Postpartum hemorrhage (PPH) is a leading cause of maternal morbidity and mortality worldwide (Obstet Gynecol 2017;130:366-73; BMC Pregnancy Childbirth 2009;9:55). Nearly half of all severe maternal morbidity in the United States is related to PPH (BMC Pregnancy Childbirth 2009;9:55). Physiologic changes of pregnancy result in adaptations seen in pregnant patients’ coagulation profile that aid in limiting the bleeding associated with PPH. Fibrinogen, a key factor in clot formation, increases throughout pregnancy, peaking in the third trimester with normal fibrinogen at term of 4-6 g/L being double that of nonpregnant patients (Br J Anaesth 2012;109:851-63; Curr Opin Anaesthesiol 2015;28:275-84). Fibrinogen has been identified as an early marker of severe PPH, with each 1 g/L decrease in fibrinogen resulting in a 2.6-fold increased odds of severe hemorrhage (J Thromb Haemost 2007;5:266-73). Further, hypofibrinogenemia defined as <2 g/L has a specificity of 99% for progression to severe hemorrhage, and as such should be used as an early marker for hemorrhage progression (Br J Anaesth 2012;108:984-9).
Fibrinogen replacement can be achieved with the administration of fresh frozen plasma (FFP), cryoprecipitate, or fibrinogen concentrate. Each of these comes with its own advantages and disadvantages. While FFP is widely available and can be quickly prepared, it must be ABO compatible, and with a fibrinogen concentration of 2 g/L, its ability to replete fibrinogen is limited. Cryoprecipitate does not require crossmatch and has a higher concentration of fibrinogen at 15 g/L. Although cryoprecipitate is an excellent source of fibrinogen, it has multiple disadvantages, including cost, risk of transfusion reactions, infection, and the potential for alloimmunization. Further, delay due to preparation time and limited availability because of the COVID-19 pandemic potentially dissuade its use in early hemorrhage (PLoS One 2022;17:e0265171). Fibrinogen concentrate is a pasteurized concentrate made from pooled human plasma that provides 1 g of fibrinogen per vial and has been demonstrated to correct hypofibrinogenemia (Int J Obstet Anesth 2010;19:218-23). A single dose of fibrinogen concentrate is expected to raise a patient’s fibrinogen by 0.25 g/L. Fibrinogen concentrate can be rapidly prepared in 5-8 minutes and is stable at room temperature, simplifying access and availability. It also avoids the typical risk profile associated with allogenic transfusions. Disadvantages of using fibrinogen concentrate include cost and the use of multiple doses to achieve the same increase in fibrinogen as a single unit of cryoprecipitate.
As of yet, there are no head-to-head comparisons of the varying methods of fibrinogen replacement in PPH in the literature. While the only current FDA-approved use for fibrinogen concentrate is congenital hypofibrinogenemia, it is a clear and obvious therapeutic option for fibrinogen replacement in PPH (Int J Obstet Anesth 2010;19:218-23). In the obstetric anesthesia literature, use of fibrinogen concentrate has focused on early administration in the setting of PPH at predefined clinical times. Wikkelsø et al. chose to administer 2 g of fibrinogen concentrate at the time of hemorrhage. While there was a significant increase in fibrinogen levels in the fibrinogen concentrate cohort compared to placebo, there was no difference in the need for red blood cell transfusion between groups (Br J Anaesth 2015;114:623-33). Alternatively, Ducloy-Bouthors et al. randomized women to receive 3 g of fibrinogen concentrate at the time of conversion from oxytocin to prostaglandins for second-line uterotnics. Similarly, there was no difference in hemoglobin decrease or need for transfusion between groups (BJOG 2021;128:1814-23). Despite both studies demonstrating that early administration did not improve hemostatic outcomes, there was also no evidence of increased thromboembolic events in patients receiving fibrinogen concentrate, alleviating some of the safety concerns about its administration in this hypercoagulable patient population (Br J Anaesth 2015;114:623-33; BJOG 2021;128:1814-23).
A quantitative approach to the patient suffering PPH is crucial and includes quantitative blood loss and timely laboratory evaluation. There are two primary methods to measure plasma fibrinogen: directly by the Clauss fibrinogen assay, and indirectly by viscoelastic point-of-care testing. Viscoelastic point-of-care testing allows for rapid in-vivo analysis of coagulation and has been validated as a predictive measure of progression to severe PPH (Blood 2014;124:1727-36). These advancements allow for early and repeated evaluation of coagulation status as hemorrhage progresses. The Obstetric Bleeding Study 2 was a randomized control trial evaluating administration of fibrinogen concentrate at the time of hemorrhage using a quantitative trigger defined as a FIBTEM A5 of ≤15 mm (Br J Anaesth 2017;119:411-21). There was no difference between groups in transfusion requirements; however, subgroup analysis of patients with a FIBTEM A5 of <12 mm demonstrated decreased blood product transfusion when fibrinogen concentrate was administered compared to placebo (Br J Anaesth 2017;119:411-21). Despite not reaching statistical significance due to small sample size, it suggests using a FIBTEM A5 <12 mm as a therapeutic threshold to replete fibrinogen with fibrinogen concentrate in PPH. In a prospective observational trial, Malliah et al. compared a “shock pack” PPH protocol, involving early transfusion and fibrinogen replacement with FFP and cryoprecipitate, to an updated PPH protocol with emphasis on ROTEM evaluation and transfusion of fibrinogen concentrate when FIBTEM A5 was <12 mm (Anaesthesia 2015;70:166-75). Though not a direct comparison of cryoprecipitate to fibrinogen concentrate, the study showed how a viscoelastic point-of-care evaluation in combination with fibrinogen concentrate can decrease transfusion of allogenic blood products.
The management of PPH has evolved dramatically over the last decade. Fibrinogen has emerged as a therapeutic target and an early biomarker of severe hemorrhage. While continued work is needed to determine the efficacy of fibrinogen concentrate compared to cryoprecipitate, there is a clear body of literature that supports the safe use of fibrinogen concentrate in PPH. As experts in resuscitation and transfusion medicine, anesthesiologists play a crucial role in the management of PPH and are stewards of judicious transfusion. Focusing our clinical efforts on early goal-directed fibrinogen replacement will improve PPH management and prevent the unnecessary use of blood products.