Comparative retrospective study on the validity of point-of-care testing device for massive obstetrical hemorrhage: dry hematology vs thromboelastography Eishin Nakamura, MD; Shigetaka Matsunaga, PhD; Akihiko Kikuchi, PhD; Yasushi Takai, PhD BACKGROUND: Early recognition of hypofibrinogenemia and prompt initiation of transfusion therapy in patients with massive obstetrical hemor- rhage can improve prognosis. There are reports on the usefulness of point-of-care testing, which provides quicker test results compared with fibrinogen measurements using the conventional Clauss method. OBJECTIVE: This study aimed to compare and investigate the diagnos- tic accuracy of dry hematology and thromboelastography in point-of-care testing for the diagnosis of hypofibrinogenemia. STUDY DESIGN: A single-center, retrospective study of 126 massive obstetrical hemorrhage cases with point-of-care testing before treatment was initiated. The correlation of fibrinogen values with the Clauss method and the diagnostic accuracy for hypofibrinogenemia were compared between dry hematology and thromboelastography. RESULTS: Fibrinogen value in dry hematology showed a strong positive correlation with values measured by the Clauss method, and the diagnostic accuracy for hypofibrinogenemia was high, but there were many residuals above 100 mg/dL, and the distribution of these residuals was not uniform. Although thromboelastography cannot be used to directly measure fibrinogen values, maximum amplitude citrated functional fibrino- gen, amplitude-10 citrated rapid thromboelastography, and amplitude-10 citrated functional fibrinogen showed a strong positive correlation with fibrinogen values using the Clauss method, and no significant difference in correlation or diagnostic accuracy was observed relative to dry hematology. CONCLUSION: Dry hematology and thromboelastography were equally accurate in diagnosing hypofibrinogenemia, with results correlating well with fibrinogen values measured by the Clauss method. Key words: hypofibrinogenemia, point-of-care testing, postpartum hemorrhage, uterine hemorrhage Introduction M assive obstetrical hemorrhage (MOH) is a life-threatening con- dition and one of the leading causes of maternal death. 1 MOH often presents with coagulopathy, especially when fibrinogen initially falls below the hemostatic threshold and requires high- dose coagulation factor replacement. Because blood fibrinogen levels corre- late with the severity of MOH, 2 it is important to diagnose hypofibrinogene- mia early and initiate appropriate coag- ulation factor replacement. In recent years, point-of-care testing (POCT), a rapid and simple measurement of blood coagulation function, has attracted attention, and there have been many reports on its clinical effectiveness in the field of obstetrics. 3,4 The CG02N whole blood coagulation analyzer (A&T Corporation, Kanagawa, Japan) can rapidly and quantitatively measure fibrinogen levels, whereas TEG 6s (Hae- monetics Corporation, Braintree, MA) does not directly measure fibrinogen levels but performs a comprehensive evaluation of coagulation and hemo- static function, including the influence of platelets, using whole blood. TEG 6s can measure the viscoelasticity of blood clots using various reagents simulta- neously, resonating the clots and expressing their amplitudes graphically. ROTEM (Pentapharm GmbH, Munich, Germany), which is based on the princi- ple of thromboelastometry, is also widely used in daily clinical practice and its use has been reported in many cases. 3 The measurement principles of thromboelastography and thromboelas- tometry are generally the same, with the only difference being the pins and cups of the testing equipment. Our medical institution uses the CP3000 (Sekisui Medical Co, Ltd, Tokyo, Japan), which measures fibrinogen using the Clauss method for the definitive diagnosis of hypofibrinogenemia, but it has drawbacks such as a long examination time, large size, and high cost of the device for installation in a primary medical institution. The aforemen- tioned POCT equipment enables testing in a short time and at low cost, and test results are reported to correlate well with fibrinogen levels in conventional blood testing. 5 Because POCT devices can quickly and easily assess blood coagulation activity, there have been many reports of their use in the field of emergency medicine, such as trauma 6 and cardiac surgery, 7 and some reports of use for MOH. 8 However, studies comparing the usefulness of each POCT instrument in treating MOH are scarce, and no studies have compared the use- fulness of dry hematology and throm- boelastography. Therefore, we retrospectively examined the diagnostic accuracy of POCT (dry-hematology, thromboelastography, or both) in MOH cases seen at our institution in correla- tion with fibrinogen levels measured by the Clauss method to detect hypofibri- nogenemia (≤150 mg/dL, ≤200 mg/dL), which is particularly important in MOH. In addition, Bland-Altman plots were used to measure the residuals Cite this article as: Nakamura E, Matsunaga S, Kikuchi A, et al. Comparative retrospective study on the validity of point-of-care testing device for massive obstetrical hemorrhage: dry hematology vs thromboelastography. Am J Obstet Gynecol MFM 2023;5:100778. 2589-9333/$36.00 © 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) http://dx.doi.org/10.1016/j.ajogmf.2022.100778 Original Research January 2023 AJOG MFM 1
Comparative retrospective study on the validity of point-of-care testing device for massive obstetrical hemorrhage: dry hematology vs thromboelastography
Dec 09, 2022
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Comparative retrospective study on the validity of point-of-care testing device for massive obstetrical hemorrhage: dry hematology vs thromboelastographyComparative retrospective study on the validity of point-of-care testing device for massive obstetrical hemorrhage: dry hematology vs thromboelastography
Eishin Nakamura, MD; Shigetaka Matsunaga, PhD; Akihiko Kikuchi, PhD; Yasushi Takai, PhD
BACKGROUND: Early recognition of hypofibrinogenemia and prompt initiation of transfusion therapy in patients with massive obstetrical hemor- rhage can improve prognosis. There are reports on the usefulness of point-of-care testing, which provides quicker test results compared with fibrinogen measurements using the conventional Clauss method. OBJECTIVE: This study aimed to compare and investigate the diagnos- tic accuracy of dry hematology and thromboelastography in point-of-care testing for the diagnosis of hypofibrinogenemia. STUDY DESIGN: A single-center, retrospective study of 126 massive obstetrical hemorrhage cases with point-of-care testing before treatment was initiated. The correlation of fibrinogen values with the Clauss method and the diagnostic accuracy for hypofibrinogenemia were compared between dry hematology and thromboelastography. RESULTS: Fibrinogen value in dry hematology showed a strong positive correlation with values measured by the Clauss method, and the
Cite this article as: Nakamura E, Matsunaga S, Kikuchi A, et al. Comparative retrospective study on the validity of point-of-care testing device for massive obstetrical hemorrhage: dry hematology vs thromboelastography. Am J Obstet Gynecol MFM 2023;5:100778.
