S1643 Your Turn: Management of the Bleeding Patient

Transcription

1 S1643 Your Turn: Management of the Bleeding Patient Thomas DeLoughery, MD Theresa A. Nester, MD, FCAP

2 Objectives Act as a transfusion medicine consultant for an actively bleeding patient Educate pathologists on the reversal of new anticoagulant agents and recent platelet transfusion guidelines Help develop protocols for patients who are on warfarin and are experiencing intracranial hemorrhage 2

3 Case 1 A 68 year old woman has sustained a hip fracture after falling off her horse. The patient takes warfarin for atrial fibrillation. Current INR is 3.5. Other coagulation tests are normal. Hemoglobin = 8.5 g/dl. 3

4 Vitamin K Both oral and IV very effective PO "targeted" to liver IV faster Sub-q and IM not effective in RCT and should not be used! Slow infusions of diluted vitamin K has very low incidence of anaphylaxis 50ml over 20 minutes No "rebound" with reversal 4

5

6 Routes of Vitamin K Route Initial INR 24hr INR LDIV HDIV SC PO

7 Oral IV 7

8 FACTOR HALF LIVES FACTOR IN VIVO ½ LIFE % NEEDED FOR HEMOSTASIS I 3-6 Days II 2-5 Days V 5-36 Hours VII 2 5 Hours > 10 VIII 8 12 Hours IX Hours X Hours XI Hours XIII 12 Days < 5 8

9 Plasma for Warfarin Reversal FFP contains all plasma coagulation proteins including the vitamin K dependent ones (2, 7, 9, 10) Factor VII with shortest half-life ~ 3-6 hours 1 unit FFP raises factors ~ 5% Dose is 15 mls of plasma/kg 9

10 Case 2 A 74 year old man on warfarin following a left lower leg deep vein thrombosis has tripped off of a curb 20 minutes ago. He now complains of headache. Head CT shows an acute subdural hematoma. INR =

11 Kcentra - a 4 factor prothrombin complex concentrate (PCC) For patients with a history of warfarin usage presenting with life-threatening bleeding the following is recommended: 1. Give vitamin K 10mg IV over minutes 2. If INR is < 4.0, infuse 25 IU/kg (+/- 10%) Kcentra. 3. If INR is , infuse 35 IU/kg (+/- 10%) Kcentra. 4. If INR is >6.0, infuse 50 IU/kg (+/- 10%) Kcentra. NOTE: USE GREAT CAUTION IF PATIENT HAS HAD THROMBOTIC EVENT IN LAST 3 MONTHS. 11

12 12

13 Take Home Point: When using a 4-factor Prothrombin complex concentrate to reverse the effect of warfarin, plasma should not be needed. But do administer IV vitamin K! IV vitamin K will have effect in 4-6 hours. 13

14 3- factor PCCs are also available Brand names: Bebulin, Profilnine These contain factors II, IX, and X but not much factor VII. Therefore, if this concentrate is used off-label, a small amount of plasma is still needed to achieve reversal. 14

15 Case 3 A 65 year old man on Dabigatran due to atrial fibrillation presents with a perforated gastric ulcer. Urgent surgery is required. 15

16 Direct Oral Anticoagulant (DOAC) Monitoring Increasing use of DOAC in population Not required for routine use Can be use to assess Compliance Need for reversal Presurgerical Routine tests variably effected by drugs 16

17 Routine Tests Dabigatran PTT Thrombin time more sensitive Rivaroxaban INR Anti-Xa more sensitive Apixaban Ø Anti-Xa more sensitive Edoxaban INR Anti-Xa more sensitive For life threatening bleeding treat without waiting for levels 17

18 DOAC Reversal Specific reversal agent available for Dabigatran Idarucizimab Coagulation factor Xa (recombinant), inactivated-zhzo 18

