The role of fibrinogen and haemostatic assessment in postpartum haemorrhage: preparations for a randomised controlled trial.

Pregnancy is a state of hypercoagulobility that might be an evolutionary way of protecting parturients from exsanguination following child birth. Observational studies suggest an association between a low level of fibrinogen (coagulation factor I) at the start of postpartum haemorrhage (PPH) and subsequent severity of bleeding. Fibrinogen concentrate may be prescribed to correct acquired hypofibrinogenaemia, but evidence is lacking regarding the treatment efficacy. This thesis assesses the current evidence for the use of fibrinogen concentrate and haemostatic assessment in bleeding patients with special attention to the obstetrical population. It includes five papers: In Paper I the benefits or harms of fibrinogen concentrate in bleeding patients in general was evaluated using a systematic Cochrane review methodology with metaanalysis of all published randomized controlled trials (RCTs). Six trials with high risk of bias were included (248 patients). Fibrinogen appeared to reduce the need of allogenic transfusions by 53%. However, the included trials were conducted only in an elective surgical setting with a population of mainly cardiac surgical patients. Paper II was also a systematic review based on Cochrane methodology evaluating the use of viscoelastic haemostatic assays to guide haemostatic transfusion in bleeding patients. Nine RCTs (776 patients) with high risk of bias were included primarily in elective cardiac surgical patients and none were specific for the obstetric subpopulation. Viscoelastic haemostatic assay guided transfusion algorithm reduced blood loss and the proportion of patients exposed to fresh frozen plasma (FFP) or platelets. In both studies, we were unable to make firm conclusion on our primary outcome, "all cause mortality" due to lack of adequate data. Paper III was based on two national Danish registries evaluating the predictability of postpartum blood transfusion. Prediction was found difficult. However, retained placental parts seemed to be the strongest predictor. Since this diagnosis is made very late and often in association with the onset of bleeding, tools to perform an early diagnosis is highly warranted. Paper IV includes recommendations of the European Society of Anaesthesiology regarding the use of fibrinogen concentrate in PPH, and is based on very weak (GRADE 2) evidence and low confidence in estimates of effect (GRADE C). Paper V describes the protocol for a RCT of early fibrinogen supplementation in women with severe postpartum haemorrhage. Several practical, ethical and trial management challenges need to be addressed when conducting independent clinical research involving parturients with severe bleeding, placebo-controlled and blinded administration of a drug in a multicenter set-up with enrolments during the entire day and with many personnel involved.