2589-9333/$36.00 © 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) http://dx.doi.org/10.1016/j.ajogmf.2022.100778
diagnostic accuracy for hypofibrinogenemia was high, but there were many residuals above 100 mg/dL, and the distribution of these residuals was not uniform. Although thromboelastography cannot be used to directly measure fibrinogen values, maximum amplitude citrated functional fibrino- gen, amplitude-10 citrated rapid thromboelastography, and amplitude-10 citrated functional fibrinogen showed a strong positive correlation with fibrinogen values using the Clauss method, and no significant difference in correlation or diagnostic accuracy was observed relative to dry hematology. CONCLUSION: Dry hematology and thromboelastography were equally accurate in diagnosing hypofibrinogenemia, with results correlating well with fibrinogen values measured by the Clauss method.
Key words: hypofibrinogenemia, point-of-care testing, postpartum hemorrhage, uterine hemorrhage
Introduction
M assive obstetrical hemorrhage (MOH) is a life-threatening con-
dition and one of the leading causes of maternal death.1 MOH often presents with coagulopathy, especially when fibrinogen initially falls below the hemostatic threshold and requires high- dose coagulation factor replacement. Because blood fibrinogen levels corre- late with the severity of MOH,2 it is important to diagnose hypofibrinogene- mia early and initiate appropriate coag- ulation factor replacement. In recent years, point-of-care testing (POCT), a rapid and simple measurement of blood coagulation function, has attracted attention, and there have been many reports on its clinical effectiveness in
the field of obstetrics.3,4 The CG02N whole blood coagulation analyzer (A&T Corporation, Kanagawa, Japan) can rapidly and quantitatively measure fibrinogen levels, whereas TEG 6s (Hae- monetics Corporation, Braintree, MA) does not directly measure fibrinogen levels but performs a comprehensive evaluation of coagulation and hemo- static function, including the influence of platelets, using whole blood. TEG 6s can measure the viscoelasticity of blood clots using various reagents simulta- neously, resonating the clots and expressing their amplitudes graphically. ROTEM (Pentapharm GmbH, Munich, Germany), which is based on the princi- ple of thromboelastometry, is also widely used in daily clinical practice and its use has been reported in many cases.3 The measurement principles of thromboelastography and thromboelas- tometry are generally the same, with the only difference being the pins and cups of the testing equipment. Our medical institution uses the CP3000 (Sekisui Medical Co, Ltd, Tokyo, Japan), which measures fibrinogen using the Clauss method for the definitive diagnosis of hypofibrinogenemia, but it has
drawbacks such as a long examination time, large size, and high cost of the device for installation in a primary medical institution. The aforemen- tioned POCT equipment enables testing in a short time and at low cost, and test results are reported to correlate well with fibrinogen levels in conventional blood testing.5 Because POCT devices can quickly and easily assess blood coagulation activity, there have been many reports of their use in the field of emergency medicine, such as trauma6
and cardiac surgery,7 and some reports of use for MOH.8 However, studies comparing the usefulness of each POCT instrument in treating MOH are scarce, and no studies have compared the use- fulness of dry hematology and throm- boelastography. Therefore, we retrospectively examined the diagnostic accuracy of POCT (dry-hematology, thromboelastography, or both) in MOH cases seen at our institution in correla- tion with fibrinogen levels measured by the Clauss method to detect hypofibri- nogenemia (≤150 mg/dL, ≤200 mg/dL), which is particularly important in MOH. In addition, Bland−Altman plots were used to measure the residuals
January 2023 AJOG MFM 1
AJOG MFM at a Glance
Why was this study conducted? The number of reports on the diagnostic accuracy of point-of-care testing (POCT) devices in massive obstetrical hemorrhage (MOH) is limited. Although various types of POCT devices are currently used in clinical practice, few com- parisons have been done between them.
Key findings POCT devices were highly accurate in diagnosing hypofibrinogenemia, and there was no difference in accuracy among POCT devices.
What does this add to what is known? We compared the diagnostic accuracy for hypofibrinogenemia in MOH between devices and found no substantial differences.
Original Research
between the POCT device measure- ments and the fibrinogen values in the Clauss method.
Materials and Methods Study setting Figure 1 shows the research targets of this study. This was a retrospective study of 320 cases of MOH seen at Sai- tama Medical University, Saitama Med- ical Center, between April 2016 and March 2019. A retrospective analysis was performed on 126 patients who underwent simultaneous blood testing with POCT (CG02N only, TEG 6s only, or both) and fibrinogen measurement with CP3000 using the conventional Clauss method during the first blood draw before transfusion, after being diagnosed with MOH. Data were col- lected retrospectively from medical records. Because of the difference in the timing of the introduction of CG02N and TEG 6s at our institution, the results were categorized into cases mea- sured only with CG02N (Group 1), cases measured only with TEG 6s (Group 2), and cases measured with both (Group 3).
About point-of-care testing devices In this study, CG02N based on dry hematology and TEG 6s based on thromboelastography were used as POCT instruments for obstetrical hem- orrhage cases. The measurement mech- anism of dry hematology is that fibrinogen can be measured directly by dry methods without using reagents,
2 AJOG MFM January 2023
and the results are available within tens of seconds. Thromboelastography is a wet method that uses reagents to evalu- ate the coagulation and fibrinolytic sys- tems of the blood, and takes approximately 30 minutes to obtain all results. The details of the POCT devices are provided in Supplemental File 1.
