Theusinger, Oliver M. MD*; Schröder, Carsten M.*; Eismon, Jennifer MD†; Emmert, Maximilian Y. MD‡; Seifert, Burkhardt PhD§; Spahn, Donat R. MD, FRCA*; Baulig, Werner MD*
In major surgery, bleeding complications are common and multifactorial. Early recognition and treatment may reduce blood loss, the use of blood products, and morbidity and mortality.1–3 In recent publications, transfusion algorithms guide goal-directed transfusion therapy based on laboratory variables and point-of-care (POC) devices such as thromboelastography (TEG®) or Rotation Thromboelastometry (ROTEM® delta, TEM® International GmbH, Munich, Germany).4 Both methods measure and graphically display the changes in viscoelasticity at all stages of the developing and resolving clot, and provide the first results within 5 to 10 minutes, whereas laboratory values take from 30 minutes and up to 90 minutes delaying treatment in patients.5,6 The method of the ROTEM has been described in detail elsewhere.7
Although there are publications comparing ROTEM results and laboratory values, they focused on fibrinogen (FBG), prothrombin time (PT), aPTT, and platelet count but not on whole blood. Results are only represented as simple correlations. None of those studies investigated the effect of factor VIII (FVIII) or of whole blood on ROTEM nor were multiple linear stepwise regression analyses made to determine the impact of these laboratory variables on ROTEM.
To monitor coagulation in the operating room, various tests are available in the institutional laboratory including International Normalized Ratio (INR), aPTT, thrombin time, FBG testing (often by the Clauss method),8 platelet count, platelet function testing, and factor XIII (FXIII) and FVIII determination. POC monitoring of blood coagulation at the bedside is not only desirable, but is becoming increasingly relevant and provides real-time results.9 Theusinger et al.10 reported the influence of FXIII on the tissue factor–triggered extrinsic pathway (EXTEM) and on whole blood with platelet inhibitor (cytochalasin D) evaluating the contribution of FBG to clot formation (FIBTEM) with in vitro supplementation of FXIII to supraphysiological levels.
Based on the institutional goal-directed transfusion algorithm implemented in 2009, FXIII and FVIII were routinely measured and replaced if continuing bleeding was expected to be caused by deficiency of these coagulation factors.4,11 FXIII contributes to the clot stability of FBG and to a certain extent inhibits hyperfibrinolysis,12,13 and FVIII deficiency might be induced by the use of starches and thus may be monitored in cases of diffuse bleeding.14,15
The aims of this clinical trial were: (1) to retrospectively compare laboratory measured blood count values, coagulation factors (FBG, FVIII, and FXIII), and standard laboratory coagulation tests such as INR, PT, aPTT, and thrombin time with ROTEM testing and (2) to determine the impact of these laboratory results, with the inclusion of gender, on the parameters of the ROTEM testing in patients scheduled for major surgery with hemorrhage.
For this study, authorization from the local ethics committee (Kantonale Ethikkommission, Kanton Zürich, Switzerland, KEK-ZH-Nr. 2010-0234/4) was obtained. Inclusion criteria were: patients having major surgery (neuro, vascular, abdominal, thoracic gynecological, orthopedic or trauma, and cardiac) needing ROTEM measurements intraoperatively because of a defuse nonsurgical bleeding/hemorrhage and where FXIII, FVIII, FBG, INR, aPTT, thrombin time, hemoglobin, leukocytes, and platelets were simultaneously determined by the institutional laboratory. Exclusion criteria included: patients with known coagulopathic disorders and preoperative thrombocytopenia (platelet count ≤100,000/μL).
In this retrospective single-center study, 45 patients who underwent major surgery and had hemorrhage (neuro, orthopedic, visceral, and cardiac surgery) in the first 6 months of 2011 were identified consecutively by chart review according to the above-mentioned criteria. Two samples of citrated (Vacutainer® Brand, Belliver Industrial Estate, Plymouth, UK, 4.5 mL, 9 NC 0.129 M) and 1 sample of EDTA (Vacutainer, 10 mL, K2E 18.0 mg) whole blood were collected during the procedure in the operating room from each patient via an arterial line when ROTEM and laboratory values were needed due to bleeding/hemorrhage. Before the first tube was drawn, 5 mL blood was discarded out of the arterial line to avoid dilution. Arterial lines used in our institution do not contain heparin or any other anticoagulant, the flush is operated by NaCl 0.9%. Platelet count, hemoglobin, and leukocytes were determined in the EDTA sample and FXIII, FVIII, FBG, INR, aPTT, and thrombin time in 1 of the 2 citrated blood samples of each patient by the institutional laboratory. The second citrated whole blood sample was used for EXTEM, ellagic acid activated intrinsic pathway (INTEM), FIBTEM, and APTEM (is an EXTEM-based assay in which fibrinolysis is inhibited by aprotinin) measurements on ROTEM. These analyses were performed directly after blood was drawn.
