SPECIAL ARTICLES

Thresholds for Perioperative Administration of Hemostatic Blood Components and Coagulation Factor Concentrates: An Unmet Medical Need Daniel Bolliger, MD,* Eckhard Mauermann, MD,* and Kenichi A. Tanaka, MD, MSc†

R

APID DIAGNOSIS and prompt correction of coagulopathy are essential in the management of massive bleeding due to cardiac surgery, trauma, or hereditary hemorrhagic conditions. In the treatment of bleeding patients, transfusion of blood components or infusions of processed coagulation factor concentrates are common medical procedures. However, the decision to transfuse or not to transfuse or to administer coagulation factor concentrates is often difficult to make, especially in the setting of cardiac surgery. Timely identification of patients who would benefit from transfusion of blood products or infusion of processed plasma components is still a matter of debate.1,2 Clear transfusion thresholds and therapeutic goals for blood products would be extremely helpful, but they remain unclear and widely disputed.3–6 The liberal transfusion of allogeneic blood products in cardiac surgery has been associated with adverse effects such as infections, organ dysfunctions, stroke, and increased mortality.7–13 Therefore, strategies to reduce blood transfusion have been developed as part of a perioperative patient blood management.14 Concurrent improvements in transfusion medicine include better donor testing, more stringent donation criteria, and improvements in both blood quality and blood component characteristics, all of which have contributed to the reduction of blood components-related complications. Appropriate criteria for processed coagulation factor concentrates also should be considered because liberal administration of factor concentrates has been associated with adverse events such as overshooting thrombin generation and thromboembolic complications.15,16 For the transfusion of red blood cell (RBC) concentrates, randomized studies evaluating different threshold values have been performed17,18 or are under way (“Transfusion Requirements in Cardiac Surgery III” NCT02042898). Today, it is

From the *Department of Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Basel, Switzerland; and †Department of Anesthesiology, Cardiothoracic Anesthesia Division, University of Maryland, Baltimore, MD. Address reprint requests to Daniel Bolliger, MD, Department of Anesthesia, University Hospital Basel, Spitalstrasse 21, CH-4031 Basel, Switzerland. E-mail: [email protected] © 2015 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2015.02.023 Key words: blood loss, blood coagulation disorders, blood component therapy 768

widely accepted that transfusion of RBCs is advantageous in patients with a hemoglobin concentration o7 g/dL as such low hemoglobin levels are associated with increased cardiac (myocardial infarction) and noncardiac morbidity (renal failure and stroke) and higher mortality.19,20 On the other hand, RBC transfusion rarely is indicated when hemoglobin is 410 g/dL.21 For hemoglobin concentrations between 7 and 10 g/dL, the decision to transfuse usually depends on hemodynamic stability, preexisting comorbidities, time course of blood loss, local practices, and the physician’s preferences. In contrast, threshold values for transfusion of plasma products and platelets and indications for the infusion of coagulation factor concentrates in coagulopathic patients after surgery mostly are based on expert opinions.3 The aim of this review is to discuss the evidence for the administration for hemostatic products in coagulopathy related to cardiac surgery. DEFINITION OF BLEEDING AND COAGULOPATHY

Most physicians would agree that less bleeding is beneficial and that the transfusion of blood products should be avoided unless it is clinically indicated. However, the consideration when bleeding and/or coagulopathy become relevant is subject to individual interpretation as it is defined according to abnormalities in laboratory tests or to the number of transfused blood products and the occurrence of surgical re-exploration. All these definitions for relevant bleeding and coagulopathy have their limitations and biases.22 Further, definitions might differ in terms of the etiology of bleeding, site of bleeding, and need for surgical intervention. Despite the arbitrary nature of defining massive bleeding and the need for surgical re-exploration, adverse effects and increased mortality appear to be associated with postoperative bleeding complications and surgical re-exploration.23,24 On the other hand, early surgical re-exploration in bleeding patients after cardiac surgery might limit the total chest tube output and total number of transfused blood products. Multiple attempts have been made to define coagulopathy according to the conventional laboratory tests such as prothrombin time or activated partial thromboplastin time (PT/ aPTT), but time-consuming processes of tests do not allow real-time assessment of coagulation, and test results seemed to have no predictive value.5,25–27 Therefore, clinical definitions such as de novo occurrence of unexplained diffuse bleeding from wound margins with no identifiable vessel stumps or from puncture sites were used to describe postoperative coagulopathy.28 However, quantification of relevant bleeding should be performed more objectively. Blood loss may be calculated from