Various definitions of hypofibrinogenemia Reported cutoff values for hypofibrino- genemia vary.9 Fibrinogen ≤200 mg/dL has been reported to be a risk factor for postpartum hemorrhage,10,11 and fibrinogen levels at ≤130 to 155 mg/dL can lead to high risk of massive blood transfusions2,12 in MOH. In this study, we measured the diagnostic accuracy of POCT for detecting fibrinogen levels ≤150 mg/dL and ≤200 mg/dL.
Inclusion criteria This study included patients who came to our institution and were diagnosed with MOH (total blood loss ≥1000 mL13) postpartum, or those who were diagnosed with MOH after delivery in another institution and were transferred to our institution.
Exclusion criteria Cases with a total blood loss of <1000 mL, cases in which endpoints could not be evaluated retrospectively (eg, incomplete medical records), and cases in which blood transfusion or tra- nexamic acid was administered before POCT measurement were excluded.
Method of analysis for Group 1 The correlation between fibrinogen lev- els from CG02N and those from CP3000 measured by the Clauss method was examined in all 65 patients who were tested only with CG02N. We also estimated the diagnostic accuracy of CG02N for hypofibrinogenemia (≤150 mg/dL and ≤200 mg/dL) using the Clauss method.
Method of analysis for Group 2 In Group 2, only 29 patients who were measured using TEG 6s were included. Because TEG 6s does not directly mea- sure fibrinogen values, we examined the correlation between those indexes that can be directly measured and fibrinogen values measured using the conventional Clauss method. We also estimated the diagnostic accuracy of each TEG 6s index against hypofibrinogenemia using the Clauss method.
Method of analysis for Group 3 A total of 32 patients who were simulta- neously tested using CG02N and TEG 6s were included in the study. The cor- relation between fibrinogen values mea- sured using both CG02N and TEG 6s and those measured using the Clauss method was determined. The diagnostic accuracy of the 2 methods for hypofibri- nogenemia was then compared.
Ethics approval and participant consent This study was approved by the Ethics Committee of the Saitama Medical Cen- ter, Saitama Medical University.
Characteristics of the medical institution where the study was conducted This study was conducted at Saitama Medical Center, Saitama Medical Uni- versity, a general perinatal medical cen- ter located in Saitama Prefecture. Our institutions accept all cases of MOH that occur in primary and secondary medical facilities in Saitama Prefecture. Therefore, we often encounter patients who have lost >1000 mL of blood but are transferred to our institution
FIGURE 1 Study flowchart
Nakamura. Comparison of diagnostic accuracy of point-of-care testing devices in massive obstetrical hemorrhage. Am J Obstet Gynecol MFM 2022.
Original Research
without receiving blood transfusions or tranexamic acid. The basic policy for MOH patients at
our institution is described below. When a patient with MOH is trans- ported to our institution, blood analysis is performed immediately on arrival. Simultaneously with the measurement of coagulation activity by POCT, fibrin- ogen measurement by the Clauss method is initiated. Blood transfusion is then started on the basis of the patient’s vital signs, total blood loss at the time of transport, and results from POCT. For hypofibrinogenemia, fibrinogen con- centrate should be administered first, with the red cell concentrate (RCC) and fresh frozen plasma (FFP) being approximately 1:1. After transfusion, frequent blood tests are performed to check for vital signs and to minimize complications from excessive transfu- sion.
Statistical analysis For the comparison between dry hema- tology and thromboelastography in Group 3, the Fisher exact ratio test was used for nominal variables, the Shapiro −Wilk test for normality, and t-tests were used for continuous variables. For comparisons of patient background among Groups 1, 2, and 3, the Fisher exact ratio test was used for nominal variables, and 1-way analysis of variance for continuous variables. The area under the curve (AUC) in the receiver operating characteristic (ROC) curve was used to determine the accuracy of the hypofibrinogenemia diagnosis. JMP version 14 (SAS Institute, Cary, NC) was used for statistical analysis.
Results Comparison between groups Table 1 shows the comparison of obstet- rical backgrounds among the groups.
Group 2 had significantly fewer gesta- tional weeks at delivery compared with Groups 1 and 3 (35.5§3.9 vs 37.9§ 4.2 vs 37.9§4.2 weeks), higher body mass index (24.0§3.7 vs 22.6§3.6 vs 21.8 §3.8), and higher cesarean delivery rates (82.8% vs 36.9% vs 59.4%), respec- tively. There were no significant differ- ences in maternal age, primiparity rates, or intrauterine fetal death rates among the 3 groups. Table 2 lists the results of a blood test
from the hospital laboratory for each group, and the amount of blood loss, transfusion volume, and causative dis- ease of MOH. Group 2 had less preexa- mination and total bleeding than Groups 1 and 3, significantly lower doses of RCC, FFP, platelet concentrate, and fibrinogen concentrate, and signifi- cantly higher hemoglobin and fibrino- gen levels on blood tests.
January 2023 AJOG MFM 3
TABLE 1 Obstetrical characteristics of each group
Characteristic
Group 2: analyzed with TEG 6s (n=29)
Group 3: analyzed with both CG02N and TEG 6s (n=32) P value
Maternal age (y) 33.8§5.7 35.4§5.4 34.9§5.9 .394
Gestational age at delivery (wk) 37.9§4.2a 35.5§3.9b 37.9§3.0a .015c
Primiparity 40 cases (61.5%) 18 cases (62.1%) 16 cases (50%) .522
Intrauterine fetal death 4 cases (6.2%) 0 case (0%) 3 cases (9.4%) .2671
Body mass index 22.6§3.6 24.0§3.7 21.8§3.8 .0676c
Cesarean delivery 24 cases (36.9%)a 24 cases (82.8%)b 19 cases (59.4%)a <.0001c
The Fisher exact ratio test was used to compare nominal variables and 1-way analysis of variance was used to compare continuous variables. a,b Multiple comparisons were performed for variables that showed statistically significant differences among the three groups. Compared to a, b showed a statistically significant difference; c There were statistically significant differences among the three groups.
