Early viscoelastometric guided fibrinogen replacement combined with escalation of clinical care reduces progression in postpartum haemorrhage: a comparison of outcomes from two prospective observational studies.

BACKGROUND: Viscoelastometric haemostatic assays (VHA) give rapid information on coagulation status, allowing individualised resuscitation. METHODS: This paper compares outcomes from two observational studies of postpartum haemorrhage (PPH) in the same institution, before and after practice changed from fixed ratio empirical transfusion of coagulation products with laboratory coagulation testing to VHA-guided fibrinogen replacement incorporated into an enhanced PPH care bundle. In both studies, all blood samples were taken near 1000 mL qualitative blood loss (QBL). In Study One, QBL started once PPH was identified, and resuscitation with coagulation blood products was empirical or based on laboratory tests of coagulation. In Study Two, QBL started at delivery and VHA was used to guide fibrinogen replacement if FIBTEM A5 was <12 mm (Claus fibrinogen ≤2 g/L) or to withhold coagulation products if FIBTEM A5 was >12 mm. RESULTS: Improved PPH outcomes were observed in Study Two, with rates of measured blood loss ≥2500 mL, ≥4 units red blood cell (RBC) transfusion, fresh frozen plasma transfusion and ≥8 units of any blood product transfusion all reduced (P < 0.01). Clinically significant improvements occurred in women with fibrinogen ≤2 g/L at study entry, where the proportion of women who received ≥4 units RBC transfusion fell from 67% in Study One to 0% in Study Two (P = 0.0007). CONCLUSIONS: These results suggest that use of VHA as part of an early bundle of PPH care targeting fibrinogen ≤2 g/L with fibrinogen concentrate reduces PPH progression. The greatest benefit was seen when fibrinogen levels were ≤2 g/L at first testing.

Comparison of haematological indices and transfusion management in severe and massive postpartum haemorrhage: analysis of a two-year national prospective observational study.

INTRODUCTION: This two-year prospective cohort study compared the management of women experiencing severe or massive postpartum haemorrhage (PPH) to explore the impact of targeted blood product administration on reducing PPH progression (from >1500 mL to ≥2500 mL blood loss). During the study, viscoelastic haemostatic assays (VHA) guided blood product transfusion. METHODS: All women experiencing blood loss after PPH >1000 mL were included in a national database. Haematological indices, transfusion and PPH aetiology were analysed in severe (>1500 mL blood loss or transfusion of any blood product) and massive PPH (≥2500 mL blood loss or transfusion ≥5 units red blood cells). RESULTS: Of the 61 094 maternities in Wales (2017 to 2018), 2111 had severe and 349 massive PPH. Red blood cells were transfused to 42.5% severe and 80.6% massive PPH cases. Hypofibrinogenaemia (fibrinogen <2 g/L and/or Fibtem A5 <12 mm) was the most frequent coagulation abnormality, occurring in 5.4% severe and 17.0% massive PPH, with blood coagulation products (fresh frozen plasma, platelets, cryoprecipitate and/or fibrinogen concentrate) administered to 3.6% and 22.9%. Women with hypofibrinogenaemia received targeted fibrinogen replacement in 97.8% severe and 93.6% massive PPH. The only aetiology with similar rates of hypofibrinogenaemia in severe and massive PPH was abruption (40.0% and 36.8%). CONCLUSION: Hypofibrinogenaemia was less frequent in severe PPH, although coagulopathy was observed across a range of PPH aetiologies, highlighting the importance of coagulation testing for all. Cases of abruption in severe and massive PPH had similar rates of hypofibrinogenaemia. Early VHA-guided fibrinogen replacement may reduce PPH progression in abruption and requires further evaluation.

The sensitivity and specificity of rotational thromboelastometry (ROTEM) to detect coagulopathy during moderate and severe postpartum haemorrhage: a prospective observational study.

