Fibrinogen replacement in trauma haemorrhage

There is a growing interest in the role that fibrinogen plays in major haemorrhage. It has been known since 1995 that fibrinogen is one of the first coagulation proteins to fall to critically low levels during major blood loss [1], but the clinical relevance of this is only now being evaluated. Injury is the leading cause of death worldwide for patients aged 1-45 and accounts for 7,800 deaths in UK annually. Uncontrolled haemorrhage is the most common treatable cause of death in this population; four out of every ten trauma patients die as a result of exsanguination, or its late effects. Most trauma deaths from haemorrhage occur within the first six hours of hospital admission and early control of bleeding may have a significant impact on mortality. By increasing understanding of the precipitants of uncontrolled bleeding (i.e. acute traumatic coagulopathy) and targeting therapy accordingly, it is expected that major haemorrhage therapy and more importantly, clinical outcomes, can be further improved. This short review briefly evaluates what is known about fibrinogen during major trauma haemorrhage, focusing on the changes that take place during traumatic coagulopathy and the role that fibrinogen supplementation may play in treatment of trauma haemorrhage. Transfusion therapy is an integral and costly part of supportive treatment for major blood loss. A large UK epidemiological study of patients with traumatic haemorrhage reported the annual cost to the NHS of treating major haemorrhage was £168 million (2012 prices) (NIHR PGfAR: ‘Traumatic Coagulopathy & Massive Transfusion: Improving Outcomes & Saving Blood, 2013). Early haemorrhage control may reduce this cost but high quality evidence evaluating transfusion practice for trauma haemorrhage is lacking. The results of a recently completed North American study, PROPPR (NCT01545232) which evaluated the effect of different ratios of blood components (1:1:1 vs. 1:1:2 FFP: platelets:RBC) on mortality in 680 trauma patients are eagerly awaited. Thrombosis, as an appropriate response to bleeding, is critically dependent on fibrinogen. Fibrinogen is cleaved and activated by thrombin to produce insoluble fibrin strands which form the basis of a stable clot. Fibrinogen also acts as the ligand for platelet aggregation, thus localising platelets to a developing clot. FXIIIa then modifies the fibrin matrix by binding to, and cross-linking, fibrin strands and this leads to stabilisation and increased resistance of the clot to fibrinolysis (FXIIIa covalently binds alpha-2 anti-plasmin to fibrinogen). Fibrinogen levels fall early during major haemorrhage reflecting many ongoing processes, including: factor consumption, dilution (as a result of fluid therapy), fibrinolysis and fibrinogenolysis. Increased fibrinolysis has been shown to be a major component of acute traumatic coagulopathy [2] and is likely due to both the high levels of free tPA released immediately after injury and the inhibition of PAI-1 by activated protein C; resulting in increased plasmin generation and clot degradation. Moreover, the effects of fibrinolysis are likely exacerbated in trauma haemorrhage by low fibrinogen levels, since fibrin strands formed in a hypofibrinogenaemic environment are more susceptible to lysis. These changes in fibrinolysis have now been tested in a large trial of tranexamic acid [3]. Hypofibrinogenaemia has been shown to be an important component of traumatic coagulopathy [4]. A recent prospective analysis of 517 trauma patients demonstrated that coagulopathic patients had significantly lower fibrinogen levels (1.6 g/L vs. 2.4 g/L; p < 0.001) upon arrival in the emergency department compared to non-coagulopathic patients [5]. Fibrinogen levels fell in association with rising base deficit; falling systolic blood pressure and high injury severity (ISS ≥ 25). The same group also demonstrated that the presence of hypofibrinogenaemia (i.e. < 1.5 g/L) at hospital admission was an independent predictor of mortality, both at 24 hours and 28 days [5]. Department of Haematology, Oxford Haemophilia & Thrombosis Centre, Oxford, UK Full list of author information is available at the end of the article Curry et al. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 2014, 22(Suppl 1):A5 http://www.sjtrem.com/content/22/S1/A5