Next Article in Journal
Children and Adolescents with Co-Occurring Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: A Systematic Review of Multimodal Interventions
Previous Article in Journal
High-Complexity Questions and Their Answers for Everyday Heart Failure
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 14
Issue 11
10.3390/jcm14114001
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Intraoperative Hemostatic Agents in Thoracic Aortic Surgery—A Scoping Review

by
Maite M. T. van Haeren
1,2,
Caitlin Bozic
1,
Jennifer S. Breel
1,
Susanne Eberl
1,
Faridi S. Jamaludin
3,
Denise P. Veelo
1,
Marcella C. A. Müller
2,
Alexander P. J. Vlaar
2 and
Henning Hermanns
1,*
1
Department of Anesthesiology, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands
2
Department of Intensive Care, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands
3
Medical Library, Amsterdam University Medical Centers, Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2025, 14(11), 4001; https://doi.org/10.3390/jcm14114001
Submission received: 7 May 2025 / Revised: 2 June 2025 / Accepted: 4 June 2025 / Published: 5 June 2025
(This article belongs to the Section Anesthesiology)
Browse Figure
Versions Notes

Abstract

:
Background/Objectives: Patients undergoing open thoracic aortic surgery have the highest bleeding complication rates within cardiac–vascular surgery, but research on coagulation management mostly targets general cardiac surgery. This scoping review evaluates current evidence on intraoperative hemostatic agents and their effect on bleeding and blood transfusions in these patients. Methods: We searched MEDLINE (PubMed), Embase, and Cochrane Library on 2 July 2024. Eligible studies included randomized controlled (RCT) and observational trials with a comparison group and at least a sub-analysis regarding thoracic aortic surgery (excluding thoracoabdominal and isolated descending aorta surgery). Results: Our search yielded 4697 articles, with 33 included. These covered antifibrinolytics (3 RCTs, 10 observational studies), fibrinogen supplementation (3 RCTs, 4 observational studies), recombinant factor VIIa (rFVIIa, 8 observational studies), blood products (3 observational studies), and factor eight inhibitor bypassing activity (FEIBA, 1 RCT, 1 observational study). The impact of blood product transfusion on bleeding control is unclear due to a lack of placebo or no-transfusion comparisons, though it appears associated with more complications. Both FEIBA studies suggest reduced blood product use in aortic dissection surgery—one as rescue therapy, the other as standard treatment. Evidence on fibrinogen supplementation is mixed: a multicenter RCT showed increased transfusions, while smaller RCTs and observational studies showed reductions, possibly due to differences in pretreatment fibrinogen levels and patient selection. Observational studies on rFVIIa show conflicting results, likely due to selection bias. Two small RCTs—one on TXA, one on aprotinin—suggest reduced transfusions and blood loss. Comparative studies of different types of antifibrinolytics yielded conflicting results. Conclusions: Evidence on hemostatic agents in thoracic aortic surgery is limited. Small studies suggest potential for the routine use of antifibrinolytics, FEIBA, and fibrinogen supplementation—but only in bleeding patients with hypofibrinogenemia. High-quality RCTs focused on thoracic aortic procedures are needed to determine optimal coagulation management.

1. Introduction

Patients undergoing open thoracic aortic surgery often have major bleeding complications requiring appropriate coagulation management [1]. Thoracic aortic surgery requires the use of cardiopulmonary bypass (CPB), where the foreign materials can activate the coagulation cascade. Heparin as an anticoagulant is, thus, routinely used and antagonized with protamine after CPB to restore hemostasis [2,3,4]. Nevertheless, both coagulopathy and massive bleeding can occur after CPB [5,6]. These bleeding complications are often a result of acquired platelet dysfunction, increased fibrinolysis, and the depletion of coagulation factors [5,7].
Within cardiac surgery, aortic procedures are associated with the highest bleeding complication rate [8]. These complications can significantly worsen patient outcomes, including transfusion-related adverse events, ischemic complications due to a reduction in organ perfusion, and higher mortality [8,9]. Patients with aortic pathology often already present with dysregulated coagulation before surgery as a result of abnormal blood flow in aortic aneurysms or an intimal tear in aortic dissections [10,11]. These disturbances may activate the coagulation cascade, resulting in coagulopathy and, in extreme cases, disseminated intravascular coagulation (DIC) [10,12].
Systematic reviews on coagulation management in cardiac surgery have been published earlier and are included in guidelines [13,14]. However, they do not make a distinction specifically on thoracic aortic surgery and no other guidelines specifically focused on thoracic aortic surgery. This scoping review aims to evaluate current knowledge on intraoperative hemostatic agents in patients undergoing thoracic aortic surgery. We provide an overview of hemostatic agents used and their impact on bleeding and transfusion requirements and identify existing knowledge gaps and directions for future research.

2. Materials and Methods

2.1. Search Strategy

The Department of Anesthesiology in the Amsterdam UMC, location AMC, performed a search strategy with the help of a medical information specialist (FJ). MEDLINE (PubMed), Embase, and Cochrane Library were searched using predefined search terms from inception until the 2nd of July 2024 (see Supplement S1 for the full search strategy). No filters were used in the search. For the identification of upcoming or ongoing trials, clinicaltrials.gov was searched with the terms “thoracic aortic surgery”, “thoracic aortic aneurysm”, and “acute aortic dissection”, without the use of other filters. This scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15].

2.2. Eligibility Criteria

Thoracic aortic surgery was defined as surgery which required the opening of the thorax, and surgery of the aortic root, ascendens, or arch, with the use of CPB. Surgeries solely on the descending aorta and endovascular surgeries were excluded. Further inclusion criteria were studies written in English, including adult patients, determining the effect of intraoperative administration of blood products, antifibrinolytics, fibrinogen supplementation or coagulation factors, and the effect of these products on bleeding and/or number of blood transfusions. Randomized controlled trials (RCT) and observational trials were included if they comprised of a control group. Studies that primarily focused on the cardiac surgery population but also included thoracic aortic surgery patients were only included if they provided a subgroup analysis. No restrictions were made for the year of publication or size of the study population. Animal studies, in vitro studies, case reports, case series, reviews, editorials, conference notes, and also reports from overlapping or duplicated populations were excluded. Furthermore, non-pharmacological studies for bleeding management (e.g., cell saver, auto-transfusion, and viscoelastic test-guided transfusion algorithms) or topical hemostatic agents were not included in this review.

2.3. Selection and Data Collection Process

Both title and abstract screening and full-text screening were performed by two independent reviewers (MH and CB) using Rayyan [16]. Disagreement on article inclusion were resolved by a third reviewer (HH).
The extraction of data was performed by one reviewer (MH). Data consisted of the first author, year of publication, years of inclusion, population, type of study, number of inclusions, methodology, intervention, outcome measurements, and findings of the included reports.

3. Results

3.1. Included Studies

The initial search after deduplication yielded 4664 articles, of which 295 articles were assessed in full-text form, resulting in 33 included articles (Figure 1). Most exclusions in the full text screening were due to absence of subgroup analysis on thoracic aortic surgery.
Of the included studies, three studies were on blood products as an intervention [17,18,19], two studies were on factor eight inhibitor bypassing activity (FEIBA) [20,21] (Table 1), seven studies were on fibrinogen supplementation [22,23,24,25,26,27,28] (Table 2), eight studies were on recombinant factor VIIa (rFVIIa) [29,30,31,32,33,34,35,36] (Table 3), and thirteen studies were on antifibrinolytics [37,38,39,40,41,42,43,44,45,46,47,48,49] (Table 4). No studies were found on other prothrombin complex concentrates (PCCs), factor XIII, or desmopressin in the context of thoracic aortic surgery.

3.2. Blood Products

Three studies on blood product transfusion were included [17,18,19] (Table 1).
Stensballe et al. (2018) conducted a single-center, single-blinded RCT comparing OctoplastGP (solvent/detergent-treated, virus-inactivated, pooled human plasma, n = 29) to FFP (n = 28) in dissection patients [17]. While patients and study assessors were blinded, clinicians were not, introducing potential bias. Dosing and transfusion protocols were not clearly reported. OctoplastGP reduced intraoperative blood loss (~600 mL), transfusion requirements, and markers of endothelial injury, with no reported safety concerns.
Wu et al. (2014) retrospectively compared dissection patients who received intraoperative platelet transfusion (n = 74) to those who did not (n = 85) [18]. In-hospital mortality was similar between the groups, but the platelet transfused group had a higher frequency of RBC transfusion in larger volumes, postoperative sternal wound infections, and neurological deficits.
Naeem et al. (2018) performed a non-matched retrospective study on aortic dissection patients [19]. Patients receiving >2 units of RBCs (n = 34) had more post-transfusion infections compared to those receiving 0–2 units RBC (n = 68). Similarly, patients given >1 unit of platelets (n = 28) had higher rates of acute kidney injury and atrial fibrillation than those receiving 0–1 unit (n = 74). Both high-transfusion groups had longer hospital stays, but mortality rates were unchanged.
In conclusion, the impact of blood product transfusion on bleeding outcomes remains unclear, as no studies compared transfusion to placebo or no transfusion while focusing on bleeding control. However, blood product transfusion appears to be associated with increased post-transfusion complications.