INTRODUCTION: Point-of-care viscoelastic haemostatic assays such as rotational thromboelastometry (including ROTEM and TEG) have been used in the management of postpartum haemorrhage (PPH). This study compared results obtained from the automated ROTEM Sigma with laboratory tests of coagulation and platelet count during PPH. METHODS: A prospective observational cohort study recruited women with PPH ≥1000 mL (or clinical concern of bleeding). The Fibtem A5, Extem CT and Pltem (Extem A5 - Fibtem A5) results were compared with laboratory tests of fibrinogen, prothrombin time (PT), activated partial thromboplastin time (APTT) and platelet count. RESULTS: 521 women were recruited, including 274/277 (98.9%) of women with PPH ≥1500 mL. Fibtem A5 results were matched with laboratory fibrinogen in 552/644 (85.7%) samples. The incidence of abnormal laboratory results was low: fibrinogen ≤2 g/L 23/464 (5.0%), PT or APTT >1.5 × midpoint of reference range 4/464 (0.9%), and platelet count <75 × 109/L 11/477 (2.3%). Area-under-the-receiver operator characteristic curve for Fibtem A5 to detect fibrinogen ≤2 g/L was 0.96 (95% Confidence Interval (CI) 0.94 to 0.98, P<0.001), with sensitivity and specificity of Fibtem A5 ≤11 mm to detect fibrinogen ≤2 g/L of 0.76 and 0.96. Prolonged Extem CT results improved after treatment of hypofibrinogenaemia alone. Intervention points for platelet and fresh frozen plasma (FFP) transfusion based on ROTEM Sigma parameters could not be established. CONCLUSION: During PPH (≥1000 mL or cases of clinical concern about bleeding), ROTEM Sigma Fibtem A5 can detect fibrinogen ≤2 g/L and guide targeted fibrinogen replacement. Laboratory results should continue to be used to guide platelet and FFP transfusion.

Utility of viscoelastography with TEG 6s to direct management of haemostasis during obstetric haemorrhage: a prospective observational study.

BACKGROUND: The TEG 6s is an automated cartridge-based device with limited description of use in obstetric haemorrhage. The aim of this analysis was to describe the utility of TEG 6s in identifying abnormal laboratory results of coagulation and platelet count, and inform an interventional treatment algorithm for postpartum haemorrhage. METHODS: A prospective observational cohort study of 521 women with moderate to severe obstetric haemorrhage (>1000 mL blood loss), including 372 women with at least one TEG 6s test. A non-pregnant control group was used for reference. TEG 6s test parameters Citrated Functional Fibrinogen (CFF), Citrated Kaolin TEG (CK) and Citrated Rapid TEG (CRT) were compared with paired laboratory tests of fibrinogen, PT/aPTT and platelet count, obtained during haemorrhage. RESULTS: Among 456 TEG 6s tests, 389 were matched with laboratory coagulation results. The receiver operator characteristic area-under-the-curve (95% CI) for CFF amplitude by 10 min to detect Clauss fibrinogen ≤2 g/L was 0.95 (0.91 to 0.99) (P<0.0001, sensitivity 0.74 and specificity 0.97 at ≤17 mm). False positives had median (IQR) Clauss fibrinogen of 2.4 (2.3-2.7) g/L. The CK-R time had some utility for detecting prolonged PT/aPTT, however a threshold for fresh frozen plasma transfusion was not established. A CRT maximum amplitude <57 mm, when CFF was ≥15 mm, identified four of eight samples with platelet count <75 × 109/L. CONCLUSION: The TEG 6s CFF can be used to identify low fibrinogen during obstetric haemorrhage. A value to identify transfusion thresholds for PT/aPTT and platelets was not established, and laboratory results should continue to be used.

The incidence, aetiology, and coagulation management of massive postpartum haemorrhage: a two-year national prospective cohort study.