Nakamura. Comparison of diagnostic accuracy of point-of-care testing devices in massive obstetrical hemorrhage. Am J Obstet Gynecol MFM 2022.
Original Research
Analysis for Group 1 and Group 2 Figure 2 shows a scatter plot of fibrino- gen values measured using the Clauss method with CP3000 and fibrinogen values measured with CG02N. The cor- relation coefficient was 0.7944 (P<.001), indicating a significant corre- lation between the 2 variables. Table 3 lists the diagnostic accuracy
of each POCT device for hypofibrinoge- nemia using the Clauss method. The AUCs calculated from ROC curves for fibrinogen <150 mg/dL and <200 mg/dL for the respective defini- tions of hypofibrinogemia were 0.969 and 0.881, respectively. Table 3 also lists the AUC for each
TEG 6s value using the ROC curve for hypofibrinogenemia and the correlation coefficient with the fibrinogen value using the Clauss method (for TEG 6s, only the 3 parameters with high AUC values are listed; other parameters are included in Supplemental File 2). The diagnostic accuracy of each of the TEG 6s parameters was high for levels of hypofibrinogenemia at ≤150 mg/dL and ≤200 mg/dL, with high AUC values for maximum amplitude citrated func- tional fibrinogen (MA-CFF), ampli- tude-10 citrated rapid thromboelastography (A-10 CRT), and amplitude-10 citrated functional fibrin- ogen (A-10 CFF), and other parameters. Significant positive correlations with
4 AJOG MFM January 2023
fibrinogen values were also observed using the Clauss method.
Figure 3 shows a Bland−Altman plot of fibrinogen values measured with CG02N vs those measured using the Clauss method. The mean difference in fibrinogen values for CG02N vs the Clauss method was 17.3 mg/dL (95% confidence interval, 0.61−33.9). The plots did not show a consistent distribu- tion, and there were a certain number of measured residuals that showed residuals of 100 mg/dL or more, regard- less of fibrinogen value.
Analysis for Group 3 Table 4 lists the AUC values for the fibrinogen values from the CG02N and each of the TEG 6s parameters using the ROC curve for hypofibrinogenemia, the P values of the ROC comparison between CG02N and each of the TEG 6s parameters, and the correlation coef- ficient of the Clauss method for fibrino- gen values (for TEG 6s, only the top 3 parameters with the highest AUC values are listed; other parameters are pre- sented in Supplemental File 3). Both CG02N and TEG 6s had high AUC val- ues for the diagnosis of hypofibrinoge- nemia and high diagnostic accuracy for both definitions of hypofibrinogenemia. There was no significant difference in the AUC values of CG02N and TEG 6s on the ROC curve for diagnostic accu- racy for hypofibrinogenemia. A strong
positive correlation was shown between the Clauss method and fibrinogen levels in CG02N (as in Analysis 1), and TEG 6s also showed strong positive correla- tions for MA-CFF, A-10 CRT, and A- 10 CFF. Figure 4 shows a scatter plot of fibrin-
ogen values from CG02N and each parameter of TEG 6s against fibrinogen values using the Clauss method. Only the 3 parameters having the highest cor- relation coefficients with fibrinogen val- ues measured by the Clauss method among all the TEG 6s parameters are shown. The nonlinear model using logistic regression is indicated by the solid line in the figure. Fibrinogen val- ues were generally linearly correlated across the entire range for CG02N and MA-CFF and A-10 CFF in TEG 6s. A- 10 CRT tended to give higher results when fibrinogen using the Clauss method was low and lower results when fibrinogen was high. Figure 5 shows a Bland−Altman plot
for the fibrinogen values measured by the Clauss method in Analysis 3. The fibrinogen values in CG02N showed a certain number of plots with large resid- uals >100 mg/dL regardless of the dis- tribution of fibrinogen values in the Clauss method, similar to the results of Analysis 1. For the other parameters in the TEG 6s (MA-CFF, A-10 CRT, A-10 CFF), the correlations were strong, but
TABLE 2 Hematological data of each group
Hematological data
Group 2: analyzed with TEG 6s (n=29)
Group 3: analyzed with both CG02N and TEG 6s (n=32) P value
Preexamination blood loss (mL) 2044§1029a 1393§906b 1992§1164a .0175
Total blood loss (mL) 3510§2386a 2360§1759b 3212§2467a .0367c
Results of a blood test from hospital laboratory
Hemoglobin (g/dL) 7.5§2.0a 8.7§2.0b 7.8§2.1a .0437c
Platelet count (104/mL) 15.6§6.8 14.5§5.7 13.4§6.2 .2922
APTT (s) 42.5§35.9 37.6§16.8 34.8§18.8 .3817
PT% (%) 79.6§25.5 89.2§21.0 82.7§27.2 .176
FDP (mg/mL) 174.4§293.3a 62.8§44.6b 196.3§309.0a .0031c
Fibrinogen (mg/dL) 202.1§95.9a 262.3§98.8b 192.3§99.4a .0129c
Total blood transfusion volume
Red cell concentrate (mL) 1620§1566a 705§1065b 1299§1500a .0062c
Fresh frozen plasma (mL) 1303§1595a 621§993b 1178§1530a .0218c
Platelet concentrate (mL) 112§243a 34§94b 144§245a .0163c
Fibrinogen concentrate (g) 2.4§2.8a 1.0§2.0b 2.7§3.4a .0163c
Cause of PPH Atonic hemorrhage 29 cases (44.6%) 21 cases (72.4%) 15 cases (46.9%)
Perineal laceration 15 cases (23.1%) 3 case (10.3%) 4 cases (12.5%)
Retained products of conception, placenta accreta
9 cases (13.8%) 3 cases (10.3%) 2 cases (6.3%)
Placental abruption 8 cases (12.3%) 2 cases (6.9%) 7 cases (21.9%)
Amniotic fluid embolism 3 cases (4.6%) 0 case (0%) 1 case (3.1%)
Others 1 case (1.5%) 0 case (0%) 3 case (9.3%) The Fisher exact ratio test was used to compare nominal variables and 1-way analysis of variance was used to compare continuous variables.