3.3. Factor Eight Inhibitor Bypassing Activity (FEIBA)

Two studies evaluated the use of FEIBA in aortic dissection surgery [20,21] (Table 1). Sera et al. (2021) conducted a pilot RCT comparing FEIBA (20 IU/kg) to a placebo in six patients per group [20]. The study found numerically lower intraoperative blood products and chest tube drainage, but it was not powered for significance.
Pupovac et al. (2022) performed a retrospective propensity-matched study with 53 patients, administering 500 IU of FEIBA as a salvage measure for persistent bleeding after RBCs, platelets, plasma, and cryoprecipitate [21]. The study showed reduced transfusion requirements in the first 48 h post-surgery, with no difference in thromboembolic complications.
In conclusion, both studies suggest that FEIBA may reduce blood product use in aortic dissection surgery. However, the timing of FEIBA administration was different in these two studies, where it was a rescue therapy in the retrospective study but standard in the pilot RCT.

3.4. Fibrinogen Supplementation

Seven studies on fibrinogen supplementation were included [22,23,24,25,26,27,28]. Several additional studies identified in the full-text review phase were excluded as they were re-analyses or post hoc analyses of the REPLACE trials. Only the original REPLACE trials were included. Both the initial single-center REPLACE trial and the subsequent larger multicenter trials were included, as they recruited different patient populations (Table 2).

3.4.1. Fibrinogen Supplementation Compared to Placebo

Three RCTs evaluated fibrinogen supplementation. The multicenter REPLACE trial (2016, 78 patients with fibrinogen vs. 74 with placebo) used ROTEM-guided dosing targeting a FIBTEM A5 of 22 mm, with a mean fibrinogen dose of 6.29 g [22]. Fibrinogen was given if the 5 min post-CPB bleeding mass (measured by sponges and suction canisters) ranged between 60 and 250 g. Unexpectedly, total 24 h blood product use was higher in the fibrinogen group (median five vs. three units), likely due to higher pretreatment bleeding mass, low overall bleeding rates, and variability in adherence to the transfusion algorithm. Notably, 31% of patients had a pretreatment fibrinogen level > 2 g/L. There were no differences in thromboembolic events.
The earlier single-center REPLACE study (2013) with 29 patients receiving fibrinogen concentrate and 32 receiving a placebo showed reduced blood product use with a median fibrinogen dose of 8 g [23].
A more recent single-center RCT by Vlot et al. (2022, 10 patients per group) used the same 5 min bleeding mass as REPLACE. However, fibrinogen dosage was based on weight without applying a target ROTEM value [24]. In their study, 90% (18 patients) had pretreatment fibrinogen levels < 2 g/L. No difference in blood product use was found, though the 5 min bleeding mass was non-significantly reduced by 52% in the fibrinogen group vs. 32% in the placebo group. The study was terminated early due to a slow inclusion rate.

3.4.2. Fibrinogen Supplementation Compared to No Treatment

Three observational studies compared fibrinogen supplementation to no supplementation.
Kikura et al. (2023) conducted a multicenter retrospective study (285 fibrinogen vs. 154 control patients) in both elective and emergency thoracic aortic surgery patients, administering 2–3 g fibrinogen after CPB cessation if fibrinogen < 1.0–1.2 g/L or FIBTEM A10 < 6 mm [25]. No differences were found in major bleeding, re-exploration, or mortality. RBC and FFP transfusions were reduced, while platelet transfusion was increased. A subgroup analysis of patients with fibrinogen levels < 1.5 g/L suggested that fibrinogen reduced major bleeding, despite the study’s transfusion protocol requiring all included patients to have low fibrinogen levels. Li et al. (2022) studied 105 aortic dissection patients receiving 2 g fibrinogen preoperatively and 54 controls, finding reduced intraoperative RBC transfusion, chest tube drainage, and shorter ventilation and hospital stays [26]. Guan et al. (2023) compared 54 aortic dissection patients receiving 25–50 mg/kg fibrinogen after protamine reversal to 30 controls, showing reduced blood transfusions and chest tube drainage [27].

3.4.3. Fibrinogen Supplementation Compared to FFP

Yamamoto et al. (2014) compared fibrinogen concentrate (n = 25, 3–5 g) to FFP (n = 24) in patients with fibrinogen < 1.5 g/L at the end of CPB, including both elective and dissection cases. Fibrinogen concentrate significantly reduced intraoperative blood loss and led to lower RBC, FFP, and platelet transfusion requirements [28].
In conclusion, the evidence on fibrinogen supplementation in thoracic aortic surgery remains inconclusive. The multicenter REPLACE RCT showed a negative effect (more blood transfusion), while the single-center REPLACE RCT and a smaller single-center RCT suggested positive effects (less blood transfusion). Three retrospective studies indicated benefits of fibrinogen supplementation with no increased thromboembolic complications, with one showing superiority over FFP. Differences in pretreatment fibrinogen levels and patient selection may explain the variability in results.

3.5. Recombinant Factor VIIa (rFVIIa)

Eight studies on rFVIIa were included [29,30,31,32,33,34,35,36] (Table 3). Yan et al. (2014) conducted a non-randomized RCT in aortic dissection patients, where treatment decisions were determined by the patients’ family, with 25 patients in the intervention group receiving rFVIIa (2.4 mg) plus platelet transfusion and 46 patients receiving conventional therapy (RBCs, FFP, platelets, and cryoprecipitate) after the cessation of CPB [29]. The intervention reduced intraoperative transfusion and postoperative platelet use, but no differences were observed in postoperative blood loss or adverse events.
Six observational studies in dissection patients and one observational study on thoracic aortic patients including dissections were included: Zindovic et al. (2017) performed a multicenter propensity-matched study on 120 dissection patients, but rFVIIa dosage and transfusion protocols were not clearly defined [30]. The rFVIIa group received more blood products, had more chest tube drainage, and had more re-explorations due to bleeding. Keyoumu et al. (2024) found that rFVIIa reduced chest tube drainage and RBC/FFP transfusions but was associated with more thromboembolic complications and higher mortality [31]. Andersen et al. (2012) reported reduced postoperative blood product use, with no difference in complications in the rFVIIa group [32]. Goksedef et al. (2012) found that rFVIIa reduced postoperative chest tube drainage, transfusion, and reoperations [33]. Ise et al. (2022) reported no difference in blood loss or transfusion between the rFVIIa and no rFVIIa group [34]. Tritapepe et al. (2007) showed that rFVIIa reduced postoperative blood loss but required more blood products [35]. Lastly, Hang et al. (2021) compared rFVIIa patient controls in both elective and dissection patients and found was no difference in postoperative transfusion, chest tube drainage, or complications, with a trend toward higher reoperation rates [36].
In conclusion, the studies on the efficacy of rFVIIa present conflicting results. Bias appears to be present, as the rFVIIa groups often show higher intraoperative blood product use, even after matching. The non-randomized prospective trial has limitations, such as unclear descriptions of the transfusion protocol in the usual care group.

3.6. Antifibrinolytics

3.6.1. Tranexamic Acid (TXA) Versus Placebo or No TXA

In an RCT, Casati et al. (2002) compared TXA (1 g bolus before incision, 400 mg/hour infusion) to a placebo in elective thoracic aortic surgery [37] (Table 4). In 29 patients per group, TXA reduced perioperative red blood cell (RBC) transfusion and postoperative blood loss. The incidence of excessive bleeding (>600 mL/24 h) was lower in the TXA group, with no difference in thromboembolic complications. Similarly, Ahn et al. (2015) compared a continuous TXA infusion (16 mg/kg/h) to no TXA in 26 dissection patients, demonstrating reduced transfusion requirements and chest tube drainage, again without increased thromboembolic complications [38].

3.6.2. TXA Versus Epsilon-Aminocaproic Acid (EACA) or Aprotinin

In an RCT comparing TXA to EACA, Makhija et al. (2013) included 61 patients undergoing thoracic aortic surgery (TXA: 31 patients, 10 mg/kg bolus, 1 mg/kg/h infusion and EACA: 30 patients, 50 mg/kg bolus, 25 mg/kg/h infusion) [39]. No significant differences in blood loss or transfusion requirements were found, though TXA showed a non-significant trend towards more seizures.
Four retrospective studies compared TXA to aprotinin. Reidy et al. (2024) matched 49 pairs of dissection patients receiving TXA (1 g bolus, 500 mg/h infusion) or aprotinin (2 million unit bolus, 500,000 units/h infusion) [40]. No differences were found in transfusions, drainage, mortality, or reoperation. Nicolau-Raducu et al. (2010) showed a trend toward lower blood product use in the aprotinin group but more renal dysfunction [41]. Sniecinski et al. (2010) found that TXA was associated with increased fresh frozen plasma (FFP) and cryoprecipitate transfusions, with a non-significant higher incidence of seizures [42]. Chivasso et al. (2018) analyzed 107 matched patients, comparing TXA to aprotinin, with no differences in major bleeding or reoperation, though FFP use was higher in the aprotinin group [43]. Sedrakyan et al. (2006) found that aprotinin (84 matched pairs) reduced platelet transfusions and chest tube drainage, but the timeframe of the outcomes was unclear [44].

