Netherlands Journal of Critical Care Submitted November 2015; Accepted March 2016

REVIEW

Risk estimation and management of coagulopathy in ICU patients in need of an invasive procedure

M.C.A. Müller1,2, N.P. Juffermans2 1Department of Intensive Care, Medical Center Haaglanden-Bronovo, The Hague, the Netherlands 2Department of Intensive Care, Academic Medical Center, Amsterdam, the Netherlands

Correspondence M.C.A. Müller - [email protected]

Keywords - coagulopathy, , plasma, viscoelastic tests

Abstract abnormalities have a high prevalence in critically ill intervention-related bleeding complications is limited. In this patients. The most commonly used tests to assess coagulation narrative review, we discuss the assessment of bleeding risk and status include assessment of the count, prothrombin management of coagulopathy in critically ill patients in need of time, and d-dimer. However, as these tests do not an invasive procedure. A practical recommendation is given. reflect in vivo haemostatic potential, their ability to assess a potential risk of bleeding is limited. Viscoelastic tests evaluate Introduction the whole process of clot formation and degradation, but Coagulopathy has a high prevalence among critically ill their value in the assessment of bleeding risk remains to be patients,[1] and is the result of the derangement of both established. procoagulant and components of the coagulation Despite their limitations, increased / system (figure 1).[2] The procoagulant elements include the international normalised ratio values or decreased platelet endothelium, thrombocytes, individual coagulation factors and counts are the most important reasons to prophylactically fibrinogen. The anticoagulant system includes proteins C and administer plasma or to critically ill patients prior S and antithrombin. The third component of coagulation is to undergoing an invasive procedure. However, evidence that the fibrinolytic system. The inflammatory response in critical prophylactic correction of coagulation abnormalities prevents illness results in activation of the coagulation system with enhanced generation, accompanied by attenuated Bleeding fibrinolysis and reduced levels of . Altogether, this leads to a hypercoagulable state with the formation of Increased levels of VWF (micro) thrombi, associated with impaired organ perfusion Decreased levels of ADAMTS-13 Increased levels of factor VIII Vitamin K de ciency and subsequent organ failure. Ongoing coagulation processes Reduced proteins C and S and antithrombin Reduced levels of during this hypercoagulable state result in consumption of Downregulation of thrombomodulin factors II, V, VII, IX, X, XI Reduced capacity of TFPI Reduced brinogen clotting factors and thrombocytes, with ensuing deficiencies. Impaired brinolysis (increased PAI-1 and TAFI) Hereby, haemostatic balance will shift to a hypocoagulable state with an increased bleeding tendency. The most common causes of deranged coagulation in the critically ill are summarised in table 1.[2] Assessment of coagulopathy in critically ill patients is a highly relevant clinical need; however, it is characterised by multiple Figure 1. Factors influencing the haemostatic balance in critically ill limitations. The most commonly used tests, including platelet patients count and coagulation times, only reflect a limited part of the ADAMTS-13 = a disintegrin and metalloproteinase with thrombospondin haemostatic process and thus cannot reliably predict potential type 1, motif 13; PAI-1 = plasminogen activator inhibitor type I; TAFI = bleeding risk.[3] The international normalised ratio (INR) was thrombin activatable fibrinolysis inhibitor; TFPI = tissue factor pathway developed to monitor with vitamin K antagonists as inhibitor; VWF= von Willebrand factor it reflects a deficiency of vitamin K dependent coagulation

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Table 1. Causes of coagulopathy in critically ill patients Procedures were diverse and included kidney and liver biopsy, PT prolongation Thrombocytopenia as well as abdominal and thoracic drainage.[3] Results of this Consumption review were confirmed in two more recent observational Sepsis DIC DIC studies of (CVC) insertion in patients [16,17] Cardiac Extracorporeal circuits with increased INR values. In three studies evaluating the risk Enlarged spleen of placement in patients with coagulopathy, observed Drug-induced [18-20] loss bleeding rates were low and not related to INR or PT values. The Multiple trauma Multiple trauma same applies to patients undergoing percutaneous insertion of a [21,22] Major blood loss Major blood loss tracheostomy. Also, in trauma patients needing placement Decreased generation of an intracranial pressure monitor, INR was not predictive for Bone marrow dysfunction the occurrence of bleeding complications.