Rotational thromboelastometry (ROTEM®) and platelet function as measured by Multiplate® in pre-eclamptic women: A prospective observational study.

Objective: Pre-eclampsia with thrombocytopaenia has implications for obstetric haemorrhage management. We aimed to describe coagulation and platelet function in women with pre-eclampsia and compare the results with those from women without pre-eclampsia. Design: A prospective, observational study. Setting: Tertiary referral hospital. Population: Women with clinically diagnosed pre-eclampsia compared to those with uncomplicated pregnancies (comparator group). Methods: We obtained pre-delivery coagulation results from pregnant women. The pre-eclampsia group had confirmed or suspected pre-eclampsia and blood samples collected on admission to birth suite. The comparator group had uncomplicated pregnancies and blood samples obtained prior to elective Caesarean delivery. Main Outcome Measures: Multiplate® and non-activated thromboelastometry (ROTEM® NATEM) results were compared between groups and with manufacturer’s reference ranges. Results: One hundred and nineteen women with pre-eclampsia were compared to 22 in the comparator group. The mean values for selected ROTEM® parameters for the pre-eclampsia and comparator groups respectively were: ROTEM® NATEM amplitudes A5, 49 and 45 mm (P=0.035); A10, 61 and 57 mm (P=0.017); A15, 65 and 62 mm (P=0.02); A20, 67 and 64 mm (P=0.026); A25, 69 and 65 (P=0.009); A30, 69 and 66 (P=0.023); area under curve (AUC), 6877 and 6642 mm 2 (P=0.044); maximum clot firmness (MCE), 230 and 201 (P=0.018) and thrombin potential index (TPI), 76 and 60 (P=0.029). Conclusions: ROTEM® values from the pre-eclampsia group indicated increased hypercoagulability compared to the comparator group, however Multiplate® parameters measuring platelet function, were not significantly different between groups. Rotational thromboelastometry (ROTEM ®) and platelet function as measured by Multiplate® in pre-eclamptic women: A prospective observational study. Julie Lee, 1,2 Kerstin H. Wyssusek, 1,2 Rebecca M.N. Kimble, 2,3 Emma Ballard, 4 Amy Krepska, 1,2 André A. van Zundert, 1,2,5 Leonie Roberts, 2,6 Claire Manning, 1,2 Victoria A. Eley. 1,2 1 Department of Anaesthesia and Perioperative Medicine, The Royal Brisbane and Women’s Hospital, Brisbane, Australia, 2 The University of Queensland, Brisbane, Australia, 3 Department of Obstetrics and Gynaecology, The Royal Brisbane and Women’s Hospital, Brisbane, Australia 4 QIMR Berghofer Medical Research Institute, Brisbane, Australia, 5 Queensland University of Technology, Brisbane, Australia 6 Department of Anaesthesia, Redcliffe Hospital, Brisbane, Australia. Address correspondence to Dr Julie Lee, Department of Anaesthesia and Perioperative Medicine, Level 4 NHB, The Royal Brisbane and Women’s Hospital, Butterfield St, Herston, QLD 4029. Ph: (617) 3646 5453, Fax: (617) 3646 4308. Email: [email protected] ORCID ID: 0000-0002-6896-5568; Twitter handle: @JulieLee01 Email addresses and ORCID-IDs [email protected] - 0000-0003-1709-4958 [email protected] - 0000-0001-9044-194X [email protected] – 0000-0002-9430-2485 [email protected] – 0000-0002-9633-6953 [email protected] - [email protected] – 0009-0005-4017-0500 [email protected] – 0009-0001-3100-0893 [email protected] - 0000-0002-6715-9193 Short Title: ROTEM ® and platelet function in pre-eclampsia Rotational thromboelastometry (ROTEM ®) and platelet function as measured by Multiplate® in pre-eclamptic obstetric patients: A prospective observational study.

Objective: Pre-eclampsia with thrombocytopaenia has implications for obstetric haemorrhage management. We aimed to describe coagulation and platelet function in women with pre-eclampsia and compare the results with those from women without pre-eclampsia. Design: A prospective, observational study. Setting: Tertiary referral hospital. Population: Women with clinically diagnosed pre-eclampsia compared to those with uncomplicated pregnancies (comparator group).

We obtained pre-delivery coagulation results from pregnant women. The pre-eclampsia group had confirmed or suspected pre-eclampsia and blood samples collected on admission to birth suite. The comparator group had uncomplicated pregnancies and blood samples obtained prior to elective Caesarean delivery. Main Outcome Measures: Multiplate® and non-activated thromboelastometry (ROTEM® NATEM) results were compared between groups and with manufacturer’s reference ranges.

One hundred and nineteen women with pre-eclampsia were compared to 22 in the comparator group. The mean values for selected ROTEM® parameters for the pre-eclampsia and comparator groups respectively were: ROTEM® NATEM amplitudes A5, 49 and 45 mm (P=0.035); A10, 61 and 57 mm (P=0.017); A15, 65 and 62 mm (P=0.02); A20, 67 and 64 mm (P=0.026); A25, 69 and 65 (P=0.009); A30, 69 and 66 (P=0.023); area under curve (AUC), 6877 and 6642 mm 2 (P=0.044); maximum clot firmness (MCE), 230 and 201 (P=0.018) and thrombin potential index (TPI), 76 and 60 (P=0.029).

ROTEM® values from the pre-eclampsia group indicated increased hypercoagulability compared to the comparator group, however Multiplate® parameters measuring platelet function, were not significantly different between groups. Funding: Australian and New Zealand College of Anaesthetists (ANZCA)/CSL Behring (16/021) provided funding for ROTEM®/Multiplate® testing and consumables; Haemoview® distributors provided discounted costings on consumables and reagents; Haematology in Obstetrics and Women’s Health (HOW) Collaborative and Haematology Society of Australia and New Zealand (HSANZ) research award provided funding for research nursing support and time to conduct the research. The National Blood Authority (ID113) and the Royal Brisbane and Women’s Hospital scholarship provided funding for time to conduct the research. None of these organisations had any involvement in the study design, data collection, analysis, interpretation of data or the writing of this report.