Laboratory analyses were performed in the quality-controlled ISO 17025 accredited university laboratories. FXIII was determined by Behring Coagulation System (Dade Behring, Düdingen, Switzerland) using the Berichrom® FXIII test (Dade Behring; normal range 70%–140% which equals 0.7–1.4 IU/mL). FBG was analyzed by the Behring Coagulation System using the Multifibrin® U test (Dade Behring, Düdingen, Switzerland; normal range 1.5–4.0 g/L). INR was determined by the Behring Coagulation System with Innovin® test (Dade Behring normal range: <1.2). aPTT was determined by Behring Coagulation System with the Actin® FS test (Dade Behring; normal range: 26–36 seconds). FVIII was measured by Behring Coagulation System with coagulation factor VIII–deficient plasma (normal range: 50%–200%). Thrombin time was analyzed by Behring Coagulation System with thrombin solution produced in the university hospital laboratory (100 IU/mL; normal range: <18 seconds). Platelet count, hemoglobin, and leukocytes were measured with Advia® 2120 (Siemens Healthcare Diagnostics GmbH, Eschborn, Germany; normal range: platelets 143–400 × 109/L, hemoglobin 11.7–15.3 g/dL, leukocytes 103/µL).
The ROTEM delta device used for this study was maintained as recommended by the manufacturer and had been calibrated and tested before the study period. ROTEM tests were performed according to the manufacturer’s instructions at 37°C with a run time of 62 minutes analyzing the following parameters: clotting time (CT), clot formation time (CFT), α-angle, and maximum clot firmness (MCF) for EXTEM, INTEM, and APTEM; and only CT and MCF for FIBTEM. Further details on that subject have been published.5
Data were transferred from the ROTEM device and from the hospital information system into Microsoft Excel (Microsoft Office 2007, Microsoft Corporation, Redmond, WA) and analyzed using SPSS® (version 19, SPSS Inc. Chicago, IL). Continuous variables were summarized as mean ± SD as well as median [range]. The CT, CFT, MCF, and α-angle obtained from EXTEM, INTEM, and FIBTEM were then correlated with the hemoglobin, platelets, leukocytes, FBG, FXIII, FVIII, INR, aPTT, and thrombin time using Spearman rank test and reporting the correlation coefficients. A Bonferroni correction was applied to address multiple comparisons regarding the correlation coefficients with the 14 ROTEM parameters considering them significant with a P-value of ≤0.0036. Confidence intervals (CIs) were calculated using the asymptotic formula based on Fisher transformation. A strong significant (P < 0.001) correlation was present above 0.7 (below −0.7) with a lower limit of the 95% CI above 0.505 (below −0.505). A moderate correlation was present between 0.3 and 0.7 (−0.3 and −0.7). The level of significance (P ≤ 0.003) was reached with a correlation of r = ±0.434 with a 95% CI of 0.152 to 0.651 (−0.152 to −0.651). In a second step comparing all ROTEM parameters with laboratory results, a multiple stepwise linear regression analysis was performed to determine which factors influence the measured ROTEM parameters (criteria used: probability-of-a factor-to-enter ≤0.050, probability-of-a factor-to-remove ≥0.100). For this analysis, normal distribution was assessed visually, and variables were logarithmically transformed if appropriate to achieve normally distributed residuals and to avoid high leverage of observations. The post hoc sample size calculation showed that a weak correlation of 0.4 with a power of 0.8 with a level of significance of ≤0.05 needs 39 patients. For the FVIII dataset of 18, post hoc analysis showed that a strong correlation of ≥0.8 with a power of 0.8 and a level of significance of ≤0.0036 needs 15 patients.
Forty-five intraoperative coagulation analyses were performed in 45 patients undergoing major surgery and presenting hemorrhage. The patients’ characteristics and procedural data are presented in Tables 1 and 2. The distribution and range of values found in the laboratory and ROTEM parameters are shown in Table 3.
