion management. Spiess et al. reported thromboelastography guided hemostatic management to significantly reduce incidence of overall transfusion and mediastinal reexploration due to excessive bleeding [9]. In addition, Rahe Mayer et co-workers [10] provided FIBTEM-guided intra-operative hemostatic therapy with fibrinogen concentrate to be more effective than placebo in controlling coagulopathic bleeding during major aortic replacement surgery [10]. Our recent study showed that not only FIBTEM test, but also all other TEM assays significantly correlated with bleeding extent [2]. Furthermore, we suggest that first line transfusion therapy should be directed according to the cutoff values that delineate bleeding outcomes among all the TEM assays. For patients preoperatively considered to be at risk of excessive bleeding, intra-operative assessment of both platelet function and assessment of viscoelastic blood clot properties may allow for timely and targeted transfusion and facilitate rapid and effective decisionmaking process in hemostatic management. However, such an approach requires further prospective studies with large number of patients that will reevaluate studies [2–4, 6] reporting positive results which we may considered as ‘preliminary findings’ until confirmed in large cohort prospective studies that will be powered enough to frame ‘safety window’ in platelet function by allowing for sufficient positive and negative predictive values.
M. Petricevic*, B. Biocina*, A. Lekic*, V. Ivancan†, D. Milicic‡ *Department of Cardiac Surgery, University of Zagreb School of Medicine, University Hospital Center Zagreb, Zagreb, Croatia †
Department of Anesthesiology and Intensive Care, University Hospital Center Zagreb, Zagreb, Croatia ‡ Department of Cardiovascular Diseases, University of Zagreb School of Medicine, University Hospital Center Zagreb, Zagreb, Croatia
E-mail: [email protected] doi: 10.1111/ijlh.12173
498
LETTER TO THE EDITOR
References 1. Chandler WL. Emergency assessment of hemostasis in the bleeding patient. Int J Lab Hematol 2013;35:339–43. 2. Petricevic M, Biocina B, Milicic D, Konosic S, Svetina L, Lekic A, Zdilar B, Burcar I, Milosevic M, Brahimaj R, Samardzic J, Gasparovic H. Bleeding risk assessment using whole blood impedance aggregometry and rotational thromboelastometry in patients following cardiac surgery. J Thromb Thrombolysis 2013;36:514–26. 3. Petricevic M, Biocina B, Milicic D, Konosic S, Ivancan V, Milosevic M, Burcar I, Gasparovic H. Bleeding risk assessment using multiple electrode aggregometry in patients following coronary artery bypass surgery. J Thromb Thrombolysis 2013;35: 31–40. 4. Ranucci M, Baryshnikova E, Soro G, Ballotta A, De Benedetti D, Conti D. Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients
receiving thienopyridines. Ann Thorac Surg 2011;91:123–9. 5. Metz CE. Basic principles of ROC analysis. Semin Nucl Med 1978;8:283–98. 6. Mahla E, Suarez TA, Bliden KP, Rehak P, Metzler H, Sequeira AJ, Cho P, Sell J, Fan J, Antonino MJ, Tantry US, Gurbel PA. Platelet function measurement-based strategy to reduce bleeding and waiting time in clopidogrel-treated patients undergoing coronary artery bypass graft surgery: The timing based on platelet function strategy to reduce clopidogrel-associated bleeding related to CABG (TARGET-CABG) study. Circ Cardiovasc Interv 2012;5:261–9. 7. Wright RS, Anderson JL, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Jneid H, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP, Jacobs AK. ACCF/ AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 Guideline):
a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:2022–60. 8. Schimmer C, Hamouda K, Sommer SP, Ozkur M, Hain J, Leyh R. The predictive value of multiple electrode platelet aggregometry (multiplate) in adult cardiac surgery. Thorac Cardiovasc Surg 2013; doi: 10.1055/ s-0033-1333659. [Epub ahead of print]. 9. Spiess BD, Gillies BS, Chandler W, Verrier E. Changes in transfusion therapy and reexploration rate after institution of a blood management program in cardiac surgical patients. J Cardiothorac Vasc Anesth 1995;9:168–73. 10. Rahe-Meyer N, Hanke A, Schmidt DS, Hagl C, Pichlmaier M. Fibrinogen concentrate reduces intraoperative bleeding when used as first-line hemostatic therapy during major aortic replacement surgery: results from a randomized, placebo-controlled trial. J Thorac Cardiovasc Surg 2013;145: S178–85.