APTT, activated partial thromboplastin time; FDP, fibrinogen degradation product; PPH, postpartum hemorrhage; PT, prothrombin time. a,b Multiple comparisons were performed for variables that showed statistically significant differences among the three groups. Compared to a, b showed a statistically significant difference; c There were statistically significant differences among the three groups.
Nakamura. Comparison of diagnostic accuracy of point-of-care testing devices in massive obstetrical hemorrhage. Am J Obstet Gynecol MFM 2022.
Original Research
the variation tended to increase as the fibrinogen values increased. Table 5 uses ROC curves to indicate
the comparison of the A-10 CFF and TEG 6s parameters that correlate best with fibrinogen values using the Clauss method for the diagnostic accuracy for hypofibrinogenemia. The A-10 CFF cutoff for the diagnosis of hypofibrino- genemia at ≤150 mg/dL was 4.0 mm (sensitivity, 0.909; specificity, 1.000), and a comparison of the AUC with CG02N showed no significant differ- ence between the two. For the diagnosis of hypofibrinogenemia at ≤200 mg/dL,
the A-10 CFF cutoff was 5.0 mm (sensi- tivity, 0.800; specificity, 1.000), and sim- ilarly, there was no significant difference between the two.
Discussion Principal findings In this study, we compared the diagnos- tic accuracy for hypofibrinogenemia between CG02N using dry hematology and TEG 6s using thromboelastogra- phy. The diagnostic accuracies of the 2 devices were equivalent. CG02N showed high diagnostic accuracy com- pared with CP3000 at fibrinogen levels
of approximately 150 mg/dL and a large residual difference in measurements of ≥300 mg/dL. TEG 6s also showed high diagnostic accuracy in MA-CFF, A-10 CRT, and A-10 CFF parameters for hypofibrinogenemia, defined as fibrino- gen ≤150 mg/dL and ≤200 mg/dL, respectively, and significant correlation with fibrinogen levels. Dry hematology provides test results
faster than thromboelastography. In the clinical situation of MOH, where imme- diate response is required, rapid diagno- sis of hypofibrinogenemia by dry hematology is extremely important for
January 2023 AJOG MFM 5
FIGURE 2 Scatter plots for fibrinogen measured by…
Eishin Nakamura, MD; Shigetaka Matsunaga, PhD; Akihiko Kikuchi, PhD; Yasushi Takai, PhD
BACKGROUND: Early recognition of hypofibrinogenemia and prompt initiation of transfusion therapy in patients with massive obstetrical hemor- rhage can improve prognosis. There are reports on the usefulness of point-of-care testing, which provides quicker test results compared with fibrinogen measurements using the conventional Clauss method. OBJECTIVE: This study aimed to compare and investigate the diagnos- tic accuracy of dry hematology and thromboelastography in point-of-care testing for the diagnosis of hypofibrinogenemia. STUDY DESIGN: A single-center, retrospective study of 126 massive obstetrical hemorrhage cases with point-of-care testing before treatment was initiated. The correlation of fibrinogen values with the Clauss method and the diagnostic accuracy for hypofibrinogenemia were compared between dry hematology and thromboelastography. RESULTS: Fibrinogen value in dry hematology showed a strong positive correlation with values measured by the Clauss method, and the
Cite this article as: Nakamura E, Matsunaga S, Kikuchi A, et al. Comparative retrospective study on the validity of point-of-care testing device for massive obstetrical hemorrhage: dry hematology vs thromboelastography. Am J Obstet Gynecol MFM 2023;5:100778.
2589-9333/$36.00 © 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) http://dx.doi.org/10.1016/j.ajogmf.2022.100778
diagnostic accuracy for hypofibrinogenemia was high, but there were many residuals above 100 mg/dL, and the distribution of these residuals was not uniform. Although thromboelastography cannot be used to directly measure fibrinogen values, maximum amplitude citrated functional fibrino- gen, amplitude-10 citrated rapid thromboelastography, and amplitude-10 citrated functional fibrinogen showed a strong positive correlation with fibrinogen values using the Clauss method, and no significant difference in correlation or diagnostic accuracy was observed relative to dry hematology. CONCLUSION: Dry hematology and thromboelastography were equally accurate in diagnosing hypofibrinogenemia, with results correlating well with fibrinogen values measured by the Clauss method.
