CME Haematology Clinical Medicine 2013, Vol 13, No 2: 200–2 why infusion of FFP before the PT becomes Treating a coagulopathy is not the same as Uses and abuses of prolonged could be key to preventing treating bleeding and there is no clear evi- (deteriorating) coagulopathy. dence that reversing coagulopathy results fresh frozen plasma in a reduction in bleeding.4 There are well- How does FFP treat coagulopathy? recognised risks to FFP transfusion and for the treatment of one study found that when trauma patients Several mechanisms have been proposed who did not require a massive transfusion bleeding for reduction in bleeding and improvement were transfused with FFP, there was a dose- in coagulopathy seen in patients who are related increase in adult respiratory distress MJ Desborough,1 academic clinical fellow in transfused with FFP. syndrome, multi-organ failure, pneumonia haematology and transfusion medicine; and sepsis.5 1 FFP contains procoagulant and anti- SJ Stanworth,1 consultant haematologist and fibrinolytic factors, which might senior clinical lecturer in blood transfusion Evidence to support FFP transfusion replenish those lost through acute medicine; NS Curry,2 consultant for bleeding patients haematologist in haemostasis and bleeding. thrombosis 2 When patients are resuscitated with The majority of the evidence for the recent 1NHS Blood and Transplant, John Radcliffe FFP rather than crystalloid or colloid, change in transfusion practice comes from Hospital, Oxford University Hospitals NHS they are less likely to develop a dilu- studies of major bleeding in trauma 1 Trust, Headington, Oxford, UK; 2Oxford tional coagulopathy. patients. These studies often involve young Haemophilia and Thombosis Centre, Churchill 3 FFP contains fibrinogen, which replen- patients who have no comorbidities, and Hospital, Oxford University Hospitals NHS ishes losses during bleeding. It is pos- their findings can be extrapolated only Trust, Headington, Oxford, UK sible that early fibrinogen use could be with caution to other patient groups who superior to FFP for patients with major might have more complex medical needs – bleeding, but this remains to be deter- for example, to patients with liver disease Background mined.3 or major gastrointestinal bleeding. Transfusion of packed red blood cells Table 1. Mechanisms of coagulopathy in bleeding patients. (PRBC) to maintain critical oxygen delivery can be lifesaving for patients who have Underlying disease Mechanisms of coagulopathy major bleeding. In addition to PRBC, All types of major haemorrhage Consumption of clotting factors transfusion of blood components, including Dilution (with crystalloid and packed red blood cells) fresh frozen plasma (FFP), is frequently considered. There is, however, uncertainty Hypoxia (endothelial activation), acidosis and hypothermia (inhibition of clotting factor and platelet function) about the optimal schedules for FFP admin- istration or the best tests to assess effective- Anaemia (leading to reduced axial blood flow and reduced contact time between clotting factors and endothelium) ness. Coagulopathy in patients with major bleeding (who have at least four units of Acute coagulopathy of trauma Local consumption of clotting factors at the site of injury PRBC transfused in the first 2–4 hours of Hyperfibrinolysis (increased clot breakdown) bleeding)1 is typically defined and moni- Liver disease Deficiencies of procoagulant and anticoagulant proteins tored by prothrombin time (PT) or inter- (both are synthesised in the liver) national normalised ratio (INR), but these Hypo- or dys-fibrinogenaemia tests have recognised limitations in their Hyperfibrinolysis ability to provide a relevant or global assess- Thrombocytopenia (thrombopoietin is synthesised in the ment of haemostatic potential. liver) The causes of coagulopathy in patients Anaemia (reduced axial blood flow) with major bleeding are varied and com- plex (Table 1). Historically, coagulopathy Disseminated intravascular Consumption of clotting factors, fibrinogen and platelets coagulation was thought to result from dilution of pro- coagulant clotting factors following infu- Hyperfibrinolysis sion of PRBC and crystalloids; but it is now Many precipitants have been identified including sepsis, recognised that in trauma haemorrhage, a trauma, severe organ dysfunction (eg pancreatitis), malignancy, severe liver failure, obstetric causes (eg pre- coagulopathy (the ‘acute coagulopathy of eclampsia) and acute haemolytic transfusion reactions trauma’) might be evident before resuscita- Warfarin Inhibition of vitamin-K-dependent procoagulant factors tion fluids and PRBC have been adminis- (II VII, IX and X) and anti-coagulant factors (protein C 2 tered. This discovery promotes early use of and