[23] These results are Use of vitamin K antagonists in line with a recent clinical trial in critically ill patients with Renal failure coagulopathy, in which INR/ PT values did not differ between patients with and without minor bleeding after undergoing an intervention.[14] Taken together, in critically ill patients undergoing an invasive factors.[4] However, this test was not intended nor validated to procedure, PT or INR values are not predictive of the risk of assess global haemostatic potential. Viscoelastic tests such as bleeding. An explanation may be that the PT/INR provides rotational thromboelastography assess the whole process of clot information on only part of the coagulation process. Thereby, formation and degradation. Thromboelastography has shown other than to detect or estimate the level of vitamin K deficiency, to detect coagulopathy in massive bleeding.[5-10] However, it is questionable whether PT/INR should be measured prior to thromboelastography data derived from critically ill patients are invasive procedures. scarce and reference standards for this population are lacking.[11] To date, these limitations preclude the incorporation of these Platelet count tests into the standard diagnostic evaluation of critically ill Overall, studies on the predictive ability of platelet count to patients with suspected coagulopathy. Other global tests of identify patients at risk of bleeding after invasive procedures haemostasis may include thrombin generation tests. However, are limited. In addition, probably not only the count but also these tests are not available at the bedside. Also, there is a lack the platelet function determines the risk of bleeding. Tests to of available tests for clinical use to detect a defective natural determine platelet function are either cumbersome or not yet anticoagulant system, and the same applies to markers of validated (such as the platelet function analyser, fibrinolysis.[12] and rotational thromboelastometry (ROTEM) with a multiplate Altogether, due to the above-mentioned limitations, reliable functionality). Here, we will only discuss the platelet count. identification of critically ill patients with coagulopathy In retrospective studies in patients undergoing tracheotomy is difficult. In clinical practice, platelet count, prolonged or liver biopsy, an inverse relationship was found between prothrombin time (PT) or an increased INR are most frequently the platelet count and risk of bleeding, although a specific used to identify patients with coagulopathy[1] and serve as the threshold value could not be given.[24,25] Using multivariate most important trigger to prophylactically correct a suspected modelling, a retrospective study in patients undergoing CVC coagulopathy.[13] However, the efficacy of blood products to placement suggested a cut-off level of a platelet count of less correct coagulopathy is also a matter of debate,[14,15] in particular than 20,000 as an independent risk factor for bleeding.[26] In for the use of plasma. another single-centre study, bleeding outcomes were reported In the current review, we discuss the ability of these tests to predict after placement of tunnelled CVCs using ultrasonography the risk of bleeding. Also, we discuss management of coagulopathy guidance.[27] During 344 procedures performed in patients that results from critical illness, reviewing both guidelines and with a platelet count less than 50,000, including 42 cases with existing data. A practical recommendation on the assessment and a platelet count less than 25,000, no bleeding complications treatment of coagulopathy in critically ill patients is given. occurred. Of note, all practitioners in this study had extensive experience in image-guided catheter insertion, which limits Value of haemostatic tests to predict bleeding following an the generalisation of these results to settings in which invasive procedure in patients with critical illness-related operators are less experienced. coagulopathy Taken together, for commonly performed procedures on the PT/INR ICU, there seems to be a relation between platelet count and A review of 25 studies, performed in 2005, showed that an risk of bleeding after a procedure, with a possible cut-off value elevated INR was not predictive of periprocedural bleeding. of 20,000.