19 Dabigatran Reversal 19

20 Idarucizumab 20

21 Clinical use of Idarucizumab Effective in ~ 98% of patients in reversing thrombin and Ecarin time 98% of patients could undergo emergency surgery ~ 2% of patients required redosing for bleeding 30 day thrombosis seen in ~ 5% patients N Engl J Med

22 Conclusion Idarucizumab reverses dabigatran But need to treat cause of bleeding also hours to stop bleeding after antibody administered Allowed emergency surgery Should be used for ICH or urgent surgery 22

23 Our Protocol 1. Indication: ICH for patient on dabigatran 2. Baseline thrombin time and aptt Not to screen for use but to assess drug use 3. Five grams administered as 2.5 gram bolus one right after other 4. Consider for emergency surgery if TT/aPTT elevated 23

24 Xa Blockers Prothrombin Complex concentrates Animal and human studies No difference in bleeding outcomes in warfarin vs DOAC ICH patients 24

25 Coagulation factor Xa (recombinant), inactivatedzhzo Andexxa Recombinant fxa derivative Catalytically inactive Lacks the Gla-domain Bolus then 2 hour infusion Reverses both direct and indirect Xa inhibitors Approved May 2018 but available in limited quantities. 25

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28 Coagulation factor Xa, inactivated-zhzo Will reverse rivaroxaban and apixaban Will likely work for other bans as well but not FDA approved Should theoretically work to reverse Fondaparinux, but is no trial data yet. Package insert contains a black box warning if patient has had recent thromboembolic events. Very expensive, use only for life threatening bleeding. 28

29 What if you don t have the fancy new drugs Prothrombin Complex Concentrates (4 factor) Increasing data on effectiveness Dose - 50 units/kg 29

30 Case 4 A 47 year old man with alcoholic cirrhosis presents with hematemesis. Hgb = 8.0/gldL PT/INR = 1.9 aptt= 42 seconds Platelet count= 50K/µL 30

31 Liver Disease Multiple defects in coagulation Decreased synthesis of factors Decreased platelets Decreased platelet function But clinical data also shows increase in thrombosis Risk of thrombosis increased three-fold 31

32 Incidence of venous thromboembolism based on Child-Pugh Stage. Dabbagh O et al. Chest 2010;137:

33 Hemostasis in Liver Disease Levels of natural anticoagulants and inhibitors of coagulation also reduced Antithrombin Protein C Protein S Coagulation is rebalanced Thrombin generation is normal 33

34 Hepatology 44: ,

35 Transfusions in Upper GI Bleeding Large Spanish study of UGI N = 921 Ulcers 49% Varices 21% RCT Restrictive: Hgb = 7 (7-9) Liberal: Hbg = 9 (9-11) NEJM 368:11-21,

36 Results Result Restrictive Liberal p Death 23 (5%) 41 (9%) 0.02 Death bleeding 3 (0.7%) 14 (3.1%) 0.01 Further bleeding 45 (10%) 71 (16) 0.01 No transfusion 225 (51%) 61 (14%) < Transfusion reaction 14 (3%) 38 (9%) Cardiac complication 49 (11%) 70 (16%)

37 Case 4 5 months later, the patient is admitted with ascites and hepatic encephalopathy. There is no evidence of bleeding. INR = 7.0 and platelet count is 60K/µL. 37

38 The INR Only standardized for stable patients on warfarin Unreliable in liver disease VII falls more than II and XI Also if fibrinogen is low will falsely raise INR Not a predictor of bleeding 38

39 TEG in Liver Disease Normal R High normal α angle High normal MA Normal LY30 Overall Normal INR 2.21 Platelets 128,000 39

40 Case 5 73 year old man presents with a ruptured abdominal aortic aneurysm. The patient is Rh(D) negative with a negative antibody screen. 40

41 Rh(D): Basic points A. Unlike ABO antibodies, Rh(D) negative individuals do not have naturally occurring anti-d. B. Even if the patient has anti-d, intravascular hemolysis is unlikely to occur. C. Group O Rh(D) negative blood constitutes only 7-9% of the community supply. 41

