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EVIDENCE BASED PLASMA TRANSFUSION

EVIDENCE BASED PLASMA TRANSFUSION. Joseph Sweeney MD FACP FRCPath Director Transfusion Medicine and Coagulation, Professor of Pathology and Laboratory Medicine Brown University Providence, Rhode island, USA. DYSPNEA AND TRANSFUSION.

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EVIDENCE BASED PLASMA TRANSFUSION

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  1. EVIDENCE BASED PLASMA TRANSFUSION Joseph Sweeney MD FACP FRCPath Director Transfusion Medicine and Coagulation, Professor of Pathology and Laboratory Medicine Brown University Providence, Rhode island, USA SABM 2012

  2. DYSPNEA AND TRANSFUSION • 78 YO female at hospital A on warfarin for NVAF requires endoscopy for rectal bleeding. INR is 4.3. Two units FFP requested • 1143: Specimen received types as Group O Rh(D) positive • 1222: 1 unit FFP dispensed • 1245: 1 unit FFP dispensed • 1315: Arrives in endoscopy suite • 1320: complains of slight dyspnea • 1330: Procedure cancelled; more severe dyspnea; CXR shows bilateral pulmonary edema; • 1330-1400: O2 saturation declines, 86%, 77%, 66%, 30% • 1404: Expires SABM 2012

  3. DYSPNEA AND TRANSFUSION • 78 YO female at hospital A on warfarin for AF requires endoscopy for rectal bleeding. INR is 4.3. Two units FFP requested • 1404: Expires • Both units were from female donors • 1st units was from a multiparous female • Returned for testing- no HLA antibodies • 2nd unit was from a female who had a single live pregnancy in 1981 and was transfused with one unit of red blood cells • 2nd unit donor returned for testing- had class I and class II anti-HLA antibodies (anti-A2 anti- A68, anti B44, anti-B45) • Recipient was DNA typed as A2,; B44, DRB1*0401 SABM 2012

  4. DYSPNEA AND TRANSFUSION • A 56 YO female at hospital B: • Preoperative coagulation tests: • PT 15.2 secs; INR 1.4 • Treated with 5 units of plasma preoperatively • Developed fever / chills/ flushing : reported to the Blood Bank as a transfusion reaction • 1-2 hours later, developed worsening dyspnea • Transferred to hospital C ICU ; dyspnea improved over a few days • Returned for surgery about one week later- • Coagulation tests at this time PT 15.3; INR 1.4 • Surgery performed uneventfully without any blood components transfused SABM 2012

  5. TRALI INVESTIGATION LL27456: Female/no children LY08232: Female/children LH52545: Female/no children LH53651: Male/ never transfused LH53652: Male/unknown if transfused SABM 2012

  6. US DATA FOR 2008 • 4,484,000 units of plasma transfused • 13.6 units/1000 population • 54% as FFP (2,411,000) • 39% as 24Hour FP ( 1,742,000) • 180,000 units of cryosupernatant plasma • 25,790 apheresis procedures in the US in 2006 (90% as TPE) • Assuming 3L exchanges on average, this means that about 100,000 FFP or 24FP used in TPE • 4,200,000 units of FFP/24FP transfused in the US for non-TPE purposes in 2008 • Mean dose transfused is 364 mls ( 2 units) • About 5 mls/Kg dose SABM 2012

  7. WHY IS PLASMA TRANSFUSED? • Clinical use of FFP/24HFP • Prophylactically • To reduce or prevent bleeding in patients with a coagulopathy prior to an invasive diagnostic or therapeutic procedure • Therapeutically • As clotting factor replacement in patients with active bleeding who have a known ( patient on warfarin) or suspected coagulopathy ( massive transfusion) SABM 2012

  8. PLASMA TRANSFUSIONS • Is prophylactic plasma transfusion efficacious in many of the clinical situations in which it is transfused? • Is plasma transfusion associated with risks? • Are there alternative strategies which could avoid some of these transfusion events? SABM 2012