Coagulation; HELLP syndrome; labouring women; Multiplate®; platelet function; pre-eclampsia; pregnancy; rotational thromboelastometry. Tweetable Abstract: Women with pre-eclampsia had significantly increased hypercoagulability assessed on ROTEM® compared to those without pre-eclampsia. Multiplate® parameters measuring platelet function were not significantly different. Word count

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Pre-eclampsia is a complex hypertensive multisystemic disorder of pregnancy that may be associated with thrombocytopenia 1 and is characterised by endothelial dysfunction, systemic inflammation, and coagulopathy. 1, 2 Thrombocytopenia affects approximately 12–20% of pre-eclamptic women, contributing to impaired haemostasis and increased risk of cerebral haemorrhage, venous thromboembolism, and postpartum haemorrhage. 3, 4 In pre-eclampsia, platelet activation, increased platelet consumption, and decreased platelet lifespan are hallmark features, yet the mechanisms underlying platelet dysfunction remain incompletely understood. 5 Viscoelastic testing, such as rotational thromboelastometry (ROTEM ® ), offers a dynamic assessment of clot formation and stability, and has shown promise in identifying haemostatic alterations that are not captured by standard tests. 6 ROTEM® or other point-of-care coagulation tests are increasingly used to manage postpartum haemorrhage, however its broader role in evaluating platelet function is unclear. Understanding the relationship between platelet count and function would allow further personalised management of postpartum haemorrhage and to assist in anaesthetic planning. Multiplate® is a rapid point-of-care test for platelet function and measures platelet aggregation in whole blood using impedance aggregometry. 7 Although widely used in cardiovascular and surgical settings, its application in obstetric populations, particularly in pre-eclampsia, remains limited. Multiplate® has three components: ASPItest® (arachidonic acid), ADPtest® (adenosine diphosphate) and TRAPtest® (thrombin activating peptide-6), with results available within six minutes. Platelet aggregation is recorded at approximately 0.5 second intervals: an increase in impedance by the attachment of platelets onto the Multiplate® sensors is transformed to aggregation units (AU) and plotted against time. Three different parameters are calculated: aggregation in aggregation units (AU), maximum velocity (maxV, maximum slope of the aggregation graph) in AU/min and AUC (area under the curve) in AU/min. The AUC is affected by the total height of the aggregation curve as well as the slope and can be used to express the overall platelet activity. Non-activated thromboelastometry (NATEM) refers to a test of ROTEM® in which whole blood clot formation can be evaluated. 8 It evaluates both intrinsic and extrinsic pathways and is more sensitive in detecting coagulopathies compared to ROTEM® FIBTEM/EXTEM/INTEM panels. 8, 9 This is because it evaluates the endogenous activation of haemostasis with a high sensitivity to detect any hyper- or hypocoagulation activity in the blood sample. 8 This prospective observational study aimed to describe the haemostatic profile and range of ROTEM® NATEM results and Multiplate® parameters in pregnant women with pre-eclampsia and to compare the results obtained to results from a comparator group without pre-eclampsia, to the known reference ranges.

This prospective single-centre observational study was undertaken at the Royal Brisbane and Women’s Hospital, approved by the hospital Human Research Ethics Committee (HREC/15/QRBW/97) and registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617001069347). This manuscript adheres to the Strengthening the Reporting of Observational Studies in Epidemiology Statement. We collected information and blood samples from two groups of pregnant women: The pre-eclampsia group included women at >30 weeks gestation with a confirmed diagnosis or suspected diagnosis of pre-eclampsia, admitted to the birth suite. An opt-out approach to consent was approved and used for this group. The comparator group included women at > 37 weeks gestation with uncomplicated pregnancies who had Caesarean delivery and provided written informed consent. Eligibility Women in the pre-eclampsia group were eligible if aged 18-45 years, greater than 30 weeks gestation with clinically diagnosed pre-eclampsia including those with HELLP syndrome (haemolysis, elevated liver enzymes, low platelets), with diagnosis made according to the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) 2014 recommendations. 10 These women could be at any stage of labour, presenting to the birth suite or for an elective Caesarean delivery. Women were eligible for the comparator group if they were aged 18-45 years, not in labour, booked for an elective Caesarean delivery at > 37 weeks gestation with an uncomplicated antenatal history, body mass index 18.5-30 kg.m -2, normotensive, not taking medications affecting coagulation and no known family or personal history of disorders affecting coagulation. They were excluded if they had gestational hypertension, gestational diabetes, gestational thrombocytopaenia, cholestasis of pregnancy, antepartum haemorrhage, pre-eclampsia and HELLP syndrome. 10 Sample collection In the pre-eclampsia group, full blood count, Multiplate, ROTEM ® NATEM sampling occurred upon insertion of an intravenous cannula or venepuncture for non-research related routine blood tests. Full blood count was performed for all patients as part of routine care. However, standard coagulation profile values (international normalised ratio, prothrombin time, activated partial thromboplastin time and fibrinogen) were only available if clinically indicated and performed as part of clinical care. Samples were taken from the comparator group prior to their elective Caesarean delivery. Tests performed included full blood count, Multiplate® and ROTEM® NATEM values. Standard coagulation profiles were not performed in this group. Samples were collected in 3.5 mL Vacutainer TM collection tubes (Becton-Dickinson, North Ryde, Australia) containing 3.2% sodium citrate for ROTEM®, ROTEM NATEM and standard coagulation testing; 3.0 mL Hirudin blood tubes (Roche Diagnostics GmbH, Mannheim, Germany) containing >15µg/mL hirudin for Multiplate® testing; 4.0 mL Vacutainer TM collection tubes (Becton-Dickinson, North Ryde, Australia) containing dipotassium ethylenediaminetetraacetic acid for full blood count testing. Analysis occurred within two hours of specimen collection. ROTEM ® and Multiplate® results were reviewed retrospectively and not used to alter clinical management. ROTEM ® Instruments and Testing All ROTEM® tests were performed by certified personnel on citrated whole blood using a ROTEM ® Delta analyser, as per the manufacturer’s instructions. 11 As a non-activated test, no activator or reagent was added for the ROTEM® NATEM analysis. The following ROTEM® NATEM parameters were tested: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), clot formation rate CFR), amplitudes at 5, 10, 15, 20, 25 and 30 minutes respectively (A5, A10, 15, A20, A25, A30), lysis index at 30 and 45 minutes (LI30, LI45), AUC, maximum lysis (ML); MAXV, area under the curve until 5, 10, 15, 20, 2, 30 minutes after clotting time (AR5, AR10, AR 15, AR20, AR25, AR30), maximum clot elasticity (MCE) and thrombin potential index (TPI). The TPI describes the patient’s overall coagulation status. Statistical Analysis At the time of study planning, there were no published data relating to these tests in pre-eclampsia. Results from 120 individuals is the recommended sample size for the purpose of establishing reference ranges. 12, 13 This was achieved during the opt-out recruitment period for the pre-eclampsia group. For the purposes of comparing values with manufacturer’s reference ranges, samples from 20 patients is considered sufficient for laboratory reporting purposes. 12 The sample of 119 in the group with pre-eclampsia was considered sufficient to describe the population and the comparator group target set at 20. Clinical characteristics were reported using descriptive statistics. Categorical data were examined using the Pearson chi-squared test or Fisher’s exact test when appropriate. Continuous data were examined using a Student t-test or Mann-Whitney U test for non-normal distribution. The percentage of participants outside of the manufacturer’s reference ranges and maximum and minimal values were also compared between the two groups. Correlations amongst coagulation factors in the standard coagulation profile (where available), ROTEM® NATEM and Multiplate® methods were examined using Pearson correlation coefficient and Spearman’s rank correlation coefficient in women in the pre-eclampsia group. P values less than 0.05 were considered significant. An exploratory analysis compared results from women in the pre-eclampsia group with platelet counts less than 100x10 9 /L and greater than or equal to 100x10 9 /L. Data analysis was performed using SPSS Statistics Software, Version 25 (IBM®, NY, USA).