42 Frequency in Caucasian Population O + 36% O- 9% A+ 34% A- 8% B+ 8% B- 2% AB+ 2.5% AB- 0.5% 42

43 Extravascular hemolysis Much less symptomatic than intravascular hemolysis. Decreased hematocrit may be the main finding. 43

44 Laboratory results are not yet available 1. Is it appropriate to transfuse at a 1:1:1 ratio? 2. What does that even mean? 3. If a 1:1:1 protocol is started, for how long should it continue? 44

45 What does a 1:1:1 ratio even mean? Definition: 1 whole blood derived platelet: 1 plasma: 1 RBC In most systems: 1 platelet dose: 6 plasma: 6 RBC 45

46 If one starts a 1:1:1 protocol, for how long should it continue? Not long. Risks: Respiratory compromise Abdominal compartment syndrome Suboptimal management of the coagulopathy eg, heparin, hemophilia, DIC 46

47 Does a 1:1:1 ratio apply in a non-trauma patient? Probably not, unless the patient has shock, acidosis, and significant tissue injury. However, some replacement of coagulation factors and (eventually) platelets is warranted. 47

48 Brief history of 1:1:1 idea Idea first suggested in field of combat. Civilian trauma centers started to look at their practice. This generated much retrospective data with many variables, making a meta-analysis difficult. PROMMTT trial PROPPR trial 48

49 49

50 Prospective, Observational, Multicenter, Major Trauma Transfusion Study 10 US level 1 trauma centers 1245 patients Received at least 1 RBC within 6 hrs of admission Received at least 3 blood products within 24hrs 50

51 PROMMTT Objective To relate in-hospital mortality to: - early transfusion of plasma and/or platelets - Time-varying plasma:rbc and platelet:rbc ratios. 51

52 PROMMTT Results Increased ratios of plasma:rbc and platelet:rbcs were independently associated with decreased 6 hr mortality, when hemorrhagic death predominated. In the first 6 hrs, patients with ratios less than 1:2 were 3-4 times more likely to die compared to 1:1. 52

53 From: The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative Effectiveness of a Time-Varying Treatment With Competing Risks JAMA Surg. 2013;148(2): doi: /2013.jamasurg.387 Figure Legend: Figure 1. Blood product use in the first 6 hours in 2 Prospective, Observational, Multicenter, Major Trauma Transfusion Study patients. Patient 1 (A) had an Injury Severity Score of 48 and died of hemorrhage at 1 hour 7 minutes after emergency department admission. Patient 2 (B) had an Injury Severity Score of 57 and was discharged to another acute care hospital at 27 days. Note the constantly changing ratios over time. For example, patient 1 received cumulative plasma:platelet:red blood cell (RBC) ratios of 0:0:1, 0:0:3, 0:0:6, 4:6:6, and 5:6:6 at 15, 30, 45, 60, and 75 minutes, respectively, while patient 2 received cumulative plasma:platelet:rbc ratios of 0:0:1, 0:0:4, 0:0:4, 2:0:6, and 2:0:10 at those same times. 53

54 From: The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative Effectiveness of a Time-Varying Treatment With Competing Risks JAMA Surg. 2013;148(2): doi: /2013.jamasurg.387 Figure Legend: Figure 2. The bars represent cumulative ratios at the start of each time interval. Most patients received a plasma:red blood cell (RBC) ratio of 1:2 or higher by 3 hours (A) and a platelet:rbc ratio of 1:2 or higher by 6 hours (B). In the last time interval (24 hours), the percentage of patients receiving 0 units of platelets or plasma increases, reflecting the dynamic cohort with newly eligible patients entering and others exiting owing to death in the previous interval. 54

55 Holcomb JB et al. JAMA 2015; 313(5):

56 PROPPR Trial RCT involving 680 patients with severe trauma. 1:1:1 vs 1:1:2 ratio. Blood products were administered in a pre-specified order to maintain assigned ratios. Primary outcomes: 24 hr and 30 day mortality. Secondary outcomes: time to hemostasis, ICU free days, functional status at discharge. 56