Journal of Cardiothoracic and Vascular Anesthesia, Vol 29, No 3 (June), 2015: pp 768–776

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THRESHOLDS FOR HEMOSTATIC AGENTS

the measured blood volume drained from the surgical field and the estimated or measured volumes in surgical sponges.29 In a recent study,30 bleeding volume was determined after heparin reversal and surgical hemostasis by weighing surgical compresses before and after applying them to the surgical field. A bleeding mass of 60 to 250 g within 5 minutes was chosen as clinically relevant and of coagulopathic nature based on former clinical experiences by the authors of that study.31 Alternatively, 2 recent studies showed that a mobile photographic blood loss monitoring system (Triton Systems, Gauss Surgical Inc., Los Altos, CA) provided accurate and reliable measurements of hemoglobin mass in surgical sponges without manual rinsing.29,32 Recently, experts from Europe and the U.S. have suggested a general definition of bleeding after cardiac surgery. Based on 9 clinical events, including postoperative chest tube output, use of blood products and infused coagulation factor concentrates and clinical endpoints, such as delayed chest closure or surgical re-exploration, 5 classes of bleeding from “insignificant” to “massive” were defined. Chest tube output volumes of 41,000 mL and 42,000 mL over 12 hours were required for “severe” and “massive” bleeding, respectively.33 However, the abovementioned definition only can be applied retrospectively and is not universally accepted. Further, it still remains disputed at which point bleeding becomes clinically significant. The latter limits the comparison among most studies dealing with perioperative hemostasis, coagulopathy, and bleeding. TRANSFUSION OF PLATELETS

It is well known that patients with severe thrombocytopenia predispose to spontaneous bleeding and that patients with low platelet count might be at increased risk for perioperative bleeding.1 Many surgeons, therefore, insist on platelet counts of at least 50  103/mL for major procedures.34,35 In contrast, clinical observations suggest no increased bleeding tendency in invasive procedures despite low platelet count (o50  103/ mL).1,35,36 In agreement with this clinical perception, recent guidelines from the American Association of Blood Banks suggest only a low-grade recommendation for prophylactic platelet transfusion in major non-neuroaxial surgery when the platelet count is o50  103/mL.37 In fact, bleeding in thrombocytopenic patients might occur at any platelet count, and prophylactic transfusions have only limited impact on bleeding frequency in the non-surgical setting.38 Threshold values for platelet transfusion depend on patients’ characteristics and the type of surgical procedure (Table 1). They might be o5  103/mL if the patient is not bleeding and not planned for intervention or surgery. In patients who are bleeding or are scheduled for surgery and invasive procedures, platelet count is recommended to be 450  103/mL.34,35,37 Finally, the threshold for patients with intracranial bleeding or planned for intracranial or spinal surgery often is set at 100  103/mL. The same threshold of 100  103/mL used commonly in cardiac surgery.6 No threshold value applies in patients with recent intake of platelet inhibitors (especially P2Y12-receptor inhibitors such as clopidogrel or prasugrel), and platelet transfusion might be indicated at values 4100  103/ mL. Studies or data that would support or refute the benefit of

Table 1. Suggested Indications for the Use of Platelet Transfusion37,123 Transfusion Indication

Prophylactic transfusion in hospitalized patients to reduce bleeding risk in non-surgical patients Prophylactic transfusion in patients with elective central venous catheter placement Prophylactic transfusion for patients having major non-intracranial or non-neuroaxial elective surgery Prophylactic transfusion in surgery involving critical sites (eg, eye, brain, neuroaxial surgery) Therapeutic transfusion in bleeding patients with thrombocytopenia and/or evidence of platelet dysfunction after cardiopulmonary bypass