3.6.3. Aprotinin Versus Placebo or No Aprotinin

Numerous studies on aprotinin use in cardiac surgery appeared following its market withdrawal after the BART trial [50] due to an increased risk of death in the trial, though debate persists within the scientific community regarding the appropriateness of this decision. In this review, we only report the studies on aprotinin in patients undergoing thoracic aortic surgery. In a placebo-controlled trial, Ehrlich et al. (1998) randomized 25 patients to receive 140 mg aprotinin and 25 patients to receive a placebo (saline). While no difference in renal function (primary outcome) was found, aprotinin reduced blood product use and chest tube drainage [45]. Westaby et al. (1994) compared 53 aprotinin patients (100 mg bolus, 25 mg/h infusion) to 29 controls and found no reduction in chest tube drainage; Interestingly, they reported increased blood loss in aprotinin-treated patients after 1989, coinciding with the introduction of hypothermic circulatory arrest, though blood loss assessment methods were unclear [46]. In contrast, Parolari et al. (1997) found reduced blood product use and blood loss in patients receiving 700 mg aprotinin (18 vs. 21 controls) but noted a trend toward more neurological deficits and complications [47]. Similarly, Seigne et al. (2000) showed reduced RBC, FFP, and platelet use with aprotinin (5 mg bolus, 5 mg/h infusion, 9 patients vs. 10 controls) without an effect on chest tube drainage [48].

3.6.4. Aprotinin Versus EACA

A single retrospective study by Eaton et al. (1998) compared aprotinin (n = 29, 100 mg bolus, 25 mg/h infusion) to EACA (n = 19, 5–40 g bolus, 25 mg/h infusion) in thoracic aortic surgery [49]. Five patients received both agents. No differences were found in RBC transfusion or chest tube drainage at six and twelve hours. Intraoperatively, the EACA group received more platelet transfusions and had a higher incidence of acute renal failure.
In conclusion, two small RCTs (each with <30 patients per group) comparing antifibrinolytics to placebo or no treatment, one with TXA and one with aprotinin, demonstrated reduced transfusion requirements and chest tube drainage without an increase in adverse events. The available retrospective studies provided inconsistent results, as follows: (1) three studies comparing aprotinin to no treatment showed mixed findings, with two suggesting a lack of benefit or potential harm, while one reported a positive effect (of note, the aprotinin studies were all published in the years 1994–2000), (2) one study comparing TXA to no treatment reported a positive effect for TXA, and (3) comparative studies between different types of antifibrinolytics gave no consistent signal favoring one over the other. The current evidence base is limited by heterogeneous study designs, varying antifibrinolytic dosages, and inconsistent outcome reporting, making a meta-analysis not feasible.

3.7. Upcoming or Ongoing Trials

Clinicaltrials.gov was searched on the 12th of March 2025 to identify upcoming or ongoing trials with the search term ‘thoracic aortic surgery’, resulting in 161 hits. No trials were found on intraoperative systemic hemostatic interventions. The search term ‘thoracic aortic aneurysm’ produced 388 hits. No relevant trials were found. The search term ‘acute aortic dissection’ yielded 396 results, of which one was a relevant non-randomized prospective trial on fibrinogen concentration (NCT02542306); however, this had not been updated since 2015 and no linked article could be found.

4. Discussion

There is limited evidence on hemostatic agents in thoracic aortic surgery patients. Smaller studies suggest potential for routine use of antifibrinolytics, FEIBA, and possibly fibrinogen supplementation, but only in bleeding patients with hypofibrinogenemia. The evidence on rFVIIa is conflicting. No studies on other prothrombin complex concentrates, FXIII, or desmopressin were found. Further high-quality, ideally randomized controlled trials, specifically focused on thoracic aortic procedures, are necessary to identify optimal coagulation management in these vulnerable patients.

4.1. Unique Challenges in Thoracic Aortic Surgery

Thoracic aortic surgery presents distinct hemostatic challenges compared to general cardiac surgery. Excessive bleeding occurs at a significantly higher rate (~15%) compared to coronary artery bypass grafting (CABG) (~5%) [8]. This is due to the complexity of the procedure, which often involves deep hypothermic circulatory arrest, prolonged aortic clamping, and extended CPB—all of which impact coagulation [51]. Furthermore, pre-existing coagulation abnormalities in aortic aneurysms and aortic dissections, as shown by elevated D-dimer levels [52,53] and coagulation factor consumption [10,11,54,55], may increase bleeding risk. Given these higher event rates, general cardiac surgery studies with lower event rates may underestimate the effect of interventions in this population. A further consideration is the difference between elective and acute aortic procedures. Elective surgeries, such as planned aortic aneurysm repairs, allow for preoperative optimization of coagulation status and blood conservation strategies. In contrast, acute aortic surgeries, particularly those for dissections, are performed under emergency conditions with high transfusion requirements, coagulopathy, and greater reliance on hemostatic interventions. This distinction is not always addressed in existing studies but may influence both clinical decision making and research outcomes.

4.2. Comparison with Guidelines

The 2024 European Association for Cardio-Thoracic Surgery (EACTS) and European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) guidelines strongly recommend antifibrinolytics, particularly TXA, to reduce bleeding, transfusions, and reoperations [13,14]. The guideline does not specifically make a distinction between cardiac surgery and thoracic aortic surgery. Of note, evidence for EACA is limited, and aprotinin, which may be effective, carries safety concerns. Our review aligns with these conclusions, finding no significant differences between TXA, EACA, and aprotinin. Additionally, a recent meta-analysis not included in the guideline further supports the benefits of TXA [56].
For fibrinogen supplementation, the guideline advises its use only in patients with confirmed hypofibrinogenemia, which aligns with our findings. While the REPLACE trials showed no overall beneficial effect, observational studies indicated benefits in patients with low fibrinogen levels. The guideline also favors PCC over FFP for coagulopathic bleeding, a recommendation supported by recent findings [57]. However, the Society of Cardiovascular Anesthesiologists (SCA) guideline does not provide a strong recommendation for routine use of PCC [14]. We found no studies for PCC in thoracic aortic surgery, apart from FEIBA, which showed promising results but requires further study.
Regarding rFVIIa, the guidelines advise against prophylactic use but allows for its use in refractory bleeding. Based on our review no definitive conclusion on rFVIIa use in thoracic aortic surgery could be drawn, as studies showed conflicting results regarding mortality and thromboembolic events.
For desmopressin and FXIII, no thoracic aortic surgery-specific studies were found. The EACTS-EACTA guidelines advise against routine use of FXIII and limits desmopressin to select cases. Regarding blood product use, both guidelines recommend restrictive RBC transfusion thresholds of ≤7.5 g/L.
While our findings largely align with current guidelines regarding antifibrinolytics and fibrinogen supplementation, specific data for thoracic aortic surgery remain sparse, and many recommendations in the guidelines are extrapolated from general cardiac surgery. Larger, targeted trials are needed to refine guidelines for this high-risk population.

4.3. Knowledge Gaps and Future Research

The EACTS/EACTAIC guidelines identify knowledge gaps in intraoperative procoagulant products, including TXA timing and dose, the role of aprotinin, and the impact of decreased FXIII activity. We argue that larger RCTs are needed specifically for thoracic aortic surgery, as these patients are at higher risk for bleeding and complications.
One key research priority is to stratify patients before study inclusion, ensuring that interventions are tested in those with certain documented coagulation profiles. For example, while the REPLACE trials on fibrinogen showed no benefit overall, a trial focusing solely on patients with hypofibrinogenemia (<1.5 g/L) could yield more meaningful results. Similarly, further studies on FEIBA, particularly in a randomized setting, are warranted.
Another challenge is the heterogeneity in study designs, including differences in dosing regimens, transfusion protocols, and outcome measures. Standardizing outcome reporting, particularly regarding bleeding assessment, is essential. Many studies lack clarity in defining blood loss, as factors, like cell saver blood, hemodilution, and gauze-absorbed bleeding, complicate accurate measurement. A promising measure could be the Universal Definition of Perioperative Bleeding (UDPB) score [58], which includes transfusions, reoperations, and chest tube drainage and is, among others, one of the recommendations in a recent consensus statement from 2025 [59]. This score has been validated for cardiac surgery and correlates with mortality. However, its application to thoracic aortic surgery remains untested and could be a valuable research direction.

5. Conclusions

Patients undergoing thoracic aortic surgery face distinct challenges in coagulation management that necessitate dedicated studies rather than extrapolation from general cardiac surgery. The current evidence base is limited, but small studies suggest potential benefits for routine antifibrinolytic use, FEIBA, and fibrinogen supplementation in bleeding patients with hypofibrinogenemia. Evidence for rFVIIa remains conflicting, and no studies on other PCCs, FXIII, or desmopressin were identified. Larger randomized trials with standardized outcome measures are required to refine hemostatic strategies for this high-risk population.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm14114001/s1, S1: Search Strategy.