INTRODUCTION: Between 2017 and 2018 a national quality improvement initiative was introduced incorporating point-of-care viscoelastic haemostatic assays (VHA) to guide blood product transfusion. Laboratory coagulation profiles, use and results of VHA, and administration of blood products were investigated. METHODS: A two-year prospective cohort study of maternal outcomes of women experiencing massive postpartum haemorrhage (PPH) >1000 mL in Wales. In this study, cases of massive PPH (≥2500 mL and/or ≥5 units red blood cell (RBC) transfusion) were identified. RESULTS: Massive PPH occurred in 349 of 60 914 maternities (rate 5.7 per 1000). There were no deaths from PPH. Intensive care unit admission and/or hysterectomy occurred in 34/311 (10.9%) and 16/347 (4.6%), respectively. The leading cause of massive PPH was genital tract trauma (107/349, 30.6%). Two hundred and seventy-nine (80.6%) required RBC transfusion and 79/345 (22.9%) received at least one blood coagulation product. Results of VHA were recorded in 245/349 (70.2%), with 44/98 (44.9%) women tested in the first six months vs 63/77 (81.8%) in the final six months. Hypofibrinogenaemia (Clauss fibrinogen <2 g/L or FIBTEM A5 <12 mm) was observed in 56/328 (17.1%) of women, thrombocytopaenia (count <75 × 109/L) in 17/334 (5.1%) and either PT or aPTT >1.5×reference range in 10/293 (3.4%). CONCLUSION: In Wales, the use of VHA in cases of massive PPH increased over time, enabling clinicians to adopt a targeted, patient-specific approach to blood product administration, with only 22.9% of women receiving blood coagulation products and 17.1% having a documented clotting abnormality.

When does obstetric coagulopathy occur and how do I manage it?

Anticipating obstetric coagulopathy is important when obstetric anaesthetists are involved in the clinical management of women with postpartum haemorrhage. Although the incidence of coagulopathy in women with postpartum haemorrhage is low, significant hypofibrinogenaemia is associated with major haemorrhage-related morbidity and thus early identification and treatment is essential to improve outcomes. Point-of-care viscoelastic haemostatic assays, including thromboelastography and rotational thromboelastometry, provide granular information about alterations in clot formation and hypofibrinogenaemia, allow near-patient interpretation of coagulopathy, and can guide goal-directed treatment. If these assays are not available, anaesthetists should closely monitor the maternal coagulation profile with standard laboratory testing during the active phase of postpartum bleeding in order to rule coagulopathy 'in or out', decide if pro-haemostatic therapies are indicated, and assess the response to haemostatic support.

Management of postpartum haemorrhage: from research into practice, a narrative review of the literature and the Cardiff experience.

Postpartum haemorrhage (PPH) is caused by obstetric complications but may be exacerbated by haemostatic impairment. In a 10-year programme of research we have established that haemostatic impairment is uncommon in moderate PPH and that fibrinogen falls earlier than other coagulation factors. Laboratory Clauss fibrinogen and the point-of-care surrogate measure of fibrinogen (FIBTEM A5 measured on the ROTEM® machine) are predictive biomarkers for progression from early to severe PPH, the need for blood transfusion and invasive procedures to control haemorrhage. Fibrinogen replacement is not required in PPH unless the plasma level falls below 2 g/L or the FIBTEM A5 is below 12 mm. Deficiencies of coagulation factors other than fibrinogen are uncommon even during severe PPH, and ROTEM® monitoring can inform withholding FFP safely in most women. In the absence of placental abruption, clinically significant thrombocytopenia is uncommon unless the platelet count is low before the bleed started, or very large bleeds (>5000 mL) occur. Measuring blood loss is feasible in routine practice during PPH and is more accurate than estimation. These research findings have been collated to design an ongoing quality improvement programme for all maternity units in Wales called OBS Cymru (Wales) (The Obstetric Bleeding Strategy for Wales).

Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial.

