5.1

Hypofibrinogenemia

In patients with moderate to severe PPH, one of the most notable hemostatic changes is the decrease in the plasma fibrinogen level. Observational studies have reported an inverse non-linear relationship between the volume of blood loss and the nadir plasma fibrinogen concentration [ , ]. Among patients who experience 1000–1500 mL blood loss the incidence of hypofibrinogenemia (<2 g/L) is around 4–5% [ ]. Several studies have demonstrated an association between low fibrinogen levels early in a PPH and total blood loss [ , , ], hence early recognition and treatment can potentially improve outcomes in these cases.

Hypofibrinogenemia becomes more prevalent with higher magnitudes of blood loss. For instance, hypofibrinogenemia occurs in 17% of PPH cases with blood loss exceeding 2500 mL and in 26% of cases with a blood loss surpassing 3000 mL [ , ]. In cohorts with major obstetric hemorrhage, such as women requiring ≥5 units RBC transfusion within a 4-h period or ≥8 units RBC transfusion in total, 40–50% have fibrinogen levels <2 g/L [ ]. Based on UK Obstetric Surveillance System (UKOSS) data, among women with median blood loss of 6000 mL, there was >60% incidence of hypofibrinogenemia [ ].

Findings from several studies indicate that pre-emptive exposure to fibrinogen concentrate in patients with mild or moderate PPH does not reduce the risk of transfusion or additional blood loss compared to placebo. Wikkelso et al. conducted a randomized trial involving 245 women with PPH, where participants were pre-emptively allocated 2g fibrinogen concentrate or placebo. In this study, PPH was classified as a blood loss >1L (post-cesarean delivery); a blood loss >500 mL with intended placental delivery (post-vaginal delivery); or a blood loss >1L and intended uterine exploration after placental removal (post-vaginal delivery). No between-group differences were reported in transfusion requirements (20% fibrinogen group vs. 22% placebo group; p = 0.88). No other differences were observed for pre-specified secondary outcomes, including blood loss after randomization, hemostatic intervention, or death [ ]. In the FIDEL trial of 437 patients, women with persistent PPH (blood loss ≥500 mL) requiring intravenous prostaglandin treatment after vaginal delivery were randomized to receive 3g of fibrinogen concentrate or placebo. No between-group differences were reported in the composite outcome for treatment failure (comprising at least 4 g/dL hemoglobin decrease and/or RBC transfusion ≥2 units); 40% fibrinogen group vs. 42% placebo group; p = 0.96 [ ]. The absence of a clinically meaningful benefit from exposure to fibrinogen concentrate exposure likely stems from the fact that only a very small percentage of patients (ranging from 1 to 2.2%) in both study cohorts exhibited hypofibrinogenemia (plasma fibrinogen level ≤2 g/L) at the time of study enrolment.

Findings from this body of research suggest that pre-emptive exposure to fibrinogen concentrate in patients with mild-to-moderate PPH and a fibrinogen level ≥2 g/L has no clear beneficial effect on reducing morbidity. Given the lack of benefit from pre-emptive administration of fibrinogen concentrate in patients with non-severe PPH and normal fibrinogen levels at the time of administration, those with reduced fibrinogen levels (<2 g/L) may potentially derive the greatest benefit from fibrinogen concentrate.

5.2

Thrombocytopenia

Thrombocytopenia is relatively uncommon in patients with mild to moderate PPH (1.3–5.1%), but the incidence substantially increases (up to 50%) in patients with severe or life-threatening hemorrhage ( Table 2 ). Jones et al. investigated thrombocytopenia (<75 × 10 ⁹ /L) among patients with PPH. They demonstrated that a platelet transfusion was only required with large volume blood loss (>5000 mL) or if bleeding was associated with placental abruption or pre-existing thrombocytopenia [ ].

5.3

Other clotting factor derangements

Prolongation of the PT and aPTT indicates clotting factor depletion. The incidence of a prolonged PT or aPTT is very low in patients with mild-to-moderate PPH (0.2–0.5%; Table 1 ). The likelihood of developing a prolonged PT or aPTT increases with worsening PPH severity, with the highest incidence observed in patients with massive PPH (13% and 18%).

The change in clotting factor levels and thrombin generation related to bleed volume was investigated in 136 women without early coagulopathy in a single centre prospective observational study [ ]. A linear fall in all clotting factors, other than platelets and factor VIII was reported. The authors suggested that the initial rise in factor VIII levels stemmed from its function as an acute stress response protein. The increase served to sustain thrombin generation until substantial blood losses (>4000 mL) occurred.