Author Contributions

Conceptualization, H.H.; methodology, M.M.T.v.H., C.B., and F.S.J.; data curation, M.M.T.v.H. and C.B.; writing—original draft preparation, M.M.T.v.H.; writing—review and editing, all authors; visualization, M.M.T.v.H.; supervision, H.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

The search strategy can be found in the Supplementary File.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
EACAEpsilon-aminocaproic acid
FEIBAFactor eight inhibitor bypassing activity
FFPFresh frozen plasma
PCCProthrombin complex concentrate
rFVIIaRecombinant factor VIIa
RCTRandomized controlled trial
TXATranexamic acid

References

  1. Zhang, C.H.; Ge, Y.P.; Zhong, Y.L.; Hu, H.O.; Qiao, Z.Y.; Li, C.N.; Zhu, J.M. Massive Bleeding After Surgical Repair in Acute Type A Aortic Dissection Patients: Risk Factors, Outcomes, and the Predicting Model. Front. Cardiovasc. Med. 2022, 9, 892696. [Google Scholar] [CrossRef]
  2. Ranucci, M.; Baryshnikova, E. Inflammation and coagulation following minimally invasive extracorporeal circulation technologies. J. Thorac. Dis. 2019, 11 (Suppl. S10), S1480–S1488. [Google Scholar] [CrossRef] [PubMed]
  3. Sniecinski, R.M.; Chandler, W.L. Activation of the hemostatic system during cardiopulmonary bypass. Anesth. Analg. 2011, 113, 1319–1333. [Google Scholar] [CrossRef] [PubMed]
  4. Boer, C.; Meesters, M.I.; Veerhoek, D.; Vonk, A.B.A. Anticoagulant and side-effects of protamine in cardiac surgery: A narrative review. Br. J. Anaesth. 2018, 120, 914–927. [Google Scholar] [CrossRef]
  5. Jimenez Rivera, J.J.; Iribarren, J.L.; Raya, J.M.; Nassar, I.; Lorente, L.; Perez, R.; Brouard, M.; Lorenzo, J.M.; Garrido, P.; Barrios, Y.; et al. Factors associated with excessive bleeding in cardiopulmonary bypass patients: A nested case-control study. J. Cardiothorac. Surg. 2007, 2, 17. [Google Scholar] [CrossRef] [PubMed]
  6. Bolliger, D.; Tanaka, K.A. Coagulation Management Strategies in Cardiac Surgery. Curr. Anesthesiol. Rep. 2017, 7, 265–272. [Google Scholar] [CrossRef]
  7. Khuri, S.F.; Wolfe, J.A.; Josa, M.; Axford, T.C.; Szymanski, I.; Assousa, S.; Ragno, G.; Patel, M.; Silverman, A.; Park, M.; et al. Hematologic changes during and after cardiopulmonary bypass and their relationship to the bleeding time and nonsurgical blood loss. J. Thorac Cardiovasc. Surg. 1992, 104, 94–107. [Google Scholar] [CrossRef]
  8. Al-Attar, N.; Johnston, S.; Jamous, N.; Mistry, S.; Ghosh, E.; Gangoli, G.; Danker, W.; Etter, K.; Ammann, E. Impact of bleeding complications on length of stay and critical care utilization in cardiac surgery patients in England. J. Cardiothorac. Surg. 2019, 14, 64. [Google Scholar] [CrossRef]
  9. Zindovic, I.; Sjogren, J.; Bjursten, H.; Bjorklund, E.; Herou, E.; Ingemansson, R.; Nozohoor, S. Predictors and impact of massive bleeding in acute type A aortic dissection. Interact. Cardiovasc. Thorac. Surg. 2017, 24, 498–505. [Google Scholar] [CrossRef]
  10. Paparella, D.; Rotunno, C.; Guida, P.; Malvindi, P.G.; Scrascia, G.; De Palo, M.; de Cillis, E.; Bortone, A.S.; de Luca Tupputi Schinosa, L. Hemostasis alterations in patients with acute aortic dissection. Ann. Thorac. Surg. 2011, 91, 1364–1369. [Google Scholar] [CrossRef]
  11. Tanigawa, Y.; Yamada, Y.; Nakamura, K.; Yamashita, T.; Nakagawachi, A.; Sakaguchi, Y. Preoperative disseminated intravascular coagulation complicated by thoracic aortic aneurysm treated using recombinant human soluble thrombomodulin: A case report. Medicine 2021, 100, e25044. [Google Scholar] [CrossRef] [PubMed]
  12. Yamada, S.; Asakura, H. Therapeutic Strategies for Disseminated Intravascular Coagulation Associated with Aortic Aneurysm. Int. J. Mol. Sci. 2022, 23, 1296. [Google Scholar] [CrossRef] [PubMed]
  13. Casselman, F.P.A.; Lance, M.D.; Ahmed, A.; Ascari, A.; Blanco-Morillo, J.; Bolliger, D.; Eid, M.; Erdoes, G.; Haumann, R.G.; Jeppsson, A.; et al. 2024 EACTS/EACTAIC Guidelines on patient blood management in adult cardiac surgery in collaboration with EBCP. Eur. J. Cardiothorac. Surg. 2024, 67, ezae352. [Google Scholar] [CrossRef]
  14. Raphael, J.; Mazer, C.D.; Subramani, S.; Schroeder, A.; Abdalla, M.; Ferreira, R.; Philip, E.R.; Nichlesh, P.; Ian, W.; Philip, E.G.; et al. Society of Cardiovascular Anesthesiologists Clinical Practice Improvement Advisory for Management of Perioperative Bleeding and Hemostasis in Cardiac Surgery Patients. Anesth. Analg. 2019, 129, 1209–1221. [Google Scholar] [CrossRef]
  15. Liberati, A.; Altman, D.G.; Tetzlaff, J.; Mulrow, C.; Gotzsche, P.C.; Ioannidis, J.P.; Clarke, M.; Devereaux, P.J.; Kleijnen, J.; Moher, D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 2009, 339, b2700. [Google Scholar] [CrossRef]
  16. Ouzzani, M.; Hammady, H.; Fedorowicz, Z.; Elmagarmid, A. Rayyan-a web and mobile app for systematic reviews. Syst. Rev. 2016, 5, 210. [Google Scholar] [CrossRef]
  17. Stensballe, J.; Ulrich, A.G.; Nilsson, J.C.; Henriksen, H.H.; Olsen, P.S.; Ostrowski, S.R.; Johansson, P.I. Resuscitation of Endotheliopathy and Bleeding in Thoracic Aortic Dissections: The VIPER-OCTA Randomized Clinical Pilot Trial. Anesth. Analg. 2018, 127, 920–927. [Google Scholar] [CrossRef] [PubMed]
  18. Wu, B.; Wang, Y.; Wang, C.; Cheng, Y.; Rong, R. Intraoperative platelet transfusion is associated with increased postoperative sternal wound infections among type A aortic dissection patients after total arch replacement. Transfus. Med. 2014, 24, 400–405. [Google Scholar] [CrossRef]
  19. Naeem, S.S.; Sodha, N.R.; Sellke, F.W.; Ehsan, A. Impact of Packed Red Blood Cell and Platelet Transfusions in Patients Undergoing Dissection Repair. J. Surg. Res. 2018, 232, 338–345. [Google Scholar] [CrossRef]
  20. Sera, V.A.; Stevens, A.E.; Song, H.K.; Rodriguez, V.M.; Tibayan, F.A.; Treggiari, M.M. Factor VIII inhibitor bypass activity (FEIBA) for the reduction of transfusion in cardiac surgery: A randomized, double-blind, placebo-controlled, pilot trial. Pilot Feasibility Stud. 2021, 7, 137. [Google Scholar] [CrossRef]
  21. Pupovac, S.S.; Levine, R.; Giammarino, A.T.; Scheinerman, S.J.; Hartman, A.R.; Brinster, D.R.; Hemli, J.M. Factor eight inhibiting bypass activity for refractory bleeding in acute type A aortic dissection repair: A propensity-matched analysis. Transfusion 2022, 62, 2235–2244. [Google Scholar] [CrossRef] [PubMed]
  22. Rahe-Meyer, N.; Levy, J.H.; Mazer, C.D.; Schramko, A.; Klein, A.A.; Brat, R.; Okita, Y.; Ueda, Y.; Schmidt, D.S.; Ranganath, R.; et al. Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): A double-blind phase III study of haemostatic therapy. Br. J. Anaesth. 2016, 117, 41–51. [Google Scholar] [CrossRef] [PubMed]
  23. Rahe-Meyer, N.; Solomon, C.; Hanke, A.; Schmidt, D.S.; Knoerzer, D.; Hochleitner, G.; Benny, S.; Christian, H.; Maximilian, P. Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: A randomized, placebo-controlled trial. Anesthesiology 2013, 118, 40–50. [Google Scholar] [CrossRef] [PubMed]
  24. Vlot, E.A.; Hackeng, C.M.; Aper, S.J.A.; Sonker, U.; Heijmen, R.H.; van Dongen, E.P.A.; Noordzij, P.G. Does Intraoperative Fibrinogen Affect Blood Loss or Transfusion Practice After Aortic Arch Surgery: A Prematurely Ended Randomized Trial. Clin. Appl. Thromb. Hemost. 2022, 28, 10760296221144042. [Google Scholar] [CrossRef]
  25. Kikura, M.; Tobetto, Y.; Yamamoto, K.; Uraoka, M.; Go, R. Effect of fibrinogen replacement therapy on bleeding outcomes and 1-year mortality in patients undergoing thoracic aortic surgery: A retrospective cohort study. J. Anesth. 2023, 37, 119–129. [Google Scholar] [CrossRef]
  26. Li, J.; Wu, Q.; Tang, M.; Shen, Y.; Qiu, Z.; Chen, X.; Chen, X.; Chen, L. Preoperative clinical application of human fibrinogen in patients with acute Stanford type A aortic dissection: A single-center retrospective study. J. Card. Surg. 2022, 37, 3159–3165. [Google Scholar] [CrossRef] [PubMed]
  27. Guan, X.; Li, L.; Lu, X.; Gong, M.; Li, H.; Liu, Y.; Jiang, W.; Lan, F.; Wang, X.; Zhang, H. Safety and efficacy of fibrinogen concentrate in aortic arch surgery involving moderate hypothermic circulatory arrest. J. Thromb. Thrombolysis 2023, 55, 67–73. [Google Scholar] [CrossRef]
  28. Yamamoto, K.; Usui, A.; Takamatsu, J. Fibrinogen concentrate administration attributes to significant reductions of blood loss and transfusion requirements in thoracic aneurysm repair. J. Cardiothorac. Surg. 2014, 9, 90. [Google Scholar] [CrossRef]
  29. Yan, W.; Xuan, C.; Ma, G.; Zhang, L.; Dong, N.; Wang, Z.; Xu, R. Combination use of platelets and recombinant activated factor VII for increased hemostasis during acute type a dissection operations. J. Cardiothorac. Surg. 2014, 9, 156. [Google Scholar] [CrossRef]
  30. Zindovic, I.; Sjögren, J.; Ahlsson, A.; Bjursten, H.; Fuglsang, S.; Geirsson, A.; Ingemansson, R.; Hansson, E.C.; Mennander, A.; Olsson, C.; et al. Recombinant factor VIIa use in acute type A aortic dissection repair: A multicenter propensity-score-matched report from the Nordic Consortium for Acute Type A Aortic Dissection. J. Thorac. Cardiovasc. Surg. 2017, 154, 1852–1859.e2. [Google Scholar] [CrossRef]
  31. Keyoumu, Y.; Mohemaiti, P.; Zhang, M.; Huo, Q.; Ma, X. Effect of the intraoperative infusion of recombinant activated coagulation factor VII on short-term prognosis and thoracic complications after acute aortic coarctation. Trop. J. Pharm. Res. 2024, 23, 731–736. [Google Scholar] [CrossRef]
  32. Andersen, N.D.; Bhattacharya, S.D.; Williams, J.B.; Fosbol, E.L.; Lockhart, E.L.; Patel, M.B.; Gaca, J.G.; Welsby, I.J.; Hughes, G.C. Intraoperative use of low-dose recombinant activated factor VII during thoracic aortic operations. Ann. Thorac. Surg. 2012, 93, 1921–1928; discussion 8–9. [Google Scholar] [CrossRef] [PubMed]
  33. Goksedef, D.; Panagopoulos, G.; Nassiri, N.; Levine, R.L.; Hountis, P.G.; Plestis, K.A. Intraoperative use of recombinant activated factor VII during complex aortic surgery. J. Thorac. Cardiovasc. Surg. 2012, 143, 1198–1204. [Google Scholar] [CrossRef]