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Viscoelastic tests were included and the study had a variety of methodological Both thromboelastography (TEG) and ROTEM have been flaws. We conducted a multicentre randomised clinical trial on applied in different critically ill patient populations, including the effectiveness of plasma to prevent bleeding complications trauma, neurosurgical and post-cardiac arrest patients. Overall, in critically ill patients with coagulopathy and the need to evidence supporting the use of TEG/ROTEM to diagnose a undergo an intervention (TOPIC trial).[32] Patients with an INR hypocoagulable state and thereby make an estimation of bleeding between 1.5 and 3.0 were randomised to receive a prophylactic risk is limited. The main reasons for this low level of evidence dose of plasma (12 ml/kg) or not, before placement of a CVC, are heterogeneity in the design of the studies, use of different percutaneous tracheostomy, chest tube or abscess drainage. The control groups, a lack of reference standards and variability in primary outcome was occurrence of post-procedural bleeding chosen endpoints.[28] A recent trial on the applicability of TEG complications. Due to the low inclusion rate and low incidence of in sepsis patients showed an association between low functional major bleeding complications, the effect of fresh frozen plasma fibrinogen maximum amplitude and the development of (FFP) on major bleeding could not be assessed. However, the bleeding. In addition, hypocoagulability according to the other combined outcome of major and minor bleeding complications TEG variables also showed a trend toward increased bleeding did not differ between the groups.[33] This is in line with recent risk.[29] observational studies, which showed no influence of plasma This promising observation needs further validation, with administration on procedure-related bleeding complications.[16,19] determination of cut-off values, before viscoelastic testing can Of note, it can be argued whether a dose of 12 ml/kg FFP is be routinely used in clinical practice to identify patients with an sufficient to induce a more procoagulant state. However, results increased bleeding risk. from audits indicate that the use of higher doses of FFP is not deemed feasible in clinical practice.[34-36] Another randomised Efficacy of blood products to correct critical illness-related controlled trial on effectiveness of prophylactic plasma in coagulopathy and prevent bleeding complications critically ill patients with coagulopathy is not feasible, at least Plasma to correct PT/INR not in the Netherlands.[37] Although outside of the scope of The efficacy of plasma to correct INR is related to the pre- this review as it concerns another patient population, it may be transfusion level of PT/INR (figure 2). If the INR is mildly worth mentioning the efficacy of prophylactic plasma in cardiac prolonged, plasma is not very effective in correcting INR. surgery. In a meta-analysis of 14 trials, plasma was shown to Presumably, this effect is caused by the INR of the plasma decrease INR, but not prevent bleeding.[38] These findings are in product itself, which has a median INR of 1.1.[30] However, it accordance with results in the critically ill. can be questioned whether a decrease in INR is related to a In addition to a lack of evidence on effectiveness, there may be decrease in the risk of bleeding. Plasma replenishes a deficiency detrimental effects of plasma. In critically ill patients, plasma of coagulation factors but also contains anticoagulant proteins. transfusion was shown to be an independent risk factor for Thereby, the net effect of plasma on thrombin generation was the occurrence of lung injury[39-42] and was associated with an found to be negligible.[14] The question of interest is not whether increased ICU length of stay.[41-43] Also, transfusion of FFP has plasma corrects INR but whether plasma prevents bleeding. been linked to occurrence of infectious complications.[44,45] The efficacy of plasma to prevent bleeding in critically ill Several guidelines address the correction of increased PT or INR patients has been studied in a small clinical trial.[31] However, values. A clinical practice guideline from the American Association both patients with active bleeding and patients without bleeding of Blood Banks (AABB) states that the use of plasma in patients undergoing surgery or other invasive procedures in the absence of bleeding is not recommended. The panel based this recommendation on the available evidence in 2010, including a trend toward increased risk of death in this patient population and the known risks of transfusion-related acute lung injury with plasma transfusion. [46] However, other guidelines do recommend to correct an INR of more than 1.5 to prevent bleeding in the case of surgery or invasive procedures.[47-49] An overview of different guidelines published in N reduction 2008 confirmed the variation in recommendations regarding the correction of increased INR values in patients without bleeding.[50] The Dutch guideline on transfusion (CBO) recommends considering N efore transfusion plasma transfusion in patients with disseminated intravascular coagulation and the need to undergo an intervention.[51] Since then, Figure 2. Correlation of INR value before fresh frozen plasma (FFP) however, more data on the absence of efficacy of plasma to improve transfusion (12 ml/kg) and magnitude of effect of FFP transfusion[33] coagulation status and reduce risk of bleeding have emerged.