protein S) plasma for trauma patients, and explains 200 © Royal College of Physicians, 2013. All rights reserved. CCMJ13-2-200-202-CME-Curry.inddMJ13-2-200-202-CME-Curry.indd 220000 33/20/13/20/13 99:57:22:57:22 AAMM CME Haematology Major bleeding associated with Patients with gastrointestinal bleeding Warfarin reversal trauma might have underlying liver disease, which is characterised by complex changes in Major bleeding in a patient taking warfarin In the past, ‘reactive’ infusions of FFP were haemostasis (Table 1). A prolonged PT in a (defined as life- or limb-threatening typically prescribed only after abnormalities patient with liver disease is often assumed bleeding that requires reversal in less than of PT were documented, but there is now a to represent ‘auto-anticoagulation’, but fre- 6–8 hours) should, in preference, be treated move towards the pro-active administration quently this is not the case as many of these with a combination of intravenous vitamin of FFP, aimed at preventing deterioration in patients have a propensity towards throm- K and prothrombin complex concentrate 11 coagulopathy. An empirical formula-driven bosis or have balanced haemostasis.8 (PCC). FFP is considerably less effective approach is often used, defined by a high Patients with liver disease often have other at reversing warfarin over-anticoagulation ratio of FFP transfusions to PRBC reasons to bleed, which can be more impor- than PCC. A commonly referenced study of approaching 1:1. Although the results appear tant than coagulopathy, such as increased reversal of warfarin over-anticoagulation promising, the limited evidence to support portal venous pressure. If extrapolated recruited and compared 12 patients who improved patient outcomes and reduced from trauma practice, early or excessive use received vitamin K and FFP to 29 patients mortality when this near 1:1 approach has of plasma could lead to excessive volume who received vitamin K and PCC. None of been used should be recognised. The obser- replacement and exacerbate portal hyper- the patients who received FFP completely vational studies that have been carried out tension. corrected their coagulopathy, whereas all suffer from survivorship bias (only those the patients in the PCC group achieved this that survived long enough were likely to Disseminated intravascular rapidly.12 There is, however, much less have received FFP).6 When this was taken coagulation information on whether more rapid into account, Snyder et al7 found no signifi- changes in laboratory-defined coagulop- Disseminated intravascular coagulation cant reduction in mortality for patients who athy translate into improved clinical out- (DIC) is predominantly a prothrombotic received high ratios of FFP. It is possible that comes. FFP is only recommended for the condition in which clotting factors, plate- concentrated sources of fibrinogen, such as reversal of warfarin over-anticoagulation if lets and fibrinogen are rapidly consumed. cryoprecipitate, might prove superior to FFP PCC is not readily available. The most important part of managing DIC in this setting, but their role remains to be is identifying and treating the underlying determined.3 cause. A bleeding patient with DIC and a Conclusions PT or activated partial thromboplastin time Major bleeding in settings outside In summary, FFP is commonly used in (APTT) greater than 1.5 times the upper trauma patients with major haemorrhage. Outside limit of normal should be transfused with trauma, there is little evidence to inform At present, there is a tendency to apply FFP, although there is no randomised con- the optimal use of FFP, and there is a trauma major haemorrhage protocols to trolled trial evidence to support this. FFP is pressing need for new clinical studies to other patient groups with bleeding. not recommended for patients who are not define best transfusion support. Locally Therefore, FFP might commonly be given bleeding.9 An exception to this rule is in the agreed major haemorrhage protocols pro- in combination with PRBC as part of a treatment of DIC in patients with acute vide a structured framework to guide the general massive-haemorrhage protocol. promyelocytic leukaemia. These patients transfusion of FFP and all blood compo- But many patients, such as those with gas- are at very high risk of bleeding and aggres- nents, ensuring that blood components can trointestinal bleeding, are often older than sive treatment of clotting abnormalities be accessed rapidly and appropriately. In an the typical trauma patient and have very until PT or activated partial thromboplastin emergency situation, delivering blood com- different comorbidities. are normalised is indicated.10 ponents, including FFP, rapidly can present Key points logistic difficulties,