Risk stratification for pregnancy-associated venous thromboembolism: Potential role for global coagulation assays

Abstract

Risk assessment for venous thromboembolism in pregnancy and the puerperium is currently limited to stratifying clinical surrogate risk factors without high-quality evidence. While the absolute risk of pregnancy-associated venous thromboembolism is low for the vast majority of women, associated morbidity and mortality remains significant. As guidelines for thromboprophylaxis vary widely, some women may be under- or over-anticoagulated, contributing to poor outcomes. New global coagulation assays provide a holistic view of coagulation and may have the potential to detect hypercoagulability in pregnancy, unlike clinically available coagulation assays. However, there are major technical challenges to overcome before global coagulation assays can be realistically proposed as an adjunct to risk assessment for pregnancy-associated venous thromboembolism. This review summarises the literature and controversies in the prediction and prevention of pregnancy-associated venous thromboembolism and outlines the new tools in haematology that may assist in our future understanding of hypercoagulability in pregnancy.

Keywords

Pregnancy risk factors venous thromboembolism thromboprophylaxis coagulation assays

Introduction

Venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality. In Australia between 2008 and 2017, VTE accounted for 20.5% of all direct maternal deaths.¹ One of the key strategies in managing VTE risk in pregnant women is the use of low molecular weight heparin (LMWH), with a recommendation for up to 85% of women to receive postpartum prophylaxis after Caesarean section in some clinical guidelines.² This is despite a Cochrane review concluding there is insufficient data from randomised controlled trials to guide its use in this population.³ Its liberal use under certain guidelines has generated some controversy, given the relative low risk of VTE (2870 per 100,000 person-years in 12 postpartum weeks)⁴ and the real, albeit small, bleeding risk associated with the use of LMWH (estimated to be 0.0–0.3%).⁵ Hence, there remains a need to further refine our risk assessment strategies to balance the numbers needed to treat and to harm in this setting.⁴ While progress in risk prediction using clinical surrogate measures has been made, there remains significant variation in prophylactic management guidelines globally.^2,6,7 Importantly, a lack of reliable laboratory assays to refine our risk assessment models has limited our ability to balance bleeding and thrombotic risk.

Although it has been well established that pregnancy generates a physiologically hypercoagulable state, current routine coagulation tests (activated prothrombin time (APTT) and prothrombin time (PT)), which only measure time to start of clot formation, are limited in their ability to detect hypercoagulable changes and cannot accurately assess VTE risk. Global coagulation assays (GCAs) such as thromboelastography, thrombin and fibrin generation, on the other hand, measure the characteristics of total clot formation as well as end-products of the coagulation cascade, and may be more representative of the coagulation process.⁸ Changes in the elastic properties of whole blood during clot formation, propagation and dissolution can be measured with thromboelastography (TEG) and rotational thromboelastometry (ROTEM). Thrombin is a key protein in the coagulation process, previously shown to predict non-pregnant women at increased risk of VTE recurrence⁹ and thrombin generation can be measured using the calibrated automated thrombogram (CAT). Fibrinolysis is less well studied but previous small studies have observed that hypercoagulable women have impaired fibrinolysis¹⁰ as measured using the overall haemostatic potential assay (OHP). By providing a more comprehensive assessment of the haemostatic profile, GCAs may have the potential to adjunctively assess VTE risk and therefore guide individualised thromboprophylaxis.¹¹

This review briefly reviews current risk stratification strategies in pregnancy and the potential role for global coagulation assays as adjunct tools for VTE risk stratification.

Literature search strategy

A medical literature search was conducted in MEDLINE (Ovid) for studies evaluating the use of GCAs in pregnancy and the puerperium published in English between 1997 and 2019. Search terms included ‘pregnancy,’ ‘postpartum,’ ‘thromboelastography,’ ‘rotational thromboelastometry,’ ‘calibrated automated thrombogram,’ ‘thrombin generation assay’ and ‘overall haemostatic potential.’ Relevant supporting references cited within the results obtained were included.