  9. PROTHROMBIN TIME AND THE INTERNATIONAL NORMALIZED RATIO • The PT is widely used to assess hemostatic risk • The PT/INR is an artificial reconstruction of the clotting system which attempt to mimic in vivo thrombin generation: end-point is clot formation which occurs after about 4% of prothrombin is converted to thrombin • Usefulness depends on the context • PT/INR useful to measure the effect of VKAs • Extreme prolongations may be ( though not necessarily) indicative of a hemostatic risk • Mild ( INR 1.2 – 2.0) or moderate ( INR 2 –3) PT prolongations are of limited usefulness in predicting clinical bleeding SABM 2012

  10. PLASMA TRANSFUSIONS • Are patients with prolongations of clotting times (PT) at increased risk of bleeding in association with invasive diagnostic or therapeutic procedures? • Is there any data that administering plasma prophylactically reduces this risk, if present? • Would administering plasma to those subpopulations who do bleed be as effective a clinical strategy? SABM 2012

  11. PROPHYLACTIC PLASMA AND INVASIVE PROCEDURES Data between 1966 - 1996 SABM 2012

  12. PLASMA TRANSFUSIONS-I • SPECTOR ET AL: N Eng J Med. 275:1032-1037, 1966 • 13 Patients with liver disease and prolonged PT: No active bleeding; no procedures intended • Transfused with plasma to decrease PT by 3 secs • Large volumes of plasma necessary to decrease PT (>1200mls) • Short lived correction • Questioned need for therapy SABM 2012

  13. PLASMA TRANSFUSIONS - 1 • SPECTOR ET AL: N Eng J Med. 275:1032-1037, 1966 • 13 Patients with liver disease and prolonged PT: transfused with plasma to decrease PT by 3 secs • Large volumes of plasma necessary to decrease PT (>600mls) • Short lived correction • Questioned need for therapy SABM 2012

  14. PLASMA TRANSFUSIONS-II • EWE, K. Dig Dis SCI. 26: 388-393, 1981 • 200 Patients having liver biopsy at time of laparoscopy • Measured liver bleeding time (LBT) • Correlated LBT and PT(None) • 10 patients with prolonged bleeding; This group did not have a range of PT different from the other 190 SABM 2012

  15. PLASMA TRANSFUSIONS-III • Ragni et al. AlcoholClin Exp Res. 6: 274-276, 1982 • 30 Patients with alcoholic cirrhosis • Hemorrhagic phenomena in 70% ( GI, bruising,epistaxis, VP sites oozing) • PT, aPTT, TT, RT : No difference between bleeders and non-bleeders SABM 2012

  16. PLASMA TRANSFUSIONS- IV • Friedmann E ,Sussmann I: Clin Lab Haematol. 11:199-204, 1989 • 39 Patients with PT 15-29 sec • Paracenteses, Lumbar puncture, Thoracenteses, CV line placement • 71 procedures • 57- did not receive plasma • 12- received plasma • 3(4%) bleed; 2/12 (same patient) and 1/57 SABM 2012

  17. PLASMA TRANSFUSIONS-V • McVay et al:Transfusion 31: 161-171, 1991 • Retrospective review of 608 procedures (paracenteses,thoracenteses) • Bleeding 0.2%; no increased bleeding in those patients with mild coagulopathy (PT>2 normal; platelet count >50,000) • Bleeding related to creatinine > 6mg/dL SABM 2012

  18. PLASMA TRANSFUSIONS-VI • Zins et al: US guided Percutaneous Liver Biopsy with Plugging of the needle track: A prospective study in 72 High Risk Patients. Radiology 1992, 184: 841-843 • 78 biopsies in 72 patients • Classified into 4 groups based on severity of coagulopathy • 2/72 bled; all in group 4 (platelet count <50,000/µL; aPTT ratio > 2) • (a) platelet count of 28,000/µL; (b) with aPTT ratio > 2.2 and liver replaced with metastatic disease (patient died) SABM 2012

  19. PLASMA TRANSFUSIONS-VII • Foster et al: Central Venous Catherization in Patients with Coagulopathy. Arch Surg 1992, 127:273-275 • 259 Catherizations (149-IJV; 110-Sub Vein) • 202/259- Abnormal PT, aPTT or platelet count • Average PT - 29% (N 65-135%) • Average aPTT- 92 sec • Average platelet count – 47 x109/L • No bleeding in any patient except one in whom inadvertent cannulation of the subclavian artery occured SABM 2012