57 Survival 1:1 vs 1:2 Less exsanguination at 24 hours with 1:1 NO increase in complications with 1:1 Holcomb et al JAMA 2015;313:

58 PROPPR Trial- results No significant difference in primary or secondary outcome >> no significant difference in mortality with either strategy. But a post-hoc analysis indicated that death by exsanguination was significantly decreased in the intervention group. 58

59 Are guidelines appropriate for severe trauma patients applicable to non-trauma patients? 2011 Consensus conference indicates no, unless the patient has shock, acidosis, and significant tissue injury. Dzik et al. Critical Care 2011;15:

60 60

61 Literature is emerging about MTP use in non-trauma patients Retrospective, with relatively small numbers. Patients are typically older and sicker at baseline than trauma patients. Similar to initial retrospective trauma literature, significant variability exists. 61

62 Association Between Ratio of FFP to RBC during Massive Transfusion and Survival Among Patients Without Traumatic Injury Retrospective review of all massive transfusions at Massachusetts General Hospital from Main measure was the examination of FFP:RBC transfusion ratios for patients without trauma. 62

63 Findings Almost 90% of massive transfusions took place in patients without trauma: Higher numbers of cardiac and liver transplant surgery, with trauma 3 rd highest patient population. Overall, there was no difference in 30 day mortality between the high FFP:RBC ratio and the low FFP:RBC ratio. 63

64 Findings, cont d However, significant differences in 30 day mortality rates were observed within individual services. For vascular surgery, a high ratio was associated with decreased mortality (p =.045). But for general surgery, orthopedic surgery, and medicine, a high ratio was associated with increased mortality. 64

65 Massive transfusion in patients without trauma 65

66 For raaa patients, there are other rare retrospective studies indicating that increased plasma: RBC ratio improves outcome. Mell et al Surgery 2010;148:

67 Coagulopathy in raaa patients Most do not start out with a coagulation disorder unless on anti-platelet therapy,etc. Dilutional coagulopathy can develop if only RBCs administered. A rare patient will have/develop DIC. 67

68 Consensus committee recommendations 1. For patients with critical bleeding, immediate application of a foundation ratio of blood components. Example, 6 RBCs and 3 FFP for the initial treatment. 2. Adjustments to the foundation ratio based on the clinical course and results of laboratory tests using goal directed therapy. 68

69 Better patient outcomes with massive transfusion may be more due to: Improved communication. Decreased time of delivery of blood products. Clearly defined roles, responsibilities, and resource allocation. 69

70 Thromboelastrography Point of care test using fresh whole blood. Measures tensile strength of forming clot. 70

71 Thromboelastrography, cont d 71

72 Thromboelastrography, cont d Drawbacks Lack of familiarity TEG based protocols Need to run sample in 4 minutes Who runs samples and QA machines? 72

73 Patient with Liver Disease Normal R High normal α angle High normal MA Normal LY30 Overall Normal INR 2.21 Platelets 128,000 73

74 TEG Based Transfusion Protocol TEG Parameter Interpretation Action R Time Time to fibrin formation Increased - FFP K time Kinetics (2-20mm ) Increased - Cryo Alpha Angle r/k slope of tracing Decreased - Cryo Maximal Amplitude Whole blood Lysis Index Strength and stability of thrombus Fibrinolysis Decreased - plts Increased - antifibrinolytic 74

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76 Sounds good, but Many of the values actually reflect a mixture of things. For example: - the angle represents a combination of coagulation factors, platelets, and fibrinogen. - the R value represents a combination of coagulation factors and platelets. Thombin is the platelet activator in TEG. It is a very powerful activator, so TEG will miss platelet dysfunction. 76