Physiological changes to coagulation in pregnancy and the puerperium

Physiological changes during pregnancy and postpartum are well described and significantly impact the coagulation system. All three arms of Virchow’s triad are implicated in the tendency to clot during this time: hypercoagulability, endothelial damage and stasis. Procoagulant activity increases during pregnancy, notably through the elevation of factors VII, VIII, X, fibrinogen and von Willebrand factor.^12,13 In addition, physiological anticoagulants such as protein S decrease during pregnancy and a resistance to activated protein C is acquired.^12,13 Fibrinolysis becomes increasingly impaired throughout gestation but returns to normal shortly after delivery.¹⁴ Endothelial damage occurs intrapartum, in particular to the uterine and pelvic blood vessels.¹⁵ Venous stasis occurs in pregnancy due to a combination of decreased mobility and reduced venous return from the lower limbs due to the mechanical obstruction of the inferior vena cava and pelvic veins by the gravid uterus.^3,15 These coagulation changes in combination contribute to a prothrombotic state during pregnancy, which is thought to be highest postpartum and resolves approximately 4–6 weeks after delivery.^16,17

Current VTE risk stratification and prevention in pregnancy

While VTE in pregnancy is relatively rare, it remains an important cause of maternal morbidity and mortality and a major clinical focus during the peripartum period. The absolute risk of VTE is estimated around 1–2 in 1000 pregnancies,^18–20 manifesting as deep vein thrombosis in 80% of cases.²⁰ There is a 4- to 5-fold increased thrombotic risk during pregnancy^18,21 and this risk increases up to 22-fold in the puerperium.²² There are a number of clinical risk factors, however, which further increase this physiological risk.

The strongest additional risk factors include a history of thrombosis (odds ratio (OR) 24.8, 95% confidence interval (CI) 17.1–36.0) and antiphospholipid syndrome (OR 15.8, 95% CI 10.9–22.8).¹⁹ Heritable thrombophilias may also increase VTE risk; however, the magnitude of risk varies by the type of defect present. Obesity and maternal age are also significant contributors to pregnancy-associated VTE risk. Observational studies have estimated the odds ratio for antenatal and postpartum thromboembolism in obese pregnant women to be 3.6–4.4 (95% CI 2.9–4.6 and 3.4–5.7 respectively),^19,23 which is particularly relevant given its increasing prevalence, with up to 20% of Australian women obese (body mass index (BMI) ≥30 kg/m²) at their first antenatal visit.²⁴ Given VTE is also associated with significant morbidities including post-thrombotic syndrome and venous insufficiency,²⁵ one of our key clinical challenges remains to prevent VTE during pregnancy.

Current methods of estimating risk of VTE in women before, during and after pregnancy are based on clinical risk factor stratification guidelines derived from case-control studies. The recently published 2018 guidelines from the American Society of Haematology provide some thorough recommendations about thromboprophylaxis in pregnant women with hereditary thrombophilia.²⁶ However, there remains no consensus in the guidelines and Table 1 provides clinical vignettes highlighting the differences in current major guidelines. These discrepancies were further demonstrated in a cross-sectional study reviewing 293 women undergoing Caesarean delivery in a UK tertiary hospital² where the proportion of women recommended for anticoagulation significantly varied based on different guidelines with 85%, 34% and 1% of women recommended for LMWH prophylaxis under Royal College of Obstetricians & Gynaecologists guidelines,⁷ 2012 American College of Chest Physicians guidelines^27,28 and the 2011 American Congress of Obstetricians and Gynaecologists guidelines respectively.²⁹ The heterogeneity in VTE guidelines is further highlighted by the National Health and Medical Research Council guidelines for prevention of VTE in Australian hospitals, which do not provide definitive guidance on maternal thromboprophylaxis and suggest the use of clinical judgement.³⁰

Table 1.

Example clinical vignettes highlighting subtle differences in recommendations for low molecular weight heparin in major venous thromboembolism prevention guidelines.

Example cases	RCOG⁷	ANZJOG⁶	ACCP^27,28	ACOG²⁹	ASH²⁶
30-year-old G1P1 with BMI 32 following uncomplicated elective LUSCS; no other risk factors	Postpartum prophylactic LMWH for ≥10 days	Postpartum prophylactic LMWH for ≥5 days	Postpartum prophylactic LMWH, duration not specified	No postpartum prophylactic LMWH	No guidance provided
37-year-old G4P4 with BMI 34 following uncomplicated vaginal delivery, no other risk factors	Consider antenatal prophylactic LMWH from 28 weeks’ gestation; postpartum prophylactic LMWH for ≥10 days	No postpartum prophylactic LMWH	No guidance provided	No guidance provided	No guidance provided
25-year-old G1P1 with previous post-operative (provoked) VTE, no known thrombophilia or additional risk factors	Consider antenatal prophylactic LMWH; postpartum prophylactic LMWH for ≥6 weeks	No antenatal prophylactic LMWH; postpartum prophylactic LMWH for ≥6 weeks	No antenatal prophylactic LMWH; postpartum prophylactic LMWH for ≥6 weeks	No antenatal or postpartum prophylactic LMWH	No antenatal prophylactic LMWH; postpartum anticoagulant prophylaxis, duration not specified
22-year-old G1P1 with homozygosity for factor V Leiden, no family history or other risk factors	Consider antenatal LMWH and refer to specialist; postpartum prophylactic LMWH for ≥6 weeks	No antenatal prophylactic LMWH; postpartum prophylactic LMWH for ≥6 weeks	No antenatal prophylactic LMWH; postpartum prophylactic or intermediate-dose LMWH	Antenatal prophylactic LMWH or UFH; postpartum anticoagulation, duration not specified	Antenatal antithrombotic prophylaxis suggested; postpartum prophylaxis suggested, duration not specified