BACKGROUND: Postpartum haemorrhage (PPH) can be exacerbated by haemostatic failure. We hypothesized that early fibrinogen replacement, guided by viscoelastometric testing, reduces blood product usage and bleed size. METHODS: Women with PPH 1000-1500 ml were enrolled. If Fibtem A5 was ≤15 mm and bleeding continued, subjects were randomized to fibrinogen concentrate or placebo. The primary outcome compared the number of units of red blood cells, plasma, cryoprecipitate and platelets transfused. RESULTS: Of 663 women enrolled 55 were randomized. The adjusted incidence rate ratio (IRR) (95% CI) for the number of allogeneic units transfused in the fibrinogen group compared with placebo was 0.72 (0.3-1.7), P =0.45. In pre-specified subgroup analyses, subjects who had a Fibtem A5 ≤12 mm at the time of randomization and who received fibrinogen concentrate received a median (25th-75th centile) of 1 (0-4.5) unit of allogeneic blood products and had an additional 300 (100-350) ml blood loss whereas those who received placebo also received 3 (0-6) units of allogeneic blood products and had 700 (200-1550) ml additional blood loss; these differences were not statistically significantly different. There was one thrombotic event in each group. CONCLUSIONS: Infusion of fibrinogen concentrate triggered by Fibtem A5 ≤15 mm did not improve outcomes in PPH. Pre-specified subgroup analyses suggest that fibrinogen replacement is not required if the Fibtem A5 is > 12 mm or Clauss fibrinogen >2 g litre -1 , but an effect below these levels cannot be excluded. The raised fibrinogen at term appears to be a physiological buffer rather than required for haemostasis. TRIAL REGISTRATION: ISRCTN46295339 ( http://www.isrctn.com/ISRCTN46295339 , last accessed 5 July 2017), EudraCT 2012-005511-11 ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-005511-11 , last accessed 5 July 2017).

Platelet count and transfusion requirements during moderate or severe postpartum haemorrhage.

Limited data exist on platelet transfusion during postpartum haemorrhage. We retrospectively analysed a consecutive cohort from a single centre of 347 women with moderate or severe postpartum haemorrhage, transfused according to national guidelines. Twelve (3%) women required a platelet transfusion. There were no differences between women who did and did not receive platelets with respect to age, mode of initiation of labour or mode of delivery. Women receiving a platelet transfusion had a lower median (IQR [range]) platelet count at study entry than women who did not receive platelets before haemorrhage (135 (97-175 [26-259])×10(9) .l(-1) vs 224 (186-274 [91-1006])×10(9) .l(-1) ), respectively), and at diagnosis of postpartum haemorrhage (median 114 (78-153 [58-238])×10(9) .l(-1) vs 193 (155-243 [78-762])×10(9) .l(-1) respectively). Six women were thrombocytopenic pre-delivery. The cause of haemorrhage that was associated with the highest rate of platelet transfusion was placental abruption, with three of 14 women being transfused. If antenatal thrombocytopenia or consumptive coagulopathy were not present, platelets were only required for haemorrhage > 5000 ml. Early formulaic platelet transfusion would have resulted in many women receiving platelets unnecessarily. Using current guidelines, the need for platelet transfusion is uncommon without antenatal thrombocytopenia, consumptive coagulopathy or haemorrhage > 5000 ml. We found no evidence to support early fixed-ratio platelet transfusion.

The epidemiology and outcomes of women with postpartum haemorrhage requiring massive transfusion with eight or more units of red cells: a national cross-sectional study.

OBJECTIVE: To ascertain the incidence of massive transfusion (MT) in obstetrics in the UK, and describe its management and clinical outcomes. DESIGN: A population-based cross-sectional study conducted through the UK Obstetric Surveillance System (UKOSS). SETTINGS: All UK hospitals with consultant-led maternity units. POPULATION: Any pregnant woman at ≥20 weeks of gestation receiving ≥8 units of red blood cells within 24 hours of giving birth, from July 2012 to June 2013. METHODS: Prospective case identification through the monthly mailing of UKOSS. RESULTS: We identified 181 women who had undergone MT, making the estimated incidence of MT associated with postpartum haemorrhage (PPH) 23 per 100 000 maternities (95% confidence interval 19-26) per year. The median estimated blood loss was 6 l (interquartile range 4.5-8.0 l). The majority of women presented outside working hours (63%), 40% had had previous caesarean sections and 3% had normal vaginal births without risk factors. The main cause for MT was uterine atony (40%) and the main mode of birth was caesarean section (69%). Of the 181 women, 15 received >20 units of red blood cells. In total, 45% of women underwent hysterectomy, and among all causes of PPH, placenta accreta had the highest hysterectomy rate. Two women died, 82% were admitted to intensive care/high-dependency units, and 28% developed major morbidities. CONCLUSION: Massive transfusion due to PPH is associated with high rates of morbidity and hysterectomy. Clinical and research efforts should focus on approaches to recognise and optimise timely resuscitation and management of these severe cases. TWEETABLE ABSTRACT: Massive transfusion due to postpartum haemorrhage is associated with high rates of morbidity and hysterectomy.