Threshold

10  109 /L 20  109 /L 50  109 /L

100  109 /L —

these arbitrarily set thresholds are scarce. A study by Avidan et al demonstrated that platelet transfusion rates were lower when using the threshold value of 50  103/mL compared to a threshold value of 100  103/mL without increasing bleeding rates or bleeding volumes in patients undergoing coronary bypass surgery.39 Besides the platelet count, reduced platelet function caused by platelet function inhibitors predisposes the patient to increased perioperative bleeding. While it is not fully clear whether the continuation of aspirin therapy in the perioperative period relevantly increases bleeding tendency in patients undergoing cardiac surgery, P2Y12-receptor inhibitors seem to put the patient at an increased risk for postoperative bleeding and surgical re-exploration,40 especially in the case of treatment with the newer and more potent P2Y12-receptor inhibitor prasugrel.41 Current guidelines, therefore, recommend stopping clopidogrel/prasugrel 5 days before cardiac surgery.42 However, this strategy might increase the risk of thrombotic vessel occlusion during this waiting period.43 The usefulness of preoperative platelet transfusion in patients with platelet dysfunction or of platelet transfusion in bleeding patients perioperatively due to platelet inhibition remains unproven.1 According to a recent study,44 platelet function testing allows shortening the preoperative waiting periods in patients treated with clopidogrel but normal or only minimally altered platelet function. In this study, no increased risk in perioperative bleeding was detected when using such stratification protocols guided by platelet function monitoring. Further, platelet function monitoring might be helpful in determining the general risk of perioperative bleeding,43,44 and in guiding the hemostatic therapy in bleeding patients.45,46 However, threshold and target values as evaluated by platelet function testing are poorly defined and often depend on local experiences. Finally, platelet count can change rapidly in the case of perioperative bleeding, and platelet count strongly affects platelet function test results.47 A recent analysis showed that hemostasis algorithms using thromboelastometry (ROTEMs; TEM International GmbH, Munich, Germany) and thromboelastography (TEGs; Haemonetics Corporation, Braintree, MA) reduced the administration of platelet concentrates as compared to algorithms based on conventional laboratory tests or clinical judgment.6 Transfusion

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thresholds differed between the 2 devices and varied widely within the same device.6 Whereas impaired platelet function hardly affects results in ROTEM, there are special assays in the TEG device allowing for the determination of platelet function (TEG-PlateletMappings).48 However, threshold values for platelet transfusion based on thromboelastographic and thromboelastometric assays are empirical and poorly evidence-based, similar to transfusion thresholds based on platelet count. Finally, in patients with established heparin-induced thrombocytopenia, at risk of it or with positive heparin-induced thrombocytopenia antibodies, the transfusion of platelets is considered as a relative contraindication even at low platelet count. Thrombin generation generally is increased in these patients, and platelet transfusion should be delayed until heparin concentration equals 0. TRANSFUSION OF PLASMA

Although the first plasma transfusion was performed in 1918,4 generally accepted and evidence-based triggers for plasma transfusion are still lacking today for the following reasons. First, the term, “plasma,” describes a variety of processed plasma products including fresh frozen plasma, plasma frozen within 24 hours (FP24), thawed plasma, and cryoprecipitate-poor plasma.49 Second, the indications for plasma transfusion are far from clear50 with relevant differences in the guidelines from different countries and organizations4,51,52 and with recommendations that generally are vague, partially passed on as heirlooms, and not evidencebased.3,45 Third, and unlike the hemoglobin value for red blood cell transfusion or the platelet count for platelet transfusion, laboratory coagulation tests have been questioned as a good surrogate for the coagulation status of the perioperative patient.25 Finally, many invasive procedures, such as liver or kidney biopsy, femoral angiography, central vein cannulation, or lumbar punctures, can easily be performed without hemostasis correction in patients with mild prolongation of prothrombin time (PT) or activated partial thromboplastin time (aPTT).53 Despite lacking evidence from randomized controlled trials, there are some indications for plasma transfusion that are not questioned (Table 2). Besides these generally accepted indications for plasma transfusion, plasma is regularly administered based on “expert opinions” rather than randomized trials. For these indications, threshold values are arbitrarily set. Some guidelines have advocated a specific threshold based on Table 2. Indications for the Use of Plasma Transfusion3,46,50 Pathology Hereditary angioedema Factor V deficiency Factor XI deficiency Plasma exchange in thrombotic thrombocytopenia purpura Multiple factor deficiency (for example, dilutional coagulopathy, consumption, disseminated intravascular coagulation) in active bleeding Multiple factor deficiency before major procedures Massive transfusion protocol with an RBC:FFP ratio of 1:1 Emergency reversal of warfarin when no factor concentrates are available Abbreviations: cell concentrate.