After exclusions, 119 women were included in the pre-eclampsia group and 22 women in the comparator group (flowcharts shown in Supplementary Figures 1 and 2). Participant characteristics are shown in Table 1. In the pre-eclampsia group, 86 (72.3%) delivered via Caesarean and 33 (27.7%) had a vaginal birth. Sixty-nine (58.0%) women in the pre-eclampsia group had standard coagulation profiles performed. Ninety-three (78.2%) had pre-eclampsia with severe features, four (3.4%) had a platelet count less than 100x10 9 /L, 105 (88.2%) had a urinary protein-creatinine ratio >0.3 and 15 (12.6%) had HELLP syndrome. Table 2 shows the comparison between haemoglobin, platelet count, Multiplate® and ROTEM® values for both groups. In the pre-eclampsia group, the following values were significantly higher, suggesting hypercoagulability: amplitudes (a descriptor of clot firmness) at 5, 10, 15, 20 and 25 minutes (A5, A10, A15, A20, A25); AUC from the start of the derivative curve until MCF was reached; maxV and ROTEM® maximum clot elasticity (MCE). The spread of MCE at high amplitudes was significantly higher in the pre-eclampsia group. AR10, AR15, AR20, AR30 (AUC from clotting time to respective time points) and thrombodynamic potential index (TPI) values were also higher in the pre-eclampsia group. Multiplate® parameter values (ADP, ASPI and TRAP) were not significantly different to the control group (Table 2). Table 3 shows the percentage of participants in each group with values outside the manufacturer’s reference ranges. Table 4 shows the ranges of haemoglobin, platelet count, Multiplate® and ROTEM® values for both groups. For obstetric patients with pre-eclampsia and platelet counts of less than 100x10 9 /L versus 100x10 9 /L or more (Supplementary Tables 1 and 2), exploratory analyses were performed and p-values were not given as there were only 4 patients with platelets below 100x10 9 /L. There is some evidence that the clot formation time is greater, and the clot formation rate, amplitude (firmness) and AUC are lower in patients with platelets below 100x10 9 /L (Supplementary Table 1). Only weak correlations were seen between the standard coagulation parameters and the ROTEM® NATEM and Multiplate® methods in the pre-eclampsia group. There was moderate correlation between Multiplate® MPADP and MPASPI and platelet count and between ROTEM® CFT, Alpha angle, MCF, CFR, amplitudes, AUC and maxV with platelets and fibrinogen, as shown in Supplementary Table 3.

Main Findings and Interpretation Women in the pre-eclampsia group had significantly higher values for clot firmness (MCF), higher amplitudes (A5–A25), and elevated thrombodynamic indices (TPI, MCE), confirming the hypercoagulable state of pre-eclampsia. These ROTEM ® parameters reflect enhanced fibrin polymerisation and clot stability, which may paradoxically coexist with increased bleeding risk due to platelet exhaustion and endothelial dysfunction. 6 Both groups had hypercoagulable profiles compared to non-pregnant patients, consistent with the known hypercoagulable state of pregnancy, an adaptive mechanism to protect against postpartum bleeding. 5, 14-16 There was moderate correlation between Multiplate® MPADP and MPASPI and platelet counts and between ROTEM® CFT, Alpha angle, MCF, CFR, amplitudes, AUC and maxV with platelets and fibrinogen. Despite these observations, there was no difference between the two groups, in terms of the proportion of patients with values outside the recommended reference ranges for these tests. Our findings contribute to the current limited knowledge, concerning thrombocytopaenia and platelet function in pre-eclampsia. Our ROTEM ® and Multiplate ® findings underscore the complexity of haemostatic changes in pre-eclampsia. ROTEM ® appears more sensitive to global coagulation dynamics, including fibrinogen contribution and clot elasticity, while Multiplate ® may be limited in detecting subtle platelet dysfunction, especially in the context of endothelial injury. 17 Recent transcriptomic studies have revealed upregulation of platelet activation pathways (e.g., PI3K-Akt, Wnt) and increased expression of CD62P and CD42b in placental tissues of pre-eclampsia patients, supporting the hypothesis of localised platelet hyperactivation. Moreover, the presence of circulating platelet microthrombi and reduced phosphatidylserine exposure in pre-eclampsia suggests a shift toward procoagulant membrane dynamics. 17 Amplitudes at 5, 10, 15, 20 and 25 minutes (A5, A10, A15, A20, A25) were higher and demonstrated greater clot firmness in pre-eclamptic women. These amplitudes reflect the degree of clot firmness at those times, following clot initiation. Higher values of AUC from the start of the derivative curve until MCF were reached, maxV and ROTEM® MCE were also observed. Hypercoagulability in the pre-eclampsia group was further supported by higher AR10, AR15, AR20, AR30) and TPI values. However, Multiplate parameters were not significantly different to the comparator group. MCF is the maximum amplitude over time and represents overall clot firmness, reflecting contributions from fibrinogen and platelets. The higher amplitudes found in this population reflect baseline hypercoagulability in pre-eclampsia. MCE is a better representation of clot strength compared with MCF and these values were significantly higher in the pre-eclampsia group. Coagulation changes in pregnancy include reduced protein S activity, increased prothrombin activity, and increased levels of procoagulant factors, particularly fibrinogen, factors VII and VIII, and von Willebrand factor. 