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Taken together, prophylactic administration of plasma to TEG patterns have been observed including hypercoagulable patients with an increased PT/INR is not recommended. An and hypocoagulable traces and attenuated fibrinolysis.[11,28] alternative option for further research is to assess whether Correction of a hypercoagulable state in patients with sepsis has patients with an increased bleeding risk could benefit from the only been evaluated as a sub-study of a trial on the effectiveness administration of four-factor prothrombin complex concentrate of antithrombin administration. No effect on hypercoagulability or fibrinogen. These products contain only procoagulant was observed.[57] In a mixed population of critically ill patients proteins, require less volume and are not associated with the with coagulopathy (defined as INR >1.5), transfusion of occurrence of lung injury. Their safety in terms of inducing a plasma slightly improved ROTEM EXTEM and FIBTEM thromboembolic event has not, however, been addressed. profiles. Observed increments were only small and the clinical significance of the observed improvement is questionable, Platelets as no effect on bleeding was detected.[14] Taken together, it is The TOPPS trial randomised haematology patients to the use of too premature to use ROTEM or TEG as a guide to correct prophylactic platelet transfusion versus no use of prophylactic coagulopathy and prevent bleeding in critically ill patients. platelet transfusion.[52] The trial showed that the use of In the guidelines, the use of viscoelastic tests to monitor prophylactic platelet transfusion decreased the proportion of coagulopathies is only addressed in the setting of massive patients with bleeding. However, this trial was performed in bleeding. In the European Guideline on the management haematology patients and did not concern invasive procedures. of bleeding and coagulopathy following trauma, the use In a retrospective study in critically ill patients undergoing chest of viscoelastic tests to monitor coagulation is a Class 1C tube insertion, platelet transfusion was not associated with recommendation.[58] However, no exact thresholds for the a decrease in bleeding events.[19] In patients undergoing CVC transfusion of blood components are defined, mainly due to placement, platelet transfusion did not reduce the incidence lack of agreement between experts and the lack of high-quality of bleeding.[26] Of note, as the incidence of bleeding is low, the data. The UK National Institute for Health and Care Excellence number of patients may have been too low to show a beneficial recommends the use of viscoelastic tests, specifically TEG and effect. Also, platelet function is not taken into account. In the ROTEM, in , but suggests they are only used as critically ill, platelet function may be compromised due to the a research tool in trauma and .[59] Nevertheless, the use of or the presence of renal failure. Lastly, platelet trend appears to be an increased use of these devices as standard dose is not studied. During critical illness, platelet refractoriness management during major haemorrhage. To date, ROTEM and can be a problem. TEG are not incorporated in the guidelines on prophylactic A guideline on management of disseminated intravascular use of blood products to decrease bleeding risk in critically ill coagulation published in 2008 suggests to administer platelets to patients. patients undergoing an invasive procedure at a platelet count of less than 50 x 109/l (Grade C, Level IV).[53] The Dutch guideline Practical recommendation (CBO) of 2010 recommends a platelet count of more than 50 x Based on current evidence, we make the following 109/l for most procedures, while a platelet count above 100 x 109/l recommendations for the assessment of bleeding risk and is recommended for procedures in the brain, neural system or correction of coagulopathies in critically ill patients. We have the eye.[51] The CBO further states that these recommendations chosen to report our recommendations as proposed by the are based on expert opinion or on observational data. A recently American College of Chest ; the strength of any published AABB guideline suggests to give prophylactic recommendation depends on the trade-off between the benefits platelet transfusion to patients undergoing CVC placement at a and the risks and burdens, and the quality of the evidence.[60] platelet count of less than 20 × 109/l and to patients undergoing 1. Assessment of bleeding risk following an invasive procedure: at a platelet count less than 50 × 109/l. These a. The use of PT/INR is recommended to monitor or recommendations are based on low to very low quality evidence.[54] detect a deficiency of vitamin K dependent coagulation Currently, the PACER trial is ongoing, in which patients with a factors but not to assess bleeding risk (Grade 1C; strong platelet count between 10 and 50 x 109/l in need of a CVC are recommendation, low-quality evidence). randomised to receive either prophylactic transfusion of platelets b. It is recommended to measure platelet count prior to an pooled from five donors or no transfusion. invasive procedure (Grade 1C; strong recommendation, low-quality evidence). Blood products to correct abnormal viscoelastic test results 2. Management of coagulopathy prior to an invasive procedure: Most data on correcting coagulation abnormalities detected a. In patients not using vitamin K antagonists, correction of by viscoelastic tests are gathered from actively bleeding increased PT or INR values with FFP is not recommended patients, mainly in the setting of trauma and cardiothoracic (Grade 1B, strong recommendation, moderate quality surgery.[55,56] In critically ill patients, different ROTEM and evidence).