FFP,

fresh

frozen

plasma;

RBC,

red

blood

hemostatic laboratory assays (eg, PT/aPTT 41.5 times normal or reduced factor levels) before invasive procedures or in the bleeding patient, while others have not given laboratory criteria or only state “significantly increased coagulation time,” “abnormal coagulation,” or “multiple factor deficiencies.”52 However, a threshold value of international normalized ratio (INR) 41.5 has never been evaluated in clinical trials but has been recommended historically.25 Using a particular value of conventional coagulation tests as a transfusion threshold assumes that they are predictive for bleeding and that their correction reduces blood loss. However, PT testing initially was used for monitoring patients taking vitamin K antagonists, and it should, therefore, only be applied to this population.25,54,55 Similarly, aPTT was developed for the diagnosis of hemophilia A, and the predictive value of PT/aPTT is limited outside the setting for which this test originally was developed.55,56 Further, PT and aPTT testing are performed in platelet-poor plasma after eliminating erythrocytes and platelets. Considering the modern cell-based model of hemostasis,57 it would be surprising if a purely plasma-based in vitro assay adequately could assess hemostatic abnormalities in vivo. In patients with liver disease, INR is frequently between 1.3 and 1.9 despite normal thrombin generation,58,59 and additional hemostatic abnormalities might be present, which are even associated with hypercoagulability.59 Finally, the efficacy of using plasma to correct mildly deranged values in conventional laboratory testing has been questioned.55 In a prospective observational study by Abdel-Wahab and colleagues,60 less than 1% of patients with an initial INR between 1.1 and 1.85 attained a normal INR (defined as o1.1) after plasma transfusion. Plasma transfusion might normalize deranged INR values and thromboelastometric variables only when transfused in amounts up to 30 mL/kg body weight, whereas lower doses were not effective in normalizing laboratory values or thromboelastometric variables.61–63 In addition to actually ameliorating laboratory parameters, benefits due to plasma transfusion (eg, prevention or reduction of bleeding) have been questioned.50 Importantly, transfusion of plasma products might be associated with adverse outcomes including allergic reactions, transfusion-related circulatory overload, transfusion-related acute lung injury, transfusion-transmitted infections,13,64 and multi-organ failure,11 albeit at a decreasing rate due to safety precautions and new techniques such as solvent/detergent plasma preparation.65 However, the recently published PROPPR trial in severely injured patients with massive hemorrhage showed no change in adverse outcomes in patients with increased plasma transfusion.66 Although some clinical settings might provide fast turnaround times within 10 minutes for conventional coagulation testing,67 PT/aPTT testing generally requires turnaround times of more than 30 minutes.68 Accordingly, plasma products commonly are transfused empirically and without any laboratory testing in bleeding patients.6,14,46,69 The time requirements of PT/aPTT testing might contribute to the finding that up to 83% of transfused plasma products have been rated as inappropriate by some authors.51,70 Point-of-care devices might be advantageous regarding rapid diagnosis of hemostatic disorders. Unfortunately, the precision of point-of-care devices for INR measurements is highly limited in the perioperative

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setting.71 Other point-of-care devices such as ROTEM or TEG have been used in the setting of cardiac surgery. The ROTEM/ TEG-based algorithm showed significant reduction in the use of plasma products compared to a coagulation management based on conventional laboratory testing in a recent review.6 However, threshold values based on ROTEM/TEG vary widely between the 2 devices and the different studies.14,39,45,46,72–74 INFUSION OF COAGULATION FACTOR CONCENTRATES

