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Trigger and Target for Fibrinogen Supplementation Using Thromboelastometry (ROTEM) in Patients Undergoing Open Thoraco-Abdominal Aortic Aneurysm Repair

Open ArchivePublished:March 24, 2021DOI:https://doi.org/10.1016/j.ejvs.2021.02.046

      Objective

      To determine the relationship between the value of fibrinogen assessed by the FIBTEM clot amplitude at 10 minutes (A10 FIBTEM) measured on admission to the intensive care unit (ICU) and the amount of drainage output at 24 hours, to investigate whether the A10 FIBTEM predicts severe bleeding (SB), and to define A10 FIBTEM thresholds to prevent (trigger) and treat (target) severe bleeding by fibrinogen supplementation.

      Methods

      In a single centre, retrospective observational study, 166 patients underwent elective open thoraco-abdominal aortic aneurysm (TAAA) repair between March 2016 and January 2019. Exclusion criteria were emergency, congenital, or acquired coagulopathy, or administration of P2Y12 inhibitor antiplatelet agents in the five days before surgery. All patients were managed intra-operatively and post-operatively according to a rotational thromboelastometry driven transfusion protocol. The principal endpoint was a composite outcome, which included bleeding, large volume transfusion, and re-operation.

      Results

      FIBTEM clot amplitude after 10 minutes measured on ICU admission and post-operative bleeding at 24 hours showed an inverse linear relationship (R2 = .03; p = .026). Performance of A10 FIBTEM in predicting SB evaluated by Receiving Operating Curve analysis showed an area under the curve of 0.63 (95% CI 0.56 – 0.70; p = .026) with a best cutoff of 9 mm. An A10 FIBTEM of 3 mm was the cutoff associated with a positive predictive value of 50%, while an A10 FIBTEM of 9 mm showed a negative predictive value of 92%. On multivariable analysis, an A10 FIBTEM ≤ 3 mm remained independently associated with SB.

      Conclusion

      The present investigation shows for the first time in a population undergoing open TAAA repair that an A10 FIBTEM ≤ 3mm on ICU admission is associated with post-operative severe bleeding. Trigger and target values for fibrinogen supplementation, based on A10 FIBTEM, have been provided. The transferability and reliability of these cutoff values require further study.

      Keywords

      Major bleeding, from surgical factors and acute coagulopathy, is a common complication after open thoraco-abdominal aortic aneurysm (TAAA) repair. The present investigation, for the first time in a population undergoing open TAAA repair, shows a significant inverse correlation between the FIBTEM clot amplitude after 10 minutes (A10 FIBTEM) and post-operative blood loss. These findings support that a low level of fibrinogen on admission to the intensive care unit, evaluated by thromboelastometry, is associated with severe post-operative bleeding. The trigger and target values for fibrinogen supplementation provided, based on A10 FIBTEM, can improve post-operative TAAA blood management.

      Introduction

      Major bleeding after open thoraco-abdominal aortic aneurysm (TAAA) repair affects morbidity and mortality.
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      Thoraco-abdominal aortic aneurysm surgery may be associated with massive blood loss from surgical factors and acute coagulopathy, which act on an altered coagulation profile.
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      Application of the aortic cross clamp, left heart bypass, and ischaemia reperfusion injury are risk factors in developing consumptive coagulopathy and fibrinolysis.
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      a decrease in fibrin generation, thrombocytopaenia, platelet dysfunction, and peri-operative bleeding with the need for blood transfusion.
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      Editor’s Choice - a rotational thromboelastometry driven transfusion strategy reduces allogenic blood transfusion during open thoraco-abdominal aortic aneurysm repair: a propensity score matched study.
      The association between fibrinogen depletion and peri-operative blood loss is well established in cardiac surgery.
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      By contrast, in vascular surgery, studies on plasma fibrinogen variation and post-operative blood loss are still lacking.
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      Treating hypofibrinogenaemia in major aortic surgery.
      Recently, Morrison et al. reported that correction of hypofibrinogenaemia with fibrinogen concentrate was more effective than fresh frozen plasma (FFP) at reducing post-operative allogeneic blood transfusion during surgery and in the first 24 hours post-operatively.
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      Fibrinogen concentrate vs. fresh frozen plasma for the management of coagulopathy during thoraco-abdominal aortic aneurysm surgery: a pilot randomised controlled trial.
      These data confirm that fibrinogen concentrate is more effective than FFP in achieving a pre-specified target level of fibrinogen. In fact, the concentration of fibrinogen in therapeutic plasma ranges between 1.6 and 5 g/L, whereas in the fibrinogen concentrate it is 20 g/L.
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      Unfortunately, no data on post-operative bleeding have been reported.
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      For this reason, the real magnitude of the proposed intervention has not been fully investigated. While intra-operative blood loss is more closely related to surgical bleeding, in which fibrinogen is not effective, post-operative blood loss is mainly related to microvascular bleeding, in which fibrinogen may play a crucial role. For these reasons, fibrinogen administration at the end of aortic surgery may be effective in restoring the optimal haemostasis, preventing bleeding. On the other hand, unnecessary supplementation of fibrinogen in patients who will not bleed may lead to thrombosis and increased costs. A deeper understanding of the variations in peri-operative fibrinogen levels is crucial to define guidelines for fibrinogen replacement. It has been largely proven that an isolated plasma fibrinogen deficit can be assessed with the FIBTEM clot amplitude at 10 minutes (A10 FIBTEM) after initiation of fibrin polymerisation.
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      Thus, the aims of this study were to define the relationship between A10 FIBTEM on ICU admission and amount of drainage output at 24 hours, to investigate whether the A10 FIBTEM predicts severe bleeding (SB), and finally to define the trigger and target of A10 FIBTEM to treat SB.