ANZJOG: Australian and New Zealand Journal of Obstetrics and Gynaecology; ACCP: American College of Chest Physicians; ACOG: American College of Obstetricians and Gynaecologists; ASH: American Society of Haematology; BMI: body mass index; LUSCS: lower uterine segment Caesarean section; LMWH: low molecular weight heparin; RCOG: Royal College of Obstetricians and Gynaecologists; UFH: unfractionated heparin; VTE: venous thromboembolism.

Furthermore, a Cochrane review has suggested there remains a lack of high-quality evidence used to guide practice, leading women to be overtreated under some guidelines and undertreated with others.³ The review called for large-scale randomised controlled trials to evaluate postpartum LMWH prophylaxis, particularly where the overall effect of LMWH is unclear in women with common risk factors such as increased parity, age and BMI.^2,4 These discrepancies amongst the VTE guidelines highlight the need for further risk tools to refine our risk stratification strategies. Some studies have developed risk score and prediction models using consensus opinions or absolute risks determined from large population studies.^31,32 Additional risk tools could be better laboratory coagulation parameters which have been shown in some other conditions to predict higher risk populations. Hence, we explore these assays in greater detail in this review.

Traditional coagulation assays and their limitations in VTE risk assessment

Traditional coagulation assays such as APTT and PT were initially developed to monitor anticoagulant therapy rather than bleeding or clotting risks. These tests measure the time to the start of blood clot formation and do not reflect the complexity of dynamic in vivo haemostasis. APTT and PT are generally unchanged during pregnancy, hence they fail to reflect known hypercoagulability in pregnancy.^33,34

The utility of other biomarkers of coagulation activation such as D-dimer have been investigated in pregnancy, with limited success. D-dimer, a fibrin degradation product used to rule out VTE in the non-pregnant population, is increased in pregnancy with longitudinal studies revealing that 98–100% of women have levels above the non-pregnant reference range at 34–36 weeks’ gestation.^35,36 While D-dimer may have a role in guiding investigation of pregnant women in whom acute pulmonary embolism is suspected, as per the pregnancy-adapted YEARS algorithm,³⁷ it does not offer value in general VTE risk assessment in pregnancy.³⁸

Principles of global coagulation assays, current knowledge and potential role in obstetrics

The GCAs refer to a new generation of haematological assays that include viscoelastic testing with TEG and ROTEM, thrombin generation assay measured with CAT and fibrin generation assay using the OHP assay. GCAs provide a more holistic overview of coagulation including clot initiation, propagation, total clot formation and fibrinolysis compared to traditional coagulation assays. This section will discuss the different types of global coagulation assays, the current research applications in other fields and their potential role in the field of obstetrics.

Viscoelastic testing – thromboelastography and rotational thromboelastometry

TEG analyses the viscoelastic properties of whole blood during clot formation, propagation and dissolution.³⁹ Two common commercially available viscoelastic testing devices are TEG^® (Haemonetics, USA) and ROTEM^® (Haemoview Diagnostics, Australia). The principles of both devices are relatively similar and assess blood clot formation by measuring changes in torsion around a pin and cup as a clot is formed and subsequently lysed (Figure 1). Assay parameters provide information on the time to clot onset (R-time), time to achieve a certain clot strength (K-time), rate of clot formation (alpha-angle), maximum clot strength (maximum amplitude) and a measure of fibrinolysis (lysis 30). Specific activators allow evaluation of the extrinsic and intrinsic coagulation systems (e.g. EXTEM and INTEM for ROTEM respectively), as well as the contribution of fibrinogen to coagulation (FIBTEM).

Figure 1.