Coagulation factor concentrates such as purified human fibrinogen concentrate and prothrombin complex concentrates (PCCs) are considered to be valuable alternatives to plasma transfusion and are used regularly for the substitution of low levels of coagulation factors during and after surgery in many European countries. The importance of sufficient plasma fibrinogen levels to reduce bleeding in the early postoperative period after cardiac surgery has been shown by several laboratory investigations and non-randomized clinical studies.5,27,54,75,76 Fibrinogen concentrate has been shown to better restore fibrinogen level than plasma.50 In bleeding patients with intake of vitamin K antagonists, PCCs have been shown to more rapidly reverse anticoagulation77 while being a safe alternative.78 Some authors also used PCCs in the treatment of coagulopathic patients due to hemodilution.14,45,46 Fibrinogen Concentrate/Cryoprecipitate The administration of fibrinogen concentrate for acquired hypofibrinogenemia is approved only in some European countries.75 In the U.S., fibrinogen concentrate is licensed for the therapy of congenital hypofibrinogenemia. As an alternative, cryoprecipitates can be used for the perioperative substitution of fibrinogen in the U.S. and the U.K.. Preliminary results suggest that the use of fibrinogen concentrate and cryoprecipitate are equally efficacious when using comparable dosages.79 Plasma products have fibrinogen levels, which are usually around 200 mg/dL.80,81 Plasma products are, therefore, poor sources for fibrinogen substitution50 unless given very early and in large amounts. Even massive transfusion protocols using an RBC:fresh frozen plasma:platelets ratio of 1:1:1 result in fibrinogen levels of about 60% of their usual concentration (eg, fibrinogen levels of about 120 to 160 mg/dL).82 The discussion regarding the perioperative administration of fibrinogen concentrate is ongoing due to missing large randomized trials.2 There is only 1 small randomized trial showing the

beneficial effect of fibrinogen administration after major cardiac surgery.30 The administration of fibrinogen concentrate or cryoprecipitate might reduce postoperative bleeding and transfusion. However, the liberal fibrinogen substitution in the perioperative setting cannot be recommended83 for several reasons. First, bleeding in the perioperative setting is often multifactorial.5 Second, threshold levels for fibrinogen substitution are discordant (Table 3).5,54,81,84 Third, current recommendations about the substitution target to reduce the incidence of allogeneic blood products transfusions are unclear5,54,81,85 due to missing adequately powered randomized trials.83 Finally, it is unclear whether fibrinogen substitution improves patients’ outcomes.83 Plasma threshold levels for fibrinogen substitution of 80 to 100 mg/dL are still widely reported and recommended in guidelines (Table 3).86–89 This minimal fibrinogen level of 100 mg/dL is more of a historic and empiric value as it results from studies in patients with afibrinogenemia and is not based on solid clinical evidence.90 Today, many experts regard that minimal level as too low of a threshold for initiating exogenous fibrinogen replacement. The national guidelines in Germany and Austria recommend higher levels of 150 to 200 mg/dL in concordance with the Task Force of Advanced Bleeding Care in Trauma84,85 and the European recommendations in perioperative bleeding.54 The latter recommendations are based on newer reports from bleeding patients after cardiac surgery,91,92 obstetric hemorrhage,93 and in vitro studies94 showing that fibrinogen levels Z200 mg/dL are associated with improved clot formation and lower bleeding tendency. Several studies used ROTEM for triggering and dosing fibrinogen concentrates.6,14,45,46 Clot firmness in thromboelastometric tests specific for fibrinogen (FIBTEM) shows a very good correlation with fibrinogen levels.95 Suggested threshold values in ROTEM ranged from 8 to 10 mm in clot firmness after 10 or 15 minutes and in maximum clot firmness.6,96 These threshold values might vary for different surgical procedures or etiologies of bleeding (eg, trauma, obstetrics, liver transplantation, cardiac surgery). Estimation of fibrinogen level is also possible in TEG using the functional fibrinogen assay;97 however, the authors are not aware of clinical studies that used this assay for fibrinogen administration. Over substitution with fibrinogen concentrates or cryoprecipitate might be associated with thromboembolic complications after cardiovascular surgery.98–100 A recent propensity-score analysis in patients undergoing cardiac surgery found that substitution of fibrinogen level by concentrates aiming for a