      Materials and methods

      Population

      This was a single centre retrospective study of a prospectively collected database including all patients undergoing elective open TAAA repair at IRCCS San Raffaele Scientific Institute between March 2016 and January 2019. As all patients gave written informed consent allowing for scientific data management, ethical committee approval was waived according to Italian law. Exclusion criteria were emergency surgery, known congenital or acquired coagulopathy, and P2Y12 inhibitor antiplatelet agents not discontinued in the five days before surgery.
      • Rossini R.
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      Perioperative management of antiplatelet therapy in patients with coronary stents undergoing cardiac and non-cardiac surgery: a consensus document from Italian cardiological, surgical and anaesthesiological societies.
      In the event of microvascular bleeding, the intra- and post-operative blood transfusion strategy was decided according to a Rotational Thromboelastometry (ROTEM) (Delta, IL Werfen, Munich Germany) guided transfusion protocol with predefined triggers, as per the present authors’ routine practice.
      • Monaco F.
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      • Licheri M.
      • Notte C.
      • De Luca M.
      • et al.
      Editor’s Choice - a rotational thromboelastometry driven transfusion strategy reduces allogenic blood transfusion during open thoraco-abdominal aortic aneurysm repair: a propensity score matched study.
      ,
      • Monaco F.
      • Nardelli P.
      • Denaro G.
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      • Franco A.
      • Bertoglio L.
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      First experience with a ROTEM-enhanced transfusion algorithm in patients undergoing aortic arch replacement with frozen elephant trunk technique. A theranostic approach to patient blood management.
      Briefly, after the evaluation of residual heparin by comparison of the clotting time (CT) of HEPTEM with the CT of INTEM (first step), assessment of EXTEM, INTEM, and FIBTEM were divided into two steps to first correct substrates (fibrinogen and platelet) and then coagulation factor deficiencies. Thus, an EXTEM maximum clotting firmness (MCF) < 45 mm at 10 minutes (A10 EXTEM) was corrected with fibrinogen when the A10 FIBTEM was < 8 mm. By contrast, when the A10 FIBTEM was > 8 mm, platelets were administered. After normalisation of the A10 EXTEM, the EXTEM CT was considered and corrected with plasma (15 – 20 mL/kg) when > 80 seconds. An INTEM CT > 240 seconds with a HEPTEM CT inferior to INTEM CT by at least 20%, was treated by protamine administration, otherwise, plasma (15 – 20 mL/kg) was used. The flow chart of the ROTEM guided transfusion protocol is summarised in the supplementary material (Fig. S1). Heparin was managed during the surgery as follows: five minutes before deployment of the LHB cannulas, heparin was administered at a starting dose of 80 – 100 UI/kg to achieve an activated clotting time (ACT) of 250 seconds. The coagulation state was serially assessed with ACT during the surgery and heparin supplemented if required. At the end of surgery, protamine was administered in a 1:1 ratio of the initial heparin dose.
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      • Gudbjartsson T.
      • van den Goor J.
      • et al.
      2019 EACTS/EACTA/EBCP guidelines on cardiopulmonary bypass in adult cardiac surgery.
      Then, as the first stage of the ROTEM transfusion algorithm, each patient was tested for heparin residual and a further dose of protamine supplemented according to the protocol. RBC transfusion was triggered by a haematocrit (Ht) ≤ 30% throughout the study. The anatomical extent of the aneurysm was defined by the Crawford classification.
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      A prospective randomized study of cerebrospinal fluid drainage to prevent paraplegia after high-risk surgery on the thoracoabdominal aorta.
      Anaesthetic and surgical management were standardised throughout the study period according to the internal protocol.
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      • Barucco G.
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      • Redaelli M.B.
      • De Luca M.
      • et al.
      Epidural analgesia in open thoraco-abdominal aortic aneurysm repair.

      Definitions

      Plasma fibrinogen was assessed by ROTEM on ICU admission and reported as millimetres of A10 FIBTEM. Post-operative severe bleeding was defined as drainage output above the 90th percentile of the distribution at 24 hours (1500 mL.24h−1) and/or RBC transfusion > 4 Units.24h−1 or re-operation for bleeding. A composite pragmatic definition of severe bleeding, based on easily measured clinical endpoints, was chosen to detect SB more effectively than a single criterion, which may be incompletely fulfilled.

      Statistical analysis

      Data were stored electronically and analysed with SPSS Statistics software version 23 (IBM Corp., Armonk, NY, USA). A p value < .05 was considered statistically significant. The Kolmogorov–Smirnov test was used to test the normal distribution of the continuous variables. No imputation for missing data was done. Continuous variables are presented as mean ± standard deviation when normally distributed and as median with interquartile range (IQR) if not. The differences between continuous variables were tested using Student t test or Mann−Whitney test according to their distribution. Categorical variables are expressed as numbers and proportions (%) and compared with the chi square test with Yates correction or the Fisher exact test when appropriated.
      The association between A10 FIBTEM on ICU admission and post-operative bleeding was investigated with a Pearson correlation test, linear and non-linear regression analysis.
      To evaluate the ability of the A10 FIBTEM to predict SB, a Receiver Operating Characteristic (ROC) curve was generated. Details of the ROC curve and area under the curve (AUC) of CT-EXTEM, MCF-EXTEM, and CT-INTEM are reported in the supplementary material (Fig. S2 and Table S1). The optimal cutoff value was chosen by maximising the Youden index (J = sensitivity + specificity − 1). The AUC and the exact binomial 95% confidence intervals (95% CIs) were calculated,
      • DeLong E.R.
      • DeLong D.M.
      • Clarke-Pearson D.L.
      Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
      together with sensitivity, specificity, negative predictive value (NPV), positive predictor value (PPV), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) with 95% CI.
      In clinical practice, cutoff values with a PPV of ≥ 50% and NPV of 90% were detected and considered as trigger and target values for fibrinogen supplementation, respectively.
      Multicollinearity was managed using only the variable with the best predictive value in a set of variables with a correlation coefficient < -.9 or > .9 in the regression analysis. With the multivariable analysis, the A10 FIBTEM was dichotomised in A10 FIBTEM ≤ 3 mm and > 3 mm according to the best combination of NPV and PPV. The main scope of the present investigation was to find a clinically useful trigger for fibrinogen supplementation. After the univariable screening, as recommended in the Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) statement,
      • Moons K.G.M.
      • Altman D.G.
      • Reitsma J.B.
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      • Macaskill P.
      • Steyerberg E.W.
      • et al.
      Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD): Explanation and Elaboration.
      Akaike’s information criterion (p < .157) was used to select a predictor to include in the forward stepwise logistic regression. Model calibration was assessed with the Hosmer–Lemeshow test for goodness of fit and p > .05 was considered a good fit of the model, as this indicates that there is no significant difference between the predicted and observed outcomes. To adjust the prediction model for overfitting, the bootstrapping technique (200 bootstraps) was used as internal validation. The calibration slope generated was used to adjust the regression coefficients and the AUC for the optimism. R V.3.0.3 was used for the internal validation.
      Historical data from the present authors indicated a 20% baseline risk of severe bleeding. To detect an odds ratio of 2.15 when the A10 FIBTEM is increased by 1 standard deviation with 90% power and an α level = .05, a sample size of at least 111 patients was required. However, as the ROTEM parameters are available in the present authors’ database from 2016, all patients with complete ROTEM coagulation parameters were included in the study to increase the power of the analysis.