  34. Ise, H.; Ushioda, R.; Kanda, H.; Kimura, F.; Saijo, Y.; Akhyari, P.; Lichtenberg, A.; Kamiya, H. Recombinant Activated Factor VII in Aortic Surgery for Patients Under Hypothermic Circulatory Arrest. Ther. Clin. Risk Manag. 2022, 18, 337–348. [Google Scholar] [CrossRef] [PubMed]
  35. Tritapepe, L.; De Santis, V.; Vitale, D.; Nencini, C.; Pellegrini, F.; Landoni, G.; Federico, T.; Fabio, M.; Paolo, P. Recombinant activated factor VII for refractory bleeding after acute aortic dissection surgery: A propensity score analysis. Crit. Care Med. 2007, 35, 1685–1690. [Google Scholar] [CrossRef]
  36. Hang, D.; Koss, K.; Rokkas, C.K.; Pagel, P.S. Recombinant activated factor VII for hemostasis in patients undergoing complex ascending aortic surgery: A single-center, single-surgeon retrospective analysis. J. Card. Surg. 2021, 36, 4558–4563. [Google Scholar] [CrossRef]
  37. Casati, V.; Sandrelli, L.; Speziali, G.; Calori, G.; Grasso, M.A.; Spagnolo, S. Hemostatic effects of tranexamic acid in elective thoracic aortic surgery: A prospective, randomized, double-blind, placebo-controlled study. J. Thorac. Cardiovasc. Surg. 2002, 123, 1084–1091. [Google Scholar] [CrossRef] [PubMed]
  38. Ahn, K.T.; Yamanaka, K.; Iwakura, A.; Hirose, K.; Nakatsuka, D.; Kusuhara, T.; Ikarashi, J. Usefulness of intraoperative continuous infusion of tranexamic acid during emergency surgery for type A acute aortic dissection. Ann. Thorac. Cardiovasc. Surg. 2015, 21, 66–71. [Google Scholar] [CrossRef]
  39. Makhija, N.; Sarupria, A.; Kumar Choudhary, S.; Das, S.; Lakshmy, R.; Kiran, U. Comparison of epsilon aminocaproic acid and tranexamic Acid in thoracic aortic surgery: Clinical efficacy and safety. J. Cardiothorac. Vasc. Anesth. 2013, 27, 1201–1207. [Google Scholar] [CrossRef]
  40. Reidy, B.; Aston, D.; Sitaranjan, D.; Fazmin, I.T.; Muir, M.; Ali, J.; De Silva, R.; Falter, F. Lack of efficacy of aprotinin over tranexamic acid in type A aortic dissection repair. Transfusion 2024, 64, 846–853. [Google Scholar] [CrossRef]
  41. Nicolau-Raducu, R.; Subramaniam, K.; Marquez, J.; Wells, C.; Hilmi, I.; Sullivan, E. Safety and efficacy of tranexamic acid compared with aprotinin in thoracic aortic surgery with deep hypothermic circulatory arrest. J. Cardiothorac. Vasc. Anesth. 2010, 24, 73–79. [Google Scholar] [CrossRef] [PubMed]
  42. Sniecinski, R.M.; Chen, E.P.; Makadia, S.S.; Kikura, M.; Bolliger, D.; Tanaka, K.A. Changing from aprotinin to tranexamic acid results in increased use of blood products and recombinant factor VIIa for aortic surgery requiring hypothermic arrest. J. Cardiothorac. Vasc. Anesth. 2010, 24, 959–963. [Google Scholar] [CrossRef]
  43. Chivasso, P.; Bruno, V.D.; Marsico, R.; Annaiah, A.S.; Curtis, A.; Zebele, C.; Angelini, G.D.; Bryan, A.J.; Rajakaruna, C. Effectiveness and Safety of Aprotinin Use in Thoracic Aortic Surgery. J. Cardiothorac. Vasc. Anesth. 2018, 32, 170–177. [Google Scholar] [CrossRef]
  44. Sedrakyan, A.; Wu, A.; Sedrakyan, G.; Diener-West, M.; Tranquilli, M.; Elefteriades, J. Aprotinin use in thoracic aortic surgery: Safety and outcomes. J. Thorac. Cardiovasc. Surg. 2006, 132, 909–917. [Google Scholar] [CrossRef]
  45. Ehrlich, M.; Grabenwöger, M.; Cartes-Zumelzu, F.; Luckner, D.; Kovarik, J.; Laufer, G.; Kocher, A.; Konetschny, R.; Wolner, E.; Havel, M. Operations on the thoracic aorta and hypothermic circulatory arrest: Is aprotinin safe? J. Thorac. Cardiovasc. Surg. 1998, 115, 220–225. [Google Scholar] [CrossRef]
  46. Westaby, S.; Forni, A.; Dunning, J.; Giannopoulos, N.; O’Regan, D.; Drossos, G.; Pillai, R. Aprotinin and bleeding in profoundly hypothermic perfusion. Eur. J. Cardiothorac. Surg. 1994, 8, 82–86. [Google Scholar] [CrossRef]
  47. Parolari, A.; Antona, C.; Alamanni, F.; Spirito, R.; Naliato, M.; Gerometta, P.; Arena, V.; Biglioli, P. Aprotinin and deep hypothermic circulatory arrest: There are no benefits even when appropriate amounts of heparin are given. Eur. J. Cardiothorac. Surg. 1997, 11, 149–156. [Google Scholar] [CrossRef] [PubMed]
  48. Seigne, P.W.; Shorten, G.D.; Johnson, R.G.; Comunale, M.E. The effects of aprotinin on blood product transfusion associated with thoracic aortic surgery requiring deep hypothermic circulatory arrest. J. Cardiothorac. Vasc. Anesth. 2000, 14, 676–681. [Google Scholar] [CrossRef] [PubMed]
  49. Eaton, M.P.; Deeb, G.M. Aprotinin versus epsilon-aminocaproic acid for aortic surgery using deep hypothermic circulatory arrest. J. Cardiothorac. Vasc. Anesth. 1998, 12, 548–552. [Google Scholar] [CrossRef]
  50. Fergusson, D.A.; Hébert, P.C.; Mazer, C.D.; Fremes, S.; MacAdams, C.; Murkin, J.M.; Teoh, K.; Duke, P.C.; Arellano, R.; Blajchman, M.A.; et al. A Comparison of Aprotinin and Lysine Analogues in High-Risk Cardiac Surgery. N. Engl. J. Med. 2008, 358, 2319–2331. [Google Scholar] [CrossRef]
  51. Lopes, C.T.; Dos Santos, T.R.; Brunori, E.H.; Moorhead, S.A.; Lopes Jde, L.; Barros, A.L. Excessive bleeding predictors after cardiac surgery in adults: Integrative review. J. Clin. Nurs. 2015, 24, 3046–3062. [Google Scholar] [CrossRef]
  52. Sundermann, A.C.; Saum, K.; Conrad, K.A.; Russell, H.M.; Edwards, T.L.; Mani, K.; Björck, M.; Wanhainen, A.; Owens, A.P. Prognostic value of D-dimer and markers of coagulation for stratification of abdominal aortic aneurysm growth. Blood Adv. 2018, 2, 3088–3096. [Google Scholar] [CrossRef] [PubMed]
  53. Yao, J.; Bai, T.; Yang, B.; Sun, L. The diagnostic value of D-dimer in acute aortic dissection: A meta-analysis. J. Cardiothorac. Surg. 2021, 16, 343. [Google Scholar] [CrossRef]
  54. Guan, X.L.; Wang, X.L.; Liu, Y.Y.; Lan, F.; Gong, M.; Li, H.Y.; Liu, O.; Jiang, W.J.; Liu, Y.M.; Zhu, J.M.; et al. Changes in the Hemostatic System of Patients with Acute Aortic Dissection Undergoing Aortic Arch Surgery. Ann. Thorac. Surg. 2016, 101, 945–951. [Google Scholar] [CrossRef] [PubMed]
  55. Liu, Y.; Han, L.; Li, J.; Gong, M.; Zhang, H.; Guan, X. Consumption coagulopathy in acute aortic dissection: Principles of management. J. Cardiothorac. Surg. 2017, 12, 50. [Google Scholar] [CrossRef] [PubMed]
  56. Tian, L.; Li, X.; He, L.; Ji, H.; Yao, Y.; The Evidence in Cardiovascular Anesthesia (EICA) Group. Hemostatic effects of tranexamic acid in cardiac surgical patients with antiplatelet therapy: A systematic review and meta-analysis. Perioper. Med. 2024, 13, 58. [Google Scholar] [CrossRef]
  57. Karkouti, K.; Callum, J.L.; Bartoszko, J.; Tanaka, K.A.; Knaub, S.; Brar, S.; Ghadimi, K.; Rochon, A.; Mullane, D.; Couture, E.J.; et al. Prothrombin Complex Concentrate vs. Frozen Plasma for Coagulopathic Bleeding in Cardiac Surgery: The FARES-II Multicenter Randomized Clinical Trial. JAMA 2025, 333, 1781–1792. [Google Scholar] [CrossRef]
  58. Dyke, C.; Aronson, S.; Dietrich, W.; Hofmann, A.; Karkouti, K.; Levi, M.; Murphy, G.J.; Sellke, F.W.; Shore-Lesserson, L.; von Heymann, C.; et al. Universal definition of perioperative bleeding in adult cardiac surgery. J. Thorac. Cardiovasc. Surg. 2014, 147, 1458–1463.e1. [Google Scholar] [CrossRef]
  59. Salenger, R.; Arora, R.C.; Bracey, A.; D’Oria, M.; Engelman, D.T.; Evans, C.; Grant, M.C.; Gunaydin, S.; Morton, V.; Ozawa, S.; et al. Cardiac Surgical Bleeding, Transfusion, and Quality Metrics: Joint Consensus Statement by the Enhanced Recovery After Surgery Cardiac Society and Society for the Advancement of Patient Blood Management. Ann. Thorac. Surg. 2025, 119, 280–295. [Google Scholar] [CrossRef]
Jcm 14 04001 g001
Figure 1. Flowchart of included studies. Wrong population included either no cardiac or thoracic aortic surgery or no subgroup analysis of thoracic aortic surgery. Wrong intervention included non-pharmacological interventions (e.g., autotransfusion, cell saver, or acute normal hemodilution) or the effect of transfusion protocols (e.g., ROTEM).
Figure 1. Flowchart of included studies. Wrong population included either no cardiac or thoracic aortic surgery or no subgroup analysis of thoracic aortic surgery. Wrong intervention included non-pharmacological interventions (e.g., autotransfusion, cell saver, or acute normal hemodilution) or the effect of transfusion protocols (e.g., ROTEM).
Jcm 14 04001 g001
Table 1. Summary of the included studies on blood products (n = 4) and FEIBA (n = 2).
Table 1. Summary of the included studies on blood products (n = 4) and FEIBA (n = 2).
Author, Year, CountryType of StudyPopulationInterventionNumber of Included PatientsFindings Effect of Intervention
Blood products
Stensballe, 2018, Denmark [17]Single-blinded RCT (clinicians not blinded)Acute type A dissectionsOctoplastLG vs. standard FFP
Trigger/timing: unclear
Dose: unclear		29/28 OctoplastLG reduced endothelial injury. Decreased 24 h total transfusion and platelet transfusion volume and goal-directed use of procoagulants. No safety concerns were raised.FFP:
Jcm 14 04001 i001
Wu, 2014, China [18]RetrospectiveAcute type A dissectionsPlatelet transfusion vs. no platelet transfusion
Trigger/timing: intraoperative, but otherwise unclear
Dose: unclear		74/85In-hospital mortality was similar. Postoperative sternal wound infection, neurological deficits, postoperative transfusion volume and percentage of RBC was increased in the platelet-transfused group.Jcm 14 04001 i002
Naeem, 2018, USA [19]RetrospectiveAcute type A dissections0–2 vs. >2 RBC, and 0–1 platelet unit vs. >1 platelet unit
Trigger/timing: unclear
Dose: as per stratification		68/34Rate of postoperative infections higher in patients receiving >2 units of RBC and independent risk factor. AKI and atrial fibrillation more frequent in patients receiving >1 unit of platelets and independent risk factor. Hospital stay longer in patients who received >2 units RBC or >1 unit platelets. No significant differences in mortality. Jcm 14 04001 i003