Table 3. Suggested Targets and Thresholds of Fibrinogen Plasma Level in Perioperative and Massive Bleeding From Different Guidelines Country

US UK

Scandinavia Germany Austria Europe

Organization

Year

Transfusion Target or Trigger Threshold

American Society of Anesthesiologists86 American Red Cross87 British Committee for Standards in Hematology89 UK Blood Service88 Association of Anaesthetists of Great Britain and Ireland124 Specialists in Trauma Care from all Scandinavian countries125 German Medical Association126 Austrian Society of Anesthesiologists, Resuscitation and Intensive Care Medicine127 European Society of Anesthesiology54 Task Force for Advanced Bleeding Care in Trauma84

2006

o0.8-1 g/L o1 g/L o1 g/L o1 g/L o1 g/L 1 g/L o1.5 g/L o1.5-2.0 g/L o1.5-2.0 g/L o1.5-2.0 g/L

2006 2007 2010 2008 2009 2010 2013 2013

772

target level of about 200 mg/dL was not associated with worse 1-year outcomes.98 Recovery of fibrinogen level happens within the first few days after surgery, as fibrinogen is an acute-phase protein.2,101 Therefore, fibrinogen or cryoprecipitate usually should be restricted to the intraoperative period and the first hours after surgery. Interestingly, no differences were found between fibrinogen levels in substituted and non-substituted patients after the first postoperative days.30,98,102 Prothrombin Complex Concentrates (PCCs) PCCs are a human plasma-derived lyophilized product containing the vitamin-K-dependent coagulation factors FII (prothrombin), FVII, FIX, and FX. PCCs are available as so-called 3factor PCCs with low levels of FVII (commonly used in the US) or as 4-factor PCCs with higher levels of FVII (mainly used in Europe). PCCs may differ considerably in their contents of the anticoagulants protein C, protein S, and antithrombin as well as heparin.103 However, concentrations of these antithrombotic agents generally are low, and their clinical relevance is unclear. Originally, PCCs were developed for FIX replacement in hemophilia B; therefore, they are standardized for FIX concentration. Today, the most common indications for their use are the rapid reversal of oral anticoagulation (vitamin K antagonists) and the treatment of patients with a deficiency of vitamin-Kdependent coagulation factor, such as in liver failure. Recently, U.S. and European guideline papers recommended the off-label use of PCCs in patients with trauma and massive bleeding after surgery.21,54 This off-label use of PCC is potentially deleterious for several reasons. First, most available PCCs are not balanced regarding their pro- and anticoagulant properties. It is not known at the moment whether or not the differences in thrombin generation potential among different PCCs is of clinical importance.104 Second, patients with massive bleeding have low antithrombin levels.16,105 Administration of PCCs might increase their risk of thromboembolic complications in the early recovery period due to prolonged elevation of thrombin generation potential16 together with the usual increases of fibrinogen level and platelet count.106 The latter has been shown in trauma patients16 but not in patients undergoing cardiac surgery. In a porcine hepatic injury model, disseminated intravascular coagulation was reported in 4 out of 9 animals receiving 50 IU/kg of PCC.107 As shown in a computational study, the supplementation of PCC in combination with antithrombin concentrate might be potentially safer,108 but the use of an anticoagulant in actively bleeding patients may be considered contradictory. Finally, standard coagulation tests including PT and aPTT do not adequately reflect the patient’s thrombin generation potential and antithrombin levels.109 PT or INR are, therefore, questionable triggers for PCC administration in the perioperative patients after hemodilution and situations other than treatment with vitamin K antagonists. Similarly, empirical threshold values based on clotting time in ROTEM (eg, clotting time [CT] 480 sec or CT 41.5  normal) have been suggested in different studies,6 but they never have been adequately tested. Recombinant Activated Factor VII (rFVIIa) The licensed indication of rFVIIa is the treatment of hemophilia with inhibitors and of some rare inherited platelet dysfunction.