(a) Principles of thromboelastography and (b) thromboelastometry. Reproduced with permission from Lim et al.⁸

The main clinical utility of TEG currently is to guide transfusion support in trauma, cardiac surgery and massive transfusion situations, including obstetric haemorrhage.³⁹ Several studies including meta-analysis have shown that viscoelastic tests have led to reduction in transfusion of blood components, particularly with fresh frozen plasma and platelets with possible reduction in red blood cell products as well.^40–42 Some studies have demonstrated that TEG-guided approach improves key patient outcomes including length of stay, bleeding rate and mortality.⁴²

However, the clinical utility of viscoelastic testing in the field of thrombosis remains under investigation. A prospective observational study demonstrated that patients with ischaemic strokes with higher maximum amplitude suffered from more severe strokes and poorer functional outcome (OR 1.92, p = 0.022).⁴³ Similarly, in a study of 313 non-cardiac non-obstetric major surgeries, pre-operative ROTEM assays detected hypercoagulability in the ten cases where a postoperative thromboembolic event occurred.⁴⁴ In addition, we have previously published that TEG is sensitive enough to detect hypercoagulability in some subsets of patients including in older healthy controls,⁴⁵ patients with plasma cell dyscrasia,⁴⁶ transgender women on oestrogen therapy⁴⁷ and patients with cardiovascular risk factors.⁴⁸ Further studies are ongoing to evaluate the role of TEG in predicting thrombotic and cardiovascular complications in these groups.

While the data in pregnancy may be sparse, several studies have described consistent findings of hypercoagulability in pregnancy using TEG,^14,49–54 particularly decreased time to clot and fibrinolysis, and increased clot formation rapidity and strength. In studies which have included postpartum measurements, it has been determined that hypercoagulability persists until at least 24 h postpartum.^50,55 Our recent study also demonstrated marked hypercoagulability in term pregnant women,⁵⁶ in particular increased alpha angle (rate of clot formation) (65.8 vs 54.1°, p < 0.001) and maximum amplitude (clot strength) (71.5 vs 60.6 mm, p < 0.001), consistent with published data.^14,49–53 ROTEM has also demonstrated the hypercoagulability of pregnancy at term in several studies.^17,57–59 A similar study in pregnant women undergoing Caesarean section would be of value in evaluating ROTEM’s ability to contribute to VTE risk assessment.

Thrombin generation with calibrated automated thrombogram

Thrombin is a factor central to the coagulation process and has numerous effects on various components of the coagulation system, including generating fibrin, activating platelets and triggering the anticoagulation pathways, typically through thrombomodulin.^60,61 CAT allows a more comprehensive assessment of potential coagulability than routine coagulation assays, given that 95% of thrombin generation occurs beyond the time to clot formation.⁶⁰ CAT determines the rate and extent of thrombin generated after the addition of tissue factor stimulus.⁶² The parameters include time to thrombin formation (lag time) and the rate (velocity index) and amount of thrombin (endogenous thrombin potential, ETP) generated (Figure 2).

Figure 2.

Example of calibrated automated thrombogram. The parameters measured are lag time (time required to reach 10-mM thrombin), peak height, velocity index (maximum slope of the initial part of the curve) and endogenous thrombin potential (ETP, total amount of thrombin generated i.e. area under the curve).

CAT has been shown in the non-pregnant population to assist with VTE risk assessment, with one study suggesting a high ETP could be considered an independent risk factor for VTE in patients with previous VTE but with no thrombophilia marker.⁶³ Tripodi et al. reported that patients with first unprovoked VTE and raised ETP or peak thrombin following discontinuation of anticoagulation had a greater risk of VTE recurrence (ETP, hazard ratio (HR) 3.41; peak thrombin, HR 4.57).⁹ In addition to VTE risk prediction, there are emerging studies investigating the role of thrombin generation in cardiovascular disease with mixed findings to date – a French prospective cohort study of over 9000 subjects found that ETP correlated with risk of ischaemic stroke while the LURIC study demonstrated an inverse association between thrombin generation and event-free survival – demonstrating the complexity of the thrombin pathway.^64,65 In a study of a heterogeneous cohort where 403 participants were stratified into risk categories based on their clinical VTE risk factors, pregnant women included, thrombin generation increased from no-risk to low-, intermediate- and high-risk participants.⁶⁶

Multiple studies with CAT demonstrate hypercoagulability in pregnancy, including a significant increase in peak thrombin generation and ETP early in pregnancy,^67–72 consistent with our recent publication.⁵⁶ We reported that term pregnant women demonstrated markedly increased ETP (1895.2 vs 1399.4 nM/min, p < 0.001), thrombin peak (320.9 vs 240.0 nM) and velocity index (110.7 vs 83.4 nM/min, p < 0.001). Joly et al. reported that thrombin generation appears to increase early on in pregnancy and remained stable during pregnancy⁶⁷ although this differed to the findings by McLean et al. who reported the increase of thrombin generation with pregnancy progression.⁷¹ Nevertheless, Bagot et al. hypothesised that the increased risk of venous thrombosis is likely to begin early in the pregnancy.⁷² There is, however, currently a paucity of studies correlating the thrombin generation parameters with vascular pregnancy complications and thromboembolic disease in pregnancy.