FEIBA vs. placebo or no FEIBA
Sera, 2021, USA [20]Double-blind RCTElective thoracic aortic surgeryFEIBA vs. placebo (saline)
Trigger/timing: post-CPB, standard, regardless of bleeding or not
Dose: 20 IU/kg concentration of 40 IU/mL, at a rate of 0.5 mL/kg via infusion over 10 min 		6/6Pilot trial.
DHCA longer in FEIBA group. Substantial variability but no difference in post-randomization blood products transfused. No difference in chest tube drainage, duration of intubation and hospital length of stay. Two patients (both in FEIBA group) experienced postoperative cerebrovascular events and died, considered not to be related to FEIBA. 		Jcm 14 04001 i004
Pupovac, 2022, USA [21]Retrospective, matched (not by intraoperative transfusion)Acute type A dissectionsFEIBA vs. no FEIBA
Trigger/timing: salvage therapy during surgery
Dose: 500 units, repeated if necessary		Before matching:
112/119
After matching:
53/53		Intraoperatively, no difference in blood product use. After surgery in the first 48 h, decreased blood product use in FEIBA group A greater proportion of the no FEIBA group received factor VIIa. No differences in incidences of thromboembolic complications Jcm 14 04001 i005
RCT = randomized controlled trial; RBC = red blood cell; FFP = fresh frozen plasma; CPB = cardiopulmonary bypass; FEIBA = factor eight inhibitor bypassing activity; AKI = acute kidney injury; USA = United States of America.
Table 2. Summary of included studies on fibrinogen suppletion (n = 7).
Table 2. Summary of included studies on fibrinogen suppletion (n = 7).
Author, Year, CountryType of StudyPopulationInterventionNumber of Included PatientsFindings Effect of Intervention
Fibrinogen suppletion versus placebo or no fibrinogen suppletion
Rahe-Meyer, 2016,
Worldwide
REPLACE-II [22]		Double-blind RCT, multicenterOpen surgical procedures with CPB on any part of the aorta, provided a 5 min bleeding rate of 60–250 g. (emergency surgery excluded, thoracoabdominal included)Fibrinogen concentrate vs. placebo (saline)
Trigger: 60–250 g 5-min bleeding post-CPB
Target: A10 FIBTEM of 22 mm
Mean dose: 6 g		78/74Fibrinogen group received more units of total blood products in the first 24 h compared to the placebo (5 vs. 3 units). FFP transfusions higher for the fibrinogen group but no significant differences in platelet or RBC transfusions. Placebo group had a higher percentage of patients avoiding transfusion. The initial 5 min bleeding mass was higher in the fibrinogen group. Furthermore, 31% of the total cohort had a pretreatment fibrinogen level of >2 g/L. Thromboembolic events occurred in 7.7% of the fibrinogen group and 13.5% of the placebo group. Jcm 14 04001 i006
Rahe-Meyer, 2013, Germany
REPLACE-I [23]		Double-blind RCT, single-centerOpen surgical procedures with CPB on any part of the aorta, provided a 5 min bleeding rate of 60–250 g. (emergency surgery excluded, thoracoabdominal included)Fibrinogen concentrate vs. placebo (saline)
Trigger: 60–250 g 5-min bleeding post-CPB
Target: A10 FIBTEM of 22 mm
Mean dose: 8 g		29/32Comparable in characteristics and 5 min bleeding mass. Fibrinogen group received fewer units of total blood products in the first 24 h after study medication. Total transfusion avoidance was achieved in 45% in fibrinogen group, while all placebo patients were transfused. No safety concerns were noted. Incidences of thromboembolic patients did not differ (one in fibrinogen group, two in placebo group). Jcm 14 04001 i007
Vlot, 2022, Netherlands [24]Double-blind RCTAortic arch surgery, provided a 5 min bleeding mass of 60–250 g
Excluded: preoperative fibrinogen concentration < 1 g/L		Fibrinogen concentrate vs. placebo (saline)
Trigger: 60–250 g 5-min bleeding post-CPB
Dose: 4 g for <70 kg; 6 g for 70–90 kg; 8 g for >90 kg		10/10There was no difference in allogeneic blood transfusion in the first 24 h after study medication.
Before treatment, 90% of patients had a fibrinogen concentration < 2 g/L. The 5 min bleeding mass decreased by 52% in the fibrinogen group and 32% in the placebo group. Thromboembolic events were reported in one patient per group. 		Jcm 14 04001 i008
Kikura, 2023, Japan [25]Retrospective, multicenterThoracic aortic surgery (including emergency)Cryoprecipitate or fibrinogen concentrate vs. no product
Trigger: fibrinogen < 1.0–1.2 g/L post-CPB or FIBTEM A10 < 6 mm during rewarming
Dose: 2–3 g		285/154No difference in incidence of major bleeding, re-exploration, or mortality. n patients with fibrinogen replacement and fibrinogen level < 1.5 g/L and a lower incidence of major bleeding compared to control. Decreased use of RBC and FFP, but increased use of platelet transfusion intraoperatively. Data on thromboembolic events were not reported. Jcm 14 04001 i009
Li, 2022, China [26]RetrospectiveAcute type A dissections Fibrinogen concentrate vs. no fibrinogen concentrate
Trigger: standard preoperatively
Dose: 2 g		105/54Reduced intraoperative blood loss and RBC transfusion. Reduced postoperative chest tube drainage. Data on thromboembolic events were not reported. Jcm 14 04001 i010
Guan, 2023, China [27]Retrospective analysis of a prospective databaseAcute type A dissectionsFibrinogen concentrate vs. no fibrinogen concentrate
Trigger: fibrinogen < 1.5 g/L after protamine
Target: fibrinogen > 2.0 g/L
Dose: initially 25–50 mg/kg (~2–5 g for 70–90 kg)		54/30Blood product use (RBC, FFP, platelets) decreased from the moment of infusion until the 5th postoperative day. Total transfusion avoidance was achieved in 17% of fibrinogen group, while all patients in control group received transfusions. The 24 h and 48 h postoperative drainage were lower in the fibrinogen group, though not maintained in total drainage volumes. Thromboembolic events were reported in none of the no fibrinogen group patietns and in two of the fibrinogen group patients. Jcm 14 04001 i011
Fibrinogen concentrate versus FFP
Yamamoto, 2014, Japan [28]Retrospective, age-matchedElective thoracic aortic surgery with fib < 1.5 at the end of CPBFibrinogen concentrate vs. FFP
Trigger: fibrinogen < 1.5 g/L after CPB
Target: fibrinogen > 2.0 g/L
Dose: 3–5 g		25/24In the fibrinogen group, the average volume of intraoperative blood loss decreased by 64%, while the average number of transfusion units was reduced by 56% in RBC, 61% in FFP, and 55% in platelets compared to cases where only FFP was administered. Data on thromboembolic events were not reported. Fibrinogen concentrate:
Jcm 14 04001 i012
RCT = randomized controlled trial; CPB = cardiopulmonary bypass; RBC = red blood cell; FFP = fresh frozen plasma.
Table 3. Summary of included studies on rFVIIa (n = 8).
Table 3. Summary of included studies on rFVIIa (n = 8).
Author, Year, CountryType of StudyPopulationInterventionNumber of Included PatientsFindings Effect of Intervention
Yan, 2014, China [29]Non-randomized prospective trial (family of patients decided allocation)Acute type A dissectionsPlatelets + rFVIIa vs. conventional (RBCs, FFPs, platelets, cryoprecipitate)
Trigger/timing: standard, during surgery
Dose: 3 units of platelets, 2.4 mg of rFVIIa		25/46Decreased intraoperative RBC, FFP, platelets and cryoprecipitate use and postoperative platelet use.
Less time to sternal closure. Blood loss similar at 1, 6 and 12 h after surgery. No difference in serious adverse events. One patient in each group experienced a stroke. 		Jcm 14 04001 i013
Zindovic, 2017, Finland [30]Retrospective, matched (not by intraoperative transfusion), multicenterAcute type A dissectionsrFVIIa vs. no rFVIIa
Trigger/timing: salvage therapy
during surgery or in the ICU
Dose: unknown		Before matching: 590/171
After matching:
120/120		The rFVIIa group received more RBCs, platelets and FFP. This group underwent re-exploration for bleeding more often and had greater 24 h chest tube drainage. No difference in mortality, stroke, or renal replacement therapy.Jcm 14 04001 i014
Keyoumu, 2024, China [31]Unclear (as it includes dissections, presumably retrospective), no matching describedAcute type A dissections (onset < 12 h, <65 year)rFVIIa vs. no rFVIIa
Trigger/timing: salvage therapy
during surgery
Dose: 100 µg/kg		60/60Duration of CPB was longer in the rFVIIa group. Decreased chest tube drainage and transfusion volumes postoperatively, but higher mortality and thromboembolic events (unclear which type of thrombosis) in the rFVIIa group. Jcm 14 04001 i015
Andersen, 2012, USA [32]Retrospective, matched (e.g., intraoperative transfusion)Thoracic aortic surgery (including emergency)
Excluded: patients who received 60 μg/kg or more of rFVIIa		Low dose rFVIIa vs. no rFVIIa
Trigger/timing: salvage therapy
during surgery
Dose: initial dose of <60 μg/kg		44/44 matchedImproved coagulation indicators (INR, aPTT) and decreased postoperative transfusions. No differences in postoperative complications (including thromboembolic complications). Two patients experience an embolic stroke in the intervention group, compared to none in the control group. Jcm 14 04001 i016
Goksedef, 2012, USA [33]Retrospective, matched (not by intraoperative transfusion)Thoracic aortic surgery (aneurysm database, also 1 dissection included)rFVIIa vs. no rFVIIa
Trigger/timing: salvage therapy
during surgery
Dose: 1 to 2 mg (10–30 μg/kg), repeated once if bleeding persisted.		Before matching:
37/339
After matching: 29/29		Decreased chest tube drainage, decreased postoperative transfusion of RBC and FFP, decreased incidence of resurgical intervention due to bleeding. No differences in thromboembolic events or mortality. In the intervention group, one patient had a stroke and one patient had a transient ischemic attack (TIA), compared to two strokes and one TIA in the control group.Jcm 14 04001 i017
Ise, 2022, Japan [34]Retrospective, matched (not by intraoperative transfusion)Thoracic aortic surgery (including dissections)rFVIIa vs. no rFVIIa
Trigger/timing: salvage therapy