18 Several studies have used ROTEM ® to confirm the hypercoagulable state of pregnancy, revealing a shorter CT and greater clot firmness (MCF, A5, A10). 5, 19-22 This study demonstrated further hypercoagulability in women with pre-eclampsia despite their increased risk of developing postpartum haemorrhage. Interestingly, Multiplate ® parameters (ASPItest ®, ADPtest ®, TRAPtest ® ) did not differ significantly between groups, aligning with recent studies 5 that suggest platelet aggregation may not fully capture the functional impairment seen in pre-eclampsia. Emerging evidence points to altered platelet gene expression and activation markers (e.g., CD62P, CD42b) at the maternal–foetal interface, which may not be reflected in impedance aggregometry. 5 In current practice, the absolute platelet count is used to decide on the timing of delivery, the need for platelet transfusion and to apply relative contraindications to neuraxial anaesthesia. 23 The ability to quantify platelet function in pre-eclampsia, in addition to absolute platelet count, would allow a more personalised approach to postpartum haemorrhage management and choice of anaesthetic, particularly in patients where there are substantial benefits in avoiding a general anaesthetic. 24 In our cohort, there was some evidence that pre-eclamptic women with platelet counts of less than 100x10 9 /L had a longer clot formation time and greater clot formation rate, reduced amplitude (firmness) and lower AUC. With only four patients with platelet counts below 100x10 9 /L, our ability to draw conclusions is limited. Impaired platelet number and function may contribute to postpartum haemorrhage and venous thromboembolism, both of which require proactive perioperative strategies to mitigate risk and optimise maternal and neonatal outcomes. 25, 26 Women with pre-eclampsia may have an increased relative benefit of ROTEM-guided transfusion, which allows targeted product replacement with reduced overall transfusion volume. 27 Strengths and Limitations The size of our pre-eclampsia group is larger than previous reports of platelet function in this population. 5 The size of our comparator group, while appropriate for comparison of reference ranges, may be insufficient to reflect the population for other comparisons. Selection bias may have occurred, as samples in the pre-eclampsia group were obtained from women requiring intravenous cannulation or venepuncture, however this occurs in approximately 70% of labouring women at our institution. Standard coagulation tests were only obtained in the pre-eclampsia group and only performed if clinically indicated. The timing of blood sampling in the pre-eclampsia group was not standardised in relation to the onset of labour or proximity to delivery and it is unknown whether this influences coagulation. We have assumed that women in both groups did not have underlying bleeding disorders, however, undiagnosed bleeding disorders may be more common in women than previously recognised. 28 Our original intention was to use the ROTEM® Platelet Mapping test, which has not yet been made available for clinical use in Australia. Future studies should explore integrating viscoelastic testing with emerging biomarkers used to diagnose pre-eclampsia such as placental growth factor (PIGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) 29 ; and transcriptomic profiling to allow detailed risk stratification. 30 Our findings support the use of ROTEM ® as a point-of-care tool for assessing haemostatic risk in pre-eclampsia, particularly in guiding transfusion and haemorrhage management. The lack of significant differences in Multiplate® results suggests that platelet aggregation alone may not be a reliable marker of bleeding risk in this population, however further evaluations are required in larger populations of pre-eclamptic women with thrombocytopaenia.

We demonstrated a difference in coagulation parameters between women with pre-eclampsia and those with uncomplicated pregnancies. There was greater hypercoagulability in women with pre-eclampsia, but no difference in the distribution of values outside of the manufacturer’s reference ranges. Further research is required before point-of-care platelet function testing can be used to guide decision-making regarding postpartum haemorrhage management, anaesthesia technique and timing of delivery. Authors’ contributions: JL led the research team and was responsible for the concept, protocol design, data interpretation, writing and revision of the manuscript. KHW provided guidance on data interpretation and helped write and revise the manuscript. RMNK contributed to writing the initial manuscript and provided advice on data interpretation. EB performed the statistical analysis of data and assisted in manuscript revisions. AAZ assisted in protocol design and assisted in manuscript revisions. AK, LR and CM helped with patient recruitment, data collection and manuscript revisions. VAE helped conceive and design the study, oversaw the work, including the data interpretation; and helped write and amend the manuscript. All authors have reviewed the final version and agree to be responsible for all aspects of the work.

The following people made significant contributions to this study: Sue Williams, Sue Freney and the RBWH Blood Bank Team for the processing of blood samples, collating of results and project planning; the RBWH obstetric anaesthesia staff, anaesthetic technicians, obstetric staff, midwifery staff and research nurse team for blood sampling and patient recruitment. Dr Joanna Pan and Dr Louis Jenkins assisted with data collection. Declaration of interests : None declared.

