Oliver Grottke, MD, PhD
Postpartum haemorrhage (PPH) causes 35% of maternal deaths at the time of childbirth, making it the leading cause of peripartum maternal mortality.1This type of bleeding differs from other settings in that substantial blood loss of 500 mL can occur before it is considered to be clinically relevant.2During pregnancy, there are profound alterations in the coagulation system (Figure 1), resulting in a procoagulant status.3,4
Figure 1. Changes in haemostatic variables observed during pregnancy.4
Fibrinogen plays a crucial role in coagulation, serving as the precursor to fibrin, which is an essential constituent of blood clots. Many studies have shown that low fibrinogen levels are associated with increased risk of bleeding.5-7Thus, fibrinogen supplementation is considered a key element of coagulation management.
Hypofibrinogenaemia is defined as ‘a deficiency of fibrinogen in the blood’, which implies a level below the normal range.8Among pregnant women the normal range is 4–7 g/L.9Plasma fibrinogen levels correlate with the incidence and severity of PPH. A large retrospective study found that plasma fibrinogen recorded within 24 hours of delivery was the parameter that correlated best with haemorrhage volume during PPH.10Fibrinogen levels <2 g/L are independently associated with prolonged bleeding events and have a positive predictive value of 100% to predict progression to severe PPH.5,11,12In peripartum women, therefore, a plasma fibrinogen concentration below 2 g/L may be considered as a critical level.13
Point-of-care viscoelastic coagulation monitoring can offer a surrogate assessment of fibrinogen level by measuring the strength of the fibrin-based clot. In peripartum women, the normal range for FIBTEM MCF is reported as 13–45 mm, and for FIBTEM A10 as 12–38 mm.14
Options for fibrinogen therapy
Fresh frozen plasma is of limited use in PPH because the concentration of fibrinogen in this product is often ~2 g/L.15Restoration of the patient’s plasma fibrinogen to ≥2 g/L requires a therapeutic agent with levels well above 2 g/L, meaning that either cryoprecipitate or fibrinogen concentrate should be used.
In a number of European countries, cryoprecipitate is not used because of safety concerns.16Unlike cryoprecipitate, all fibrinogen-concentrate products undergo multiple viral inactivation/removal procedures during manufacture to ensure safety.7In addition, the dose provided by fibrinogen concentrate is highly consistent, and the time needed for administration is typically shorter than with cryoprecipitate. Therefore, although the concentration of fibrinogen in cryoprecipitate may be adequate, there are reasons to favour the use of fibrinogen concentrate.
Studies of fibrinogen supplementation in PPH
Two large randomised controlled trials on fibrinogen supplementation have been published in recent years. The first of these investigated early, pre-emptive administration of 2 g fibrinogen concentrate to patients with PPH regardless of their plasma fibrinogen level or bodyweight.17Study participants with a mean pre-treatment plasma fibrinogen level of 4.5 g/L received fibrinogen concentrate or placebo. There was no significant difference in the percentage of patients receiving red blood cells (fibrinogen concentrate, 20%; placebo, 22%). In the second study, women with PPH and FIBTEM A5 ≤15 mm were treated with fibrinogen concentrate or placebo. The ratio for transfusion of allogeneic blood products (fibrinogen concentrate vs placebo) was 0.72 (statistical significance not reached). The authors concluded that fibrinogen concentrate did not improve outcomes in patients with FIBTEM A5 ≤15 mm, but a beneficial effect in patients with FIBTEM A5 ≤12 mm (or plasma fibrinogen level ≤2 g) cannot be excluded.
Other studies have reported more positive results. One study showed that the introduction of goal-directed treatment with fibrinogen concentrate for patients with FIBTEM A5 <7 mm reduced overall transfusion by 51%, with statistically significant reductions in the use of cryoprecipitate, FFP, platelets, and red blood cells.18In July 2009, the Irish Blood Transfusion Service replaced cryoprecipitate with fibrinogen concentrate, and the impact of this change was assessed. Fibrinogen concentrate was found to be as efficacious as cryoprecipitate for correction of hypofibrinogenemia.19In another study of PPH patients, early administration of fibrinogen and FFP increased the mean plasma fibrinogen levels from 3.3 g/L to 4.4 g/L and enabled a 99% survival rate.20
Routine use of fibrinogen concentrate in diverse perioperative bleeding settings has a favourable safety profile (e.g., extremely rare reports of thrombotic complications).21No safety signal has been identified in the PPH setting.
Treatment algorithms and guidelines for managing PPH
Use of fibrinogen supplementation in PPH has been advocated in a number of treatment algorithms. In one example, fibrinogen concentrate is recommended as the initial intervention for patients with hypofibrinogenemia,22while in two further algorithms it is the first-line procoagulant therapy after administration of tranexamic acid.23,24Recommendations for fibrinogen supplementation are less well-defined in national and international treatment guidelines for PPH. However, the relevant guidelines acknowledge the association of fibrinogen levels below 2 g/L with severe haemorrhage and support supplementation in patients fulfilling this criterion.
Low fibrinogen levels are associated with increased incidence and severity of PPH. Two randomised controlled trials have yielded inconclusive results regarding fibrinogen supplementation in PPH; this may be attributable to a lack of focus on patients with hypofibrinogenemia (FIBTEM A5 ≤12 mm or plasma fibrinogen level ≤2 g). Other studies have shown that fibrinogen supplementation may control bleeding and decrease exposure to allogeneic blood components. National and international guidelines are aligned on the need to maintain plasma fibrinogen levels of at least 2 g/L in PPH. This topic will be discussed during the next ESA Focus Meeting in Sofia in November 2018.
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