Fibrin generation with the overall haemostatic potential assay

Fibrin, the final product of the coagulation cascade, is a protein which polymerises from fibrinogen under the influence of thrombin and, together with platelets, forms a haemostatic plug over damaged endothelium. While there are several assays available for fibrinolysis, for the purpose of this review, we will focus on OHP including reporting our recent findings in pregnant women using OHP. OHP provides a measure of fibrin generation and fibrinolysis in platelet-poor plasma over time using repeated spectrophotometric readings.⁷³ A graphical representation of fibrin aggregation is produced when fibrin generation is triggered by exogenous thrombin and fibrinolysis by tissue-type plasminogen activator (Figure 3).⁷³ This curve represents the balance between these processes, namely the overall haemostatic potential.

Figure 3.

Example of typical curves generated by the overall haemostatic potential assay. The curves generated by the OHP assay represent the balance between the generation and proteolysis of fibrin. The overall haemostatic potential (OHP) curve is derived with the addition of tissue plasminogen activator and thrombin to a platelet-poor plasma sample. The overall coagulation potential (OCP) curve is derived with the addition of thrombin only. The overall fibrinolytic potential (OFP) is calculated using ((OCP−OHP)/OCP × 100%).

The data in OHP is limited and predominantly in small observational studies. In research settings, OHP has demonstrated the ability to characterise a number of hypercoagulable states such as antiphospholipid syndrome, pulmonary embolism, and coronary artery disease.⁷³ We recently reported the trend of OHP in term pregnancy in 60 women – compared to healthy controls, pregnant women had significant higher fibrin generation as measured with overall coagulation potential (57.6 vs 36.2 units, p < 0.001) and overall haemostatic potential (13.4 vs 6.7 units, p < 0.001) with reduced overall fibrinolytic potential; (76.3 vs 82.1%, p < 0.001).⁵⁶ Goldenberg et al. also demonstrated hypercoagulability in pregnant women using their assay, CloFAL (clot formation and fibrinolysis), which also utilised turbidimetric assay.⁷⁴ In addition, a study of 88 non-pregnant women who had experienced a prior pregnancy-related DVT revealed increased OHP levels compared with controls.⁷⁵ This suggests that increased fibrin generation and decreased fibrinolysis in some women may represent a prothrombotic phenotype. Nonetheless, fibrin generation assays such as OHP assays remain in their infancy and further obstetric and non-obstetric studies are required.^76,77

Challenges ahead for the validation of global coagulation assays as biomarkers of pregnancy-associated VTE

GCAs appear to be more sensitive than traditional coagulation assays in detecting hypercoagulability and have shown some promising results in the VTE area, particularly using thrombin generation. However, while applying GCAs to the task of risk stratification for pregnancy-associated VTE is an attractive proposition, there is much work that needs to be done before GCAs could be considered for clinical use (Figure 4). While the techniques for viscoelastic testing have largely been optimised, particularly in the setting of massive transfusion, CAT and OHP are still in their infancy with regard to analytical validation. The analytical validation of each assay would require inter-operator and inter-operator standardisation and importantly the development of reproducible, robust pregnancy-specific reference values. The coagulation changes during each trimester and during the post-partum period should also be accounted for.

Figure 4.

Translating global coagulation assays into clinical practice.

In addition, whilst detecting hypercoagulability is useful, it is critical to show correlation between GCA parameters and predicting clinical outcomes. This needs to take into account the various risk groups in pregnancy, including evaluating common higher risk scenarios like obesity. Finally, the incorporation of these assays in routine laboratory and clinical risk assessment models are required.

Conclusion

VTE risk assessment and prevention remains a major challenge during pregnancy and the puerperium with varying guidelines and lack of currently available biomarkers to assist with risk stratification. Early data on GCAs have been able to reflect the hypercoagulable state of pregnancy, which traditional coagulation assays are unable to do. The development of a multiple biomarker approach to individualise VTE thromboprophylaxis would be a significant advance from the traditional screening with clinical risk factors alone. However, whether GCAs will eventually be applied to pregnancy-associated VTE risk prediction will depend on a dedicated effort to demonstrate their analytical and clinical validity in the obstetric population.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Not applicable.

Informed consent

Not applicable.

Guarantor

PH is the guarantor of the present work.

Contributorship

HYL, LH and PH conceived the topic of review and researched the literature. DO researched the literature and drafted the review. All authors reviewed and edited the manuscript and approved the final version to be published.

ORCID iD

David O’Keefe

References

Australian Institute of Health and Welfare. Maternal deaths in Australia. Canberra: Australian Institute of Health and Welfare, 2019

Palmerola

D'Alton

Brock

, et al. A comparison of recommendations for pharmacologic thromboembolism prophylaxis after caesarean delivery from three major guidelines. BJOG. 2016; 123: 2157–2162.