  20. PLASMA TRANSFUSIONS-VIII • Caturelli E et al: Fine needle Liver Biopsy in Patients with severely impaired Coagulation. Liver 1993: 13: 270-273 • 229 procedures in 85 patients • All had platelet count < 50,000/µL or PT < 50% control • No preproceedure FFP or Platelets • No bleeding in any of the patients SABM 2012

  21. PLASMA TRANSFUSIONS-IX • Kozak EA, Brath LK: Do “Screening Coagulation Tests Predict Bleeding in Patients Undergoing Fiberoptic Bronchoscopy With Biopsy? Chest 1994, 106:703-705. • Chart review of 274 patients w/FOB • 28/274 (11%) abnormal PT,aPTT, platelet count • 35 Bleed: 3/28 (11%) and 32/246 (13%) • Conclusion: Do not perform tests pre-FOB since these tests do not predict bleeding SABM 2012

  22. PLASMA TRANSFUSIONS-X • Inabnet WB, Deziel DJ: Laparoscopic Liver Biopsy in Patients with Coagulopathy, portal hypertension and Ascites. Amer Surgeon 1995, 61: 603-606 • 58 biopsies in 22 patients • Some patients received preproceedure FFP or Platelets; some not • 1 patient bled requiring transfusion; that patient received FFP pre procedure!! SABM 2012

  23. PLASMA TRANSFUSIONS-XI • Delougherty et al. Transfusion 36: 827-831, 1996 • 938 invasive line placements to 490 ICU patients: 388 had hemostatic defects • 16 Bleed (1.7%); two life threatening (0.02%) • 15/16 had coagulation abnormality • 144 patients received plasma prophylactically • No single test predictive of bleeding but a score based on PT/aPTT, platelet count and creatinine correlated with bleeding risk • Experience of personnel is most important SABM 2012

  24. PLASMA TRANSFUSIONS-XII • Doerfler ME et al: Central Venous catheter Placement in Patients with Disorders of Hemostasis Chest 1996, 110:185-188 • 104 procedures; 76 patients • 73% plat < 100,000/µL • 40% prolonged PT, aPTT or both • 7 bleeds; all in thrombocytopenic patients • 1 patient transfused with platelet count 6,000/µL SABM 2012

  25. EVIDENCE FOR PROPHYLACTIC PLASMA NONE SABM 2012

  26. WHY DO WE GIVE PLASMA? • Historical precedent: • This is the way I have learned and the way I/we have always done it • Eminence based medicine: • Dr X , with whom I trained at the world’s most prestigious Institute , is an expert on liver biopsy and always said to make sure to give plasma before a liver biopsy if the INR is greater than I.5- make sure that you “stay on the safe side” • Fear of Litigation: • You are probably right that nearly all this plasma is a waste of time but , look, if any of these patients has a major hemorrhage I am going to be hung out to dry by my colleagues and sued. So I need to be “on the safe side “ SABM 2012

  27. REAL VERSUS PERCEIVED RISK OF BLEEDING 15 8 5 3.5 2.5 1.2 SABM 2012

  28. REAL VERSUS PERCEIVED RISK OF BLEEDING 15 13 10 8 5 3.5 2.5 2 1.2 SABM 2012

  29. CHANGES IN INR WITHIN 6 HOURS AFTER FFP TRANSFUSION SABM 2012

  30. CHANGES IN INR WITHIN 6 HOURS AFTER FFP TRANSFUSION SABM 2012

  31. PROPHYLACTIC PLASMA FOR ELEVATED INR Data from MGH, Boston SABM 2012

  32. METHODS • In 2000, we decided to attempt to reduce FFP transfusion at hospital A using an educational approach with guidelines that FFP transfusions should not be given prophylactically if the INR was < 2 and that vitamin K should be given preferentially if the patient was taking warfarin • This educational program was continued form 2001 to 2003 • In 2004, we commenced a passive enforcement program where physicians were informed if the FFP requests were not consistent with guidelines, but the requests were not denied • This passive enforcement program was continued from 2004-2006 • In 2007, we began to interdict requests for FFP which did not meet guidelines; Requests were blocked unless approved by the medical director • This active enforcement program continued from 2007-2009 SABM 2012