Key words: hypofibrinogenemia, point-of-care testing, postpartum hemorrhage, uterine hemorrhage
Introduction
M assive obstetrical hemorrhage (MOH) is a life-threatening con-
dition and one of the leading causes of maternal death.1 MOH often presents with coagulopathy, especially when fibrinogen initially falls below the hemostatic threshold and requires high- dose coagulation factor replacement. Because blood fibrinogen levels corre- late with the severity of MOH,2 it is important to diagnose hypofibrinogene- mia early and initiate appropriate coag- ulation factor replacement. In recent years, point-of-care testing (POCT), a rapid and simple measurement of blood coagulation function, has attracted attention, and there have been many reports on its clinical effectiveness in
the field of obstetrics.3,4 The CG02N whole blood coagulation analyzer (A&T Corporation, Kanagawa, Japan) can rapidly and quantitatively measure fibrinogen levels, whereas TEG 6s (Hae- monetics Corporation, Braintree, MA) does not directly measure fibrinogen levels but performs a comprehensive evaluation of coagulation and hemo- static function, including the influence of platelets, using whole blood. TEG 6s can measure the viscoelasticity of blood clots using various reagents simulta- neously, resonating the clots and expressing their amplitudes graphically. ROTEM (Pentapharm GmbH, Munich, Germany), which is based on the princi- ple of thromboelastometry, is also widely used in daily clinical practice and its use has been reported in many cases.3 The measurement principles of thromboelastography and thromboelas- tometry are generally the same, with the only difference being the pins and cups of the testing equipment. Our medical institution uses the CP3000 (Sekisui Medical Co, Ltd, Tokyo, Japan), which measures fibrinogen using the Clauss method for the definitive diagnosis of hypofibrinogenemia, but it has
drawbacks such as a long examination time, large size, and high cost of the device for installation in a primary medical institution. The aforemen- tioned POCT equipment enables testing in a short time and at low cost, and test results are reported to correlate well with fibrinogen levels in conventional blood testing.5 Because POCT devices can quickly and easily assess blood coagulation activity, there have been many reports of their use in the field of emergency medicine, such as trauma6
and cardiac surgery,7 and some reports of use for MOH.8 However, studies comparing the usefulness of each POCT instrument in treating MOH are scarce, and no studies have compared the use- fulness of dry hematology and throm- boelastography. Therefore, we retrospectively examined the diagnostic accuracy of POCT (dry-hematology, thromboelastography, or both) in MOH cases seen at our institution in correla- tion with fibrinogen levels measured by the Clauss method to detect hypofibri- nogenemia (≤150 mg/dL, ≤200 mg/dL), which is particularly important in MOH. In addition, Bland−Altman plots were used to measure the residuals
January 2023 AJOG MFM 1
AJOG MFM at a Glance
Why was this study conducted? The number of reports on the diagnostic accuracy of point-of-care testing (POCT) devices in massive obstetrical hemorrhage (MOH) is limited. Although various types of POCT devices are currently used in clinical practice, few com- parisons have been done between them.
Key findings POCT devices were highly accurate in diagnosing hypofibrinogenemia, and there was no difference in accuracy among POCT devices.
What does this add to what is known? We compared the diagnostic accuracy for hypofibrinogenemia in MOH between devices and found no substantial differences.
Original Research
between the POCT device measure- ments and the fibrinogen values in the Clauss method.
Materials and Methods Study setting Figure 1 shows the research targets of this study. This was a retrospective study of 320 cases of MOH seen at Sai- tama Medical University, Saitama Med- ical Center, between April 2016 and March 2019. A retrospective analysis was performed on 126 patients who underwent simultaneous blood testing with POCT (CG02N only, TEG 6s only, or both) and fibrinogen measurement with CP3000 using the conventional Clauss method during the first blood draw before transfusion, after being diagnosed with MOH. Data were col- lected retrospectively from medical records. Because of the difference in the timing of the introduction of CG02N and TEG 6s at our institution, the results were categorized into cases mea- sured only with CG02N (Group 1), cases measured only with TEG 6s (Group 2), and cases measured with both (Group 3).
About point-of-care testing devices In this study, CG02N based on dry hematology and TEG 6s based on thromboelastography were used as POCT instruments for obstetrical hem- orrhage cases. The measurement mech- anism of dry hematology is that fibrinogen can be measured directly by dry methods without using reagents,
2 AJOG MFM January 2023
and the results are available within tens of seconds. Thromboelastography is a wet method that uses reagents to evalu- ate the coagulation and fibrinolytic sys- tems of the blood, and takes approximately 30 minutes to obtain all results. The details of the POCT devices are provided in Supplemental File 1.
Various definitions of hypofibrinogenemia Reported cutoff values for hypofibrino- genemia vary.9 Fibrinogen ≤200 mg/dL has been reported to be a risk factor for postpartum hemorrhage,10,11 and fibrinogen levels at ≤130 to 155 mg/dL can lead to high risk of massive blood transfusions2,12 in MOH. In this study, we measured the diagnostic accuracy of POCT for detecting fibrinogen levels ≤150 mg/dL and ≤200 mg/dL.
Inclusion criteria This study included patients who came to our institution and were diagnosed with MOH (total blood loss ≥1000 mL13) postpartum, or those who were diagnosed with MOH after delivery in another institution and were transferred to our institution.
Exclusion criteria Cases with a total blood loss of <1000 mL, cases in which endpoints could not be evaluated retrospectively (eg, incomplete medical records), and cases in which blood transfusion or tra- nexamic acid was administered before POCT measurement were excluded.
Method of analysis for Group 1 The correlation between fibrinogen lev- els from CG02N and those from CP3000 measured by the Clauss method was examined in all 65 patients who were tested only with CG02N. We also estimated the diagnostic accuracy of CG02N for hypofibrinogenemia (≤150 mg/dL and ≤200 mg/dL) using the Clauss method.
Method of analysis for Group 2 In Group 2, only 29 patients who were measured using TEG 6s were included. Because TEG 6s does not directly mea- sure fibrinogen values, we examined the correlation between those indexes that can be directly measured and fibrinogen values measured using the conventional Clauss method. We also estimated the diagnostic accuracy of each TEG 6s index against hypofibrinogenemia using the Clauss method.
Method of analysis for Group 3 A total of 32 patients who were simulta- neously tested using CG02N and TEG 6s were included in the study. The cor- relation between fibrinogen values mea- sured using both CG02N and TEG 6s and those measured using the Clauss method was determined. The diagnostic accuracy of the 2 methods for hypofibri- nogenemia was then compared.
Ethics approval and participant consent This study was approved by the Ethics Committee of the Saitama Medical Cen- ter, Saitama Medical University.
Characteristics of the medical institution where the study was conducted This study was conducted at Saitama Medical Center, Saitama Medical Uni- versity, a general perinatal medical cen- ter located in Saitama Prefecture. Our institutions accept all cases of MOH that occur in primary and secondary medical facilities in Saitama Prefecture. Therefore, we often encounter patients who have lost >1000 mL of blood but are transferred to our institution
FIGURE 1 Study flowchart
Nakamura. Comparison of diagnostic accuracy of point-of-care testing devices in massive obstetrical hemorrhage. Am J Obstet Gynecol MFM 2022.