      Results

      One hundred and sixty-six consecutive patients underwent open TAAA repair during the study period. Twenty-six (16%) suffered severe SB and in two cases required surgical re-exploration. In both circumstances, a diffuse oozing rather than a clear source of bleeding was detected. The extent of TAAA was similar between the no SB and SB groups (p = .31). Fifty-seven patients (34%) received fibrinogen to treat intra-operative bleeding: 15 (58%) in the SB group and 42 (30%) in the no SB group (p = .008).
      Table 1, Table 2, Table 3 summarise all pre-operative and intra-operative characteristics and the number of blood transfusions for the entire population, along with the results of the univariable analysis. Patients with post-operative SB were more often diabetic (p = .041), on an oral anticoagulant (p = .047), and with low pre-operative platelet count (p = .024) compared with the no SB group.
      Table 1Baseline clinical characteristics of 166 patients undergoing elective open thoraco-abdominal aortic aneurysm repair
      Population (n = 166)No severe bleeding (n = 140)Severe bleeding (n = 26)p value
      Age – y64 ± 10.765 ± 10.264 ± 6.7.47
      Female sex49 (29)42 (30)7 (27).75
      BMI – kg/m226 ± 3.926.4 ± 3.927.2 ± 4.2.27
      Hypertension147 (89)122 (87)25 (96).31
      Dyslipidaemia83 (50)69 (49)14 (54).83
      Diabetes18 (11)12 (8.6)6 (23).041
      COPD36 (22)28 (20)8 (31).33
      Smoking history120 (72)101 (72)19 (73)1.0
      Chronic renal failure36 (22)30 (21)6 (23)1.0
      Coronary artery disease38 (23)28 (20)10 (30).71
      Prior myocardial infarction26 (16)21 (15)5 (19).56
      Chronic atrial fibrillation15 (9)12 (9)3 (11).78
      Prior PCI/CABG32 (19)26 (19)6 (23).79
      Previous cardiac surgery30 (18)25 (18)5 (19).79
      Previous aortic open surgery21 (13)16 (11)5 (19).33
      Previous aortic endovascular surgery38 (23)31 (22)7 (27).78
      Pre-operative Ht – %39 ± 4.239 ± 4.439 ± 4.5.68
      Marfan15 (9)12 (9)3 (11).78
      Type B aortic dissection28 (17)23 (16)5 (19).78
      Cerebrovascular disease11 (7)10 (7)1 (4)1.0
      Previous stroke7 (4)4 (3)3 (11).078
      Pre-operative PLT – × 1000/μL198 [80]201 [80]177 [71].024
      INR1.05 [0.11]1.05 [0.11]1.06 [0.16].66
      aPTT – s33 [3.2]32 [3.3]32 [2.9].20
      Aspirin93 (56)76 (54)17 (65).40
      Other platelet inhibitors19 (11)14 (10)5 (19).18
      Dual antiplatelet therapy9 (5)6 (4)3 (11).15
      Oral anticoagulant14 (8)9 (6)5 (19).047
      β-Blockers111 (67)91 (65)20 (77).34
      Diuretics56 (34)45 (32)11 (42).43
      ACE inhibitors/angiotensin II receptor antagonist98 (59)86 (61)12 (46).22
      Data are presented as mean ± standard deviation or as median [interquartile range] with Student’s t test or Mann-Whitney U test, respectively, or as n (%) with the Chi square test or Fisher exact test. The variables reported have no missing data. BMI = body mass index; COPD = chronic obstructive pulmonary disease; PCI = percutaneous coronary intervention; CABG = coronary artery bypass grafting; Ht = haematocrit; INR = international ratio; aPTT = activate partial thromboplastin time.
      Table 2Surgical and operative characteristics of 166 patients undergoing elective open thoraco-abdominal aortic aneurysm repair
      Population (n = 166)No severe bleeding (n = 140)
      The missing data for the no severe bleeding group were: LHB time 3.5%, Aortic cross clamp time 1.4%; Heparin cumulative dose, blood losses and salvaged blood 0.7%; Crystalloids 7%. The percentage missing data for the severe bleeding group was: LHB time and Crystalloids 3.8%. The other variables have no missing data.
      Severe bleeding (n = 26)
      The missing data for the no severe bleeding group were: LHB time 3.5%, Aortic cross clamp time 1.4%; Heparin cumulative dose, blood losses and salvaged blood 0.7%; Crystalloids 7%. The percentage missing data for the severe bleeding group was: LHB time and Crystalloids 3.8%. The other variables have no missing data.
      p value
      TAAA extent.30
       Extent I34 (20)30 (21)4 (15)
       Extent II49 (29)39 (28)8 (38)
       Extent III44 (26)26 (26)10 (31)
       Extent IV29 (17)25 (18)4 (15)
       Extent V10 (6)10 (7)0 (0)
      Use of LHB138 (83)127 (84)21 (81).78
      LHB time – min52 [29]51 [29]57 [34].63
      Aortic cross clamp time – min52 [23]52 [23]55 [18].33
      Surgical time – min310 [120]300 [108]367 [90]<.001
      Heparin cumulative dose – UI5 000 [2 300]5 000 [2 000]7 000 [3 700].13
      Blood losses – mL5 100[5 300]4 900 [4 600]7 000 [8 000].020
      Crystalloids – mL5 600 [3 000]5 400 [3 300]6 400 [2 200]<.001
      Colloids – ml0 [500]0 [500]0 [500]<.001
      Albumin – mL0 [200]200 [200]200 [70].57
      Salvaged blood – mL1 700 [1 800]1 600 [1 700]2 200 [2 500].020
      Fibrinogen – g0 [2]0 [2]2.5 [4].001
      Red blood cells – U0 [2]0 [2]1 [2.25].086
      Fresh frozen plasma – mL0 [262]0 [250]0 [560].15
      Platelet – U0 [0]0 [0]0 [1].034
      Data are presented as mean ± standard deviation or median [interquartile range] with Student t test or Mann–Whitney U test, respectively, or n (%) with the Chi square test or Fisher exact test. TAAA = thoraco-abdominal aortic aneurism; LHB = left heart bypass.
      The missing data for the no severe bleeding group were: LHB time 3.5%, Aortic cross clamp time 1.4%; Heparin cumulative dose, blood losses and salvaged blood 0.7%; Crystalloids 7%. The percentage missing data for the severe bleeding group was: LHB time and Crystalloids 3.8%. The other variables have no missing data.
      Table 3Post-operative characteristics of 166 patients undergoing elective open thoraco-abdominal aortic aneurysm repair
      Population (n = 166)No severe bleeding (n = 140)Severe bleeding (n = 26)p value
      A10 FIBTEM – mm9 [6]9 [5]8 [5].030
      Ht on ICU admission – %35 [6]36 [5]33 [5].006
      Drainage output
       12 h – mL500 [370]490 [310]1 100 [500]<.001
       24 h – mL780 [640]745 [450]1 590 [290]<.001
      Transfusion within 12 h from ICU admission
       Red blood cells – U0 [1]0 [1]0 [3].024
       Fresh frozen plasma – mL0 [0]0 [0]0 [0].029
       Platelet – U0 [0]0 [0]0 [0.25]<.001
       Fibrinogen – g0 [0]0 [0]0 [0].91
      Transfusion after 24 h from ICU admission
       Red blood cells – U2 [3.25]2 [3]4 [4.25]<.001
       Fresh frozen plasma – mL0 [0]0 [0]0 [0].021
       Platelet – U0 [0]0 [0]0 [0].10
       Fibrinogen – g0 [0]0 [0]0 [0].54
      Data are presented as median [interquartile range] with Mann–Whitney U test. The variables reported have no missing data. A10 = Amplitude 10 of the FIBTEM at 10 min; Ht = haematocrit; ICU = intensive care unit.
      Intra-operatively, the SB group had a longer operating time (p < .001) and greater blood loss (p = .020), required more extensive use of salvage blood (p = .020), colloids (p = .006), crystalloids (p = .006), fibrinogen (p = .001), and PLT units (p = .034) than the no SB group. There was no difference in RBC and PFC administration between groups.
      On ICU admission, the A10 FIBTEM was higher in the no SB group compared with the SB group (p = .030) (supplementary material Fig. S3), whereas the haematocrit was lower in the latter than the former (33% vs. 36%; p = .005). At 12 and 24 hours from the ICU admission, the drainage output was significantly greater in those who suffered SB. During the first 24 hours, patients with SB received more PFC, RBC, and PLT units than the standard group. After 24 hours from ICU admission, the no SB group had received statistically significantly fewer transfusions of RBC, and PFC than those with SB. By contrast, there were no differences in fibrinogen and PLT administration between the groups. A10 FIBTEM at the ICU admission and post-operative bleeding at 24 hours showed an inverse correlation (R = -173; p < .05) and linear relationship (R2 = .03; p = .026) (Fig. 1). Fig. 2 reports the performance of A10 FIBTEM in predicting SB, evaluated by the ROC analysis expressed as AUC and 95% CI. The AUC for A10 FIBTEM was 0.63 (95% CI 0.56 − .70; p = .026) (Fig. 2). No other ROTEM parameters were significantly associated with SB.
      Figure 1
      Figure 1Inverse (R = -173; p < .05) and linear relationship (R2 = .03; p = .026) between the FIBTEM clot amplitude at 10 minutes (A10 FIBTEM) on intensive care unit (ICU) admission and post-operative bleeding at 24 hours in 166 patients undergoing open thoraco-abdominal aortic aneurysm repair.
      Figure 2
      Figure 2Receiving Operating Curve (ROC) analysis of performance of FIBTEM clot amplitude after 10 minutes (A10 FIBTEM) in predicting severe bleeding in 166 patients undergoing open thoraco-abdominal aortic aneurysm repair. The area under the curve for A10 FIBTEM was 0.63 (95% CI 0.56 – 0.70; p = .026). Shaded areas represent the ROC curve 95% confidence intervals. The best cutoff for A10 FIBTEM (9 mm) established by the Youden index along with the 95% confidence intervals for sensitivity and specificity (whiskers) are shown.
      A10 FIBTEM’s best cutoff of 9 mm was associated with a fairly low PPV (22 %), which makes this threshold a poor trigger for fibrinogen supplementation. To establish clinically useful criteria for fibrinogen supplementation, several thresholds have been investigated according to PPV and NPV and the results are reported in the supplementary material (Table S2). A cutoff with ≥ 50% of PPV was considered a clinical trigger for fibrinogen supplementation, while a NPV of ≥ 90% was a reasonable A10 FIBTEM target value to achieve in patients who were bleeding. According to this, an A10 FIBTEM of 3 mm was associated with a PPV of 50%, while an A10 FIBTEM of 9 mm showed a NPV of 92%, providing the trigger and target values in the present study. Pre-operative platelets, previous use of oral anticoagulants, diabetes, surgical time, blood loss, crystalloids, colloids, salvaged blood, fibrinogen intra-operative administration, and A10 FIBTEM ≤ 3 mm on ICU admission were significantly associated with the SB in the univariable analysis. As blood loss showed significant collinearity with surgical time, the latter was included in the multivariable analysis. Surgical time (OR 1.01; 95% CI 1 – 1.02 in minutes, which in hours is equivalent to OR 1.82; 95% CI 1 – 3.28), fibrinogen intra-operative administration (OR 1.35; 95% CI 1.05 – 1.75), colloids (OR 0.998; 95% CI 0.995 – 0.999 in mL; which in dL corresponds to OR 0.82; 95% CI 0.60 – 0.90), haematocrit (OR 0.85; 95% CI 0.742 – 0.96), and A10 FIBTEM ≤ 3 mm at ICU admission (OR 9.28; 95% CI 1.79 – 57) remained independently associated with severe bleeding. The Hosmer–Lemeshow goodness of fit test was not significant, with a p value of .297. Fig. 3 shows the calibration curve of the predicted and observed probabilities for SB. The mean slope shrinkage factor after bootstrapping was 0.7261. This led to adjusted ORs for all the predictors as summarised in Table 4. The AUC of the model corrected for the optimism decreased from 0.85 (95% CI 0.776 – 0.94) to 0.79 (95% CI 0.54 – 0.88). The outcome and the complications are summarised in Table 5. Notably, those suffering SB compared with those who did not showed a statistically significantly higher rate of re-operation for bleeding (7.7% vs. 0%, p = .024), dialysis (30.8 % vs. 5.7%; p = .001), pneumonia (38.5% vs. 10%; p = .001), longer ICU stay (73 hours [0, 185] vs. 21 hours [18, 39]; p = .001), and hospital stay (15 days [9, 21] vs. 15 days [7, 13]; p < .001).
      Figure 3
      Figure 3Calibration plot of the frequencies of observed (y axis) and predicted (x axis) probabilities for severe bleeding in 166 patients undergoing elective open thoraco-abdominal aortic aneurysm repair.
      Table 4Multivariable logistic regression model of association of different variables with severe bleeding in 166 patients undergoing elective open thoraco-abdominal aortic aneurysm repair
      VariableORAdjusted OR95% CIp
      A10 FIBTEM ≤ 3 mm9.285.031.79–57.009
      Surgical time1.011.0071–1.02.002
      Fibrinogen administration1.351.231.05–1.75.018
      Ht on ICU admission0.850.8890.742–0.96.013
      Colloids0.9980.9980.995–0.999.011
      A10 = amplitude of the FIBTEM at 10 min; OR = odds ratio; adjusted OR = OR corrected for overoptimism after internal validation; CI = confidence interval; Ht = haematocrit; ICU = intensive care unit.
      Table 5Outcome and complications of 166 patients undergoing elective open thoraco-abdominal aortic aneurysm repair
      Population (n = 166)No severe bleeding (n = 140)Severe bleeding (n = 26)p value
      In hospital mortality9 (5.4)6 (4.3)3 (11.5).15
      Re-operation for bleeding2 (1.2)0 (0)2 (7.7).024
      Dialysis16 (9.6)8 (5.7)8 (30.8).001
      Spinal cord injury14 (8.4)10 (7.1)4 (15.4).24
      Peri-operative MI6 (3.6)4 (2.9)2 (7.7).24
      Atrial fibrillation15 (9)12 (8.6)3 (11.5).74
      Pneumonia24 (14.5)14 (10)10 (38.5).001
      Tracheostomy6 (3.2)4 (2.9)2 (7.7).23
      ICU stay – h22 [30]21 [21]73 [175].001
      LCOS – days9 (6)9 (5)15 (12)<.001
      Data are presented as n (%) with Chi square test or Fisher exact test, or as median [interquartile range] with Mann–Whitney U test. The variables reported have no missing data. MI = myocardial infarction; ICU = intensive care unit; LCOS = length of hospital stay.

      Discussion

      The main findings of the study include the association between A10 FIBTEM and post-operative bleeding at 24 hours in open TAAA repair. Additionally, it was identified that a 9 mm A10 FIBTEM is a reasonable target to achieve with fibrinogen supplementation to avoid severe bleeding. Finally, values of A10 FIBTEM ≤ 3 mm should be corrected promptly as they may lead to severe bleeding and transfusions. In practice, as an A10 FIBTEM ≤ 3 mm showed a PPV of 50% and an A10 FIBTEM of 9 mm a NPV of 92%, they can be considered, respectively, the trigger and target of fibrinogen supplementation in patients undergoing open TAAA repair.
      In cardiac surgery, the association between low plasma fibrinogen levels and bleeding has been largely proven. A meta-analysis by Gielen et al. showed a significant correlation between pre- and post-operative fibrinogen levels and post-operative blood loss in an adult cardiac surgery population.
      • Gielen C.
      • Dekkers O.
      • Stijnen T.
      • Schoones J.
      • Brand A.
      • Klautz R.
      • et al.
      The effects of pre- and postoperative fibrinogen levels on blood loss after cardiac surgery: a systematic review and meta-analysis.
      The present work demonstrates that this association is valid even in patients undergoing TAAA when the plasma fibrinogen is evaluated with the A10 FIBTEM of ROTEM. The use of A10 FIBTEM for assessment of fibrinogen plasma concentration allows for further generalisation of results than does Clauss’s method, in which different reagents in different laboratories may lead to different fibrinogen levels in the same plasma.
      • Solomon C.
      • Baryshnikova E.
      • Tripodi A.
      • Schlimp C.J.
      • Schöchl H.
      • Cadamuro J.
      • et al.
      Fibrinogen measurement in cardiac surgery with cardiopulmonary bypass: Analysis of repeatability and agreement of Clauss method within and between six different laboratories.
      As high fibrinogen concentration enhances clot firmness, restoration of depleted reserves has been introduced in clinical practice as a cost effective treatment able to decrease post-operative bleeding and transfusion. In a meta-analysis of 13 RCTs, Ng et al.
      • Ng K.T.
      • Yap J.L.L.
      • Kwok P.E.
      The effect of fibrinogen concentrate on postoperative blood loss: A systematic review and meta-analysis of randomized controlled trials.
      observed that fibrinogen concentrate supplementation in adult surgical patients minimises post-operative bleeding in cardiac surgery,
      • Rahe-Meyer N.
      • Levy J.H.
      • Mazer C.D.
      • Schramko A.
      • Klein A.A.
      • Brat R.
      • et al.
      Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of haemostatic therapy.
      ,
      • Ranucci M.
      • Baryshnikova E.
      • Crapelli G.B.
      • Rahe-Meyer N.
      • Menicanti L.
      • Frigiola A.
      • et al.
      Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery.
      urology,
      • Soleimani M.
      • Masoumi N.
      • Nooraei N.
      • Lashay A.
      • Safarinejad M.R.
      The effect of fibrinogen concentrate on perioperative bleeding in transurethral resection of the prostate: a double-blind placebo-controlled and randomized study.
      liver transplantation,
      • Sabate A.
      • Gutierrez R.
      • Beltran J.
      • Mellado P.
      • Blasi A.
      • Acosta F.
      • et al.
      Impact of preemptive fibrinogen concentrate on transfusion requirements in liver transplantation: a multicenter, randomized, double-blind, placebo-controlled trial.
      and orthopaedics.
      • Najafi A.
      • Shariat Moharari R.
      • Orandi A.A.
      • Etezadi F.
      • Sanatkar M.
      • Khajavi M.R.
      • et al.
      Prophylactic administration of fibrinogen concentrate in perioperative period of total hip arthroplasty: a randomized clinical trial study.
      Notably, no patients undergoing open TAAA repair were included in the meta-analysis, albeit this surgery can be considered an archetype when analysing factors and therapies related to peri-operative haemorrhage. Only Morrison et al., in a small single centre pilot study involving 20 type IV open TAAA repair, reported that in patients with hypofibrinogenaemia evaluated with ROTEM, the administration of fibrinogen concentrate is superior to FFP in reducing the need for allogeneic blood products during surgery and in the first 24 hours.
      • Morrison G.A.
      • Koch J.
      • Royds M.
      • McGee D.
      • Chalmers R.T.A.
      • Anderson J.
      • et al.
      Fibrinogen concentrate vs. fresh frozen plasma for the management of coagulopathy during thoraco-abdominal aortic aneurysm surgery: a pilot randomised controlled trial.
      As transfusion is strongly dependent on the institutional protocol,
      • Karkouti K.
      • von Heymann C.
      • Jespersen C.M.
      • Korte W.
      • Levy J.H.
      • Ranucci M.
      • et al.
      Efficacy and safety of recombinant factor XIII on reducing blood transfusions in cardiac surgery: a randomized, placebo-controlled, multicenter clinical trial.
      the need for allogeneic blood products, as a unique outcome, might affect the magnitude of the intervention. Therefore, according to the universal definition of bleeding in cardiac surgery,
      • Dyke C.
      • Aronson S.
      • Dietrich W.
      • Hofmann A.
      • Karkouti K.
      • Levi M.
      • et al.
      Universal definition of perioperative bleeding in adult cardiac surgery.
      a composite outcome including bleeding, large volume transfusion, and re-operation, was considered a more reliable endpoint. In the present study on 166 patients with mixed TAAA extent, the amount of plasma fibrinogen on ICU admission showed both a significant inverse relationship with post-operative bleeding and a modest discriminative power in the detection of patients at high risk of severe post-operative bleeding.
      These results are nonetheless of great importance for daily clinical practice. Pieri et al. have already demonstrated that the need for large volume transfusion is strongly linked to high post-operative mortality, longer ICU stay, and prolonged mechanical ventilation.
      • Pieri M.
      • Nardelli P.
      • De Luca M.
      • Landoni G.
      • Frassoni S.
      • Melissano G.
      • et al.
      Predicting the need for intra-operative large volume blood transfusions during thoraco-abdominal aortic aneurysm repair.
      As a consequence, fibrinogen given at the right time after surgery may potentially affect the outcome. As there are no studies in patients undergoing open TAAA repair on this topic, the present experience tries to fill the knowledge gap, providing pragmatic thresholds based on A10 FIBTEM for fibrinogen administration. Current guidelines on bleeding management recommend fibrinogen supplementation for values of fibrinogen < 1.5–2.0 g/L or when there are signs of hypofibrinogenaemia on viscoelastic tests, “lumping together” cardiac surgery with vascular surgery. Although the level of recommendation is high (2C), the experience gained in cardiac surgery cannot simply be translated in patients undergoing TAAA.
      • Kozek-Langenecker S.A.
      • Afshari A.
      • Albaladejo P.
      • Santullano C.A.A.
      • De Robertis E.
      • Filipescu D.C.
      • et al.
      Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology.
      While bleeding plays a key role in the peri-operative management of both, the pathophysiological basis differs completely and deserves specific consideration. In cardiac surgery, cardiopulmonary bypass (CPB) is the major determinant of thrombin generation, which activates the coagulation cascade through the contact of blood with a foreign thrombogenic surface.
      • Paparella D.
      • Brister S.J.
      • Buchanan M.R.
      Coagulation disorders of cardiopulmonary bypass: a review.
      Other causes of thrombin generation are the air exposure in the cardiotomy and the aspiration of shed mediastinal blood.
      • Paparella D.
      • Brister S.J.
      • Buchanan M.R.
      Coagulation disorders of cardiopulmonary bypass: a review.
      Conversely, in open TAAA repair, the use of cell saver washing blood coming from the surgical field, avoids a massive activation of the extrinsic pathway, removing tissue factors, but also inducing platelets and plasma depletion. In addition, the CPB needs full systemic heparinisation to avoid the formation of fibrin rich thrombus, as opposed to the LHB in which mild anticoagulation is usually required. Thus, not surprisingly, A10 FIBTEM for severe bleeding in cardiac surgery has an AUC around 0.72,
      • Petricevic M.
      • Biocina B.
      • Milicic D.
      • Konosic S.
      • Svetina L.
      • Lekić A.
      • et al.
      Bleeding risk assessment using whole blood impedance aggregometry and rotational thromboelastometry in patients following cardiac surgery.
      ,
      • Ranucci M.
      • Baryshnikova E.
      Fibrinogen supplementation after cardiac surgery: insights from the Zero-Plasma trial (ZEPLAST).
      while, as observed in the present study, in open TAAA repair this is much lower (AUC 0.63). It is plausible that in the coagulopathy following open TAAA surgery other factors act on top of low fibrinogen levels. Notably, in this specific setting, beyond the level of fibrinogen evaluated with ROTEM (A10 FIBTEM ≤ 3 mm), surgical bleeding, intra-operative fibrinogen administration, low Ht on ICU admission, and the use of colloids were independently associated with severe bleeding. While it does not come as a surprise that a longer surgical time and a lower haematocrit on ICU admission are predictors of severe post-operative bleeding,
      • Pieri M.
      • Nardelli P.
      • De Luca M.
      • Landoni G.
      • Frassoni S.
      • Melissano G.
      • et al.
      Predicting the need for intra-operative large volume blood transfusions during thoraco-abdominal aortic aneurysm repair.
      the association between fibrinogen administration in the operating theatre and SB may be considered a marker of a complicated intra-operative course. Conversely, the modest reduction of SB associated with colloid administration may depend on the lower degree of haemodilution produced to achieve a better haemodynamic profile when compared with other fluids. It is very well known that colloids are more effective than crystalloids in expanding the intravascular volume, at the cost of dose dependent haemostatic disorders.
      • László I.
      • Demeter G.
      • Öveges N.
      • Érces D.
      • Kaszaki J.
      • Tánczos K.
      • et al.
      Volume-replacement ratio for crystalloids and colloids during bleeding and resuscitation: an animal experiment.
      In the present study, colloids were administered at a very low dose making the development of coagulopathy unlikely.
      All the considerations mentioned above further corroborate the need for setting specific studies. As fibrinogen supplementation is not a risk free treatment, its administration should rely on solid trigger values, based much more on NPV and PPV rather than sensitivity and specificity. On this topic, the present study demonstrates that the cutoff value of 8 mm, adopted in Morrison’s trial,
      • Morrison G.A.
      • Koch J.
      • Royds M.
      • McGee D.
      • Chalmers R.T.A.
      • Anderson J.
      • et al.
      Fibrinogen concentrate vs. fresh frozen plasma for the management of coagulopathy during thoraco-abdominal aortic aneurysm surgery: a pilot randomised controlled trial.
      is a too high trigger for fibrinogen supplementation as a PPV of 22% leads to an inappropriate correction of the plasma fibrinogen levels in 78% of treated patients. In fact, with this threshold, only 22% of patients would develop a post-operative SB if not treated. On the other hand, a value ≤ 3 mm of A10 FIBTEM seems a more reasonable trigger with a NPV of 86% and inappropriate treatment in 5% of cases. Similarly, decreasing the A10 FIBTEM target for fibrinogen administration from 10 mm11 to 9 mm would allow for maintaining a similar PPV and NPV, reducing risks linked to fibrinogen administration and costs.
      The present investigation has some strengths and limitations, such as the limited sample size and the use of ROTEM rather than Clauss’s method to assess the plasma level of fibrinogen. However, to the best of the present authors’ knowledge, it is the largest vascular population so far in which post-operative bleeding and fibrinogen level has been considered. Concerning the use of ROTEM, this approach can be seen both as a strength, by reducing the variability of fibrinogen assessment from inter-laboratory variability, or weakness, as it is not considered the “gold standard”. Nevertheless, a ROTEM guided protocol is now advocated in vascular surgery to provide a scientific, rational, and goal directed haemostatic therapy.
      • Chee Y.E.
      • Liu S.E.
      • Irwin M.G.
      Management of bleeding in vascular surgery.
      Notably more than one third of patients undergoing open TAAA repair required fibrinogen supplementation on the basis of a validated ROTEM protocol,
      • Monaco F.
      • Barucco G.
      • Nardelli P.
      • Licheri M.
      • Notte C.
      • De Luca M.
      • et al.
      Editor’s Choice - a rotational thromboelastometry driven transfusion strategy reduces allogenic blood transfusion during open thoraco-abdominal aortic aneurysm repair: a propensity score matched study.
      which strongly reduced the attending physician related variability in transfusion of allogeneic blood products. In particular, the patients with post-operative SB required more fibrinogen supplementation in the operating theatre compared with those who did not (2.5 [0, 4] vs. 0 [0, 2]; p = .001). Nevertheless, the A10 FIBTEM observed in ICU was higher in the no SB group compared with the SB group. All these findings taken together support both that the fibrinogen deficiency may be relatively common after aortic surgery and that the daily clinical practice may benefit from a scientifically solid trigger and target of fibrinogen supplementation.
      The evaluation of FIBTEM (and all other ROTEM parameters) for the first 24 – 72 hours after surgery may have allowed a less restricted view on the post-operative clotting disaster associated with TAAA surgery.
      • Waldén K.
      • Jeppsson A.
      • Nasic S.
      • Backlund E.
      • Karlsson M.
      Low preoperative fibrinogen plasma concentration is associated with excessive bleeding after cardiac operations.
      Indeed, the overall goal of the paper does not analyse all aspects, of bleeding/coagulation control after open TAAA surgery, but tries to mechanistically link the depletion of fibrinogen (evaluated with ROTEM) with patients who have severe bleeding after open TAAA repair. Nevertheless, the use of ICU admission as a single time point, occurring temporally after the correction of the surgical and microvascular bleeding in the operating theatre, is a reliable and homogenous starting point for who will and who will not suffer SB. In addition, it is largely known that the first 24 hours are the most precarious, with the highest risk of severe bleeding, surgical revision for bleeding, and transfusion of allogeneic blood products, while beyond that period, the bleeding is unlikely to be severe even in patients undergoing TAAA. Finally, in a previous study by the present authors, it had already been demonstrated that a careful intra-operative ROTEM guided transfusion algorithm may avoid the post-operative clotting disaster in the vast majority of patients undergoing TAAA (85% of cases).
      • Monaco F.
      • Barucco G.
      • Nardelli P.
      • Licheri M.
      • Notte C.
      • De Luca M.
      • et al.
      Editor’s Choice - a rotational thromboelastometry driven transfusion strategy reduces allogenic blood transfusion during open thoraco-abdominal aortic aneurysm repair: a propensity score matched study.
      This study may represent a further step in the patient’s blood management, investigating when the fibrinogen deficiency assessed by ROTEM has to be corrected to decrease the rate of the SB.
      Interestingly, although all ROTEM parameters have been considered, only the FIBTEM was associated with SB. These results, albeit not yet reported in aortic surgery, are in line with the experience observed in other settings in which the fibrinogen supplementation decreases bleeding.
      • Ranucci M.
      • Baryshnikova E.
      • Crapelli G.B.
      • Rahe-Meyer N.
      • Menicanti L.
      • Frigiola A.
      • et al.
      Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery.
      • Soleimani M.
      • Masoumi N.
      • Nooraei N.
      • Lashay A.
      • Safarinejad M.R.
      The effect of fibrinogen concentrate on perioperative bleeding in transurethral resection of the prostate: a double-blind placebo-controlled and randomized study.
      • Sabate A.
      • Gutierrez R.
      • Beltran J.
      • Mellado P.
      • Blasi A.
      • Acosta F.
      • et al.
      Impact of preemptive fibrinogen concentrate on transfusion requirements in liver transplantation: a multicenter, randomized, double-blind, placebo-controlled trial.
      The correlation between A10 FIBTEM/ROTEM parameters with further endpoints such as 30 day mortality and midterm survival during follow up has not been investigated. However, it is the authors’ opinion that a panoply of events acts on hard outcomes in patients undergoing TAAA surgery. Thus, while it is unlikely that a single strategy, technique, or drug may affect hard outcomes, it is believed that severe bleeding should be considered the primary endpoint in studies investigating ROTEM guided administration of fibrinogen concentrate. As observed even in this study, severe bleeding is a marker of worse outcome carrying a high rate of complications and mortality.
      • Pieri M.
      • Nardelli P.
      • De Luca M.
      • Landoni G.
      • Frassoni S.
      • Melissano G.
      • et al.
      Predicting the need for intra-operative large volume blood transfusions during thoraco-abdominal aortic aneurysm repair.
      Hence, as fibrinogen is the cornerstone of the coagulation cascade and fibrinogen administration an effective therapy, giving a scientific background for fibrinogen supplementation even in aortic surgery may be useful in daily clinical practice and may potentially improve the outcome.
      Although the present study is one of the largest systematic assessments of fibrinogen level with ROTEM for the evaluation of severe bleeding post open TAAA repair so far, the adverse events are relatively scarce. Nevertheless, although this association has been confirmed with the multivariable analysis, it cannot be excluded that the relatively low number of patients with SB (26) and the use of a composite endpoint rather than a single outcome may have acted as relevant confounders for the findings of the present investigation. Larger prospective studies are required to confirm these results.
      In conclusion, the present study shows, for the first time in a population undergoing open TAAA repair, a significant inverse correlation between A10 FIBTEM and post-operative blood loss, supporting that a low level of fibrinogen at the time of ICU admission, as evaluated with ROTEM, may be associated with post-operative severe bleeding after aortic surgery. The analysis also defines trigger and target values for fibrinogen supplementation, based on A10 FIBTEM, in clinical practice. Overall, the present study fills a gap in this topic in the current guidelines,
      • Riambau V.
      • Böckler D.
      • Brunkwall J.
      • Cao P.
      • Chiesa R.
      • Coppi G.
      • et al.
      Editor’s Choice - Management of Descending Thoracic Aorta Diseases: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
      and investigating the role of fibrinogen supplementation in preventing severe bleeding adds new insights to an issue not fully understood. In this sense, the data observed in the present study might fuel new larger prospective and randomised trials on haemostatic therapy in aortic surgery. Further studies are required to test these findings even in endovascular surgery in which severe bleeding is an uncommon complication with different haemostatic derangement.

      Conflict of interest

      None.

      Funding

      None.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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