  33. SABM 2012

  34. FFP Transfused Baseline Education Early Enforcement Active Enforcement SABM 2012

  35. FFP Transfused Baseline Education Early Enforcement Active Enforcement SABM 2012

  36. FFP Transfused Baseline Education Early Enforcement Active Enforcement SABM 2012

  37. FFP Transfused Baseline Education Early Enforcement Active Enforcement 157 ± 19 90% decrease SABM 2012

  38. Relation between Overall Mortality Rate and Units FFP Transfused R = -0.94 Mortality rates decreasing SABM 2012

  39. VITAMIN K SABM 2012

  40. VITAMIN K1 • Orally as a 5 mg tablet –Phytonadionne • Parenteral preparation • 1 mg (for newborns) • 10mg /mL • Should be given as an infusion in 5% dextrose or saline over 20 – 30 minutes • NOT AS AN INTRAVENOUS PUSH • Anaphylaxis is about 1 :3,700 Intravenous formulation is generic vitamin K1 at a concentration of 10 mg/mL SABM 2012

  41. RELATIONSHIP BETWEEN INR AND AVERAGE CLOTTING FACTOR LEVELS OF FII, FVII, FIX AND FX This is a 25% increase in clotting factors and requires 25 x 70 = 1,750 mls FFP or about 8 units This is a 75% increase in clotting factors and requires 75 x 70 = 5,250 mls FFP or about 16 units SABM 2012

  42. RELATIONSHIP OF AVERAGE CLOTTING FACTORS TO INR SABM 2012

  43. VITAMIN K ADMINISTRATION SABM 2012

  44. RELATIONSHIP BETWEEN DOSE AND CHANGE IN INR AFTER VITAMIN K ADMINISTRATION( PO AND IV COMBINED) SABM 2012

  45. RELATIONSHIP OF AVERAGE CLOTTING FACTORS TO INR INR = 12.36 – 11.5LogACF+ 2.96 (Log ACF)2 INR = 12.36 – 11.5Log3t+ 2.96( Log 3t)2 R= 0.994

  46. RESPONSE TO 5MG IV VITAMIN K

  47. RETURN OF VITAMIN K FACTORS AFTER IV VITAMIN K- I SABM 2012

  48. RETURN OF VITAMIN K FACTORS AFTER IV VITAMIN K-II SABM 2012

  49. RELATIONSHIP BETWEEN INR AND AVERAGE CLOTTING FACTOR LEVELS OF FII, FVII, FIX AND FX INR 2.1: Given 5 mg IV vitamin K Seven hours later: INR = 2.1 : factors = about 22% 7 hours x 3 = 21% 22% + 21% = 43% 43% = 1.7 INR= 1.8

  50. RELATIONSHIP OF AVERAGE CLOTTING FACTORS TO INR INR = 12.36 – 11.5Log3t+ 2.96( Log 3t)2 Patient in ED with an INR = 9.0. Mild epistaxis not requiring transfusion. What is the INR 6 hours after 2-5 mg IV vitamin K? INR = 12.36 – 11.5 log 18 + 2.96( Log 18) 2 INR= 12.36 – 11.5 (1.26) + 2.96 (1.26) 2 INR = 12.36 – 14.5 + 4.70 INR= 2.56 Patient in ED with an INR = 5.2 at 8 pm. He needs to go to the OR at 7 30 am . 2-5 mg IV vitamin K is given at 10 pm. What will the INR be at 7:30 am? ( 9.5 hours later) INR = 12.36 – 11.5 log28.5 + 2.96( Log 28.5) 2 INR= 12.36 – 11.5 (1.45) + 2.96 (1.45) 2 INR = 12.36 – 16.7 + 6.22 INR = 1.9 If vit K given at 8 pm, what would be the difference ? INR = 12.36 – 11.5 (1.54) + 2.96 ( 1.54) 2 INR = 12.36 – 17.71 + 7.02 INR = 1.67 SABM 2012

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