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 496–498
LETTER TO THE EDITOR
INTERNAT IONAL JOURNAL OF LABORATO RY HEMATO LOGY
Letter to the Editor
Can we predict excessive bleeding using point-of-care assays? Sir, We read with great interest the recently published review article by Chandler [1]. We agree with author that emergency assessment of hemostasis requires short turnaround time as slow testing may be of no clinical benefit [1]. Our working group has experience with the use of viscoelastic global hemostasis assay such as rotational thromboelastometry (TEM) [2] as well as with use of multiple electrode aggregometry (MEA) [3]. In contrast to Chandler [1], our recently published results suggest the evidence that platelet function testing might be useful for preoperative bleeding risk assessment and/or diagnosing the cause of acquire bleeding syndromes [2,3]. Herein, we will provide some recent literature evidence confirming our hypothesis. Ranucci et co-workers performed a retrospective analysis of prospectively collected data on cardiosurgical patients who were preoperatively exposed to thienopyridine treatment [4]. The authors concluded that the adenosine diphosphate (ADP) test value was associated with postoperative bleeding and platelet transfusion and provided an accurate preoperative prediction of postoperative bleeding [4]. Recently, we conducted prospective observational study with aim to elucidate the possibility of bleeding prediction in patients undergoing coronary artery surgery (CAS) [3]. Aspirin sensitive (ASPI test, P = 0.014) and thienopyridines sensitive (ADP test, P = 0.003) platelet function test values significantly correlated with the extent of chest tube output [3]. Using the receiver operating curve analysis [5], we defined both ASPI and ADP test cutoff values that delineated bleeding tendency [3]. Such a prospective observational trial allowed us to preoperatively stratify patients according to bleeding risk [3]. In addition, Mahla and co-workers [6] reported that a strategy based on preoperative platelet function testing to determine the timing of CAS in clopidogrel-treated patients was associated with the same amount of bleeding observed in clopidogrel-naive patients and 50% shorter waiting time than recommended in the current
496
guidelines [7]. Therefore, recommendations on empiric preoperative antiplatelet medication adjustments, not based on laboratory assessment of platelet function, might be obsolete and could probably be changed as there is growing recent evidence supporting the fact that platelet function testing is useful in predicting bleeding outcomes [2–4,8]. However, further research in this field is required as not all studies investigating this issue reported positive findings, thus lacking strong evidence and clear recommendations with precise cutoffs that would be reliably used in everyday practice. Furthermore, different study settings, and different assays used, as well as different definitions of excessive bleeding and transfusion outcomes hamper definitive conclusions on relationship between point-of-care testing findings and bleeding extent. Noteworthy, disturbances of coagulation consequent to cardiopulmonary bypass (CPB) in cardiosurgical patients have multifactorial etiology, such as loss of platelet reactivity, coagulation factor consumption, hemodilution due to CPB priming procedure, etc. [2]. Therefore, intraoperative use of point-of-care devices to predict excessive bleeding deems reasonable, providing even more accurate assessment of hemostatic disorder by accounting the role of preoperative platelet inhibitors intake, the role of CPB as well as surgical stress on blood hemostatic properties. Intra-operative assessment of hemostatic properties and platelet dysfunction may further enhance positive predictive value, which was found to be weak in some studies although simultaneously have had a high negative predictive value. With aim to evaluate if intra-operative assessment of hemostatic properties using point-of-care devices provides bleeding prediction, we conducted prospective trial in which we showed that both MEA and TEM were accurate in predicting excessive bleeding [2]. Put briefly our study showed that pre – and intra-operative MEA and TEM findings were useful for prediction of excessive bleeding after cardiosurgical procedures [2]. The best predictors were the tests performed after completion of surgical procedure [2]. The reason for higher accuracy of intra-operatively performed testing is probably in the fact that intra-operative
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 496–498
LETTER TO THE EDITOR