Correlation of Laboratory Parameters and Tests with ROTEM Parameters
Overall nonparametric correlations of the investigated coagulation analyses are presented in Tables 4 and 5. FVIII, where only 18 measurements were available, strongly correlated with the CFT of EXTEM (r = −0.855, P < 0.001), α-angle of EXTEM (r = 0.903, P < 0.001), and MCF of EXTEM (r = 0.839, P < 0.001), and CFT of INTEM (r = −0.875, P < 0.001), α-angle of INTEM (r = 0.879, P < 0.001), MCF of INTEM (r = 0.903, P < 0.001); the MCF of FIBTEM (r = 0.973, P < 0.001); and α-angle of APTEM (r = 0.837, P < 0.001) (Table 4). FBG showed the strongest correlation with FIBTEM-MCF (r = 0.909, P < 0.001) (Table 4). FBG further correlated moderately to strong and from being significant to nonsignificant (Pranging from <0.001 to 0.007) with all other ROTEM parameters in EXTEM, APTEM, and INTEM, excluding the CT of INTEM, EXTEM, and APTEM. FXIII correlated moderately and significantly (P < 0.001) with the MCF of EXTEM (r = 0.479), INTEM (r = 0.482), FIBTEM (r = 0.510), and APTEM (r = 0.514); and also moderately with the α-angle of EXTEM (r = 0.436, P < 0.001) (Table 4). Significant moderate to strong correlations (P < 0.001) were found for platelets and the CFT, MCF, and α-angle of EXTEM, INTEM, and APTEM. The MCF of APTEM, EXTEM, and INTEM correlated moderately and only significantly for APTEM (P < 0.001) with hemoglobin (Table 4).
A moderate significant correlation (P < 0.001) was found between INR and CFT, MCF and α-angle of INTEM, EXTEM, and APTEM (Table 5). The MCF of FIBTEM showed a strong and significant correlation (P < 0.001) whereas the CT showed a moderate and significant correlation (P < 0.001) with the INR. The aPTT and thrombin time correlated moderately and only partially significantly (P < 0.001) with all ROTEM parameters excluding the CT of EXTEM and APTEM (Table 5).
Regression Analysis of Laboratory Parameters and Tests Including Gender with ROTEM Parameter
Table 6 presents the significance (P ≤ 0.001 only) level of the multiple stepwise linear regression analysis of the laboratory tests, coagulation factors, and gender, with ROTEM parameters. Excluding the CT of EXTEM, INTEM, APTEM, α-angle of EXTEM, and the MCF of FIBTEM, all measurement points of the ROTEM were strongly associated with the platelet count. Additionally, FBG was strongly associated with all measurement points of the ROTEM, CT of INTEM, APTEM, MCF of APTEM, and α-angle of INTEM excluded (Table 6).
FXIII and INR were associated with MCF of APTEM, aPTT was with the CT of INTEM and APTEM, thrombin time with the CFT of APTEM, and leukocytes with the CT of APTEM (Table 6). An association of gender was found for the CT of EXTEM, FIBTEM, and APTEM.
The main findings of this clinical trial are: (1) the moderate to strong significant correlation of FVIII concentration with all parameters of EXTEM, INTEM, FIBTEM, and APTEM excluding CT of EXTEM, FIBTEM, and APTEM; (2) confirmation that EXTEM, INTEM, and APTEM are significantly associated with FBG (excluding CT in INTEM) and platelets levels (excluding CT); and (3) the moderate correlation of the standard coagulation tests with all ROTEM parameters in particular the CT, which was not able to show an influence of the INR on all ROTEM parameters, and as expected the highly significant impact of the aPTT on INTEM-CT.
As ROTEM assesses the 2 coagulation pathways, correlations can be found in coagulation factors and laboratory values. Fibrin formation, which is the final result of the secondary hemostasis has 2 pathways, contact activation or via tissue factor. Coagulation factors generally circulate as inactive zymogens; most of them are serine proteases. The exceptions are FVIII and FV both being glycoproteins and the transglutaminase which is FXIII. The factor with the highest circulating concentration is FBG with a concentration of 200 to 400 mg/dL. Cross-linked fibrin is produced by a series of catalytic reactions implicating zymogens of serine proteases and their glycoprotein cofactors in an activated form. The main role of thrombin and the thrombin burst remains the conversion of FBG to fibrin. Protein C being a major physiological anticoagulant is a vitamin K-dependent serine protease enzyme that is activated by thrombin into activated protein C.