Haemostatic management of obstetric haemorrhage.

The haemostatic management of major obstetric haemorrhage remains challenging, and current published guidance relies heavily on experience from the non-pregnant population and expert opinion. In recent years, an interest in the implications of relative hypofibrinogenaemia, point-of-care monitoring of coagulation abnormalities, and the potential to give goal-directed therapy to correct coagulopathies, have created the possibility of significantly challenging and changing guidance. There is evidence that the haemostatic impairment in the pregnant population is different from trauma-induced bleeding, and the type and rate of onset of coagulopathies differ depending on the underlying cause. This review examines areas such as possible intervention points, describes evidence for over-transfusion of fresh frozen plasma in some situations and challenges conventional thinking on formulaic management. It also examines the rationale for other therapeutic options, including fibrinogen concentrate and tranexamic acid.

Measurement of blood loss during postpartum haemorrhage.

BACKGROUND: We set out to validate the accuracy of gravimetric quantification of blood loss during simulated major postpartum haemorrhage and to evaluate the technique in a consecutive cohort of women experiencing major postpartum haemorrhage. The study took part in a large UK delivery suite over a one-year period. All women who experienced major postpartum haemorrhage were eligible for inclusion. METHODS: For the validation exercise, in a simulated postpartum haemorrhage scenario using known volumes of artificial blood, the accuracy of gravimetric measurement was compared with visual estimation made by delivery suite staff. In the clinical observation study, the blood volume lost during postpartum haemorrhage was measured gravimetrically according to our routine institutional protocol and was correlated with fall in haemoglobin. The main outcome measure was the accuracy of gravimetric measurement of blood loss. RESULTS: Validation exercise: the mean percentage error of gravimetrically measured blood volume was 4.0±2.7% compared to visually estimated blood volume with a mean percentage error of 34.7±32.1%. Clinical observation study: 356 out of 6187 deliveries were identified as having major postpartum haemorrhage. The correlation coefficient between measured blood loss and corrected fall in haemoglobin for all patients was 0.77; correlation was stronger (0.80) for postpartum haemorrhage >1500mL, and similar during routine and out-of-hours working. CONCLUSION: The accuracy of the gravimetric method was confirmed in simulated postpartum haemorrhage. The clinical study shows that gravimetric measurement of blood loss is correlated with the fall in haemoglobin in postpartum haemorrhage where blood loss exceeds 1500mL. The method is simple to perform, requires only basic equipment, and can be taught and used by all maternity services during major postpartum haemorrhage.

Haemostatic monitoring during postpartum haemorrhage and implications for management.

Postpartum haemorrhage (PPH) is a major risk factor for maternal morbidity and mortality. PPH has numerous causative factors, which makes its occurrence and severity difficult to predict. Underlying haemostatic imbalances such as consumptive and dilutional coagulopathies may develop during PPH, and can exacerbate bleeding and lead to progression to severe PPH. Monitoring coagulation status in patients with PPH may be crucial for effective haemostatic management, goal-directed therapy, and improved outcomes. However, current PPH management guidelines do not account for the altered baseline coagulation status observed in pregnant patients, and the appropriate transfusion triggers to use in PPH are unknown, due to a lack of high-quality studies specific to this area. In this review, we consider the evidence for the use of standard laboratory-based coagulation tests and point-of-care viscoelastic coagulation monitoring in PPH. Many laboratory-based tests are unsuitable for emergency use due to their long turnaround times, so have limited value for the management of PPH. Emerging evidence suggests that viscoelastic monitoring, using thrombelastography- or thromboelastometry-based tests, may be useful for rapid assessment and for guiding haemostatic therapy during PPH. However, further studies are needed to define the ranges of reference values that should be considered 'normal' in this setting. Improving awareness of the correct application and interpretation of viscoelastic coagulation monitoring techniques may be critical in realizing their emergency diagnostic potential.