during surgery
Dose: 5, 2 or 1 mg		Before matching:
42/102
After matching: 29/29		More blood loss and transfusion and fibrinogen concentrate intraoperatively. Postoperative bleeding and amount of transfusion significantly higher in the rFVIIa group in the unmatched cohort, but not in the matched cohort. No difference in mortality and thrombosis-related AESs. One patient per group experienced a stroke. Jcm 14 04001 i018
Tritapepe, 2007, Italy [35]Retrospective, matched (not by intraoperative transfusion)Acute type A dissectionsrFVIIa vs. no rFVIIa
Trigger/timing: on the ICU, if surgical cause was excluded and if bleeding exceeded 150 mL/h
Dose: 70 μg/kg, repeated if no reduction of bleeding to <150 mL/h. 		Before matching: 23/150
After matching:
23/23		Significant reduction in hourly blood loss was found 1 h after rFVIIa administration, as opposed to no difference in hourly blood loss in the control group. Treated patients received larger amounts of blood products. Blood product usage after rFVIIa was lower than before administration. No effect of rFVIIa on adverse events and mortality. One patient in the intervention group experienced a stroke, while none did in the control group. Jcm 14 04001 i019
Hang, 2021, USA [36]RetrospectiveThoracic aortic surgery (including dissections)rFVIIa vs. no rFVIIa
Trigger/timing: salvage therapy during surgery
Dose: range of 20–90 µg/kg at the physicians discretion.		20/39More intraoperative blood products transfused the rFVIIa group. Chest tube drainage in the first 24 h was similar. No difference in total additional blood products and the percentage of patients who required them in the ICU. There was a trend towards higher rate of reoperation for bleeding in rFVIIa group. Postoperative thromboembolic events and mortality were similar. Two patients in the intervention group and five patients in the control group experienced a stroke.Jcm 14 04001 i020
rFVIIa = recombinant activated factor VII; RBC = red blood cell; FFP = fresh frozen plasma; CPB = cardiopulmonary bypass; ICU = intensive care unit; USA = United States of America.
Table 4. Summary of included studies on antifibrinolytics (n = 13).
Table 4. Summary of included studies on antifibrinolytics (n = 13).
Author, Year, CountryType of StudyPopulationInterventionNumber of Included PatientsFindingsEffect of Intervention
TXA vs. placebo or no TXA
Casati, 2002, Italy [37]Double-blind RCTElective thoracic aortic surgeryTXA vs. placebo
Dose: 1 g bolus, 400 mg/h infusion		29/29Lower incidence of excessive bleeding (>600 mL chest tube drainage/24 h). Less blood loss in the first 24h and decreased perioperative RBC use. No difference in complications. One patient in the TXA group experienced a stroke, while none did in the placebo group. One patient per group experienced myocardial infarctions. Jcm 14 04001 i021
Ahn, 2015, Japan [38]RetrospectiveAcute type A dissectionsTXA vs. no TXA
Dose: no bolus, 16 mg/kg/h infusion, max 1000 mg/h		26/29Decreased intraoperative and postoperative blood product use (RBC, FFP, platelets). Decreased chest tube drainage. No difference in complications. Five patients in the TXA group experienced a stroke, while seven did in the control group. One patient had a seizure in the TXA group, while none did in the control group. Jcm 14 04001 i022
TXA versus EACA or aprotinin
Makhija, 2013, India [39]RCTThoracic aortic surgery (including emergency surgery)EACA vs. TXA
Dose: TXA 10 mg/kg bolus, 1 mg/kg/h infusion. EACA 50 mg/kg bolus, 25 mg/kg/h infusion		30/31No difference in intra- or postoperative blood product use. No difference in chest tube drainage. More renal injury in the EACA group. Possibly more seizures in the TXA group. One patient had a seizure in the EACA group, while three did in the TXA group. One patient per group experienced a stroke.Jcm 14 04001 i023
Reidy, 2024, UK [40]Retrospective, matchedAcute type A dissectionsAprotinin vs. TXA
Dose: TXA 1 g bolus, 500 mg/h infusion. Aprotinin 2 million unit bolus, 500,000 units/h infusion		Before matching 82/149
After matching
49/49		No differences in the amount of blood products transfused, 0chest tube drainage, mortality, return to theater, or CVVH (both in matched and unmatched cohorts). In the matched cohort, there were more patients with an open chest in the aprotinin group (2 vs. 0) but not in the unmatched cohort.
After matching, 7 patients in the aprotinin group versus 9 patients in the TXA group experienced a stroke.		Jcm 14 04001 i024
Nicolau-Raducu, 2010, USA [41]RetrospectiveThoracic aortic surgery with DHCAAprotonin vs. TXA
Dose: TXA 30 mg/kg bolus, 15 mg/kg/h infusion. Aprotinin 2 million unit bolus, 500,000 units/h infusion		48/36Aprotinin group: longer CPB time. Trend toward fewer intraoperative blood product transfusions, but not statistically significant. No difference in chest tube drainage. More renal dysfunction, though not identifiable as risk factor in regression. Postoperative complications were similar between groups. Eight patients in the aprotinin group versus seven patients in the TXA group experienced a stroke.Jcm 14 04001 i025
Sniecinski, 2010, USA [42]RetrospectiveThoracic aortic surgery with DHCA (including emergency surgery)Aprotinin vs. TXA
Dose: TXA 2 g bolus, 500 mg/h infusion. Aprotinin 2 million unit bolus, 500,000 units/h infusion		82/78Increased use of RBC, FFP, platelets, cryoprecipitate, and rFVIIa in TXA group. Trend towards more seizures in the TXA group but not significant (5 patients in the TXA group versus none in the aprotinin group). No difference in other complications. Two patients per group experienced a stroke. Aprotinin:
Jcm 14 04001 i026
TXA:
Jcm 14 04001 i027
Chivasso, 2018, UK [43]Retrospective, matchedThoracic aortic surgery (including dissections)Aprotinin vs. no aprotinin (they state) but actually vs. TXA
Dose: TXA 15 mg/kg bolus, 4.5 mg/kg/h infusion. Aprotinin 2 million unit bolus, 420,000 units/h infusion (70 mg/h)		107/425 before matching
107/107 matched		Higher use of FFP in both matched and unmatched cohorts in the aprotinin group. No difference in other blood products, postoperative bleeding or complications. Five patients in the aprotinin group experienced a stroke, while seven did in the no aprotinin (TXA) group. Aprotinin:
Jcm 14 04001 i028
Sedrakyan, 2006, USA [44]Retrospective, matchedThoracic aortic surgery (aneurysms, dissections, ulcers, and hematomas)Aprotinin vs. no aprotinin (but actually compared to EACA and TXA)
Dose aprotinin: 2 million unit bolus, 500,000 units/h infusion		No before matching available
After matching
84/84		Difference at baseline after matching: controls were more likely to receive antifibrinolytics (EACA or TXA), essentially comparing aprotinin to an alternative blood loss reduction strategy that included antifibrinolytic therapy > 50% of the time. Aprotinin reduced the intraoperative amount of platelet transfusion and resulted in less chest tube drainage in the first 24 h. There were no associations with thromboembolic complications. Aprotinin:
Jcm 14 04001 i029
Aprotinin versus placebo or no aprotinin
Ehrlich, 1998, Austria [45]Double-blind RCTElective thoracic aortic surgery (including chronic dissections)Aprotinin vs. placebo (saline)
Dose aprotinin: 1 million unit bolus before CPB		25/25Aprotinin decreased chest tube output in the first 24 h and decreased transfusion requirements (RBC, FFP, platelets, cryoprecipitate). One patient in the no aprotinin group experienced a stroke, while none did in the aprotinin group. Jcm 14 04001 i030
Westaby, 1994, UK [46]Both retrospective and prospectiveAcute type A dissectionsAprotinin vs. no aprotinin
Dose aprotinin: 2 million unit bolus, 500,000 units/h infusion		53/29No reduction in overall blood loss and transfusion requirements for aprotinin patients. After the introduction of hypothermic circulatory arrest (1989), aprotinin patients consistently experienced more blood loss. There were 5 deaths per group. In the aprotinin group, two of those were due to myocardial infarction and one due to pulmonary embolisms, in the control group none were due to thromboembolic complications. Jcm 14 04001 i031
Parolari, 1997, Italy [47]RetrospectiveThoracic aortic surgery with DHCA (including dissections)Aprotinin vs. no aprotinin
Dose: 700 mg. 		18/21No difference in postoperative blood loss, blood product use, re-exploration, mortality or complications. However, the aprotinin group showed a higher trend towards neurological deficit and a more complicated postoperative course. Jcm 14 04001 i032
Seigne, 2000, USA [48]RetrospectiveElective or urgent thoracic aortic surgery with DHCA (all Bentalls)Aprotinin vs. no aprotinin
Dose aprotinin: 1 million unit bolus, 100,000 units/h infusion		9/10Aprotinin decreased RBC, FFP, and platelet use intraoperatively and FFP postoperatively. No difference in chest tube drainage. Two patients in the non-aprotinin group developed seizures (none in the aprotinin group), while one patient experienced a stroke in the aprotinin group (none in the non-aprotinin group). Jcm 14 04001 i033
Aprotinin versus EACA
Eaton, 1998, USA [49]RetrospectiveThoracic aortic surgery (including dissections)Aprotinin vs. EACA
Dose: aprotinin 2 million unit bolus, 500,000 units/h infusion. EACA 5–40 g with a bolus/infusion scheme 		29/19No difference in chest tube output or postoperative transfusion. Possibly more renal failure in the EACA group. No differences in other complications. Three patients in the aprotinin group and five patients in the EACA group experienced strokes.Jcm 14 04001 i034
RCT = randomized controlled trial; TXA = tranexamic acid; EACA = epsilon-aminocaproic Acid; DHCA = deep hypothermic circulatory arrest; CPB = cardiopulmonary bypass; RBC = red blood cell; FFP = fresh frozen plasma; UK = United Kingdom; USA = United States of America.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