testing evaluated effects of preoperatively administered antithrombotic drugs as well as the effects of CPB and surgery trauma itself on blood hemostatic properties. Our experience [2, 3] together with evidence published by other authors [4, 6] is not in line with statement provided by Chandler that platelet function testing is useless for preoperative bleeding assessment. However, the data indicating an association between platelet function testing and extent of bleeding are still controversial, and the fact is that literature evidence provides both pro’s and con’s regarding this issue. Different study designs and data analysis methodologies certainly affect the reported results, thus making respective results to be the only preliminary thus requiring further research, but such discussion is beyond the scope of this letter. We will briefly discuss it through our experience [2, 3]. In our recent study, aspirin sensitive platelet function test value that delineated bleeding tendency was below the normal range values as provided by manufacturer (ASPI test 22 AUC, normal range 51–109 AUC) [3]. Thus, it is possible that certain patients may have values that are lower than normal range values, but still will not be considered to be at high risk of excessive bleeding. On the other hand, adenosine diphosphate receptor blockers sensitive platelet function test value (ADP test) that delineated bleeding tendency was within normal range values as provided by the manufacturer [3] (ADP test 70 AUC, normal range 56–96 AUC). Therefore, despite the fact that patient has platelet function test value within normal range, still may be at increased risk of bleeding if observed value is below 70 AUC [3]. When considering the possibility for excessive bleeding prediction using point-of-care tests, we suggest cutoff values to be defined through prospective observational study. Such a research setting allows for correlations between platelet function and observed bleeding outcome, and if significantly positive correlations exist, ROC analysis may delineate the cutoff value that has the best sensitivity/ specificity ratio. Use of predefined normal range of platelet function as provided by the manufacturer may hinder the optimal sensitivity and/or specificity as we observed in our study [3]. Thus, investigations based on the assessment of bleeding risk through predefined ‘normal range’ of platelet reactivity may reveal diminished accuracy of platelet function testing. Predefined normal range values are suitable for the assessment of platelet inhibitory response to antiplatelet drug, but still they are not validated for the assessment and prediction of particular clinical outcomes. Thus, validation of point-of-care device through specific cohort and specific outcomes in prospective observational study may elucidate more accurately the possibility for bleeding risk prediction. It is apparent
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 496–498
497
that platelet function tests should be firstly evaluated in particular group of patients (i.e., cardiac surgery patients) and obtained values should be correlated with observed bleeding outcomes through prospective observational study. In cases of significant correlations, receiver operating curve analysis [5] should be performed to provide cutoff values that have best sensitivity and specificity in predicting particular outcome such as excessive bleeding. Such an approach allows for bleeding risk prediction and stratification. Furthermore, according to cutoff values, it is possible to direct transfusion management. Spiess et al. reported thromboelastography guided hemostatic management to significantly reduce incidence of overall transfusion and mediastinal reexploration due to excessive bleeding [9]. In addition, Rahe Mayer et co-workers [10] provided FIBTEM-guided intra-operative hemostatic therapy with fibrinogen concentrate to be more effective than placebo in controlling coagulopathic bleeding during major aortic replacement surgery [10]. Our recent study showed that not only FIBTEM test, but also all other TEM assays significantly correlated with bleeding extent [2]. Furthermore, we suggest that first line transfusion therapy should be directed according to the cutoff values that delineate bleeding outcomes among all the TEM assays. For patients preoperatively considered to be at risk of excessive bleeding, intra-operative assessment of both platelet function and assessment of viscoelastic blood clot properties may allow for timely and targeted transfusion and facilitate rapid and effective decisionmaking process in hemostatic management. However, such an approach requires further prospective studies with large number of patients that will reevaluate studies [2–4, 6] reporting positive results which we may considered as ‘preliminary findings’ until confirmed in large cohort prospective studies that will be powered enough to frame ‘safety window’ in platelet function by allowing for sufficient positive and negative predictive values.