5.4

Coagulopathy and clear fluid resuscitation

Another important consideration during significant blood loss is the potential impact of intravenous fluid resuscitation on diluting plasma, consequently reducing the concentration of coagulation factors. While this phenomenon has been studied in hemorrhage during major surgery and trauma settings [ ], evidence in PPH is relatively limited. Two studies from the Netherlands investigating fluid administration in PPH found that increasing volumes of IV fluids correlated with significant decreases in coagulation parameters. Additionally, in a severe PPH cohort, more than 4000 mL of clear fluid prior to RBC transfusion was associated with worse maternal outcomes (measured as composite of maternity mortality, hysterectomy, arterial embolization or intensive care unit admissions) and more severe changes in coagulation [ , ]. In contrast, a single centre study of 252 women with ongoing PPH of >500 mL found no difference in coagulation parameters, blood transfusion requirements or adverse events between restrictive (0.7–1 mL per 1 mL blood loss) and liberal (>1.5 mL per 1 mL blood loss) clear fluid resuscitation. However, in this study, participants exited the study protocol once blood loss exceeded 1500 mL and the actual difference in fluid volume infused to the two groups was only 500 mL [ ]. Further research is therefore required to understand optimal strategies for clear fluid resuscitation during PPH, including avoidance of coagulation factor dilution.

5.5

Etiologies of coagulopathy

The majority of obstetric hemorrhage is caused by uterine atony, surgical and/or genital tract trauma (>80%), yet coagulation is often preserved unless bleeding is massive. This was illustrated in a report describing severe hemorrhage cases (>1500 mL) in which the observed incidence of hypofibrinogenemia in the whole cohort was only 5% yet when subdivided into different PPH aetiologies, the incidence was lower (only 3%) for both uterine atony and genital tract trauma [ ].

Abnormal placental implantation is the leading cause of massive blood loss. In cases of abnormal placental implantation, precipitous blood loss can rapidly induce coagulopathy due to both depletion and dilution of clotting factors. This was exemplified by Green et al. who described 29 cases of placenta accreta and massive hemorrhage (median blood loss 6000 mL) and found that 60% of cases exhibited fibrinogen levels <2 g/L at the time of initial blood sampling [ ].

5.6

Coagulopathy unrelated to volume of blood loss

Coagulopathy has been described in cases of placental abruption and amniotic fluid embolism (AFE) [ , ]. In both etiologies, coagulation impairment can occur early or even before bleeding is observed and is often unrelated to blood loss volume, with disproportionately low fibrinogen levels and signs of hyperfibrinolysis being recurrent features [ ]. This was highlighted by data describing massive PPH (≥8 units RBC transfusion), in which those with placental abruption had the lowest first fibrinogen levels and largest fall in platelet count [ ]. Additional data from massive PPH cases (>2500 mL blood loss) in the OBS Cymru quality improvement project found that the etiologies with the highest proportion of fibrinogen levels <2 g/L and/or a ROTEM FIBTEM A5<12 mm recorded during the bleeding were both abruption and AFE [ ]. In a separate observational study from a single center in the UK, patients with obstetric hemorrhage from abruption had substantially increased fibrinogen concentrate requirements compared to PPH cases resulting from uterine atony or surgical trauma [ ], with the highest doses (18 g) administered to two patients with abruption associated with intrauterine death.

Alternative causes of coagulopathy unrelated to volume of blood loss include sepsis and pre-eclampsia incorporating hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome [ , , ].

In a recent prospective observational study by De Lloyd et al., a distinct coagulopathic phenotype – Acute Obstetric Coagulopathy (AOC) – was characterized, with no correlation with blood loss volume [ ]. This coagulopathic phenotype manifested in outliers who exhibited markedly elevated markers of fibrinolysis (plasmin antiplasmin complex >40,000 ng/mL and D dimers >40,000 ng/mL), hypofibrinogenemia, dysfibrinogenemia and reduced levels of factor V and VIII. These findings are consistent with those from published case reports of AFE, in which large doses of fibrinogen replacement (for example, 14g fibrinogen concentrate) were required [ ]. Importantly, in this study, the observed coagulation changes occurred during hemorrhage due to different etiologies including abruption, uterine atony, abnormal placentation, and AFE. AOC was observed in approximately 1 per 1000 maternities and was associated with poor fetal outcomes [ ]. The critically low fibrinogen level, fibrinogen inhibition and hyperfibrinolysis seen in AOC suggests that targeted fibrinogen replacement and antifibrinolytic infusion (potentially at high doses) may be required to achieve hemostatic competence. However, further research is required to validate these findings.