Thrombomodulin activates protein C in combination with thrombin. Activated protein C then in combination with protein S inhibits activity of FVa and FVIIIa. Fibrinolysis which is a physiological process reabsorbs blood clots via plasmin, a massive activation of plasmin leads to the pathological state of hyperfibrinolysis.
There are few data available comparing ROTEM parameters with standard laboratory tests and selected clotting factors. The strong correlation of FVIII concentration with the CFT, α-angle, and MCF of EXTEM, INTEM, and FIBTEM of the ROTEM device is a new finding that might be explained by the physiological process of the coagulation cascade. After cleaving by thrombin (FIIa), in the late period of the initiation phase, activated FVIII (FVIIIa) has an enormous impact on thrombin and activated factor X generation in the transition to the amplification phase of the coagulation cascade.16 Activated protein C inhibits FVIII from being activated; taking the influence on FVIII into consideration, it would theoretically be possible that other unmeasured coagulation factors might also correlate with the same ROTEM parameters as FVIII and thus FVIII not solely being responsible for our finding. In 1979, Kao et al.17 first reported that the interaction between human FVIII/von Willebrand protein and its receptors on the platelet membrane is an important mechanism by which platelet aggregation occurs during primary phase hemostasis. Two studies suggested that some parameters of the ROTEM may be able to indicate possible FVIII deficiency. In patients with hemophilia A, 11 with severe and 11 with moderate symptoms, Ingerslev et al.18 found a considerable degree of heterogeneity in the coagulation profiles displayed by ROTEM. Sorensen and Ingerslev19 reported a wide variation of the CT of ROTEM, corresponding to the initiation phase and of the maximum velocity and time to maximum velocity (t) parameters, corresponding to the amplification phase of the coagulation cascade in patients with severe hemophilia A. In this investigation, no significant correlation was found for the CT of EXTEM, FIBTEM and APTEM, and FVIII. A possible reason for this fact might be that the lowest measured FVIII concentration in this study was 34% (normal range: 50%–200%, Table 3) which is much higher than those concentrations found in patients suffering from severe hemophilia A and that it is not possible to establish the level of FVIII activity at which CT is impacted and correlations could begin. Another consideration might be that activation of FVIII starts at the end of the initiation phase, just at the transition to the amplification phase of the coagulation cascade, and is consumed during the process of fibrin polymerization and clot stabilization by platelets and FXIII. Amplification and propagation phases of the coagulation cascade might be shown by the CFT and possibly by the α-angle of the ROTEM measurements, whereas fibrin polymerization and clot stabilization are represented by the MCF of ROTEM.
The current study confirms the results of other investigators by having significant correlation of all parameters of EXTEM, INTEM, and APTEM with the platelet count, excluding the CT. However, the FBG concentration was significantly correlated with all ROTEM parameters (EXTEM, INTEM, FIBTEM, and APTEM), in particular with the FIBTEM-MCF (r = 0.909) excluding the CT. The multiple stepwise linear regression analysis confirmed these findings. Most recently, Ogawa et al.20 reported strong correlations between FIBTEM amplitude at 10 minutes and FBG level (r = 0.87; P < 0.001) and between EXTEM/INTEM amplitude at 10 minutes and platelet count (r = 0.77 and 0.67) in patients after cardiopulmonary bypass. They concluded that ROTEM variables demonstrated clinically relevant correlations with platelet count and FBG levels. Nearly similar findings were reported in patients during orthotropic liver transplantation by Roullet et al.21 and by Herbstreit et al.22 In patients with colorectal cancer, Ustuner et al.23 demonstrated that platelet count significantly correlated with the MCF of INTEM (r = 0.627) and EXTEM (r = 0.699) and that FBG levels showed a significant negative correlation with the CFT of INTEM (r = −0.617) and EXTEM (r = −0.512). This study shows only a moderate correlation of the standard coagulation tests (INR, aPTT, and thrombin time) with all ROTEM parameters, in particular the CT and CFT.