BOLLIGER ET AL

Especially in the US, rFVIIa has undergone tremendous off-label use within the first 10 years after its approval.110 Thereby, rFVIIa was used prophylactically as a treatment option in Jehovah’s witness patients111 or as a rescue medication in refractory bleeding in postoperative patients (“last ditch” therapy).110 Whereas a Cochrane review on the prophylactic administration of rFVIIa in non-hemophilia patients was not associated with increased morbidity,112 a more recent report on the off-label use of rFVIIa suggested an association with relevantly increased morbidity and mortality.113 In agreement, another meta-analysis of off-label use of rFVIIa in cardiac surgery suggested a higher rate of thromboembolic adverse events, especially in the arterial system.15 Given its “off-label” indication, unclear treatment triggers, such as “intractable bleeding after cardiac surgery,” questionable efficacy,112 and an increased thromboembolic risk,15 the Canadian National Advisory Council recommended that rFVIIa should no longer be used off-label for the prevention and treatment of bleeding non-hemophilic patients after cardiac surgery.114 In contrast, the current guidelines from the Society for Thoracic Surgery and the Society of Cardiovascular Anesthesiologists recommend the use of rFVIIa in patients with refractory microvascular bleeding after cardiac surgery (recommendation IIb).21 Further, in vitro data suggests a favorable effect of rFVIIa on thrombin generation in patients with recent intake of platelet inhibitors.115 Patients undergoing urgent or emergent cardiac surgery while under the treatment of highly effective antiplatelet agents (eg, clopidogrel, prasugrel, and ticagrelor) might be an exception for the very strict recommendation of the Canadian National Advisory Council. Despite suggested increased risk of adverse events in meta-analysis and Cochrane reviews, this safety risk might be counter balanced by the risk of uncontrolled bleeding potentially increasing morbidity and mortality. Others Factor Concentrates Activated factor XIII (FXIII) is essential for clot stability by interacting with alpha 2–antiplasmin. It has been suggested that FXIII levels o60% should be substituted with FXIII concentrate.54 However, FXIII levels were not associated with increased postoperative bleeding in an observational study,116 and a recent randomized study in patients undergoing cardiac surgery failed to demonstrate any beneficial effect of FXIII administration.117 The evidence for the perioperative use of FXIII concentrate is low, and the use of FXIII concentrate in massive postoperative bleeding, therefore, cannot be recommended at the moment. Further, there is no evidence that factor concentrates other than the above-described might be indicated in the perioperative treatment of patients undergoing cardiac surgery except for the treatment of specific single factor deficiencies. As mentioned above, plasma exchange can be performed using donor plasma or solvent/detergent plasma in the case of rare factor deficiency.118 Further case reports119–122 suggest that patients with hereditary coagulation disorders can undergo cardiac surgery without increased risk of bleeding when meticulous hemostatic treatment regimens are considered. CONCLUSIONS

No medical intervention is without risks, but in principle, these risks should be offset or justified by immediate or long-

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term benefits by the intervention itself. Given the low amount of evidence in the field of perioperative hemostatic therapy, it is obvious that there are extensive debates pertaining to specific treatment options. The preemptive transfusion of plasma and platelet concentrates to prevent or treat coagulopathy is unproven and puts the patient at risk for adverse effects of unnecessarily or inappropriately transfused hemostatic products.7,13 Transfusion algorithms based on ROTEM/TEG showed lower transfusion rates for plasma, platelets, and also RBC concentrates, whereas the frequency and amount of

infused coagulation factor concentrates were comparable with transfusion algorithms based on conventional coagulation testing or on clinical guidance only.6 However, threshold values on ROTEM/TEG might be set individually and should be adjusted based on the locally available coagulation tests and hemostatic products. Additionally, antifibrinolytics, desmopressin, and topical hemostatic agents might be helpful in successful bleeding control after cardiac surgery. Adequately powered and performed studies are urgently required to better define evidence-based and generally accepted transfusion thresholds.

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