Bain

Wilson

Tooher

, et al. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database of Systematic Reviews, 2014.

Kotaska

Postpartum venous thromboembolism prophylaxis may cause more harm than benefit: a critical analysis of international guidelines through an evidence-based lens. BJOG 2018; 125: 1109–1116.

Rodger

Pregnancy and venous thromboembolism: ‘TIPPS’ for risk stratification. Hematology 2014; 2014: 387–392.

McLintock

Brighton

Chunilal

, et al. Recommendations for the prevention of pregnancy-associated venous thromboembolism. Aust NZ J Obstet Gynaecol 2012; 52: 3–13.

Nelson-Piercy

MacCallum

Mackillop

Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Green-top guideline no. 73a. London: Royal College of Obstetricians & Gynaecologists, 2015.

Lim

O’Malley

Donnan

, et al. A review of global coagulation assays – is there a role in thrombosis risk prediction? Thromb Res 2019; 179: 45–55.

Tripodi

Legnani

Chantarangkul

, et al. High thrombin generation measured in the presence of thrombomodulin is associated with an increased risk of recurrent venous thromboembolism. J Thromb Haemost 2008; 6: 1327–1333.

10.

Curnow

Morel-Kopp

M-C

Roddie

, et al. Reduced fibrinolysis and increased fibrin generation can be detected in hypercoagulable patients using the overall hemostatic potential assay. J Thromb Haemost 2007; 5: 528–534.

11.

Ataullakhanov

Koltsova

Balandina

, et al. Classic and global hemostasis testing in pregnancy and during pregnancy complications. Semin Thromb Hemost 2016; 42: 696–716.

12.

Brenner

Haemostatic changes in pregnancy. Thromb Res 2004; 114: 409–414.

13.

Lipets

Ataullakhanov

FI.

Global assays of hemostasis in the diagnostics of hypercoagulation and evaluation of thrombosis risk. Thromb J 2015; 13: 4.

14.

Karlsson

Sporrong

Hillarp

, et al. Prospective longitudinal study of thromboelastography and standard hemostatic laboratory tests in healthy women during normal pregnancy. Anesth Analg 2012; 115: 890–898.

15.

Boer

Den Hollander

Meijers

JCM

, et al. Tissue factor-dependent blood coagulation is enhanced following delivery irrespective of the mode of delivery. J Thromb Haemost 2007; 5: 2415–2420.

16.

Maybury

Waugh

JJS

Gornall

, et al. There is a return to non-pregnant coagulation parameters after four not six weeks postpartum following spontaneous vaginal delivery. Obstet Med 2008; 1: 92–94.

17.

Saha

Stott

Atalla

Haemostatic changes in the puerperium ‘6 weeks postpartum’ (HIP Study) – implication for maternal thromboembolism. BJOG 2009; 116: 1602–1612.

18.

Heit

Kobbervig

James

, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005; 143: 697–706.

19.

James

Jamison

Brancazio

, et al. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006; 194: 1311–1315.

20.

Kourlaba

Relakis

Kontodimas

, et al. A systematic review and meta-analysis of the epidemiology and burden of venous thromboembolism among pregnant women. Int J Gynaecol Obstet 2016; 132: 4–10.

21.

Pomp

Lenselink

Rosendaal

, et al. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008; 6: 632–637.

22.

Sultan

West

Tata

, et al. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol 2012; 156: 366–373.

23.

Butwick

Bentley

Leonard

, et al. Prepregnancy maternal body mass index and venous thromboembolism: a population-based cohort study. BJOG 2019; 126: 581–588.

24.

Australian Institute of Health and Welfare. Australia’s mothers and babies 2014-in brief. Perinatal statistics series no. 32. Cat no. PER87. Canberra: AIHW, 2016.

25.

Middeldorp

van Hylckama Vlieg

Does thrombophilia testing help in the clinical management of patients?

Br J Haematol 2008; 143: 321–335.

26.

Bates

Rajasekhar

Middeldorp

, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv 2018; 2: 3317–3359.

27.

Bates

Greer

Middeldorp

, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e691S–e736S.

28.

Kearon

Akl

Ornelas

, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149: 315–352.

29.

The American College of Obstetricians and Gynecologists Committee on Practice Bulletins-Obstetrics. Bulletin No. 196: Thromboembolism in pregnancy. Obstet Gynecol 2018; 132: e1–17.

30.

National Health and Medical Research Council. Clinical practice guideline for the prevention of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to Australian hospitals. Melbourne: National Health and Medical Research Council, 2009.

31.