Original Research
without receiving blood transfusions or tranexamic acid. The basic policy for MOH patients at
our institution is described below. When a patient with MOH is trans- ported to our institution, blood analysis is performed immediately on arrival. Simultaneously with the measurement of coagulation activity by POCT, fibrin- ogen measurement by the Clauss method is initiated. Blood transfusion is then started on the basis of the patient’s vital signs, total blood loss at the time of transport, and results from POCT. For hypofibrinogenemia, fibrinogen con- centrate should be administered first, with the red cell concentrate (RCC) and fresh frozen plasma (FFP) being approximately 1:1. After transfusion, frequent blood tests are performed to check for vital signs and to minimize complications from excessive transfu- sion.
Statistical analysis For the comparison between dry hema- tology and thromboelastography in Group 3, the Fisher exact ratio test was used for nominal variables, the Shapiro −Wilk test for normality, and t-tests were used for continuous variables. For comparisons of patient background among Groups 1, 2, and 3, the Fisher exact ratio test was used for nominal variables, and 1-way analysis of variance for continuous variables. The area under the curve (AUC) in the receiver operating characteristic (ROC) curve was used to determine the accuracy of the hypofibrinogenemia diagnosis. JMP version 14 (SAS Institute, Cary, NC) was used for statistical analysis.
Results Comparison between groups Table 1 shows the comparison of obstet- rical backgrounds among the groups.
Group 2 had significantly fewer gesta- tional weeks at delivery compared with Groups 1 and 3 (35.5§3.9 vs 37.9§ 4.2 vs 37.9§4.2 weeks), higher body mass index (24.0§3.7 vs 22.6§3.6 vs 21.8 §3.8), and higher cesarean delivery rates (82.8% vs 36.9% vs 59.4%), respec- tively. There were no significant differ- ences in maternal age, primiparity rates, or intrauterine fetal death rates among the 3 groups. Table 2 lists the results of a blood test
from the hospital laboratory for each group, and the amount of blood loss, transfusion volume, and causative dis- ease of MOH. Group 2 had less preexa- mination and total bleeding than Groups 1 and 3, significantly lower doses of RCC, FFP, platelet concentrate, and fibrinogen concentrate, and signifi- cantly higher hemoglobin and fibrino- gen levels on blood tests.
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TABLE 1 Obstetrical characteristics of each group
Characteristic
Group 2: analyzed with TEG 6s (n=29)
Group 3: analyzed with both CG02N and TEG 6s (n=32) P value
Maternal age (y) 33.8§5.7 35.4§5.4 34.9§5.9 .394
Gestational age at delivery (wk) 37.9§4.2a 35.5§3.9b 37.9§3.0a .015c
Primiparity 40 cases (61.5%) 18 cases (62.1%) 16 cases (50%) .522
Intrauterine fetal death 4 cases (6.2%) 0 case (0%) 3 cases (9.4%) .2671
Body mass index 22.6§3.6 24.0§3.7 21.8§3.8 .0676c
Cesarean delivery 24 cases (36.9%)a 24 cases (82.8%)b 19 cases (59.4%)a <.0001c
The Fisher exact ratio test was used to compare nominal variables and 1-way analysis of variance was used to compare continuous variables. a,b Multiple comparisons were performed for variables that showed statistically significant differences among the three groups. Compared to a, b showed a statistically significant difference; c There were statistically significant differences among the three groups.
Nakamura. Comparison of diagnostic accuracy of point-of-care testing devices in massive obstetrical hemorrhage. Am J Obstet Gynecol MFM 2022.
Original Research
Analysis for Group 1 and Group 2 Figure 2 shows a scatter plot of fibrino- gen values measured using the Clauss method with CP3000 and fibrinogen values measured with CG02N. The cor- relation coefficient was 0.7944 (P<.001), indicating a significant corre- lation between the 2 variables. Table 3 lists the diagnostic accuracy
of each POCT device for hypofibrinoge- nemia using the Clauss method. The AUCs calculated from ROC curves for fibrinogen <150 mg/dL and <200 mg/dL for the respective defini- tions of hypofibrinogemia were 0.969 and 0.881, respectively. Table 3 also lists the AUC for each
TEG 6s value using the ROC curve for hypofibrinogenemia and the correlation coefficient with the fibrinogen value using the Clauss method (for TEG 6s, only the 3 parameters with high AUC values are listed; other parameters are included in Supplemental File 2). The diagnostic accuracy of each of the TEG 6s parameters was high for levels of hypofibrinogenemia at ≤150 mg/dL and ≤200 mg/dL, with high AUC values for maximum amplitude citrated func- tional fibrinogen (MA-CFF), ampli- tude-10 citrated rapid thromboelastography (A-10 CRT), and amplitude-10 citrated functional fibrin- ogen (A-10 CFF), and other parameters. Significant positive correlations with
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fibrinogen values were also observed using the Clauss method.
Figure 3 shows a Bland−Altman plot of fibrinogen values measured with CG02N vs those measured using the Clauss method. The mean difference in fibrinogen values for CG02N vs the Clauss method was 17.3 mg/dL (95% confidence interval, 0.61−33.9). The plots did not show a consistent distribu- tion, and there were a certain number of measured residuals that showed residuals of 100 mg/dL or more, regard- less of fibrinogen value.
