Uses and Abuses of Fresh Frozen Plasma for the Treatment of Bleeding

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 administration 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 complex (Table 1). Historically, coagulopathy Disseminated intravascular Consumption of clotting factors, fibrinogen and platelets coagulation was thought to result from dilution of procoagulant 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

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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, so the Care Quality Commission recommends that a major The causes of coagulopathy in patients with major bleeding are varied. They include haemorrhage protocol should be in place in the dilution and consumption of clotting factors, hyperfibrinolysis, hypoxia, acidosis 13 and anaemia every hospital.

Some of the protocols for treatment of coagulopathy in trauma advocate using a 1:1 ratio of fresh frozen plasma (FFP) and packed red blood cells (PRBC), but the evidence References base for formula driven transfusion strategies is limited. There are concerns about 1 Harris T, Thomas GO, Brohi K. Early fluid extrapolating these strategies to patients with major bleeding outside trauma resuscitation in severe trauma. BMJ 2012;345:e5752. Prothrombin complex concentrate (PCC) rather than FFP should be used to reverse 2 Hess JR. Blood and coagulation support in warfarin over-anticoagulation trauma care. Hematology Am Soc Hematol Patients with disseminated intravascular coagulation (DIC) should only be treated Educ Program 2007:187–91. with FFP if they are bleeding 3 Rourke C, Curry N, Khan S et al. Fibrinogen levels during trauma KEY WORDS: coagulopathy, bleeding, fresh frozen plasma haemorrhage, response to replacement

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therapy, and association with patient 8 Tripodi A, Mannucci PM. The coagulop- reversal: the relative efficacy of infusions outcomes. J Thromb Haemost athy of chronic liver disease. N Engl J Med of fresh frozen plasma and clotting 2012;10:1042–51. 2011;365:147–56. factor concentrate on correction of the 4 Curry N, Hopewell S, Doree C et al. 9 Levi M, Toh CH, Thachil J et al. Guidelines coagulopathy. Thromb Haemost 1997;77: The acute management of trauma for the diagnosis and management of dis- 477–80. haemorrhage: a systematic review of seminated intravascular coagulation. British 13 National Patient Safety Agency. Rapid randomized controlled trials. Crit Care Committee for Standards in Haematology. Response Report. The transfusion of blood 2011;15:R92. Br J Haematol 2009;145:24–33. and blood components in an emergency. 5 Inaba K, Branco BC, Rhee P et al. Impact 10 Sanz MA, Grimwade D, Tallman MS NPSA: London, 2010. www.nrls.npsa.nhs. of plasma transfusion in trauma patients et al. Management of acute promyelocytic uk/alerts/?entryid45=83659 [Accessed 26 who do not require massive transfusion. leukemia: recommendations from an expert February 2013]. J Am Coll Surg 2010, 210:957–65. panel on behalf of the European 6 Curry NS, Davenport RA, Hunt BJ et al. LeukemiaNet. Blood 2009;113:1875–91. Transfusion strategies for traumatic coagu- 11 Keeling D, Baglin T, Tait C et al. Guidelines Address for correspondence: lopathy. Blood Rev 2012;26:223–32. on oral anticoagulation with warfarin — Dr NS Curry, Oxford Haemophilia and 7 Snyder CW, Weinberg JA, McGwin G Jr fourth edition. Br J Haematol et al. The relationship of blood product 2011;154:311–24. Thrombosis Centre, Churchill Hospital, ratio to mortality: survival benefit or 12 Makris M, Greaves M, Phillips WS Old Road, Oxford OX3 7LE. survival bias? J Trauma 2011;66:358–62. et al. Emergency oral anticoagulation Email: [email protected]

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