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Bleeding disorders in adolescents with heavy menstrual bleeding: the Queensland Statewide Paediatric and Adolescent Gynaecology Service. J Pediatr Adolesc Gynecol . 2019; 32 : 122-7. 29. Ng KW, Chaturvedi N, Cote GL, Fisher SA, Mabbott S. Biomarkers and point of care screening approaches for the management of preeclampsia. Commun Med . 2024; 4 : 208. 30. Kontovazainitis C-G, Gialamprinou D, Theodoridis T, Mitsiakos G. Hemostasis in Pre-Eclamptic Women and Their Offspring: Current Knowledge and Hemostasis Assessment with Viscoelastic Tests. Diagn . 2024; 14 : 347. LEGEND OF TABLES Table 1: Comparison of participant characteristics in pregnant women with pre-eclampsia and uncomplicated pregnancies Table 2: Comparison of full blood count, Multiplate® and ROTEM® parameters in obstetric patients with pre-eclampsia and uncomplicated pregnancies. Table 3: Comparison of obstetric patients with pre-eclampsia and uncomplicated pregnancies with values outside the manufacturer’s reference ranges. Table 4: Minimum and maximum values for the coagulation factors in obstetric patients with pre-eclampsia and uncomplicated pregnancies. Table 1: Comparison of participant characteristics in pregnant women with pre-eclampsia and uncomplicated pregnancies | n = 119 | n = 22 | || | Age (years, mean (SD)) | 31.8 (6.5) | 32.6 (5.9) | 0.57 | | Nulliparous ( n (%)) | 73 (61.3) | 4 (18.2) | <0.001 | | Parity~ | 0 [0-1] | 1 [1-1] | 0.004 | | Gestation (weeks) | 36.6 [32.3-37.9] | 38.4 [38.1-39.3] | <0.001 | | BMI (kg.m -2 ) | 27.6 [22.9-32.8] | 27.8 [25.9-34.0] | 0.33 | | Mode of delivery Elective Caesarean Emergency Caesarean Vaginal Birth | 19 (16%) 67 (56%) 33 (28%) | 22 (100%) 0 (0%) 0 (0%) | SD: standard deviation; BMI: body mass index; IQR: interquartile range; ~ multiparous only. Table 2: Comparison of full blood count, Multiplate® and ROTEM® parameters in obstetric patients with pre-eclampsia and uncomplicated pregnancies. | n = 119 | n = 22 | || | mean (SD) | mean (SD) | || | Haemoglobin, g/L | 116 (18) | 116 (12) | 0.95 | | Platelets, x10 9 /L (median [IQR]) | 224 [172, 300] | 236 [197, 281] | 0.72 | | Multiplate ® | ||| | MPADP, U | 77 (27) | 77 (26) | 0.97 | | MPASPI, U | 95 (29) | 97 (27) | 0.83 | | MPTRAP, U | 107 (30) | 114 (30) | 0.29 | | ROTEM ® | ||| | CT, s | 460 [376, 496] | 437 [380, 522] | 0.70 | | CFT, s (median [IQR]) | 86 [72, 105] | 97 [79, 109] | 0.15 | | Alpha angle, o (median [IQR]) | 73 [69, 76] | 71 [67, 74] | 0.075 | | MCF, mm | 69 (5) | 66 (4) | 0.056 | | CFR (median [IQR]), o | 76 [73, 78] | 74 [71, 77] | 0.055 | | A5, mm | 49 (8) | 45 (7) | 0.035 | | A10, mm | 61 (6) | 57 (5) | 0.017 | | A15, mm ( n = 140) | 65 (6) | 62 (5) | 0.020 | | A20, mm ( n = 136) | 67 (5) | 64 (5) | 0.026 | | A25, mm ( n = 133) | 69 (5) | 65 (5) | 0.009 | | A30, mm (n = 131) | 69 (5) | 66 (5) | 0.023 | | LI30, % ( n = 131, median [IQR]) | 100 [100, 100] | 100 [100, 100] | 0.35 | | LI45, % ( n = 130, median [IQR]) | 99 [98, 100] | 99 [98, 100] | 0.26 | | AUC, mm 2 | 6877 (508) | 6642 (437) | 0.044 | | ML, % (median [IQR]) | 2 [1, 4] | 1 [0, 3] | 0.21 | | MAXV, mm/min | 16 (5) | 14 (4) | 0.044 | | MCFt, s | 1724 (311) | 1774 (316) | 0.49 | | CLR (n=55), o | 4 (2) | 3 (1) | 0.18 | | AR5, mm 2 | 298 (62) | 271 (55) | 0.064 | | AR10, mm 2 | 857 (130) | 795 (114) | 0.038 | | AR15, mm 2 | 1486 (193) | 1395 (164) | 0.038 | | AR20 ( n = 140), mm 2 | 2145 (241) | 2015 (201) | 0.019 | | AR25 ( n = 136), mm 2 | 2824 (304) | 2638 (246) | 0.009 | | AR30 ( n = 133), mm 2 | 3525 (328) | 3286 (319) | 0.003 | | ROTEM MCE ( n = 130) | 230 (49) | 201 (40) | 0.018 | | TPI (n = 130, median [IQR]) | 76 [57, 110] | 60 [44, 83] | 0.029 | | MAXVt (median [IQR]), s | 522 [445, 571] | 500 [432, 593] | 0.74 | SD: standard deviation; IQR: interquartile range; U: units; mm: millimetres; s: seconds; 0 : degrees; %: percentage; MPADP: Multiplate® adenosine diphosphate; MPASPI: Multiplate® arachidonic acid; MPTRAP: Multiplate® thrombin activating peptide-6; CT: clotting time; CFT: clot formation time; MCF: maximum clot firmness; CFR: clot formation rate; A5, A10, 15, A20, A25, A30: amplitude at 5, 10, 15, 20, 25 and 30 minutes respectively; LI30, LI45: lysis index at 30 and 45 minutes; AUC: area under the curve; ML: maximum lysis; MAXV: maximum velocity; AR5, AR10, AR 15, AR20, AR25, AR30: area under the curve until 5, 10, 15, 20, 2, 30 minutes after CT; MCE: maximum clot elasticity; TPI: thrombin potential index. Table 3: Comparison of obstetric patients with pre-eclampsia and uncomplicated pregnancies with values outside the manufacturer’s