Analysis for Group 3 Table 4 lists the AUC values for the fibrinogen values from the CG02N and each of the TEG 6s parameters using the ROC curve for hypofibrinogenemia, the P values of the ROC comparison between CG02N and each of the TEG 6s parameters, and the correlation coef- ficient of the Clauss method for fibrino- gen values (for TEG 6s, only the top 3 parameters with the highest AUC values are listed; other parameters are pre- sented in Supplemental File 3). Both CG02N and TEG 6s had high AUC val- ues for the diagnosis of hypofibrinoge- nemia and high diagnostic accuracy for both definitions of hypofibrinogenemia. There was no significant difference in the AUC values of CG02N and TEG 6s on the ROC curve for diagnostic accu- racy for hypofibrinogenemia. A strong
positive correlation was shown between the Clauss method and fibrinogen levels in CG02N (as in Analysis 1), and TEG 6s also showed strong positive correla- tions for MA-CFF, A-10 CRT, and A- 10 CFF. Figure 4 shows a scatter plot of fibrin-
ogen values from CG02N and each parameter of TEG 6s against fibrinogen values using the Clauss method. Only the 3 parameters having the highest cor- relation coefficients with fibrinogen val- ues measured by the Clauss method among all the TEG 6s parameters are shown. The nonlinear model using logistic regression is indicated by the solid line in the figure. Fibrinogen val- ues were generally linearly correlated across the entire range for CG02N and MA-CFF and A-10 CFF in TEG 6s. A- 10 CRT tended to give higher results when fibrinogen using the Clauss method was low and lower results when fibrinogen was high. Figure 5 shows a Bland−Altman plot
for the fibrinogen values measured by the Clauss method in Analysis 3. The fibrinogen values in CG02N showed a certain number of plots with large resid- uals >100 mg/dL regardless of the dis- tribution of fibrinogen values in the Clauss method, similar to the results of Analysis 1. For the other parameters in the TEG 6s (MA-CFF, A-10 CRT, A-10 CFF), the correlations were strong, but
TABLE 2 Hematological data of each group
Hematological data
Group 2: analyzed with TEG 6s (n=29)
Group 3: analyzed with both CG02N and TEG 6s (n=32) P value
Preexamination blood loss (mL) 2044§1029a 1393§906b 1992§1164a .0175
Total blood loss (mL) 3510§2386a 2360§1759b 3212§2467a .0367c
Results of a blood test from hospital laboratory
Hemoglobin (g/dL) 7.5§2.0a 8.7§2.0b 7.8§2.1a .0437c
Platelet count (104/mL) 15.6§6.8 14.5§5.7 13.4§6.2 .2922
APTT (s) 42.5§35.9 37.6§16.8 34.8§18.8 .3817
PT% (%) 79.6§25.5 89.2§21.0 82.7§27.2 .176
FDP (mg/mL) 174.4§293.3a 62.8§44.6b 196.3§309.0a .0031c
Fibrinogen (mg/dL) 202.1§95.9a 262.3§98.8b 192.3§99.4a .0129c
Total blood transfusion volume
Red cell concentrate (mL) 1620§1566a 705§1065b 1299§1500a .0062c
Fresh frozen plasma (mL) 1303§1595a 621§993b 1178§1530a .0218c
Platelet concentrate (mL) 112§243a 34§94b 144§245a .0163c
Fibrinogen concentrate (g) 2.4§2.8a 1.0§2.0b 2.7§3.4a .0163c
Cause of PPH Atonic hemorrhage 29 cases (44.6%) 21 cases (72.4%) 15 cases (46.9%)
Perineal laceration 15 cases (23.1%) 3 case (10.3%) 4 cases (12.5%)
Retained products of conception, placenta accreta
9 cases (13.8%) 3 cases (10.3%) 2 cases (6.3%)
Placental abruption 8 cases (12.3%) 2 cases (6.9%) 7 cases (21.9%)
Amniotic fluid embolism 3 cases (4.6%) 0 case (0%) 1 case (3.1%)
Others 1 case (1.5%) 0 case (0%) 3 case (9.3%) The Fisher exact ratio test was used to compare nominal variables and 1-way analysis of variance was used to compare continuous variables.
APTT, activated partial thromboplastin time; FDP, fibrinogen degradation product; PPH, postpartum hemorrhage; PT, prothrombin time. a,b Multiple comparisons were performed for variables that showed statistically significant differences among the three groups. Compared to a, b showed a statistically significant difference; c There were statistically significant differences among the three groups.
Nakamura. Comparison of diagnostic accuracy of point-of-care testing devices in massive obstetrical hemorrhage. Am J Obstet Gynecol MFM 2022.
Original Research
the variation tended to increase as the fibrinogen values increased. Table 5 uses ROC curves to indicate
the comparison of the A-10 CFF and TEG 6s parameters that correlate best with fibrinogen values using the Clauss method for the diagnostic accuracy for hypofibrinogenemia. The A-10 CFF cutoff for the diagnosis of hypofibrino- genemia at ≤150 mg/dL was 4.0 mm (sensitivity, 0.909; specificity, 1.000), and a comparison of the AUC with CG02N showed no significant differ- ence between the two. For the diagnosis of hypofibrinogenemia at ≤200 mg/dL,
the A-10 CFF cutoff was 5.0 mm (sensi- tivity, 0.800; specificity, 1.000), and sim- ilarly, there was no significant difference between the two.
Discussion Principal findings In this study, we compared the diagnos- tic accuracy for hypofibrinogenemia between CG02N using dry hematology and TEG 6s using thromboelastogra- phy. The diagnostic accuracies of the 2 devices were equivalent. CG02N showed high diagnostic accuracy com- pared with CP3000 at fibrinogen levels
of approximately 150 mg/dL and a large residual difference in measurements of ≥300 mg/dL. TEG 6s also showed high diagnostic accuracy in MA-CFF, A-10 CRT, and A-10 CFF parameters for hypofibrinogenemia, defined as fibrino- gen ≤150 mg/dL and ≤200 mg/dL, respectively, and significant correlation with fibrinogen levels. Dry hematology provides test results
faster than thromboelastography. In the clinical situation of MOH, where imme- diate response is required, rapid diagno- sis of hypofibrinogenemia by dry hematology is extremely important for
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FIGURE 2 Scatter plots for fibrinogen measured by…
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