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78 Studies done often compare TEG or ROTEM to traditional lab testing that takes minutes. What is needed is a comparison of TEG or ROTEM to traditional testing that takes 20 minutes. If we cannot achieve a 20 minute turn around time, TEG will be used because it is available within the golden hour. 78

79 Goal: Reasonably accurate coagulation tests within 20 minutes for an actively bleeding patient. Stopped performing checks for clotting or hemolysis >> >> 9% exceeded the 20 minute goal. Revised the fibrinogen assay with an expanded calibration range. >> 2% exceeded the 20 minute goal 79

80 What can we take away from the trauma literature? Hypothermia Coagulopathy Acidosis The Lethal Triad 80

81 Other Ideas we can take away: Laboratory value turn around time must be more rapid than traditional testing, and often requires a special signal, such as activation of a hemorrhage protocol. 81

82 And possibly: Improved predictors for who will require massive transfusion: Trauma patients requiring >3 units PRBCs per hour. Shock index: ratio of heart rate to systolic blood pressure. 82

83 In Summary For patients with significant blood loss, early plasma infusion is likely to improve outcome. During cases of ongoing blood loss, component therapy based on rapid laboratory values should be pursued as soon as possible. 83

84 Case 6 A 30 year old Rh(D) negative woman delivers a baby. Upon delivery of the placenta, the patient experiences blood loss estimated at 1700mL. The clinical team begins their hemorrhage protocol. 84

85 Remember By convention: Screening cell I is always Rh(D) positive (R 1 R 1 = DCe/DCe) Screening cell II is always Rh(D) positive (R 2 R 2 = DcE/DcE) Screening cell III is always Rh(D) negative (rr = ce/ce) Good prenatal care will result in cells I and II showing agglutination due to Rh immune globulin administration at 28 weeks gestation. 85

86 Post Partum Hemorrhage (PPH) Rare: > 10 units of blood 6/100,000 deliveries Deadly: 3-11% of maternal deaths Incidence is increasing Can be truly massive audible bleeding 86

87 PPH - Plasma: RBC 1:1 Ratio Recent data suggesting that a fix ratio of 1:1 RBC:FFP associated with better outcomes in trauma Deemphasizes on laboratory testing for initiation hemostatic resuscitation Logic extending to non-trauma massive transfusions such as PPH but limited data Why early plasma? Takes time to run coagulation tests Many patients with coagulopathies at time of hemorrhage Placenta previa, abruptions, amniotic fluid embolism Plasma may contain beneficial factors that help in massive bleeding 87

88 Recommendations Start with 4 RBCs Transfuse 4 units plasma Transfuse 4 more RBCs 4 more units of plasma 2 cryopools and 1 dose platelets J Thromb Haemost Jan;14(1):

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90 Why Early Plasma? Takes time to run coagulation tests Many patients with coagulopathies at time of hemorrhage Plasma may contain beneficial factors that help in massive bleeding 90

91 Effect of FFP:RBC Ratio on Overall Mortality 70 65% Mortality % % Chi Square RB: p=0.006 RG: p<0.001 BG: p= % n=31 n=56 n= :22-1:4 1:3.9-1:2.1 1:2-1:0.59 Borgman et al. J Trauma. 2007;63: FFP:RBC Ratio 91

92 However in PPH Thrombocytopenia less common Unless severe bleeding or DIC 92

93 Fibrinogen; the Forgotten Factor Crucial for forming hemostatic plug Crucial for INR and PTT testing Levels rise in normal pregnancy Lower levels predictors of post-partum hemorrhage Newer data indicate higher targets in obstetrical bleeding > 200 mg/dl 93

94 94

95 Plasmin LysLysLys Lys Lys Lys Lys Lys Fibrin 95

96 Lysine EACA TXA LysLysLysLysLys Lys Lys Lys Fibrin 96

97 Fig 2 Cumulative meta-analysis of the effect of tranexamic acid in surgery on risk of blood transfusion in adequately concealed trials. Katharine Ker et al. BMJ 2012;344:bmj.e by British Medical Journal Publishing Group 97