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11. Muller MC, Meijers JC, Vroom MB, et al. Utility of thromboelastography and/ b. In patients using vitamin K antagonists, increased PT/ or thromboelastometry in adults with sepsis: a systematic review. Crit Care. INR values should be corrected by administration of factor 2014;18:R30. 12. Levi M, Meijers JC. DIC: which laboratory tests are most useful. Blood Rev. concentrate (Grade 1C; strong recommendation, low- 2011;25:33-7. quality evidence). 13. Tinmouth A. Evidence for a rationale use of frozen plasma for the treatment and prevention of bleeding. Transfus Apher Sci. 2012;46:293-8. c. Correction of low platelet count with platelet transfusion is 14. Muller MC, Straat M, Meijers JC, et al. Fresh frozen plasma transfusion fails to recommended at a level of 20 x 109/l for CVC insertion and influence the hemostatic balance in critically ill patients with a coagulopathy. J 9 Thromb Haemost. 2015;13:989-97. 50 x 10 /l for diagnostic lumber puncture (Grade 2C, weak 15. Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence recommendation, low quality of evidence). and clinical consequences. Blood. 2010;116:878-85. 16. Carino GP, Tsapenko AV, Sweeney JD. Central line placement in patients with and 3. The use of viscoelastic tests to assess bleeding risk in critically without prophylactic plasma. J Crit Care. 2012;27:529 e9-13. ill patients is recommended for research purposes only as it 17. Weigand K, Encke J, Meyer FJ, et al. Low levels of prothrombin time (INR) and platelets do not increase the risk of significant bleeding when placing central requires standardisation and determination of cut-off values venous catheters. Med Klin (Munich). 2009;104:331-5. (Grade 2C, weak recommendation, low quality of evidence). 18. Puchalski JT, Argento AC, Murphy TE, et al. The safety of thoracentesis in patients with uncorrected bleeding risk. Ann Am Thorac Soc. 2013;10:336-41. 19. Hibbert RM, Atwell TD, Lekah A, et al. Safety of ultrasound-guided thoracentesis Conclusion in patients with abnormal preprocedural coagulation parameters. Chest. 2013;144:456-63. Despite the high prevalence of coagulopathies in critically ill 20. McVay PA, Toy PT. Lack of increased bleeding after paracentesis and thoracentesis patients, there is currently no test available to reliably assess in patients with mild coagulation abnormalities. Transfusion. 1991;31:164-71. 21. Auzinger G, O’Callaghan GP, Bernal W, et al. Percutaneous tracheostomy in bleeding risk in these patients. Observational data suggest patients with severe liver disease and a high incidence of refractory coagulopathy: that insertion of CVCs, percutaneous tracheotomy and a prospective trial. Crit Care. 2007;11: R110. 22. Veelo DP, Vlaar AP, Dongelmans DA, et al. Correction of subclinical coagulation thoracocentesis can be carried out with a low risk of bleeding disorders before percutaneous dilatational tracheotomy. Blood Transfus. complications. Low platelet counts are associated with 2012;10:213-20. 23. Davis JW, Davis IC, Bennink LD, et al. Placement of intracranial pressure monitors: increased bleeding risk and correction of platelet counts below are “normal” coagulation parameters necessary? J Trauma. 2004;57: 1173-7. 20,000 should be considered in patients needing to undergo an 24. Rosseland LA, Laake JH, Stubhaug A. Percutaneous dilatational tracheotomy in intensive care unit patients with increased bleeding risk or obesity. A prospective intervention. Assessment of PT/INR does not predict bleeding analysis of 1000 procedures. Acta Anaesthesiol Scand. 2011;55:835-41. risk and correction of increased PT/INR values with plasma is 25. Seeff LB, Everson GT, Morgan TR, et al. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. not recommended. To date there are insufficient data to support Clin Gastroenterol Hepatol. 2010;8:877-83. 26. Zeidler K, Arn K, Senn O, et al. Optimal preprocedural platelet transfusion threshold the use of viscoelastic tests to assess bleeding risk. for central venous catheter insertions in patients with thrombocytopenia. Transfusion. 2011;51:2269-76. Disclosure 27. Haas B, Chittams JL, Trerotola SO: Large-bore tunneled central venous catheter insertion in patients with coagulopathy. J Vasc Interv Radiol. 