reference ranges. | N = 141 | n = 119 | n = 22 | ||| | N (%) | n (%) | n (%) | ||| | Haemoglobin, g/L | low | 47 (33.3 %) | 41 (34.5 %) | 6 (27.3 %) | 0.51 | | normal | 94 (66.7 %) | 78 (65.5 %) | 16 (72.7 %) | || | high | 0 (0.0 %) | 0 (0.0 %) | 0 (0.0 %) | || | Platelets, x10 9 /L | low | 15 (10.6 %) | 12 (10.1 %) | 3 (13.6 %) | 0.68 | | normal | 120 (85.1 %) | 101 (84.9 %) | 19 (86.4 %) | || | high | 6 (4.3 %) | 6 (5.0 %) | 0 (0.0 %) | || | Multiplate ® | ||||| | MPADP, U | low | 38 (27.0%) | 33 (27.7%) | 5 (22.7%) | 0.83 | | normal | 88 (62.4%) | 73 (61.3%) | 15 (68.2%) | || | high | 15 (10.6%) | 13 (10.9%) | 2 (9.1%) | || | MPASPI, U | low | 28 (19.9%) | 24 (20.2 %) | 4 (18.2%) | 0.96 | | normal | 73 (51.8%) | 61 (51.3%) | 12 (54.5%) | || | high | 40 (28.4%) | 34 (28.6%) | 6 (27.3%) | || | MPTRAP, U | low | 29 (20.6%) | 26 (21.8%) | 3 (13.6%) | 0.33 | | normal | 72 (51.1%) | 62 (52.1%) | 10 (45.5%) | || | high | 40 (28.4%) | 31 (26.1%) | 9 (26.1%) | || | ROTEM ® | ||||| | CT, s | low | 6 (4.3%) | 5 (4.2%) | 1 (4.5%) | 1.00 | | normal | 135 (95.7%) | 114 (95.8%) | 21 (95.5%) | || | high | 0 (0.0 %) | 0 (0.0 %) | 0 (0.0 %) | || | CFT, s | low | 133 (94.3%) | 113 (95.0%) | 20 (90.9%) | 0.61 | | normal | 8 (5.7%) | 6 (5.0%) | 2 (9.1%) | || | high | 0 (0.0 %) | 0 (0.0 %) | 0 (0.0 %) | || | Alpha angle, o | low | 0 (0.0 %) | 0 (0.0 %) | 0 (0.0 %) | 0.33 | | normal | 45 (31.9%) | 36 (30.3%) | 9 (40.9%) | || | high | 96 (68.1%) | 83 (69.7%) | 13 (59.1%) | || | A20, mm ( n = 136) | low | 0 (0.0 %) | 0 (0.0 %) | 0 (0.0 %) | 0.27 | | normal | 16 (11.8%) | 12 (10.4%) | 4 (19.0 %) | || | high | 120 (88.2%) | 103 (89.6%) | 17 (81.0%) | || | MCF, mm | low | 0 (0.0 %) | 0 (0.0 %) | 0 (0.0 %) | 0.31 | | normal | 33 (23.4%) | 26 (21.8%) | 7 (31.8%) | || | high | 108 (76.6%) | 93 (78.2%) | 15 (68.2%) | U: units; mm: millimetres; s: seconds; 0 : degrees; %: percentage; MPADP: Multiplate® adenosine diphosphate; MPASPI: Multiplate® arachidonic acid; MPTRAP: Multiplate® thrombin activating peptide-6; CT: clotting time; CFT: clot formation time; MCF: maximum clot firmness; A20: amplitude at 20 minutes. Table 4: Minimum and maximum values for the coagulation factors in obstetric patients with pre-eclampsia and uncomplicated pregnancies. | n = 119 | n = 22 | | | min, max | min, max | | | Haemoglobin, g/L | 63,157 | 94,134 | | Platelet count, x10 9 /L | 59,588 | 122,375 | | Multiplate® | || | MPADP, U | 21,145 | 23,128 | | MPASPI, U | 23,163 | 37,138 | | MPTRAP, U | 36,177 | 40,162 | | ROTEM® | || | CT, s | 186,705 | 281,666 | | CFT, s | 48,275 | 61,184 | | Alpha angle, o | 53,81 | 57,78 | | A20, mm | 49,77 | 55,72 | | MCF, mm | 50,78 | 58,73 | | CFR, o | 58,82 | 62,80 | | A5, mm | 23,64 | 33,55 | | A10, mm | 42,72 | 47,66 | | A15, mm | 47,76 | 52,70 | | A25, mm | 50,78 | 57,73 | | A30, mm | 50,78 | 58,73 | | LI30, % | 98,100 | 100,100 | | LI45, % | 90,100 | 97,100 | | AUC, mm 2 | 5201,7885 | 5805,7273 | | ML, % | 0,14 | 0,5 | | MAXV, mm/min | 6,29 | 8,22 | | MCFt, s | 754,2588 | 1074,2361 | | CLR, o | 2,9 | 2,5 | | AR5, mm 2 | 105,441 | 164,357 | | AR10, mm 2 | 511,1133 | 596,957 | | AR15, mm 2 | 954,1876 | 1095,1633 | | AR20, mm 2 | 1482,2638 | 1636,2339 | | AR25, mm 2 | 1785,3413 | 2199,3061 | | AR30, mm 2 | 2481,4195 | 2676,3789 | | ROTEM® MCE | 100,365 | 137,267 | | TPI | 18,224 | 26,104 | | MAXVt, s | 229,1032 | 311,772 | U: units; mm: millimetres; s: seconds; 0 : degrees; %: percentage; MPADP: Multiplate® adenosine diphosphate; MPASPI: Multiplate® arachidonic acid; MPTRAP: Multiplate® thrombin activating peptide-6; CT: clotting time; CFT: clot formation time; MCF: maximum clot firmness; CFR: clot formation rate; A5, A10, 15, A20, A25, A30: amplitude at 5, 10, 15, 20, 25 and 30 minutes respectively; LI30, LI45: lysis index at 30 and 45 minutes; AUC: area under the curve; ML: maximum lysis; MAXV: maximum velocity; AR5, AR10, AR 15, AR20, AR25, AR30: area under the curve until 5, 10, 15, 20, 2, 30 minutes after CT; MCE: maximum clot elasticity; TPI: thrombin potential index. Supplementary Material Supplementary Figure 1: Recruitment flowchart detailing participant exclusions in the pre-eclampsia group Supplementary Figure 2: Recruitment flowchart detailing participant exclusions in the comparator group Supplementary Table 1: Comparison of haemoglobin and coagulation factors in obstetric patients with pre-eclampsia and platelet counts less than 100x10 9 /L and 100x10 9 /L or more. Supplementary Table 2: Comparison of haemoglobin and coagulation factor values within and outside the manufacturer’s reference ranges in obstetric patients with pre-eclampsia and platelet