M. Petricevic*, B. Biocina*, A. Lekic*, V. Ivancan†, D. Milicic‡ *Department of Cardiac Surgery, University of Zagreb School of Medicine, University Hospital Center Zagreb, Zagreb, Croatia †
Department of Anesthesiology and Intensive Care, University Hospital Center Zagreb, Zagreb, Croatia ‡ Department of Cardiovascular Diseases, University of Zagreb School of Medicine, University Hospital Center Zagreb, Zagreb, Croatia
E-mail: [email protected] doi: 10.1111/ijlh.12173
498
LETTER TO THE EDITOR
References 1. Chandler WL. Emergency assessment of hemostasis in the bleeding patient. Int J Lab Hematol 2013;35:339–43. 2. Petricevic M, Biocina B, Milicic D, Konosic S, Svetina L, Lekic A, Zdilar B, Burcar I, Milosevic M, Brahimaj R, Samardzic J, Gasparovic H. Bleeding risk assessment using whole blood impedance aggregometry and rotational thromboelastometry in patients following cardiac surgery. J Thromb Thrombolysis 2013;36:514–26. 3. Petricevic M, Biocina B, Milicic D, Konosic S, Ivancan V, Milosevic M, Burcar I, Gasparovic H. Bleeding risk assessment using multiple electrode aggregometry in patients following coronary artery bypass surgery. J Thromb Thrombolysis 2013;35: 31–40. 4. Ranucci M, Baryshnikova E, Soro G, Ballotta A, De Benedetti D, Conti D. Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients
receiving thienopyridines. Ann Thorac Surg 2011;91:123–9. 5. Metz CE. Basic principles of ROC analysis. Semin Nucl Med 1978;8:283–98. 6. Mahla E, Suarez TA, Bliden KP, Rehak P, Metzler H, Sequeira AJ, Cho P, Sell J, Fan J, Antonino MJ, Tantry US, Gurbel PA. Platelet function measurement-based strategy to reduce bleeding and waiting time in clopidogrel-treated patients undergoing coronary artery bypass graft surgery: The timing based on platelet function strategy to reduce clopidogrel-associated bleeding related to CABG (TARGET-CABG) study. Circ Cardiovasc Interv 2012;5:261–9. 7. Wright RS, Anderson JL, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Jneid H, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP, Jacobs AK. ACCF/ AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 Guideline):
a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:2022–60. 8. Schimmer C, Hamouda K, Sommer SP, Ozkur M, Hain J, Leyh R. The predictive value of multiple electrode platelet aggregometry (multiplate) in adult cardiac surgery. Thorac Cardiovasc Surg 2013; doi: 10.1055/ s-0033-1333659. [Epub ahead of print]. 9. Spiess BD, Gillies BS, Chandler W, Verrier E. Changes in transfusion therapy and reexploration rate after institution of a blood management program in cardiac surgical patients. J Cardiothorac Vasc Anesth 1995;9:168–73. 10. Rahe-Meyer N, Hanke A, Schmidt DS, Hagl C, Pichlmaier M. Fibrinogen concentrate reduces intraoperative bleeding when used as first-line hemostatic therapy during major aortic replacement surgery: results from a randomized, placebo-controlled trial. J Thorac Cardiovasc Surg 2013;145: S178–85.
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 496–498