2010;21:212-7. All outhors declare no conflict of interest. No funding or financial 28. Balvers K, Müller MCA, Juffermans NP. The utility of thromboelastometry (ROTEM) or thromboelastography (TEG) in non-bleeding ICU patients; Annual update support was received. in Intensive Care and Emergency . Heidelberg, Springer International Publishing, 2014: p. 583-91. References 29. Haase N, Ostrowski SR, Wetterslev J, et al. Thromboelastography in patients with severe sepsis: a prospective cohort study. Intensive Care Med. 2015;41:77-85 1. Walsh TS, Stanworth SJ, Prescott RJ, et al. Prevalence, management, and 30. Holland LL, Foster TM, Marlar RA, et al. Fresh frozen plasma is ineffective for outcomes of critically ill patients with prothrombin time prolongation in United correcting minimally elevated international normalized ratios. Transfusion. Kingdom intensive care units. Crit Care Med. 2010;38: 1939-46 2005;45:1234-5. 2. Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med. 2014;370: 31. Tinmouth A, Chatelain E, Fergusson D, et al. A Randomized Controlled Trial of 847-59. High and Standard Dose Fresh Frozen Plasma Transfusions in Critically Ill Patients. 3. Segal JB, Dzik WH: Paucity of studies to support that abnormal coagulation test Transfusion. 2008;48:26A-7A. results predict bleeding in the setting of invasive procedures: an evidence-based 32. Muller MC, de Jonge E, Arbous MS, et al. Transfusion of fresh frozen plasma review. Transfusion. 2005;45:1413-25. in non-bleeding ICU patients--TOPIC trial: study protocol for a randomized 4. van den Besselaar AM, Broekmans AW, Loeliger EA: [INR: an internationally controlled trial. Trials 2011;12:266. accepted standard for the monitoring of oral anticoagulant treatment]. Ned 33. Muller MC, Arbous MS, Spoelstra-de Man AM, et al. Transfusion of fresh-frozen Tijdschr Geneeskd. 1986;130:1975-6. plasma in critically ill patients with a coagulopathy before invasive procedures: a 5. Rourke C, Curry N, Khan S, et al. Fibrinogen levels during trauma hemorrhage, randomized clinical trial. Transfusion. 2015;55:26-35. response to replacement therapy, and association with patient outcomes. J 34. Tinmouth A, Thompson T, Arnold DM, et al. Utilization of frozen plasma in Thromb Haemost. 2012;10:1342-51. Ontario: a provincewide audit reveals a high rate of inappropriate transfusions. 6. Rugeri L, Levrat A, David JS, et al. Diagnosis of early coagulation abnormalities in Transfusion. 2013;53:2222-9. trauma patients by rotation thrombelastography. J Thromb Haemost. 2007;5:289-95. 35. Stanworth SJ, Grant-Casey J, Lowe D, et al. The use of fresh-frozen plasma in 7. Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid thrombelastography England: high levels of inappropriate use in adults and children. Transfusion. can replace conventional coagulation tests in the emergency department: 2011;51:62-70. experience with 1974 consecutive trauma patients. Ann Surg. 2012;256:476-86. 36. Triulzi D, Gottschall J, Murphy E, et al. A multicenter study of plasma use in the 8. Schochl H, Frietsch T, Pavelka M, et al. Hyperfibrinolysis after : United States. Transfusion. 2015;55:1313-9. differential diagnosis of lysis patterns and prognostic value of thrombelastometry. 37. Muller MC, de Haan RJ, Vroom MB, et al. Evaluation of a multi-center randomised J Trauma. 2009;67:125-31. clinical trial on prophylactic transfusion of fresh frozen plasma: implications for 9. Theusinger OM, Wanner GA, Emmert MY, et al. Hyperfibrinolysis diagnosed by future trials. Transfus Med. 2014;24:292-6. rotational thromboelastometry (ROTEM) is associated with higher mortality in 38. Desborough M, Sandu R, Brunskill SJ, et al. Fresh frozen plasma for cardiovascular patients with severe trauma. Anesth Analg. 2011;113:1003-12. surgery. Cochrane Database Syst Rev. 2015;7: CD007614. 10. Raza I, Davenport R, Rourke C, et al. The incidence and magnitude of fibrinolytic 39. Khan H, Belsher J, Yilmaz M, et al. Fresh-frozen plasma and platelet transfusions activation in trauma patients. J Thromb Haemost. 2013;11: 307-14. are associated with development of acute lung injury in critically ill medical patients. Chest. 2007;131:1308-14.