counts less than 100x10 9 /L and 100x10 9 /L or more. Supplementary Table 3: Correlation between coagulation factors in obstetric patients with pre-eclampsia. Supplementary Material Supplementary Figure 1: Recruitment flowchart detailing participant exclusions in the pre-eclampsia group a Pre-eclampsia and gestational hypertension as described in the SOMANZ Guidelines. Sourced from The SOMANZ Guidelines for the Management of Hypertensive Disorders of Pregnancy. https://www.somanz.org/content/uploads/2020/07/HTguidelineupdatedJune2015.pdf Accessed October 1, 2017. b Gestational diabetes mellitus as described in the guidelines from the Queensland Clinical Guidelines. Sourced from The Maternity and Neonatal Clinical Guidelines: Gestational diabetes mellitus, published by Queensland Health, Australia. 2015. URL://htpps://www.health.qld.gov.au/__data/assets/pdf_file/0023/140099/g-gdm.pdf Accessed October 1, 2017. Supplementary Figure 2: Recruitment flowchart detailing participant exclusions in the comparator group a Pre-eclampsia and gestational hypertension as described in the SOMANZ Guidelines. Sourced from The SOMANZ Guidelines for the Management of Hypertensive Disorders of Pregnancy. https://www.somanz.org/content/uploads/2020/07/HTguidelineupdatedJune2015.pdf Accessed October 1, 2017. b Gestational diabetes mellitus as described in the guidelines from the Queensland Clinical Guidelines. Sourced from The Maternity and Neonatal Clinical Guidelines: Gestational diabetes mellitus, published by Queensland Health, Australia. 2015. URL://htpps://www.health.qld.gov.au/__data/assets/pdf_file/0023/140099/g-gdm.pdf Accessed October 1, 2017. Supplementary Table 1: Comparison of haemoglobin and coagulation factors in obstetric patients with pre-eclampsia and platelet counts less than 100x10 9 /L and greater than or equal to 100x10 9 /L. | n = 115 | N = 4 | | | mean (SD) | mean (SD) | | | Standard coagulation profile | || | Haemoglobin, g/L | 116 (17) | 116 (29) | | INR ( n = 69, median (IQR)) | 0.90 [0.90, 1.00] | 1 [1, 1] | | PT, s ( n = 69, median (IQR)) | 10 [10, 11] | 11 [9, 14] | | APTT, s ( n = 69, median (IQR)) | 26 [24, 28] | 26 [24, 35] | | Multiplate® | || | MPADP, U | 75 [54, 94] | 54 [28, 89] | | MPASPI, U | 96 (28) | 82 (47) | | MPTRAP, U | 107 (29) | 89 (50) | | ROTEM® | || | CT, s | 460 [391, 496] | 457 [362, 646] | | CFT, s (median (IQR)) | 86 [72, 104] | 170 [104, 253] | | alpha angle, o (median (IQR)) | 73 [70, 76] | 59 [54 69] | | MCF, mm | 69 (5) | 60 (8) | | CFR (median (IQR)), o | 76 [73, 78] | 64 [59, 72] | | A5, mm | 50 (7) | 32 (9) | | A10, mm | 61 (6) | 49 (7) | | A15, mm | 65 (5) | 56 (8) | | A20, mm ( n = 115) | 67 (5) | 58 (8) | | A25, mm ( n = 112) | 69 (5) | 62 (8) | | A30, mm ( n = 113) | 69 (5) | 62 (8) | | LI30, % ( n = 112, median (IQR)) | 100 [100, 100] | 100 [100, 100] | | LI45, % ( n = 111, median (IQR)) | 99 [98, 100] | 99 [n/a] | | AUC, mm 2 | 6908 (472) | 6009 (802) | | ML, % (median (IQR)) | 2 [1, 4] | 1 [0, 3] | | MAXV, mm/min | 17 (4) | 9 (4) | | MCFt, s | 1723 (312) | 1743 (306) | | CLR ( n = 49), o | 4 (2) | 6 (2) | | AR5, mm 2 | 302 (58) | 184 (74) | | AR10, mm 2 | 866 (122) | 603 (132) | | AR15, mm 2 | 1499 (181) | 1130 (176) | | AR20 ( n = 118), mm 2 | 2161 (226) | 1700 (231) | | AR25 ( n = 115), mm 2 | 2845 (280) | 2228 (378) | | AR30 ( n = 113), mm 2 | 3550 [3360, 3780] | 3126 [n/a] | | ROTEM_MCE ( n = 111) | 229 [178, 262] | 173 [144, 202] | | TPI ( n = 111, median (IQR)) | 78 [58, 111] | 25 [n/a] | | MAXVt (median (IQR)), s | 522 [442, 571] | 535 [451, 925] | SD: standard deviation; IQR: interquartile range; U: units; mm: millimetres; s: seconds; 0 : degrees; %: percentage; INR: international normalised ratio; PT: prothrombin time; APTT: activated partial thromboplastin time; MPADP: Multiplate® adenosine diphosphate; MPASPI: Multiplate® arachidonic acid; MPTRAP: Multiplate® thrombin activating peptide-6; CT: clotting time; CFT: clot formation time; MCF: maximum clot firmness; CFR: clot formation rate; A5, A10, 15, A20, A25, A30: amplitude at 5, 10, 15, 20, 25 and 30 minutes respectively; LI30, LI45: lysis index at 30 and 45 minutes; AUC: area under the curve; ML: maximum lysis; MAXV: maximum velocity; AR5, AR10, AR 15, AR20, AR25, AR30: area under the curve until 5, 10, 15, 20, 2, 30 minutes after CT; MCE: maximum clot elasticity; TPI: thrombin potential index; n/a: not applicable. Supplementary Table 2: Comparison of haemoglobin and coagulation factor values within and outside the manufacturer’s reference ranges in obstetric patients with pre-eclampsia and platelet counts less than 100x10 9 /L and 