van Haeren, M.M.T.; Bozic, C.; Breel, J.S.; Eberl, S.; Jamaludin, F.S.; Veelo, D.P.; Müller, M.C.A.; Vlaar, A.P.J.; Hermanns, H. Intraoperative Hemostatic Agents in Thoracic Aortic Surgery—A Scoping Review. J. Clin. Med. 2025, 14, 4001. https://doi.org/10.3390/jcm14114001

AMA Style

van Haeren MMT, Bozic C, Breel JS, Eberl S, Jamaludin FS, Veelo DP, Müller MCA, Vlaar APJ, Hermanns H. Intraoperative Hemostatic Agents in Thoracic Aortic Surgery—A Scoping Review. Journal of Clinical Medicine. 2025; 14(11):4001. https://doi.org/10.3390/jcm14114001

Chicago/Turabian Style

van Haeren, Maite M. T., Caitlin Bozic, Jennifer S. Breel, Susanne Eberl, Faridi S. Jamaludin, Denise P. Veelo, Marcella C. A. Müller, Alexander P. J. Vlaar, and Henning Hermanns. 2025. "Intraoperative Hemostatic Agents in Thoracic Aortic Surgery—A Scoping Review" Journal of Clinical Medicine 14, no. 11: 4001. https://doi.org/10.3390/jcm14114001

APA Style

van Haeren, M. M. T., Bozic, C., Breel, J. S., Eberl, S., Jamaludin, F. S., Veelo, D. P., Müller, M. C. A., Vlaar, A. P. J., & Hermanns, H. (2025). Intraoperative Hemostatic Agents in Thoracic Aortic Surgery—A Scoping Review. Journal of Clinical Medicine, 14(11), 4001. https://doi.org/10.3390/jcm14114001

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop