Purpose
Pathologic thromboelastometric results may indicate a coagulation disorder. During bleeding, the prolongation of CTEXTEM (Clotting Time) measured by rotational thromboelastometry (ROTEM) can detect alterations in the extrinsic pathway. However, the significance of a prolonged CTEXTEM for risk stratification in patients with bleeding remains unclear.
Methods
A total of 2035 consecutive patients were retrospectively examined between 2014 and 2020 from a bleeding database at Saarland University Hospital. The database includes patients tested with ROTEM during bleeding. The study population was split into three groups: Cardiothoracic surgery with cardiopulmonary bypass (CPB, n = 753), trauma (n = 206) and medical bleeding (n = 1076). The impact of CTEXTEM on 30-day mortality was assessed using C-statistic. Threshold values for CTEXTEM reaching a specificity > 90% for 30-day mortality were selected. Adjusted hazard ratios (adjHR [95% confidence interval]) were calculated with multivariable Cox models.
Results
The C-statistic showed that CTEXTEM (C-statistic for groups 1–3: 0.62, threshold ≥ 110 s (CPB); 0.65, threshold ≥ 98 s (trauma); 0.63, threshold ≥ 99 s (medical bleeding)) had a predictive power for 30-day mortality in all groups. The determined threshold value of CTEXTEM reaching a specificity > 90% remained an independent risk predictor for 30-day mortality even after adjustment for confounding factors (CPB: adjHR 2.5 [1.5–4.2], p < 0.001; trauma: adjHR 3.9 [1.8–8.7], p = 0.001; medical bleeding: adjHR 1.8 [1.4–2.5], p < 0.001). The 30-day mortality rate was significantly increased (CPB: CTEXTEM ≥ 110 s, 26% versus 9%, p < 0.001; trauma: CTEXTEM ≥ 98 s, 41% versus 11%, p < 0.001; medical bleeding: CTEXTEM ≥ 99 s, 41% versus 22%, p < 0.001).
Conclusion
Our results indicate that CTEXTEM-detected alterations in the extrinsic pathway may be an independent predictor of 30-day mortality in patients with bleeding.
Supplementary information
The online version contains supplementary material available at 10.1007/s00068-025-03079-z.
Keywords: Mortality, Risk factor, Bleeding, Rotational thromboelastometry
Key points
Question: Bleeding can result in coagulation disorders. Rotational thromboelastometry can detect alterations in the extrinsic pathway by measuring clotting time (CTEXTEM). The significance of a prolonged CTEXTEM for risk stratification remains unclear.
Findings: 2035 consecutive patients between 2014 and 2020 were retrospectively analysed and threshold value of CTEXTEM remained an independent risk predictor for 30-day mortality.
Meaning: Elevated CTEXTEM could be an independent predictor of 30-day mortality in patients with bleeding.
Supplementary information
The online version contains supplementary material available at 10.1007/s00068-025-03079-z.
Introduction
Bleeding is associated with rapid loss and consumption of coagulation factors and remains a leading cause of preventable morbidity and mortality in trauma, major, and cardiac surgery with cardiopulmonary bypass. Early, targeted hemostatic therapy is essential, and functional point-of-care methods, such as rotational thromboelastometry (ROTEM), enable the rapid assessment of coagulation deficits [1–3].
In EXTEM, coagulation is triggered by tissue factor, initiating clot formation within about 70 s and allowing assessment within 10 min. Key ROTEM parameters include clotting time (CT), clot formation time (CFT), clot firmness (A5, A10, A20, and MCF), and fibrinolytic activity (ML and LI60) [4]. A prolonged clotting time in EXTEM (CTEXTEM) in trauma patients was strongly linked to increased mortality. The most common causes of death in trauma patients within the first 24 h are brain injury, followed by haemorrhage [5].
Following the algorithm of Weber et al. CTEXTEM, A10EXTEM, CTINTEM, A10FIBTEM, and CTAPTEM were used for decision-making for coagulation therapy in bleeding patients [3]. Therapeutic strategies for patients with prolonged CTEXTEM commonly include prothrombin complex concentration [3].
Our aim was therefore to investigate the relationship between prolonged CTEXTEM, 30-day mortality, and the therapeutic addition of prothrombin complex concentrate. Patients were divided into three groups - cardiothoracic surgery with cardiopulmonary bypass, trauma, and medical bleeding- reflecting differences in bleeding pathophysiology. Our primary hypothesis was that there is an independent association between CTEXTEM and 30-day mortality in patients with bleeding.
Second, we hypothesized that prothrombin complex concentrate might improve 30-day survival in patients with prolonged CTEXTEM.
Materials and methods
The study was registered in the German Clinical Trials registration (registration number DRKS00026153) prior to data analysis in September 2021 (principal investigator: PD Dr. med. Sven Oliver Schneider, Saarland University, Department of Anaesthesiology, Intensive Care Medicine and Pain Medicine, Homburg/Saar, Germany). After approval of the Ethical committee (Ärztekammer Saarland; number 93/20), the data were retrospectively collected. The requirement for written informed consent was waived by the Ethical Committee. The data set used in this study is based on the bleeding database of Saarland University Hospital. Data from the bleeding database were previously published about CTINTEM [6].
Bleeding episodes were identified and defined according to the treating physician’s clinical judgement. The decision for the treatment with the coagulation factors was made by the treating physician based on the ROTEM-guided bleeding management protocol and the clinical situation. All patients were managed according to the ROTEM-guided bleeding management protocol as described by Weber et al. [3] Clinical practice remained constant throughout the study period (2014–2020), and no subsequent updates to the guideline were implemented during this time. ROTEM testing was systematically performed in all patients with bleeding and suspected coagulation disorders.
Inclusion/exclusion criteria
All patients tested in the Saarland University Hospital by rotational thromboelastometry between 2014 and 2020 were included. Rotational thromboelastometry is available for all patients with bleeding and/or coagulation disorders in the Saarland University Hospital.
Exclusion criteria for the study population were missing information about CTEXTEM measurement, A10EXTEM, CTINTEM, A10FIBTEM, CTAPTEM, and missing information on outcome (Table 2), covariates (Table 1), or implausible data.
Table 2.
Outcome related to CTEXTEM (Clotting Time) in seconds (s)
| Cardiothoracic surgery with CPB | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Before Rotem analysis | After Rotem analysis | |||||||||
| CTEXTEM < 110s | CTEXTEM ≥ 110s | p-value | CTEXTEM < 110s | CTEXTEM ≥ 110s | p-value | |||||
| (n = 663) | (n = 90) | (n = 663) | (n = 90) | |||||||
| Mech. ventilated (h) | 4 | (3–6) | 4 | (3–9) | 0.02 | 10 | (5–19) | 8 | (1–30) | 0.1 |
| Renal replacement therapy (%) | 53 | (8) | 15 | (17) | 0.007 | 119 | (18) | 30 | (33) | 0.001 |
| Length of stay (days) | ||||||||||
| In ICU | 1 | (0–1) | 1 | (1–1) | < 0.001 | 2 | (1–7) | 4 | (1–4) | 0.1 |
| In hospital | 2 | (2–4) | 3 | (2–6) | 0.3 | 10 | (7–17) | 11 | (5–21) | 0.4 |
| 30-day mortality (%) | ─ | ─ | 59 | (9) | 23 | (26) | < 0.001 | |||
| Packed red blood cells (n) | 0 | (0–2) | 1 | (0–4) | 0.001 | 2 | (2–4) | 2 | (0–5) | 0.3 |
| Platelet concentrate (n) | 1 | (1–2) | 0 | (0–2) | 0.1 | 2 | (2–2) | 2 | (0–4) | 0.2 |
| Fresh frozen plasma (n) | 0 | (0–0) | 0 | (0–0) | 0.03 | 0 | (0–0) | 0 | (0–3) | 0.04 |
| Prothrombin complex concentrate (IU) | 0 | (0–0) | 0 | (0–0) | 0.2 | 0 | (0–0) | 1500 | (1500–3000) | < 0.001 |
| Fibrinogen (g) | 0 | (0–0) | 0 | (0–0) | 0.1 | 0 | (0–0) | 0 | (0–0) | 0.009 |
| Recombinant Factor VIIa (IU) | 0 | (0–0) | 0 | (0–0) | 0.4 | 0 | (0–0) | 0 | (0–0) | 0.5 |
| Antithrombin III (IU) | 0 | (0–0) | 0 | (0–0) | 0.9 | 0 | (0–0) | 0 | (0–0) | 0.7 |
| Factor XIII (IU) | 0 | (0–0) | 0 | (0–0) | 0.3 | 0 | (0–0) | 0 | (0–0) | 0.7 |
| Adverse events | ||||||||||
| Pneumonia (%) | 22 | (3) | 4 | (4) | 0.5 | 104 | (16) | 15 | (17) | 0.8 |
| Pulmonary embolism (%) | 5 | (1) | 3 | (3) | 0.1 | 5 | (1) | 1 | (1) | 0.5 |
| Acute myocardial infarction (%) | 49 | (7) | 5 | (6) | 0.7 | 2 | (0) | 2 | (2) | 0.1 |
| Embolic apoplexy (%) | 26 | (4) | 6 | (7) | 0.3 | 23 | (3) | 3 | (3) | 1 |
| Peripheral arterial embolism and thrombosis (%) | 14 | (2) | 4 | (4) | 0.3 | 4 | (1) | 4 | (4) | 0.009 |
| Gastrointestinal ischemia (%) | 13 | (2) | 8 | (9) | 0.002 | 35 | (5) | 8 | (9) | 0.2 |
| Gastrointestinal bleeding (%) | 2 | (0) | 2 | (2) | 0.1 | 2 | (0) | 0 | (0) | 1 |
| Trauma | ||||||||||
| Before Rotem analysis | After Rotem analysis | |||||||||
| CTEXTEM < 98s | CTEXTEM ≥ 98s | p-value | CTEXTEM < 98s | CTEXTEM ≥ 98s | p-value | |||||
| (n = 179) | (n = 27) | (n = 179) | (n = 27) | |||||||
| Mech. ventilated (h) | 0 | (0–2) | 0 | (0–2) | 1 | 1 | (0–51) | 2 | 0(−6) | 0.9 |
| Renal replacement therapy (%) | 10 | (6) | 2 | (7) | 0.7 | 16 | (9) | 4 | (15) | 0.3 |
| Length of stay (days) | ||||||||||
| In ICU | 1 | (1–1) | 1 | (1–1) | 1 | 5 | (2–15) | 7 | (1–7) | 0.5 |
| In hospital | 2 | (1–5) | 1 | (1–2) | 0.1 | 21 | (12–34) | 13 | (1–22) | 0.005 |
| 30-day mortality (%) | ─ | ─ | 19 | (11) | 11 | (41) | < 0.001 | |||
| Packed red blood cells (n) | 0 | (0–2) | 0 | (0–1) | 0.4 | 2 | (0–6) | 2 | (0–5) | 0.4 |
| Platelet concentrate (n) | 0 | (0–0) | 0 | (0–0) | 0.4 | 0 | (0–1) | 0 | (0–1) | 0.9 |
| Fresh frozen plasma (n) | 0 | (0–0) | 0 | (0–0) | 0.9 | 0 | (0–0) | 0 | (0–0) | 0.1 |
| Prothrombin complex concentrate (IU) | 0 | (0–0) | 0 | (0–0) | 0.1 | 0 | (0–0) | 1000 | (0–2000) | < 0.001 |
| Fibrinogen (g) | 0 | (0–0) | 0 | (0–0) | 0.7 | 0 | (0–0) | 0 | (0–2) | 0.4 |
| Recombinant Factor VIIa (IU) | 0 | (0–0) | 0 | (0–0) | 1 | 0 | (0–0) | 0 | (0–0) | 1 |
| Antithrombin III (IU) | 0 | (0–0) | 0 | (0–0) | 0.6 | 0 | (0–0) | 0 | (0–0) | 0.1 |
| Factor XIII (IU) | 0 | (0–0) | 0 | (0–0) | 1 | 0 | (0–0) | 0 | (0–0) | 0.4 |
| Adverse events | ||||||||||
| Pneumonia (%) | 21 | (12) | 0 | (0) | 0.1 | 13 | (7) | 2 | (7) | 1 |
| Pulmonary embolism (%) | 6 | (3) | 0 | (0) | 1 | 3 | (2) | 1 | (4) | 0.4 |
| Acute myocardial infarction (%) | 1 | (1) | 0 | (0) | 1 | 1 | (1) | 0 | (0) | 1 |
| Embolic apoplexy (%) | 3 | (2) | 2 | (7) | 0.1 | 3 | (2) | 1 | (4) | 0.4 |
| Peripheral arterial embolism and thrombosis (%) | 1 | (1) | 0 | (0) | 1 | 1 | (1) | 0 | (0) | 1 |
| Gastrointestinal ischemia (%) | 1 | (1) | 0 | (0) | 1 | 1 | (1) | 0 | (0) | 1 |
| Gastrointestinal bleeding (%) | 1 | (1) | 1 | (4) | 0.2 | 1 | (1) | 0 | (0) | 1 |
| Medical bleeding | ||||||||||
| Before Rotem analysis | After Rotem analysis | |||||||||
| CTEXTEM < 99s | CTEXTEM ≥ 99s | p-value | CTEXTEM < 99s | CTEXTEM ≥ 99s | p-value | |||||
| (n = 940) | (n = 136) | (n = 940) | (n = 136) | |||||||
| Mech. ventilated (h) | 0 | (0–5) | 1 | (0–7) | 0.003 | 2 | (0–22) | 3 | (0–26) | 0.2 |
| Renal replacement therapy (%) | 136 | (14) | 30 | (22) | 0.03 | 188 | (20) | 49 | (36) | < 0.001 |
| Length of stay (days) | ||||||||||
| In ICU | 1 | (1–2) | 1 | (1–2) | 0.02 | 4 | (1–12) | 7 | (2–14) | 0.03 |
| In hospital | 2 | (2–9) | 2 | (1–12) | 1 | 17 | (8–30) | 13 | (4–30) | 0.01 |
| 30-day mortality (%) | ─ | ─ | 203 | (22) | 56 | (41) | < 0.001 | |||
| Packed red blood cells (n) | 0 | (0–4) | 1 | (0–4) | 0.2 | 2 | (0–5) | 2 | (0–5) | 0.5 |
| Platelet concentrate (n) | 0 | (0–0) | 0 | (0–0) | 0.5 | 0 | (0–1) | 0 | (0–2) | 0.04 |
| Fresh frozen plasma (n) | 0 | (0–0) | 0 | (0–0) | 0.2 | 0 | (0–0) | 0 | (0–2000) | 0.005 |
| Prothrombin complex concentrate (IU) | 0 | (0–0) | 0 | (0–875) | 0.004 | 0 | (0–0) | 0 | (0–2) | < 0.001 |
| Fibrinogen (g) | 0 | (0–0) | 0 | (0–0) | 0.4 | 0 | (0–0) | 0 | (0–0) | < 0.001 |
| Recombinant Factor VIIa (IU) | 0 | (0–0) | 0 | (0–0) | 0.5 | 0 | (0–0) | 0 | (0–0) | 0.6 |
| Antithrombin III (IU) | 0 | (0–0) | 0 | (0–0) | 0.4 | 0 | (0–0) | 0 | (0–0) | 1 |
| Factor XIII (IU) | 0 | (0–0) | 0 | (0–0) | 0.3 | 0 | (0–0) | 0 | (0–0) | 0.7 |
| Adverse events | ||||||||||
| Pneumonia (%) | 113 | (12) | 27 | (20) | 0.01 | 63 | (7) | 9 | (7) | 1 |
| Pulmonary embolism (%) | 22 | (2) | 4 | (3) | 0.6 | 7 | (1) | 2 | (1) | 0.3 |
| Acute myocardial infarction (%) | 27 | (3) | 2 | (1) | 0.6 | 6 | (1) | 1 | (1) | 1 |
| Embolic apoplexy (%) | 24 | (3) | 3 | (2) | 1 | 3 | (0) | 1 | (1) | 0.4 |
| Peripheral arterial embolism and thrombosis (%) | 40 | (4) | 12 | (9) | 0.03 | 2 | (0) | 2 | (1) | 0.1 |
| Gastrointestinal ischemia (%) | 44 | (5) | 12 | (9) | 0.1 | 8 | (1) | 1 | (1) | 1 |
| Gastrointestinal bleeding (%) | 101 | (11) | 16 | (12) | 0.8 | 11 | (1) | 3 | (2) | 0.4 |
The outcome was split into the time before and after the Rotem analysis. Continuous variables are expressed as median and interquartile range and were compared with Mann Whitney U test. Categorical variables are presented as numbers (column percentages) and were compared with chi tests. Threshold values reaching a specificity of >90% were determined and selected for the analysis. ICU (Intensive care unit). Rotem (Rotational thromboelastometry). Packed red blood cells (450mL), Platelet concentrate (270mL), and Fresh frozen plasma (300mL). CT: clotting time in seconds (s). EXTEM: extrinsic pathway. The leading department is selected in all 3 groups. Groupe 1: Cardiothoracic surgery with CPB includes patients undergoing surgery with cardiopulmonary bypass (CPB). Groupe 2: Trauma includes traumatically injured patients, with 115 patients suffering from multiple injuries that involve multiple organs. Groupe 3: Medical bleeding includes all patients with surgery without cardiopulmonary bypass (general surgery (without liver), liver surgery, orthopedic surgery, pediatric, eye, thoracic surgery without CPB, vascular surgery without CPB, gynecology, urology, neurosurgery, ear, nose, throat, and maxillofacial surgery) and 79 patients from internal medicine
Table 1.
Population characteristics, Comorbidities, and rotational thromboelastometry analysis
| Cardiothoracic surgery with CPB | Trauma | Medical bleeding | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CTEXTEM < 110s | CTEXTEM ≥ 110s | CTEXTEM < 98s | CTEXTEM ≥ 98s | CTEXTEM < 99s | CTEXTEM ≥ 99s | |||||||
| (n = 663) | (n = 90) | (n = 179) | (n = 27) | (n = 940) | (n = 136) | |||||||
| Age (yrs) | 67 | (57–74) | 67 | (55–76) | 61 | (46–78) | 77 | (63–81)# | 64 | (56–75) | 64 | (54–74) |
| Male (%) | 476 | (72) | 64 | (71) | 112 | (63) | 17 | (63) | 555 | (59) | 87 | (64) |
| Body mass index (kg/m 2 ) | 26 | (24–30) | 26 | (24–29) | 26 | (23–29) | 26 | (24–29) | 26 | (23–29) | 26 | (23–30) |
| Emergency | 106 | (16) | 10 | (11) | 136 | (76) | 23 | (85) | 301 | (32) | 62 | (46)* |
| Re-operation after post-operative bleeding | 116 | (17) | 24 | (27)* | 26 | (15) | 3 | (11) | 258 | (27) | 46 | (34) |
| Comorbidities | ||||||||||||
| Coronary heart disease | 293 | (44) | 34 | (38) | 14 | (8) | 2 | (7) | 181 | (19) | 32 | (24) |
| Cardiac insufficiency (EF < 45%) | 72 | (11) | 14 | (16) | 5 | (3) | 0 | (0) | 40 | (4) | 10 | (7) |
| Chronic obstructive pulmonary disease | 43 | (6) | 7 | (8) | 6 | (3) | 2 | (7) | 103 | (11) | 25 | (18)+ |
| Insulin-dependent diabetes mellitus | 30 | (5) | 5 | (6) | 11 | (6) | 2 | (7) | 76 | (8) | 12 | (9) |
| Liver disease Child C | 3 | (0) | 0 | (0) | 4 | (2) | 1 | (4) | 72 | (8) | 13 | (10) |
| Coagulation disorders | 21 | (3) | 10 | (11)* | 21 | (12) | 3 | (11) | 158 | (17) | 21 | (15) |
| Anticoagulation prior Rotem analysis | ||||||||||||
| Aspirin 100mg | 284 | (43) | 35 | (39) | 18 | (10) | 0 | (0) | 136 | (14) | 24 | (18) |
| High molecular weight heparin | 40 | (6) | 6 | (7) | 31 | (17) | 0 | (0)# | 202 | (21) | 32 | (24) |
| Low molecular weight heparin | 8 | (1) | 0 | (0) | 31 | (17) | 2 | (7) | 145 | (15) | 8 | (6)+ |
| Other anticoagulation | 50 | (8) | 19 | (21)* | 6 | (3) | 5 | (19)# | 49 | (5) | 17 | (13)+ |
| Rotational thromboelastometry | ||||||||||||
| CT EXTEM | 74 | (67–83) | 142 | (120–184)* | 59 | (52–68) | 119 | (106–151)# | 61 | (54–72) | 132 | (109–182)+ |
| CT INTEM | 221 | (195–257) | 346 | (247–452)* | 161 | (148–183) | 230 | (195–279)# | 177 | (155–206) | 270 | (209–356)+ |
| A10 EXTEM | 57 | (50–63) | 51 | (38–60)* | 53 | (46–59) | 46 | (34–61) | 54 | (45–63) | 44 | (31–58)+ |
| A10 FIBTEM | 13 | (10–18) | 13 | (7–17)* | 13 | (9–18) | 10 | (5–17) | 15 | (10–21) | 10 | (4–20)+ |
| CT APTEM | 71 | (63–82) | 131 | (116–182)* | 57 | (49–66) | 114 | (101–157)# | 59 | (51–70) | 124 | (100–172)+ |
Continuous variables are expressed as median and interquartile range and were compared with Mann Whitney U test. Categorical variables are presented as numbers (column percentages) and were compared with chi2 tests. Threshold values reaching a specificity of > 90% were determined and selected for the analysis. A10: clot formation after 10 min. CT: clotting time in seconds (s). EF: ejection fraction. ROTEM: rotational thromboelastometry. APTEM: extrinsic pathway with Inhibition of fibrinolysis. EXTEM: extrinsic pathway. FIBTEM: fibrin contribution to clot firmness. INTEM: intrinsic pathway without heparin neutralization. The leading department is selected in all 3 groups. Groupe 1: cardiothoracic surgery with CPB includes patients undergoing surgery with cardiopulmonary bypass (CPB). Groupe 2: trauma includes traumatically injured patients, and with 115 patients suffering from multiple injuries that involve multiple organs. Groupe 3: medical bleeding includes all patients with surgery without cardiopulmonary bypass (general surgery (without liver), liver surgery, orthopedic surgery, pediatric, eye, thoracic surgery without CPB, vascular surgery without CPB, gynecology, urology, neurosurgery, ear, nose, throat, and maxillofacial surgery) and 79 patients from internal medicine. Emergency at hospital admission is defined as a surgical intervention necessary within 6 h after hospital admission. Coagulation disorders: known bleeding coagulation disorder, e.g., thrombocytopenia, factor deficiency, von Willebrand disease. Anticoagulation before the Rotem analysis includes anticoagulation in the hospital ward or at home. Other anticoagulants: Argatroban, Phenprocoumon, factor Xa inhibitor, Dabigatran, and P2Y12 inhibitors. * p < 0.05 versus CTEXTEM < 110s. # p < 0.05 versus CTEXTEM < 98s. + p < 0.05 versus CTEXTEM < 99s
Data source
Rotational thromboelastometry data are recorded during patient care and stored in the hospital’s medical reports and the bleeding database. These include patients with and without surgery. Detailed information about the medical conditions of patients, along with the procedure, was extracted from the hospital database (Tables 1 and 2).
Rotational thromboelastometry analyses
The ROTEM (ROTEM delta®, Tem Innovations, Munich, Germany) analyses in this study include measurements of tissue factor–activated EXTEM (extrinsic pathway activation without heparin neutralization), FIBTEM (fibrin contribution to clot firmness), and APTEM (extrinsic pathway with inhibition of fibrinolysis). All assays estimate clotting time (CT) and clot formation after 10 min (A10). The reference range for CTEXTEM on our ROTEM thromboelastometry device is 38–82 s. Each patient was considered only once. If more than one ROTEM analysis was done in one patient, only the first analysis was considered.
Proof of plausibility
Data integrity was evaluated according to specific rules to delete erroneously entered data and cases with missing information (proof of plausibility, Appendix 1).
Missing data handling/sensitivity analyses
Patients with missing data were excluded from the analysis. Several sensitivity analyses were performed.
Definitions of the groups
Groupe 1: Cardiothoracic surgery with CPB includes patients undergoing surgery with cardiopulmonary bypass (CPB).
Groupe 2: Trauma includes traumatically injured patients, and with 115 patients suffering from multiple injuries that involve multiple organs.
Groupe 3: Medical bleeding includes all patients with surgery without cardiopulmonary bypass (general surgery (without liver), liver surgery, orthopedic surgery, pediatric, eye, thoracic surgery without CPB, vascular surgery without CPB, gynecology, urology, neurosurgery, ear, nose, throat, and maxillofacial surgery) and 79 patients from internal medicine.
Subgroup 1: Patients without anticoagulation (without high molecular weight heparin, low molecular weight heparin, Argatroban, Phenprocoumon, Factor Xa inhibitor, Dabigatran, and P2Y12 inhibitors). Aspirin 100 mg was not considered anticoagulant.
Subgroup 2: Patients treated with packed red blood cells ≥ 6.
Definition of the outcomes
The primary outcome was overall survival with a follow-up period of 30 days.
The secondary outcomes were: Severe adverse events were defined by the occurrence of pneumonia, pulmonary embolism, acute myocardial infarction, embolic apoplexy, peripheral arterial embolism, thrombosis, and gastrointestinal bleeding. Gastrointestinal ischemia was defined as occlusive or non-occlusive mesenteric ischemia, with diagnosis confirmed by laparotomy, computed tomography, or mesenteric angiography.
Data analysis
Receiver operating characteristic (ROC) curves were constructed (C-statistic) to evaluate the predictive power of CTEXTEM for the occurrence of 30-day mortality. The Youden Index was used to calculate the optimal threshold for CTEXTEM in predicting 30-day mortality. Threshold values achieving a specificity of > 90% were determined with their corresponding specificities and selected for analysis. Continuous variables are expressed as median and interquartile range and were compared with Mann Whitney U test. Categorical variables are presented as absolute and relative frequencies and were compared with chi2 tests.
The number needed to screen was calculated to measure how many patients must be screened with values CTEXTEM ≥ 110 s, CTEXTEM ≥ 98 s, and CTEXTEM ≥ 99 s to avoid one death. The positive predictive value was defined as the number of true positives/(number of true positives + number of false positives). The negative predictive value was defined as the number of true negatives/(number of true negatives + number of false negatives).
Survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards models were used to adjust for confounding factors, including all variables from Table 1 with p < 0.05. Pairwise dependent variable constellations with Pearson or Spearman correlation coefficients exceeding + 0.4 or less than − 0.4 were a priori specified as interaction terms in multivariable analyses to account for the issue of multicollinearity. CTEXTEM was analysed a threshold value and as a continuous variable (per 10-second increase). Sensitivity analyses were performed, including confounding factors listed in Tables 1 and 2.
We developed a propensity score for each patient based on the potential confounders listed in Tables 1 and 2. Patients given prothrombin complex concentrate were matched to patients with the closest propensity score who were not given prothrombin complex concentrate, keeping the maximum difference in propensity score less than 0.05. The matching algorithm was nearest neighbour matching without replacement. Two-sided p-values > 0.1 were considered balanced. Data analysis was performed using SPSS Statistics 29™ (IBM, Ehningen, Germany). Two-sided p-values < 0.05 were considered statistically significant.
Results
During the study period, 2656 patients had documented index rotational thromboelastometry (ROTEM) analyses. Among these, 375 patients had no information about CTEXTEM analysis, 74 patients had missing information on outcome, covariates, or implausible data, and 172 patients had missing information about A10EXTEM, CTINTEM, A10FIBTEM, and CTAPTEM. The final study population included 2035 patients and was divided into three groups: Cardiothoracic surgery with cardiopulmonary bypass (CPB, n = 753), trauma (n = 206), and medical bleeding (n = 1076).
The C-statistic showed that CTEXTEM predicted 30-day mortality in all three groups (Fig. 1A). The number needed to screen (NNS), the positive predictive value (PPV), and the negative predictive value (NPV) were calculated for 30-day mortality using the threshold value of CTEXTEM reaching a specificity of > 90% (CPB: CTEXTEM ≥ 110 s (NNS: 6, PPV: 0.26, NPV: 0.91; trauma: CTEXTEM ≥ 98 s (NNS: 3, PPV: 0.48, NPV: 0.88; medical bleeding: CTEXTEM ≥ 99 s (NNS: 5, PPV: 0.41, NPV: 0.78).
Fig. 1.
CTEXTEM (Clotting Time) and ROC analysis for mortality in all patients. Figure 1B: CTEXTEM (Clotting Time) and ROC analysis for mortality in patients without anticoagulation Box and whisker plot with the 10th and 90th percentiles. Solid dash: median values of CTEXTEM. The plus symbol: mean values of CTEXTEM. Blue solid dashed line: optimal threshold. Receiver operating characteristic curves (ROC) were constructed (C-statistic) to evaluate the predictive power of CTEXTEM for 30-day mortality. AUC (area-under-the-curve). The Youden Index was used to calculate the optimal threshold for CTEXTEM in the prediction of 30 days. Data were collected in real time by the attending physician or nurse in parallel to the patient’s treatment. Each patient was considered only once. If more than one Rotem (Rotational thromboelastometry) analysis was done for one patient, only the first Rotem analysis was considered. The leading department is selected in all 3 groups. Groupe 1: Cardiothoracic surgery with CPB includes patients undergoing surgery with cardiopulmonary bypass (CPB). Groupe 2: Trauma includes traumatically injured patients, and with 115 patients suffering from multiple injuries that involve multiple organs. Groupe 3: Medical bleeding includes all patients with surgery without cardiopulmonary bypass (general surgery (without liver), liver surgery, orthopaedic surgery, paediatric, eye, thoracic surgery without CPB, vascular surgery without CPB, gynaecology, urology, neurosurgery, ear, nose, throat, and maxillofacial surgery) and 79 patients from internal medicine
Patients with a threshold value of CTEXTEM reaching a specificity > 90% were quite comparable in their population characteristics to patients with lower CTEXTEM values (Table 1). However, diagnostic rotational thromboelastometry shows impaired blood clotting in all groups (Table 1).
The outcome was split into the time before and after the ROTEM analysis. Patients with increased CTEXTEM had more renal replacement therapy and required more coagulation factors (Table 2).
Patients with elevated CTEXTEM had an increased 30-day mortality compared to patients with lower CTEXTEM (CPB: CTEXTEM ≥ 110 s, 26% versus 9%, p < 0.001; trauma: CTEXTEM ≥ 98 s, 41% versus 11%, p < 0.001; medical bleeding: CTEXTEM ≥ 99 s, 41% versus 22%, p < 0.001; Table 2; Fig. 2). Even after adjustment, elevated CTEXTEM remained an independent risk factor for 30-day mortality. This remained true in sensitivity analyses for the CPB and the medical bleeding group (Table 3). In the trauma group with a smaller sample size, the results were not significant (Table 3).
Fig. 2.
Kaplan-Meier survival plots for elevated CTEXTEM versus lower CTEXTEM in all patients and in patients without anticoagulation (except aspirin 100 mg) during 30-day follow-up. Rotem (Rotational thromboelastometry). The leading department is selected in all 3 groups. Groupe 1: Cardiothoracic surgery with CPB includes patients undergoing surgery with cardiopulmonary bypass (CPB). Groupe 2: Trauma includes traumatically injured patients, and with 115 patients suffering from multiple injuries that involve multiple organs. Groupe 3: Medical bleeding includes all patients with surgery without cardiopulmonary bypass (general surgery (without liver), liver surgery, orthopaedic surgery, paediatric, eye, thoracic surgery without CPB, vascular surgery without CPB, gynaecology, urology, neurosurgery, ear, nose, throat, and maxillofacial surgery) and 79 patients from internal medicine
Table 3.
Cox proportional hazards models: CT EXTEM threshold a risk factor for 30-day mortality
| Cardiothoracic surgery with CPB | Trauma | Medical bleeding | All patiens | |||||
|---|---|---|---|---|---|---|---|---|
| (n = 753) | (n = 206) | (n = 1076) | (n = 2035) | |||||
| CTEXTEM≥ 110s | CTEXTEM≥ 98s | CTEXTEM ≥ 99s | CTEXTEM | |||||
| Model | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value |
| crude in all patients | 2.9 (1.8–4.7) | < 0.001 | 4.9 (2.3–10.4) | < 0.001 | 2.1 (1.6–2.9) | < 0.001 | 1.03 (1.02–1.03) | < 0.001 |
| Primary model | ||||||||
| adjusted all population characteristics, comorbidities with p < 0.05 | 2.5 (1.5–4.2) | < 0.001 | 3.9 (1.8–8.7) | 0.001 | 1.8 (1.4–2.5) | < 0.001 | 1.03 (1.02–1.03) | < 0.001 |
| Sensitivity Analyses | ||||||||
| adjusted all population characteristics, comorbidities | 2.9 (1.7–4.8) | < 0.001 | 2.6 (1.1–6.2) | 0.03 | 1.9 (1.4–2.6) | < 0.001 | 1.03 (1.02–1.04)* | < 0.001 |
| adjusted all population characteristics, comorbidities, CT INTEM and A10 FIBTEM | 2.7 (1.6–4.6) | < 0.001 | 1.1 (0.3–3.4) | 0.9 | 1.6 (1.2–2.3) | 0.003 | 1.04 (1.02–1.05)* | < 0.001 |
| adjusted all population characteristics, comorbidities, CT INTEM and A10 FIBTEM, all variables before Rotem analysis from Table 2 | 2.3 (1.2–4.3) | 0.01 | 2.0 (0.5–7.8) | 0.3 | 1.5 (1.1–2.1) | 0.03 | 1.03 (1.01–1.05)* | 0.003 |
| adjusted all population characteristics, comorbidities, CT INTEM and A10 FIBTEM, all variables before Rotem analysis from Table 2, year of Rotem analysis | 2.2 (1.2–4.2) | 0.02 | 2.4 (0.6–10.2) | 0.2 | 1.5 (1.1–2.1) | 0.03 | 1.03 (1.01–1.05)* | < 0.001 |
Primary model and sensitivity analyses. Data are expressed as HR (hazard ratio) with a 95% confidence interval (CI). Hazards ratio of CTEXTEM (Clotting Time) in seconds (s) adjusted for confounders. Cox proportional hazard models were used to adjust for confounding factors. Rotem (Rotational thromboelastometry). Threshold values reaching a specificity of >90% were determined and selected for the analysis. In all patients. CTEXTEM was analysed as a threshold value and as a continuous variable (per 10-second increase). * Adjusted for medical departments Rotem: Rotational thromboelastometry. APTEM: extrinsic pathway with inhibition of fibrinolysis. EXTEM: extrinsic pathway. FIBTEM: fibrin contribution to clot firmness. INTEM: intrinsic pathway without heparin neutralization. The leading department is selected in all 3 groups. Groupe 1: Cardiothoracic surgery with CPB includes patients undergoing surgery with cardiopulmonary bypass (CPB). Groupe 2: Trauma includes traumatically injured patients, with 115 patients suffering from multiple injuries that involve multiple organs. Groupe 3: Medical bleeding includes all patients with surgery without cardiopulmonary bypass (general surgery (without liver), liver surgery, orthopedic surgery, pediatric, eye, thoracic surgery without CPB, vascular surgery without CPB, gynecology, urology, neurosurgery, ear, nose, throat, and maxillofacial surgery) and 79 patients from internal medicine
In several subgroup analyses C-statistic showed similar results compared to the final study population. In patients without anticoagulation, the results were similar (Figs. 1B and 2). In patients treated with packed red blood cells ≥ 6, the results were similar as well (threshold value of CTEXTEM reaching a specificity of > 90% CTEXTEM ≥ 103 s, C-statistic 0.62, sensitivity 30%, and specificity 90%). Also, in a larger population of 2207 patients, including 172 patients with missing information, the results were similar (threshold value of CTEXTEM reaching a specificity of > 90%, CTEXTEM ≥ 109 s, sensitivity 26%, and specificity 90%).
We compared survivors versus non-survivors in patients suffering from elevated CTEXTEM. Interestingly, adverse events were quite comparable; however, rotational thromboelastometry shows in all non-survivors an impaired blood clotting (Appendix 2).
One therapeutic approach for patients with elevated CTEXTEM is the administration of prothrombin complex concentrate. Propensity matching successfully paired 372 without and 372 with treatment of prothrombin complex concentrate. The matched groups were balanced on covariables (smallest p-value > 0.2). In this population, prothrombin complex concentrate is not associated with an increased 30-day mortality rate, in contrast to all patients (Fig. 3).
Fig. 3.
Kaplan-Meier survival plots for therapy with prothrombin complex concentrate versus no therapy with prothrombin complex concentrate during 30-day follow-up for all patients and in subgroup analysis after 1:1 propensity score matching for therapy with prothrombin concentrate. CTEXTEM (Clotting Time). Rotem (Rotational thromboelastometry)
Discussion
Given the distinct underlying pathophysiology, patients were categorized into three main groups – cardiothoracic surgery with cardiopulmonary bypass, trauma and medical bleeding – and further stratified into two clinically relevant subgroups (pre-existing anticoagulation and massive transfusion defined as > 6 packed red blood cells). Group-specific thresholds were applied to the specificity of more than 90% (CTEXTEM over ≥ 110 s for cardiothoracic surgery, ≥ 98 s for trauma, and ≥ 99 s for medical bleeding). Despite this heterogeneity, prolonged CTEXTEM above these thresholds was consistently associated with higher transfusion requirements as a marker of bleeding severity and with increased mortality across cohorts.
Mortality in our cardiothoracic surgery and medical bleeding cohorts was 26% and 41%, respectively. Overall 30-day mortality in our trauma cohort was 41%, which is higher than reported, reflecting our small sample size [7, 8].
Callcut et al. found that trauma patients most commonly died from traumatic brain injury, followed by haemorrhage [5]. Deaths related to bleeding peaked within the first 24 h [5, 7].
In this study, bleeding was defined at the discretion of the treating physician. No universal definition of major bleeding exists [9]. The International Society on Thrombosis and Hemostasis provides a standardized definition for non-surgical patients and proposes a less objective definition for surgical patients [10, 11]. Management principles are largely similar; however, the underlying pathophysiology varies.
Bleeding in trauma as well as surgical patients results from a complex interaction of different pathophysiologic mechanisms resulting in an acquired platelet dysfunction, consumption of coagulation factors, activation of fibrinolytic pathways, and an increased inflammatory response [12, 13].
Ongoing haemorrhage, haemorrhagic shock, trauma-induced coagulopathy, and inadequate resuscitation cause early mortality. Risk factors associated with complications and death after significant bleeding include advanced age, coagulation disorders, emergency admission, acute kidney and lung injury, and gastrointestinal ischemia [8, 14–18].
Even after adjusting for potential confounders (Table 3), prolonged CTEXTEM over ≥ 110 s for cardiothoracic surgery, ≥ 98 s for trauma, and ≥ 99 s for medical bleeding further remained an independent risk factor for 30-day mortality. In trauma, the association is less consistent, likely due to a small sample size, and the results must be interpreted with caution.
We hypothesize that the primary cause of death with an increased CTEXTEM may be related to haemostatic dysfunction within the extrinsic pathway.
Prolongation of CTEXTEM reflects impaired initiation of coagulation in a tissue factor-activated system and is primarily influenced by factor VII-dependent thrombin generation and the availability of coagulation substrates. Because EXTEM initiates coagulation via tissue factor, deficiencies or functional impairment of factor VII — whether inherited or acquired (e.g., liver dysfunction, vitamin K deficiency, anticoagulation, or disseminated intravascular coagulation) — can lead to delayed clot initiation. In addition, reduced fibrinogen concentration limits effective thrombin-mediated fibrin formation and may further prolong CTEXTEM, highlighting the substrate dependence of early clot formation.
Beyond factor deficiencies, global physiology disturbances such as haemodilution, acidosis, and hypothermia impair enzymatic activity and thrombin generation, contributing to prolonged CTEXTEM [19, 20]. Therapeutic administration of blood products, like fibrinogen and thrombocyte concentrate, can lead to significant improvement of CTEXTEM [21–25]. Hence, the sequence of haemostatic therapy is important. Fibrinogen, often the first factor to drop, should be replaced early, typically with tranexamic acid [26–28]. If CTEXTEM remains prolonged, prothrombin complex concentrate should be given [3]. However, some institutions use fresh frozen plasma instead of prothrombin complex concentrate, depending on local transfusion protocols [29]. Some studies have reported that prothrombin complex concentrate is more effective than fresh frozen plasma in this setting; however, most of this evidence comes from cardiac surgery populations [30–32].
At our hospital, we followed recommendations by Weber et al. for goal-directed rotational thrombelastography-based coagulation management during major bleeding [3]. According to these recommendations, prothrombin complex concentrate was administered at a CTEXTEM >80 s. However, newer recommendations from 2024 substitute prothrombin complex concentrate only when CTEXTEM exceeds 100 s, which is consistent with the patterns observed in our results [13, 33].
Furthermore, the administration of prothrombin complex concentrate was associated with a higher incidence of thromboembolic events [34], probably due to an increase in thrombin generation [25]. This coincides with our results, showing that peripheral arterial embolism and thrombosis in our group of patients undergoing cardiothoracic surgery with cardiopulmonary bypass, with CTEXTEM >110 s, were more frequent. Renal replacement therapy and coagulation therapy, especially requiring more fresh frozen plasma, prothrombin complex, and fibrinogen, remained higher in the group of cardiothoracic surgery and medical bleeding. The study by Cappabianca et al. showed an increased risk for acute kidney injury with the use of prothrombin complex concentrate [35]. However, the incidence of acute kidney injury was significantly lower in the prothrombin complex concentrate compared with the fresh frozen plasma group in the randomized multicentre FARES-II trial [30]. This is in agreement with the studies published by Görlinger et al. and Weber et al. more than 10 years ago [2, 36]. In our study, after propensity score matching, prothrombin complex concentrate is not associated with an increased 30-day mortality rate in bleeding patients. In contrast, in 13 healthy volunteers, conflicting results were published, showing no effect of prothrombin complex concentrate in CTEXTEM [37]. Therefore, applying prothrombin complex concentrate is to be avoided in patients without bleeding with prolonged CTEXTEM.
The most important limitation is that our analysis is based on a single-centre study population. However, in several sensitivity analyses, we were able to confirm the consistency of our results. Another limiting factor is the lack of detailed information on the sequence of haemostatic therapy – specifically, whether prothrombin complex concentrate was administered as the initial intervention or preceded by agents such as fibrinogen, tranexamic acid, or factor XIII. This is relevant, as previous studies have demonstrated that fibrinogen administration alone can shorten CTEXTEM values [21, 22].
Another key limitation of our study is the small size of the trauma subgroup, which consisted primarily of severely injured polytrauma patients with a high mortality rate (41%). Consequently, sensitivity analyses within this group were heavily adjusted and must be interpreted with caution. These factors may limit the generalizability of our findings to broader trauma populations. Accordingly, another limitation of our study is that CTEXTEM results were analysed in isolation and not together with A5EXTEM and A5FIBTEM [23, 24, 38]. Therefore, a larger multicentre study population is needed to confirm our results.
In conclusion, in our study, CTEXTEM is an independent risk factor for 30-day mortality in bleeding patients. After multivariate analysis, bleeding patients with prothrombin complex concentrate do not seem to be associated with increased 30-day mortality. However, fibrinogen levels should be corrected before prothrombin complex concentrate administration, particularly in this high-risk subgroup with evidence of impaired clotting via the extrinsic pathway.
Supplementary information
Below is the link to the electronic supplementary material.
(DOCX 20.1 KB)
(DOCX 28.2 KB)
Acknowledgements
We would like to thank Neeti Sharma for her support in writing this article.
Author contributions
H. Bomberg and Sven O. Schneider, had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of data analysis. Additionally, they made substantial contributions to the analysis and the interpretation of data, drafting the article, and revising it critically for important intellectual content. Thomas Volk, Stefan Wagenpfeil, and Klaus Goerlinger made substantial contributions to the analysis and the interpretation of data, drafting the article, and revising it critically for important intellectual content.
Funding
Open Access funding enabled and organized by Projekt DEAL. The study was funded by departmental resources.
Data availability
Data will be made available on reasonable request.
Declarations
KG works as the Medical Director of Tem Innovations GmbH, Munich, Germany. The other authors do not report any potential conflict of interest.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
2/24/2026
Affiliation 1 contained a typo. This has been corrected.
References
- 1.Drotarova M, Zolkova J, Belakova KM, Brunclikova M, Skornova I, Stasko J, et al. Basic principles of rotational thromboelastometry (ROTEM(®)) and the role of ROTEM-guided fibrinogen replacement therapy in the management of coagulopathies. Diagnostics. 2023. 10.3390/diagnostics13203219. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Gorlinger K, Dirkmann D, Hanke AA, Kamler M, Kottenberg E, Thielmann M, et al. First-line therapy with coagulation factor concentrates combined with point-of-care coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular surgery: a retrospective, single-center cohort study. Anesthesiology. 2011;115:1179–91. [DOI] [PubMed] [Google Scholar]
- 3.Weber CF, Zacharowski K, Brün K, Volk T, Martin EO, Hofer S, et al. [Basic algorithm for Point-of-Care based hemotherapy: perioperative treatment of coagulopathic patients]. Anaesthesist. 2013;62:464–72. [DOI] [PubMed] [Google Scholar]
- 4.Abdelfattah K, Cripps MW. Thromboelastography and rotational thromboelastometry use in trauma. Int J Surg. 2016;33:196–201. [DOI] [PubMed] [Google Scholar]
- 5.Callcut RA, Kornblith LZ, Conroy AS, Robles AJ, Meizoso JP, Namias N, et al. The why and how our trauma patients die: a prospective Multicenter Western Trauma Association study. J Trauma Acute Care Surg. 2019;86:864–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Bomberg H, Görlinger K, Wagenpfeil S, Volk T, Schneider SO. A clotting time longer than 226 s in the INTEM channel of the thromboelastometer is an independent risk factor for mortality during bleeding. Anaesthesiologie. 2025;74:818–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Abuzeid AM, O’Keeffe T. Review of massive transfusion protocols in the injured, bleeding patient. Curr Opin Crit Care. 2019;25:661–67. [DOI] [PubMed] [Google Scholar]
- 8.Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma. 2006;60:S3–11. [DOI] [PubMed] [Google Scholar]
- 9.Shah A, Kerner V, Stanworth SJ, Agarwal S. Major haemorrhage: past, present and future. Anaesthesia. 2023;78:93–104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost. 2010;8:202–4. [DOI] [PubMed] [Google Scholar]
- 11.Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–4. [DOI] [PubMed] [Google Scholar]
- 12.Ghadimi K, Levy JH, Welsby IJ. Perioperative management of the bleeding patient. Br J Anaesth. 2016;117:iii18–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Schneider SO, Pilch J, Graf M, Schulze-Berge J, Kleinschmidt S. [Diagnostics and management of perioperative bleeding disorders]. Anaesthesiologie. 2025;74:244–60. [DOI] [PubMed] [Google Scholar]
- 14.Dixon A, Kenny JE, Buzzard L, Holcomb J, Bulger E, Wade C, et al. Acute respiratory distress syndrome, acute kidney injury, and mortality after trauma are associated with increased circulation of syndecan-1, soluble thrombomodulin, and receptor for advanced glycation end products. J Trauma Acute Care Surg. 2023. 10.1097/TA.0000000000004096. [DOI] [PubMed] [Google Scholar]
- 15.Duchesne JC, Islam TM, Stuke L, Timmer JR, Barbeau JM, Marr AB et al. Hemostatic resuscitation during surgery improves survival in patients with traumatic-induced coagulopathy. J Trauma. 2009;67:33 – 7; discussion 37 – 9. [DOI] [PubMed]
- 16.Dyke C, Aronson S, Dietrich W, Hofmann A, Karkouti K, Levi M, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1458–e631. [DOI] [PubMed] [Google Scholar]
- 17.Maani CV, DeSocio PA, Holcomb JB. Coagulopathy in trauma patients: what are the main influence factors? Curr Opin Anaesthesiol. 2009;22:255–60. [DOI] [PubMed] [Google Scholar]
- 18.Ahmed N, Mathew RO, Kuo Y, Asif A. Risk of in-hospital mortality in severe acute kidney injury after traumatic injuries: a National trauma quality program study. Trauma Surg Acute Care Open. 2021;6:e000635. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Casella J, Perry M. EMS Tactical Paramedic Lethal Triad. StatPearls. Treasure Island (FL) ineligible companies. 2024.