In our study, thrombin time was abnormal in nearly all patients (mean 26.7 ± 39.5 seconds; range 16–200 seconds). The cause of this could be high levels of D-dimers, direct anti-FIIa, fibrin, and fibrin cleaving products which can be present in situations of massive hemorrhage. This also shows that tests like thrombin time are not adequate in situations of massive hemorrhage because a pathological value does not mean that clot formation and stability must be impaired.24
Additionally, the multiple stepwise linear regression analysis showed no significant impact of INR on all ROTEM parameters, but a significant impact of the aPTT on INTEM-CT in contrast to the Spearman rank test results. Comparable results were reported by other investigators in adults22,25,26 and in children.27 During orthotropic liver transplantation in 20 patients, Herbstreit et al.22 reported a poor correlation between PT and the CT of EXTEM, and aPTT correlated only moderately with the CT of INTEM. In 90 trauma patients, Rugeri et al.26 reported significant but only moderate correlation between PT and the clot strengths after 15 minutes of EXTEM (r = 0.66) and rather poor correlation between aPTT and the CT of INTEM (r = 0.47). In contrast to the results of our study, they presented a strong correlation between aPTT and the CFT of INTEM (r = 0.91).26
Recently, Haas et al.27 compared ROTEM parameters (EXTEM, INTEM, FIBTEM) against the standard coagulation tests (PT, aPTT) and the FBG level. In a total of 288 blood samples of 50 children, they reported only a poor correlation between PT and aPTT to the CT of EXTEM and INTEM, respectively; however, a good correlation was reported between the CFT of EXTEM and INTEM with the PT and aPTT, respectively. Of note, the results of Haas etal.27 showed that 94% of all aPTT values were outside the reference range (25–36 seconds); whereas only 6.3% of the CT values of INTEM were detected outside the normal range (100–231 seconds). The authors explanation is contingent on the fact that standard coagulation tests are performed in plasma, while ROTEM uses whole blood. In this investigation, the correlation between INR and aPTT with the CFT of EXTEM and INTEM was only moderate with r= 0.535 and r = 0.544, respectively. The results of this study clearly show that results of CT in ROTEM and INR and aPTT cannot be used interchangeably to detect intraoperative coagulation disturbances.
The majority of the patients were anemic (9.1 ± 2.1 g/dL, range 4.9–15.7 g/dL) at the time blood was drawn. This fact might have reduced the viscoelastic properties of the ROTEM samples and thus influenced CT, CFT, MCF, and α-angle of EXTEM, INTEM, and APTEM. As the mean values of ROTEM results are still all within the reference ranges of the manufacturer, we believe that this fact did not have an influence on the associations found.
There are some limitations in this study. First, the study was retrospectively designed. In particular, only reduced numbers of data pairs for the comparison of FVIII values and ROTEM parameters were present for analysis (18 of 45). Measuring the FVIII concentration is not routinely performed during surgery, and we suspect that FVIII determination was performed because of diffuse bleeding and its cause could not be elicited with routine laboratory tests and the POC monitoring. In an acute massive bleeding situation, infusion of crystalloids and colloids such as hydroxyethyl starch 130/04 6% (HES) was the routine first-line intravascular volume replacement therapy. Second, ROTEM analyses were performed promptly in the event of a coagulation disorder, whereas the results of the standard laboratory tests were delayed due to delayed transportation, unknown sample storage time before analysis was performed, and other unknown factors. This could have had a nonnegligible impact on the laboratory results. Third, the contributing cause of the intraoperative coagulation disorder, whether it was dilutional or surgical coagulopathy, was not possible as volume and type of crystalloid and or colloid solutions used for fluid resuscitation were not documented. According to the institutional bleeding management rules, red blood cells, fresh frozen plasma, and platelet substitution during the procedure was only performed based on the results of POC testing in combination with the results of blood gas analysis. It is expected that most patients were diluted mostly using crystalloids and colloids as HES. We cannot exclude any impact of colloid substitution on platelet function, fibrin polymerization, FBG, FVIII, and von Willebrand Factor (vWF).28,29 We included 5 patients who had cardiopulmonary bypass. In this group of patients undergoing off-pump coronary artery bypass grafting, Muralidhar et al.30 reported significant decreases in vWF concentration after infusion of HES 200/05 and HES 130/04. vWF levels remained lower than the baseline value in the first 24 hours with HES 200/05, whereas the vWF level increased above the baseline values within 6 hours with HES 130/04.
This clinical study showed that FVIII had a significant correlation with all ROTEM parameters except CT of EXTEM, INTEM, FIBTEM, and CFT and MCF of APTEM. Additionally, these results confirm the clinical assumption that EXTEM, INTEM, and APTEM are significantly associated to FBG levels and platelets count; INTEM-CT significantly by aPTT; and FIBTEM significantly by FBG. Further studies are needed regarding specific subgroups (e.g., hemophilia, hypofibrinogenemia) of patients and their influence on ROTEM as ROTEM is useful to guide hemostatic therapy with an algorithm-based approach and considering the clinical parameters such as bleeding. This study also suggests the need for further studies of the direct impact of FVIII activity and its modification in the surgical setting during defuse bleeding.