Cavazza

Rainaldi

Adduci

, et al. Thromboprophylaxis following cesarean delivery: one site prospective pilot study to evaluate the application of a risk score model. Thromb Res 2012; 129: 28–31.

32.

Sultan

West

Grainge

, et al. Development and validation of risk prediction model for venous thromboembolism in postpartum women: multinational cohort study. BMJ 2016; 355: i6253.

33.

Szecsi

Jorgensen

Klajnbard

, et al. Haemostatic reference intervals in pregnancy. Thromb Haemost 2010; 103: 718–727.

34.

Hui

Lili

Libin

, et al. Changes in coagulation and hemodynamics during pregnancy: a prospective longitudinal study of 58 cases. Arch Gynecol Obstet 2012; 285: 1231–1236.

35.

Reger

Peterfalvi

Litter

, et al. Challenges in the evaluation of D-dimer and fibrinogen levels in pregnant women. Thromb Res 2013; 131: e183–e187.

36.

Kovac

Mikovic

Rakicevic

, et al. The use of D-dimer with new cutoff can be useful in diagnosis of venous thromboembolism in pregnancy. Eur J Obstet Gynecol Reprod Biol 2010; 148: 27–30.

37.

van der Pol

Tomeur

Bistervels

, et al. Pregnancy-adapted YEARS algorithm for diagnosis of suspected pulmonary embolism. N Engl J Med 2019; 380: 1139–1149.

38.

Hunt

Parmar

Horspool

, et al. The DiPEP (Diagnosis of PE in Pregnancy) biomarker study: an observational cohort study augmented with additional cases to determine the diagnostic utility of biomarkers for suspected venous thromboembolism during pregnancy and puerperium. Br J Haematol 2018; 180: 694–704.

39.

Othman

Kaur

Thromboelastography (TEG). In: Favaloro EJ and Lippi G (eds) Haemostasis and thrombosis: methods and protocols. New York: Springer Nature, 2017, pp. 533–543.

40.

Isbir

Tetik

, et al. Thromboelastography-based transfusion algorithm reduces blood product use after elective CABG: a prospective randomized study. J Card Surg 2009; 24: 404–410.

41.

Dias

Sauaia

Achneck

, et al. Thromboelastography-guided therapy improves patient blood management and certain clinical outcomes in elective cardiac and liver surgery and emergency resuscitation: a systematic review and analysis. J Thromb Haemost 2019; 17: 984–994.

42.

Zhao

Yang

, et al. Thromboelastography or rotational thromboelastometry for bleeding management in adults undergoing cardiac surgery: a systematic review with meta-analysis and trial sequential analysis. J Thorac Dis 2019; 11: 1170.

43.

Yao

Dong

Song

, et al. Thrombelastography maximal clot strength could predict one-year functional outcome in patients with ischemic stroke. Cerebrovasc Dis 2014; 38: 182–190.

44.

Hincker

Feit

Sladen

, et al. Rotational thromboelastometry predicts thrombolic complications after major non-cardiac surgery. Crit Care 2014; 18: 549.

45.

Lim

Lui

Tacey

, et al. Global coagulation assays in healthy controls: are there compensatory mechanisms within the coagulation system? J Thromb Thrombolysis 2021. DOI: 10.1007/s11239-021-02400-y.

46.

Lim

Brook

Krishnamoorthi

, et al. Global coagulation assays in patients with multiple myeloma and monoclonal gammopathy of unknown significance. Thromb Res 2019; 183: 45–48.

47.

Lim

Leemaqz

Torkamani

, et al. Global coagulation assays in transgender women on oral and transdermal estradiol therapy. J Clin Endocrinol Metab 2020; 105: e2369–e2377.

48.

Lui

Lim

HY.

Evaluation of global coagulation assays in patients with chronic kidney disease. In: Poster session presented at Blood 2019 meeting, Perth, 20–23 October 2019.

49.

Della Rocca

Dogareschi

Cecconet

, et al. Coagulation assessment in normal pregnancy: thrombelastography with citrated non activated samples. Minerva Anestesiol 2012; 78: 1357–1364.

50.

Sharma

Philip

Wiley

Thromboelastographic changes in healthy parturients and postpartum women. Anesth Analg 1997; 85: 94–98.

51.

Polak

Kolnikova

Lips

, et al. New recommendations for thromboelastography reference ranges for pregnant women. Thromb Res 2011; 128: e14–e17.

52.

Macafee

Campbell

Ashpole

, et al. Reference ranges for thromboelastography (TEG®) and traditional coagulation tests in term parturients undergoing caesarean section under spinal anaesthesia. Anaesthesia 2012; 67: 741–747.

53.

Antony

Mansouri

Arndt

, et al. Establishing thromboelastography with platelet-function analyzer reference ranges and other measures in healthy term pregnant women. Am J Perinatol 2015; 32: 545–554.