- 20.Dang XT, Nguyen TX, Nguyen HTT, Ha HT. Correlations between rotational thromboelastometry (ROTEM) and standard coagulation tests following viper snakebites. J Int Med Res. 2022;50:3000605211067321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Maegele M. Modern coagulation management in bleeding trauma patients : point-of-care guided administration of coagulation factor concentrates and hemostatic agents. Med Klin Intensivmed Notfmed. 2019;114:400–9. [DOI] [PubMed] [Google Scholar]
- 22.Ponschab M, Voelckel W, Pavelka M, Schlimp CJ, Schöchl H. Effect of coagulation factor concentrate administration on ROTEM® parameters in major trauma. Scand J Trauma Resusc Emerg Med. 2015;23:84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Katz DJ, Hira SK, Sison ML, Getrajdman CS. Impact of fibrinogen and prothrombin complex concentrate on clotting time in a model of obstetric hemorrhage. J Clin Anesth. 2022;78:110687. [DOI] [PubMed] [Google Scholar]
- 24.Ranucci M, Aloisio T, Di Dedda U, Anguissola M, Barbaria A, Baryshnikova E. Fibrinogen and prothrombin complex concentrate: the importance of the temporal sequence-a post-hoc analysis of two randomized controlled trials. J Clin Med. 2024. 10.3390/jcm13237137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Gratz J, Ponschab M, Iapichino GE, Schlimp CJ, Cadamuro J, Grottke O, et al. Comparison of fresh frozen plasma vs. coagulation factor concentrates for reconstitution of blood: an in vitro study. Eur J Anaesthesiol. 2020;37:879–88. [DOI] [PubMed] [Google Scholar]
- 26.Davenport R, Manson J, De’Ath H, Platton S, Coates A, Allard S, et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med. 2011;39:2652–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Hofmann N, Schöchl H, Oberladstätter D, Zipperle J, Schmitt F, von der Forst M et al. Viscoelastic coagulation testing in bleeding trauma patients: a retrospective analysis and development of a treatment algorithm. Br J Anaesth. 2025. [DOI] [PubMed]
- 28.Kashuk JL, Moore EE, Sawyer M, Wohlauer M, Pezold M, Barnett C et al. Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma. Ann Surg. 2010;252:434 – 42; discussion 43 – 4. [DOI] [PubMed]
- 29.Bell SF, Roberts TCD, Freyer Martins Pereira J, De Lloyd L, Amir Z, James D, et al. The sensitivity and specificity of rotational thromboelastometry (ROTEM) to detect coagulopathy during moderate and severe postpartum haemorrhage: a prospective observational study. Int J Obstet Anesth. 2022;49:103238. [DOI] [PubMed] [Google Scholar]
- 30.Karkouti K, Callum JL, Bartoszko J, Tanaka KA, Knaub S, Brar S, et al. Prothrombin complex concentrate vs frozen plasma for coagulopathic bleeding in cardiac surgery: the FARES-II multicenter randomized clinical trial. JAMA. 2025;333:1781–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Biancari F, Ruggieri VG, Perrotti A, Gherli R, Demal T, Franzese I, et al. Comparative analysis of prothrombin complex concentrate and fresh frozen plasma in coronary surgery. Heart Lung Circ. 2019;28:1881–7. [DOI] [PubMed] [Google Scholar]
- 32.Hassan Waseem M, Abideen ZU, Cheema AH, Shoaib A, Waheed A, Mukhlis M, et al. Prothrombin complex concentrate versus fresh frozen plasma in patients undergoing cardiac surgery: a systematic review and meta-analysis. Clin Med Insights Cardiol. 2025;19:11795468251391024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Schmitt FCF, Schöchl H, Brün K, Kreuer S, Schneider S, Hofer S, et al. [Update on point-of-care-based coagulation treatment: Systems, reagents, device-specific treatment algorithms]. Anaesthesiologie. 2024;73:110–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Bouzat P, Charbit J, Abback PS, Huet-Garrigue D, Delhaye N, Leone M, et al. Efficacy and safety of early administration of 4-Factor prothrombin complex concentrate in patients with trauma at risk of massive transfusion: the PROCOAG randomized clinical trial. JAMA. 2023;329:1367–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Cappabianca G, Mariscalco G, Biancari F, Maselli D, Papesso F, Cottini M, et al. Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery. Crit Care. 2016;20:5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Weber CF, Görlinger K, Meininger D, Herrmann E, Bingold T, Moritz A, et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology. 2012;117:531–47. [DOI] [PubMed] [Google Scholar]
- 37.Hofmann N, Schöchl H, Zipperle J, Gratz J, Schmitt FCF, Oberladstätter D. Altered thrombin generation with prothrombin complex concentrate is not detected by viscoelastic testing: an in vitro study. Br J Anaesth. 2025;134:1392–401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Görlinger K, Pérez-Ferrer A, Dirkmann D, Saner F, Maegele M, Calatayud ÁAP, et al. The role of evidence-based algorithms for rotational thromboelastometry-guided bleeding management. Korean J Anesthesiol. 2019;72:297–322. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
(DOCX 20.1 KB)
(DOCX 28.2 KB)
Data Availability Statement
Data will be made available on reasonable request.