Name: Oliver M. Theusinger, MD.
Contribution: Oliver M. Theusinger designed the study, conducted the study, analyzed the data, and wrote the manuscript.
Attestation: Oliver M. Theusinger approved the final manuscript.
Conflicts of Interest: Oliver M. Theusinger has received honoraria or travel support for consulting or lecturing from the following companies: CSL Behring Schweiz, Zurich, Switzerland; Vifor SA, Villars-sur-Glâne, Switzerland; Roche Pharma (Schweiz) AG, Reinach, Switzerland; Pentapharm AG, München, Germany; and TEM International, München, Germany.
Name: Carsten M. Schröder.
Contribution: Carsten M. Schröder helped to collect the data and write the manuscript.
Attestation: Carsten M. Schröder approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Jennifer Eismon, MD.
Contribution: Jennifer Eismon helped to write the manuscript and edited it.
Attestation: Jennifer Eismon approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Maximilian Y. Emmert, MD.
Contribution: Maximilian Y. Emmert helped to collect the data, and to write the manuscript.
Attestation: Maximilian Y. Emmert approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Burkhardt Seifert, PhD.
Contribution: Burkhardt Seifert made the statistical analysis and helped to write the manuscript.
Attestation: Burkhardt Seifert approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Donat R. Spahn, MD, FRCA.
Contribution: Donat R. Spahn designed the study, conducted the study, and wrote the manuscript.
Attestation: Donat R. Spahn approved the final manuscript.
Conflicts of Interest: Donat R. Spahn academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland (grant numbers: 33CM30_124117 and 406440-131268); the Swiss Society of Anesthesiology and Reanimation (SGAR), Berne, Switzerland (no grant numbers are attributed); the Swiss Foundation for Anesthesia Research, Zurich, Switzerland (no grant numbers are attributed); Bundesprogramm Chancengleichheit, Berne, Switzerland (no grant numbers are attributed); CSL Behring, Berne, Switzerland (no grant numbers are attributed); and Vifor SA, Villars-sur-Glâne, Switzerland (no grant numbers are attributed). Dr. Spahn was the chairman of the ABC Faculty and a member of the ABC Trauma Faculty which both are managed by Thomson Physicians World GmbH, Mannheim, Germany and sponsored by an unrestricted educational grant from Novo Nordisk A/S, Bagsvärd, Denmark. In the past 5 years, Dr. Spahn has received honoraria or travel support for consulting or lecturing from the following companies: Abbott AG, Baar, Switzerland; AstraZeneca AG, Zug, Switzerland; Bayer (Schweiz) AG, Zürich, Switzerland; Baxter S.p.A., Roma, Italy; B. Braun Melsungen AG, Melsungen, Germany; Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland; Bristol-Myers-Squibb, Rueil-Malmaison Cedex, France; CSL Behring GmbH, Hattersheim am Main, Germany and Bern, Switzerland; Curacyte AG, Munich, Germany; Ethicon Biosurgery, Sommerville, NJ; Fresenius SE, Bad Homburg v.d.H., Germany; Galenica AG, Bern, Switzerland (including Vifor SA, Villars-sur-Glâne, Switzerland); GlaxoSmithKline GmbH & Co. KG, Hamburg, Germany; Janssen-Cilag AG, Baar, Switzerland; Novo Nordisk A/S, Bagsvärd, Denmark; Octapharma AG, Lachen, Switzerland; Organon AG, Pfäffikon/SZ, Switzerland; Oxygen Biotherapeutics, Costa Mesa, CA, Pentapharm GmbH (now tem Innovations GmbH), Munich, Germany; Roche Pharma (Schweiz) AG, Reinach, Switzerland; and Schering-Plough International, Inc., Kenilworth, NJ.
Name: Werner Baulig, MD.
Contribution: Werner Baulig designed the study, conducted the study, analyzed the data, and wrote the manuscript.
Attestation: Werner Baulig approved the final manuscript.
Conflicts of Interest: Werner Baulig has received honoraria or travel support for consulting or lecturing from the following companies: CSL Behring Schweiz, Zurich, Switzerland; Fresenius-Kabi, Bad Homburg, Germany; and OrPha Swiss GmbH, Küsnacht, Switzerland.
This manuscript was handled by: Jerrold H. Levy, MD, FAHA.
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