Standard haemostatic tests following major obstetric haemorrhage.

BACKGROUND: Postpartum haemorrhage is an important cause of maternal morbidity and mortality. It is associated with haemostatic impairment which may exacerbate bleeding. METHODS: All deliveries over a 3-year period in a large UK unit were reviewed and cases of haemorrhage of 1500 mL or more identified. Laboratory records were reviewed and the lowest value for haemoglobin, platelet count and fibrinogen, and longest value for prothrombin time and activated partial thromboplastin time within 24h of delivery were recorded. RESULTS: Of 18,501 deliveries there were 456 bleeds of 1500 mL or more (2.5%). Fibrinogen levels correlated best with blood loss (r -0.48 P<0.01) and fell progressively as volume increased. Activated partial thromboplastin time was less sensitive (r 0.4 P<0.01) to increasing blood loss. Prothrombin time did not correlate with blood loss (r 0.01). Activated partial thromboplastin time and prothrombin time remained within the normal range in most women despite large bleeds. Similar results were observed in women who received four or more units of red blood cells. Haemoglobin level was adequately maintained irrespective of blood loss. Based on UK national guidelines only 13 of 456 (3%) women should have received fresh frozen plasma, although it was given to 45; despite this, fibrinogen levels below the pregnancy-related normal range were observed in most cases. CONCLUSION: Fibrinogen level was the parameter that best correlated with increasing volume of haemorrhage and was the most useful marker of developing haemostatic impairment. Guidelines for fresh frozen plasma use in major postpartum haemorrhage were rarely followed and should be reviewed.

The use of fibrinogen concentrate to correct hypofibrinogenaemia rapidly during obstetric haemorrhage.

Haemorrhage is a common complication of childbirth with 0.65% of deliveries associated with significant (>1500 mL) peripartum blood loss. Hypofibrinogenaemia secondary to dilutional and consumptive coagulopathies can be challenging to correct quickly with conventional blood and plasma therapy. Fibrinogen concentrate offers rapid restoration of fibrinogen levels with a small volume infusion and minimal preparation time. It is effective in treating patients with congenital hypofibrinogenaemia, but there are few reports of its use in association with continuing obstetric haemorrhage. Six cases of obstetric haemorrhage, associated with hypofibrinogenaemia, treated with fibrinogen concentrate in conjunction with platelets, fresh frozen plasma, packed red blood cells, uterotonics and obstetric intervention are described. In all cases, laboratory assessed coagulation was rapidly normalised and severe haemorrhage improved. These cases suggest that fibrinogen concentrate may be an effective addition to conventional treatments for obstetric haemorrhage associated with hypofibrinogenaemia.

Shape of the thecal sac: L3/4 interspace compared with L4/5.

We retrospectively reviewed 60 normal magnetic resonance imaging scans to assess the anatomical shape of the thecal sac at the L3/4 and L4/5 vertebral interspaces. In all cases the thecal sac was oval at L3/4 but in 26 (43%; 95% CI 31-55%) the thecal sac changed from oval at the L3/4 interspace to triangular at L4/5 (with the apex of the triangle presenting to the posterior epidural space). We propose that this anatomical variant would make it more difficult to obtain cerebrospinal fluid at the lower level, as a slightly lateral approach could lead to identification of the epidural space but failure to puncture the thecal sac. This may offer an explanation for a 'dry tap' when a lower interspace is chosen.