6.1

Point of care tests of coagulation in pregnancy

Previous research using TEG and ROTEM has successfully identified the hypercoagulable state associated with pregnancy compared to non-pregnant controls [ ].

Longitudinal studies investigating maternal coagulation profiles using TEG and ROTEM have demonstrated increased coagulability and decreased fibrinolysis with advancing gestation. Karlsson et al. reported decreases in r-time, k-time, and fibrinolysis, alongside increases in alpha angle and MA throughout gestation [ ]. Similar longitudinal trends, including a trend towards a decrease in CT (INTEM and FIBTEM) and an increase in alpha angle (EXTEM, and FIBTEM), and MCF (INTEM, EXTEM, and FIBTEM), have been reported in two other studies using ROTEM [ , ]. Although Quantra has not been examined in PPH in the literature, good correlation (r = 0.72) between Clauss fibrinogen and fibrinogen parameters for this device have been shown in a cohort of third trimester women [ ].

6.2

Point of care tests of coagulation during obstetric hemorrhage

Studies have examined VHA profiles of patients who experienced PPH and the relationship between ROTEM FIBTEMA5, TEG Citrated Functional Fibrinogen Maximal Amplitude (CFF MA) and laboratory Clauss fibrinogen levels. In a cohort of 45 patients with major obstetric hemorrhage (estimated blood loss ≥2000 mL), TEG-MA (performed on the TEG 5000) had a strong correlation with Clauss fibrinogen (r = 0.7) [ ]. Moderate correlations between Clauss fibrinogen levels and the ROTEM sigma FIBTEM A5 (r = 0.63) and CFF MA using the TEG 6S device (r = 0.68) have also been reported in PPH [ , ]. Gillissen et al. reported stronger correlations between Clauss fibrinogen levels with FIBTEM A5 values obtained using the ROTEM sigma device compared to ROTEM delta device (r = 0.85 vs 0.70 respectively) [ ]. Evaluation of the dual platelet inhibition FIBTEM A5 has demonstrated a stronger correlation (r = 0.88) with Clauss fibrinogen when compared with the single platelet inhibitor assay [ ]. Results of ROTEM parameters should therefore be considered within device and assay specific reference values since the correlations for individual parameters, including CT and Fibtem values, may vary considerably between the ROTEM sigma and delta devices [ , ]. No study has compared TEG5000, TEG6S and laboratory fibrinogen, in pregnancy or PPH. Although close correlation between the two devices has been demonstrated in trauma studies, at present, interpretation in obstetric bleeding should remain device specific [ ].

The reliability of VHA devices to detect hypofibrinogenemia during PPH has been examined. In a prospective observational study of 521 women with PPH, ROTEM sigma FIBTEM A5 ≤11 mm had sensitivity and specificity of 0.76 and 0.96 in detecting fibrinogen levels ≤2 g/L [ ] with a negative predictive value (NPV) of 0.98. The positive predictive value (PPV) was only 0.57, partly due to the low incidence (4%) of hypofibrinogenemia. When serial FIBTEM tests were incorporated into an analysis of the performance of an algorithm (i.e. at a patient, rather than individual test level), the overall PPV increased to >0.85 due to borderline tests being repeated and integration of the clinical setting into interpretation. A recent retrospective study of 208 women with hypofibrinogenemia assessed ability of the dual platelet inhibitionor sigma FIBTEM assay in detecting fibrinogen levels <2g/L. It found a sensitivity and specificity of 0.82 and 0.94 for an A5 value of <8, a 3mm reduction when compared to the single platelet inhibition FIBTEM [ ]. In a study of the TEG 6S in a subgroup of the same cohort with PPH, the CFF amplitude by 10 min had similar sensitivity (0.74) and specificity (0.97) in detecting a fibrinogen level <2 g/L [ ]. In a retrospective cohort study of 98 women with PPH, Rigouzzo et al. reported that a TEG 5000 FF-MA value ≤ 12.7 mm had a high sensitivity (1.0) and specificity (0.92) for identifying hypofibrinogenemia (fibrinogen <2 g/L) [ ].