100x10 9 /L or more. | n = 115 | n = 4 | || | n (%) | n (%) | || | Haemoglobin, g/L | low | 39 (33.9%) | 2 (50.0%) | | normal | 76 (66.1%) | 2 (50.1%) | | | high | 0 (0.0 %) | 0 (0.0 %) | | | INR ( n = 69) | low | 2 (3.1%) | 1 (25.0%) | | normal | 61 (93.8%) | 2 (50.0%) | | | high | 2 (3.1%) | 1 (25.0%) | | | PT, s ( n = 69) | low | 0 (0.0 %) | 0 (0.0 %) | | normal | 63 (96.9%) | 3 (75.0%) | | | high | 2 (3.1%) | 1 (25.0%) | | | APTT, s ( n = 69) | low | 16 (24.6%) | 0 (0.0 %) | | normal | 45 (69.2%) | 4 (100.0%) | | | high | 4 (6.2%) | 0 (0.0 %) | | | Multiplate ® | ||| | MPADP, U | low | 31 (27.0%) | 2 (50.0%) | | normal | 71 (61.7%) | 2 (50.0%) | | | high | 13 (11.3%) | 0 (0.0 %) | | | MPASPI, U | low | 22 (19.1%) | 2 (50.0%) | | normal | 60 (52.2%) | 1 (25.0%) | | | high | 33 (28.7%) | 1 (25.0%) | | | MPTRAP, U | low | 24 (20.9%) | 2 (50.0%) | | normal | 61 (53.0%) | 1 (25.0%) | | | high | 30 (26.1%) | 1 (25.0%) | | | ROTEM ® | ||| | CT, s | low | 5 (4.3%) | 0 (0.0 %) | | normal | 110 (95.7%) | 4 (100.0%) | | | high | 0 (0.0 %) | 0 (0.0 %) | | | CFT, s | low | 112 (97.4%) | 1 (25.0%) | | normal | 3 (2.6%) | 3 (75.0%) | | | high | 0 (0.0 %) | 0 (0.0 %) | | | Alpha angle, o | low | 0 (0.0 %) | 0 (0.0 %) | | normal | 33 (28.7%) | 3 (75.0%) | | | high | 82 (71.3%) | 1 (25.0%) | | | A20, mm ( n = 115) | low | 0 (0.0 %) | 0 (0.0 %) | | normal | 10 (9.0%) | 2 (50.0%) | | | high | 101 (91.0%) | 2 (50.0%) | | | MCF, mm | low | 0 (0.0 %) | 0 (0.0 %) | | normal | 23 (20.0%) | 3 (75.0%) | | | high | 92 (80.0%) | 1 (25.0%) | U: units; mm: millimetres; s: seconds; 0 : degrees; %: percentage; INR: international normalised ratio; PT: prothrombin time; APTT: activated partial thromboplastin time; MPADP: Multiplate® adenosine diphosphate; MPASPI: Multiplate® arachidonic acid; MPTRAP: Multiplate® thrombin activating peptide-6; CT: clotting time; CFT: clot formation time; MCF: maximum clot firmness; CFR: clot formation rate; A20: amplitude at 20 minutes. Supplementary Table 3: Correlation between coagulation factors in obstetric patients with pre-eclampsia. | n | Spearman’s rho | P -value | n | Pearson’s Correlation | P -value | | | Fibrinogen | 69 | 0.449 | <0.001 | ||| | INR | 69 | 0.161 | 0.187 | 69 | 0.240 | 0.047 | | PT, s | 69 | 0.191 | 0.116 | 69 | 0.372 | 0.002 | | APTT, s | 69 | 0.085 | 0.489 | 69 | 0.241 | 0.046 | | Multiplate ® | |||||| | MPADP, U | 119 | 0.426 | <0.001 | 69 | 0.070 | 0.567 | | MPASPI, U | 119 | 0.507 | <0.001 | 69 | 0.218 | 0.073 | | MPTRAP, U | 119 | 0.391 | <0.001 | 69 | 0.071 | 0.563 | | ROTEM ® | |||||| | CT, s | 119 | -0.170 | 0.065 | 69 | -0.091 | 0.459 | | CFT, s | 119 | -0.441 | <0.001 | 69 | -0.427 | <0.001 | | Alpha angle, o | 119 | 0.473 | <0.001 | 69 | 0.477 | <0.001 | | MCF, mm | 119 | 0.483 | <0.001 | 69 | 0.500 | <0.001 | | CFR | 119 | 0.493 | <0.001 | 69 | 0.463 | <0.001 | | A5, mm | 119 | 0.534 | <0.001 | 69 | 0.586 | <0.001 | | A10, mm | 119 | 0.514 | <0.001 | 69 | 0.588 | <0.001 | | A15, mm | 118 | 0.482 | <0.001 | 68 | 0.583 | <0.001 | | A20, mm | 115 | 0.495 | <0.001 | 67 | 0.569 | <0.001 | | A25, mm | 113 | 0.464 | <0.001 | 65 | 0.543 | <0.001 | | A30, mm | 112 | 0.481 | <0.001 | 65 | 0.508 | <0.001 | | LI30, % | 112 | -0.022 | 0.820 | 65 | -0.188 | 0.135 | | LI45, % | 111 | -0.045 | 0.643 | 64 | -0.291 | 0.019 | | AUC, mm 2 | 119 | 0.483 | <0.001 | 69 | 0.522 | <0.001 | | ML, % | 119 | 0.161 | 0.080 | 69 | 0.317 | 0.008 | | MAXV, mm/min | 119 | 0.489 | <0.001 | 69 | 0.468 | <0.001 | U: units; mm: millimetres; s: seconds; 0 : degrees; %: percentage; INR: international normalised ratio; PT: prothrombin time; APTT: activated partial thromboplastin time; MPADP: Multiplate® adenosine diphosphate; MPASPI: Multiplate® arachidonic acid; MPTRAP: Multiplate® thrombin activating peptide-6; CT: clotting time; CFT: clot formation time; MCF: maximum clot firmness; CFR: clot formation rate; A5, A10, 15, A20, A25, A30: amplitude at 5, 10, 15, 20, 25 and 30 minutes respectively; LI30, LI45: lysis index at 30 and 45 minutes; AUC: area under the curve; ML: maximum lysis; MAXV: maximum velocity. 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Authors Metrics & Citations Metrics Article Usage 188views 111downloads Citations Download citation Julie Lee, Kerstin H. Wyssusek, Rebecca Kimble, et al. Rotational thromboelastometry (ROTEM®) and platelet function as measured by Multiplate® in pre-eclamptic women: A prospective observational study.. Authorea. 25 November 2025. DOI: https://doi.org/10.22541/au.176409211.12273292/v1 DOI: https://doi.org/10.22541/au.176409211.12273292/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.