54.

Yang

Tang

, et al. Trimester-specific reference intervals for kaolin-activated thromboelastography (TEG®) in healthy Chinese pregnant women. Thromb Res 2019; 184: 81–85. Dec

55.

Shreeve

Barry

Deutsch

, et al. Changes in thromboelastography parameters in pregnancy, labor, and the immediate postpartum period. Int J Gynaecol Obstet 2016; 134: 290–293.

56.

O'Keefe

Lim

Tham

, et al. Assessing maternal clotting function with novel global coagulation assays: a prospective pilot study. Int J Lab Hematol 2021; 43: 458–467.

57.

Armstrong

Fernando

Ashpole

, et al. Assessment of coagulation in the obstetric population using ROTEM® thromboelastometry. Int J Obstet Anesth 2011; 20: 293–298.

58.

Huissoud

Carrabin

Benchaib

, et al. Coagulation assessment by rotation thrombelastometry in normal pregnancy. Thromb Haemost 2009; 101: 755–761.

59.

de Lange

van Rheenen-Flach

Lancé

, et al. Peri-partum reference ranges for ROTEM® thromboelastometry. Br J Anaesth 2014; 112: 852–859.

60.

Hemker

Giesen

Al Dieri

, et al. The Calibrated Automated Thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32: 249–253.

61.

Hemker

Al Dieri

de Smedt

, et al. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost 2006; 96: 553–561.

62.

Salvagno

Berntorp

Thrombin generation assays (TGAs). In: Favaloro EJ and Lippi G (eds) Haemostasis and thrombosis: methods and protocols. New York: Springer Nature, 2017, pp. 515–522.

63.

Dargaud

Trzeciak

Bordet

, et al. Use of calibrated automated thrombinography +/− thrombomodulin to recognise the prothrombotic phenotype. Thromb Haemost 2006; 96: 562–567.

64.

Carcaillon

Alhenc-Gelas

Bejot

, et al. Increased thrombin generation is associated with acute ischemic stroke but not with coronary heart disease in the elderly: the Three-City cohort study. Arterioscler Thromb Vasc Biol 2011; 31: 1445–1451.

65.

Schneider

Isermann

Kleber

, et al. Inverse association of the endogenous thrombin potential (ETP) with cardiovascular death: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Int J Cardiol 2014; 176: 139–144.

66.

Tripodi

Martinelli

Chantarangkul

, et al. The endogenous thrombin potential and the risk of venous thromboembolism. Thromb Res 2007; 121: 353–359.

67.

Joly

Barbay

Borg

, et al. Comparison of markers of coagulation activation and thrombin generation test in uncomplicated pregnancies. Thromb Res 2013; 132: 386–391.

68.

Rosenkranz

Hiden

Leschnik

, et al. Calibrated automated thrombin generation in normal uncomplicated pregnancy. Thromb Haemost 2008; 99: 331–337.

69.

Dargaud

Hierso

Rugeri

, et al. Endogenous thrombin potential, prothrombin fragment 1 + 2 and D-dimers during pregnancy. Thromb Haemost 2010; 103: 469–471.

70.

Macey

Bevan

Alam

, et al. Platelet activation and endogenous thrombin potential in pre-eclampsia. Thromb Res 2010; 125: e76–e81.

71.

McLean

Bernstein

Brummel-Ziedins

KE.

Tissue factor-dependent thrombin generation across pregnancy. Am J Obstet Gynecol 2012; 207: 135.

72.

Bagot

Leishman

Onyiaodike

, et al. Normal pregnancy is associated with an increase in thrombin generation from the very early stages of the first trimester. Thromb Res 2017; 157: 49–54.

73.

Curnow

The overall hemostatic potential (OHP) assay. In: Favaloro

EJ and

Lippi

(eds) Haemostasis and thrombosis: methods and protocols. New York: Springer Nature, 2017, pp. 523–531.

74.

Goldenberg

Hathaway

Jacobson

, et al. A new global assay of coagulation and fibrinolysis. Thromb Res 2005; 116: 345–356.

75.

Antovic

Blomback

Bremme

, et al. Increased hemostasis potential persists in women with previous thromboembolism with or without APC resistance. J Thromb Haemost 2003; 1: 2531–2535.

76.

Bremme

Blombäck

A laboratory method for determination of overall haemostatic potential in plasma. I. Method design and preliminary results. Thromb Res 1999; 96: 145–156.

77.

Antovic

Blombäck

A simple and rapid laboratory method for determination of haemostasis potential in plasma: II. Modifications for use in routine laboratories and research work. Thromb Res 2001; 103: 355–361.