FIBTEM results have been shown, like fibrinogen, to be predictors of predictors of progression of blood loss [ ]. A recent retrospective study examined ROTEM parameters at the initiation of obstetric massive transfusion protocol and found that both FIBTEM and EXTEM values were significantly lower in patients who progressed to severe hemorrhage (peripartum fall in Hb concentration >4 g/dL, transfusion >4units of blood products, need for invasive procedures for hemorrhage control, ICU admission or death) [ ].

The OBS2 study incorporated ROTEM into a clinical trial examining the efficacy of fibrinogen concentrate in patients with PPH. In this randomized placebo-controlled trial, 55 patients diagnosed with PPH, ongoing bleeding, and a FIBTEM A5 ≤15 mm (approximate fibrinogen level of 3 g/L) were allocated to receive a weight-adjusted dose of fibrinogen concentrate versus placebo [ ]. No between-group difference in RBC transfusion was reported (adjusted incidence rate ratio = 0.72 (95% CI: 0.3–1.7); p = 0.45). In a subgroup analysis of patients with a FIBTEM A5 ≤12 mm at randomization, patients who received fibrinogen concentrate had fewer allogenic blood products, less blood loss, and lower intensity of postpartum care than those who received placebo [ ]. These data suggest that pre-emptive exposure to fibrinogen concentrate in patients with PPH and a FIBTEM A5>15 mm has no clear beneficial effect on reducing morbidity. Further research is needed to investigate the potential benefit of fibrinogen concentrate in patients with severe PPH and a single platelet inhibition FIBTEM A5 ≤12 mm or a dual platelet inhibition of <8.

The efficacy of ROTEM and TEG in identifying clotting factor and platelet deficiencies remains uncertain. Within PPH cohorts, the incidence of thrombocytopenia (platelet count <75 × 10 ⁹ /L) and prolonged PT and aPTT is low (see section on Coagulopathy during PPH). In an observational study which included 203 women experiencing PPH exceeding 1500 mL, only 11 had acquired hypofibrinogenemia (<2 g/L) and prolonged EXTEM CT (>100s) [ ]. The low incidence of clotting factor derangements in patients with PPH poses a clinical challenge in evaluating the reliability of VHA devices in detecting coagulation deficiencies other than hypofibrinogenemia. However, the EXTEM CT has a high negative predictive value (≥0.95) in identifying PT/aPTT abnormalities [ ]. Prolongation of the ROTEM EXTEM CT and the TEG R can therefore suggest clotting factor deficiency, but these derangements may also be corrected by fibrinogen infusion alone [ ], further complicating interpretation.

The Pltem (EXTEM A10 – FIBTEM A10) also has a high NPV (0.99) in identifying thrombocytopenia although only moderate correlation was observed between Pltem and platelet count (r = 0.42) [ ]. Moderate correlation between the Citrated rapid TEG 6S MA and platelet count in 373 women with PPH was also reported (r = 0.41) [ ]. In contrast, a strong correlation with platelet count (r = 0.79) was described in 100 women with severe PPH [ ] and, in addition, Rigouzzo found TEG 5000 K-MA ≤63.5 mm and K-alpha angle ≤64.2° had high sensitivity (0.94 and 1.0) and specificity (0.91 and 0.81) in identifying hypofibrinongenemia (≤2 g/L) and/or a platelet count <80 × 10 ⁹ /L in 98 women with ongoing PPH >500 mL [ ]. While these results may be helpful in recognizing patients with coagulation disturbance, the clinical significance of being unable to distinguish between hypofibrinogenemia and thrombocytopenia warrants further examination.

A systematic review of viscoelastic testing in obstetrics indicated that current reference ranges for ROTEM LY30 are not able to distinguish between normal lysis and hyperfibrinolysis during pregnancy [ ]. Low LY30 values have been reported after delivery in patients with PPH [ ]. However, it is unclear whether this is due to reduced lysis after delivery or an antifibrinolytic effect from early tranexamic acid exposure. These limitations highlight the challenges in identifying hyperfibrinolysis using TEG or ROTEM during PPH. However, severe hyperfibrinolysis has been identified using TEG and ROTEM in patients with life-threatening PPH from amniotic fluid embolism (see section on Coagulopathy unrelated to blood volume).