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40. Gajic O, Rana R, Winters JL, et al. Transfusion-related acute lung injury in the 50. Iorio A, Basileo M, Marchesini E, et al. The good use of plasma. A critical analysis of critically ill: prospective nested case-control study. Am J Respir Crit Care Med. five international guidelines. Blood Transfus. 2008;6:18-24. 2007;176:886-91. 51. CBO: Richtlijn Bloedtransfusie. Utrecht, the Netherlands, CBO, 2011. 41. Gajic O, Rana R, Mendez JL, et al. Acute lung injury after blood transfusion in 52. Stanworth SJ, Estcourt LJ, Powter G, et al. A no-prophylaxis platelet-transfusion mechanically ventilated patients. Transfusion. 2004;44:1468-74. strategy for hematologic cancers. N Engl J Med. 2013;368: 1771-80. 42. Rana R, Fernandez-Perez ER, Khan SA, et al. Transfusion-related acute lung injury 53. Levi M, Toh CH, Thachil J, et al. Guidelines for the diagnosis and management and pulmonary edema in critically ill patients: a retrospective study. Transfusion. of disseminated intravascular coagulation. British Committee for Standards in 2006;46:1478-8. Haematology. Br J Haematol. 2009;145: 24-33. 43. Lauzier F, Cook D, Griffith L, et al. Fresh frozen plasma transfusion in critically ill 54. Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Platelet transfusion: a clinical patients. Crit Care Med. 2007;35:1655-9. practice guideline from the AABB. Ann Intern Med. 2015;162: 205-13. 44. Sarani B, Dunkman WJ, Dean L, et al. Transfusion of fresh frozen plasma in critically 55. Schochl H, Nienaber U, Maegele M, et al. Transfusion in trauma: ill surgical patients is associated with an increased risk of infection. Crit Care Med. thromboelastometry-guided coagulation factor concentrate-based therapy 2008;36:1114-8. versus standard fresh frozen plasma-based therapy. Crit Care. 2011;15: R83. 45. Bochicchio GV, Napolitano L, Joshi M, et al. Blood product transfusion and 56. Whiting P, Al M, Westwood M, et al. Viscoelastic point-of-care testing to assist with ventilator-associated pneumonia in trauma patients. Surg Infect (Larchmt). the diagnosis, management and monitoring of haemostasis: a systematic review 2008;9:415-22. and cost-effectiveness analysis. Health Technol Assess. 2015;19:1-228, v-vi. 46. Roback JD, Caldwell S, Carson J, et al. Evidence-based practice guidelines for 57. Gonano C, Sitzwohl C, Meitner E, et al. Four-day antithrombin therapy does not plasma transfusion. Transfusion. 2010;50:1227-39. seem to attenuate hypercoagulability in patients suffering from sepsis. Crit Care. 47. Liumbruno G, Bennardello F, Lattanzio A, et al. Recommendations for the 2006;10:R160. transfusion of plasma and platelets. Blood Transfus. 2009;7:132-50. 58. Spahn DR, Bouillon B, Cerny V, et al. Management of bleeding and coagulopathy 48. O’Shaughnessy DF, Atterbury C, Bolton MP, et al. Guidelines for the use of fresh-frozen following major trauma: an updated European guideline. Crit Care. 2013;17: R76. plasma, cryoprecipitate and cryosupernatant. Br J Haematol. 2004;126:11-28. 59. http://www.nice.org.uk/dg13. 49. De Backer D, Vandekerckhove B, Stanworth S, et al. Guidelines for the use of fresh 60. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations frozen plasma. Acta Clin Belg. 2008;63:381-90. and quality of evidence in clinical guidelines: report from an american college of chest physicians task force. Chest. 2006;129:174-81.

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