98 TXA reduces bleeding in surgery Transfusion Mortality RR (95% CI) RR (95% CI) TX A 0.61 ( ) TX A 0.57 ( ) TXA better TXA worse TXA better TXA worse 65 trials (4,842 patients) 30 trials (2,917 patients) 98

99 TXA Small trials showed reduced blood loss in PPH WOMEN Trial Blood loss > 500 ml after vaginal birth or 1000 ml after C-section or any blood loss sufficient to compromise hemodynamic stability. Intervention: one gram of TXA Patients: TXA: 10,036 Placebo: 9,985 Lancet 2017:389:

100 TXA: WOMEN TRIAL: RESULTS Death due to PPH TXA 1.5% (155/10,036) vs Placebo 1.9% (191/9,985) RR: 0.81 (CI , p = 0.045) Absolute risk reduction = 0.4% No increased in thrombosis TXA should be used if significant PPH present. A second dose can be given if needed. Administer within 3 hours of the onset of PPH. 100

101 TXA: WOMEN TRIAL: CONCLUSIONS TXA should be used if significant PPH present. A second dose can be given if needed. Administer within 3 hours of the onset of PPH. 101

102 Prohemostastic Drug: rviia Decreasing use in massive transfusions with negative trial data and increase risk of thrombosis Open label study in PHH showed 60 ug/kg reduced need for procedure but not blood loss or blood product usage If bleeding is ongoing and labs are normal consider ug/kg Remember Need fibrinogen > 200mg/dl Need ph >

103 Prohemostastic Drugs: PCC Increasing use of PCC in massive bleeding in order to give coagulation factors with decrease volume Increasing use in trauma: 50 units/kg if coagulopathy persist despite ongoing hemostatic resuscitation RCT ongoing Thrombosis is a concern Not recommend for PPH until there is more data 103

104 104

105 PPH: Massive Transfusion Protocols Key to get the right blood products fast to the right place Need to know Who can initiate (providers, transfusion service) Sending out the right products Box of blood Trauma 4x4 Keeping track of products and labs Practice runs for less busy hospitals MTP associated with better outcomes 105

106 Case 7 A 39 year old man requires a renal biopsy. The patient is oliguric and rapidly progressive glomerulonephritis is suspected. Platelets are requested. Current platelet count = 57K PT/INR and aptt are within normal limits. Serum creatinine = 5.0 mg/dl Blood urea nitrogen = 100mg/dL 106

107 Uremia and Platelets Milieu of uremia inhibitors platelet function Transfused platelets rapidly inhibited Recommendations Dialysis to lower toxin level DDAVP improved platelet function Cryoprecipitate often recommend but unreliable 107

108 108

109 AABB Platelet Guidelines Recommendation 1: The AABB recommends transfusing hospitalized adult patients who have therapy-induced hypoproliferative thrombocytopenia with a platelet count of cells/l or less to reduce the risk for spontaneous bleeding. Recommendation 2: The AABB suggests prophylactic platelet transfusion for patients having elective central venous catheter placement with a platelet count less than cells/l. Recommendation 3: The AABB suggests prophylactic platelet transfusion for patients having elective diagnostic lumbar puncture with a platelet count less than cells/l. 109

110 AABB Platelet Guidelines, cont d Recommendation 4: The AABB suggests prophylactic platelet transfusion for patients having major elective nonneuraxial surgery with a platelet count less than cells/l. Recommendation 5: The AABB recommends against routine prophylactic platelet transfusion for patients who are nonthrombocytopenic and have cardiac surgery with cardiopulmonary bypass (CPB). Recommendation 6: The AABB cannot recommend for or against platelet transfusion for patients receiving antiplatelet therapy who have intracranial hemorrhage (traumatic or spontaneous). 110

111 - Helps to show the strength of the evidence behind the recommendations. Kumar et al. Platelet transfusion: a systematic review of the clinical evidence. Transfusion 2015;55:

112 PATCH Trial- Platelet transfusion Versus Standard Care After Acute Stroke due to Spontaneous Cerebral Haemorrhage Associated with Antiplatelet Therapy Lancet Multicenter, open-label, masked endpoint, Randomized trial. 60 hospitals in Netherlands, UK, and France Enrolled adult patients with non-traumatic ICH on anti-platelet therapy. Glasgow Coma Scale of at least Platelet transfusion available within 6 hours of onset of symptoms. Randomized to standard care or standard care with platelet transfusion within 90 minutes of allocation. 112

113 Patients Platelets Control Age Men % Aspirin Asprin/dipyridamole ADP inhibitors 4 1 ICH volume ICH score 1 1 GCS

114 PATCH- Outcome measures Primary: Shift toward death or difference in functional outcome at 3 months after randomization rated on a modified Rankin Scale (mrs). Secondary: Survival at 3 months Poor outcome defined as mrs 4-6 Growth in hemorrhage after 24 hrs Serious adverse events such as complications of the hemorrhage 114

115 PATCH- Results posted in Clinical Neurology by Salim Rezaie 115

116 PATCH conclusions Platelet transfusion increases the risk of death or dependence in patients with an acute intracerebral hemorrhage while taking antiplatelet therapy. Avoid making this part of standard care. Baharoglu MI et al. Lancet 2016 June 25;387 (10038):

117 The evidence for adequate platelet count and neuraxial anesthesia in pregnancy exists in small studies; no RCT available. Standard of care is often 80K despite this lack of data. No RCT exist for platelet count and central venous catheter placement. One relatively small trial is being done in patients with chronic liver disease. Risk appears to be low if an ultrasound-guided technique is used. Stanworth, SJ. Cochrane database of Systematic Reviews 2015 and

118 Summary TM Consultation: 1. Evaluate available data prior to calling clinical team. History, drugs, coagulation results, products given so far. 2. Determine causes for bleeding and the most appropriate treatment. 118

119 Pearls 1. Subcutaneous vitamin K is not effective. 2. KCentra is FDA approved to reverse warfarin effect in the face of life-threatening bleeding factor PCCs still require plasma for the factor VII. 4. Know which type of crossmatch is being done and whether the clinical situation calls for something faster. 119

120 Pearls, cont d 5. ESLD patients have relatively normal thrombin generation, despite the abnormal PT/INR. 6. The indications for plasma infusion are few; the indication for prophylactic infusion are nonexistent. 7. Plasma is needed early to prevent irreversible coagulopathy in the setting of massive transfusion. 120

121 Pearls, cont d 8. Fibrinogen less than 200mg/dL is a predictor of severe post-partum hemorrhage. 9. TXA should be used early in post-partum hemorrhage. 10. Cryoprecipitate is much more effective at increasing serum fibrinogen level quickly, compared to plasma. 11. Infusing new platelets into a uremic environment is ineffective. 121

122 References Abdelfattah, Cripps International Journal of Surgery 2015; 1-6 Abdul-Kadir et al Transfusion 2014;54: Carson et al Annals of Internal Medicine 2012;157:49-60 Chandler et al Transfusion Practice 2010;50: Collins et al, Management of coagulopathy associated with PPH, In press. Desborough et al Transfusion 2012;52:20-29 Dzik et al. Critical Care 2011;15:242. Holcomb et al JAMA 2015;313: Holcomb et al JAMA 2013;148: Kaufman et al Annals of Internal Medicine 2015;162: Kreuziger et al British Blood Transfusion Society 2013;24: Lockhart ASH 2015; Mell et al Surgery 2010;148: Nester et al AABB Technical Manual 2014;18: Nester T, ed. Transfusion Management of the Obstetrical patient. Springer Nature Tripodi et al NEJM 2011;365: Mesar et al JAMA Surg. 2017;152(6): Baharoglu MI et al Lancet 2016; 387(10038): WOMAN TRIAL collaborators Lancet, online April 26,

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