--Session Current Issues in Blood Banking, Apheresis & Coagulation: A Primer for Speed Dating

Transcription

1 --Session Current Issues in Blood Banking, Apheresis & Coagulation: A Primer for Speed Dating Jeanne E. Hendrickson, MD Delores Mo, MD Kimberly W. Sanford, MD Christopher A. Tormey, MD September 14, :15-10:45AM

2 Disclosures In the past 12 months, the speakers (JEH, DM, or CAT) have not had a significant financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s) that will be discussed in our presentation

3 Session Outline Talks on three important, but diverse areas of consultative transfusion medicine & coagulation Anticoagulants & their reversal Transfusion support for sickle cell disease patients Platelet refractoriness This session will serve as a primer to our later flipped classroom session Join us later today!

4 Our Speaker Order & Moderator Christopher A. Tormey, MD Anticoagulants and their reversal Jeanne E. Hendrickson, MD Transfusion support for SCD patients Delores Mo, MD Platelet refractoriness Kimberly Sanford, MD Moderator

5 Anticoagulants & Their Reversal: The Blood Bank Perspective Christopher A. Tormey, MD Associate Professor of Laboratory Medicine Yale University School of Medicine VA Connecticut Healthcare System September 14, 2016

6 Talk Outline Discussion of the various types of anticoagulation & their mechanism of action Review of reversal of these forms of anticoagulation from the BB perspective As applicable (i.e., not all can be reversed with transfusion)

7 Anticoagulants: Overview on Mechanism of Action Anticoagulants, which exploit the mechanisms of normal hemostasis, come in essentially one of three varieties: Agents to induce factor depletion For example, warfarin Agents that inhibit coagulation factor activity For example, heparin Agents that inhibit PLT function For example, aspirin We won t be talking about their reversal today, but keep them in mind for your bleeding patients!

8 FACTOR DEPLETION

9 Warfarin Anticoagulation Warfarin (Coumadin) is among the most commonly utilized anticoagulants in hypercoaguable patients It was developed from a natural plant source (sweet clover) after cows were found to have massive hemorrhage post-ingestion It works by markedly inhibiting vitamin K dependent coagulation factors: fii, fvii, fix, fx = vitamin K dependent

10 Warfarin/VKA Reversal Since warfarin depletes factors, it can be reversed by one of two primary mechanisms: Vitamin K repletion Transfusion of plasma and/or factor concentrates The American College of Chest Physicians (ACCP) has released a guideline on the optimal approach to VKA reversal

11 ACCP Guidelines for VKA Reversal The non-bleeding patient: INR = hold dose of VKA only INR > 10.0 = hold dose + oral vitamin K No indication for transfusion The bleeding patient with an elevated INR: Reversal using either fresh frozen plasma (FFP) or a four-factor prothrombin complex concentrate (PCC) and, Administration of vitamin K by IV (5-10 mg) Holbrook A, et al. Chest 2012;141:152S-84S.

12 Warfarin Reversal: Plasma Plasma (or FFP) should be used for routine, nonurgent reversal of patients on warfarin Typically INR should be >1.7 FFP/plasma is ineffective for INRs below 1.7 We should employ a weight-based dose for plasma of ml / kg If give for procedural prophylaxis, should be given immediately prior to or during a procedure Half-life of it s effect on INR is about 4 hours

13 FFP Dosing Example Case For dosing of FFP, we are essentially targeting fvii replacement to normalize PT/INR Goal = ~30% factor replacement for hemostasis We will also assume that the patient has essentially 0% fvii activity for dosing Let s attempt reversal for an adult who is 80 kg undergoing paracentesis: 80 kg x 10 ml / kg = 800 ml of plasma needed The average FFP unit is ~200 ml 800 ml / 200 ml = 4.0 units Best approach = give 2 units before procedure, 1 during, and 1 after

14 Warfarin Reversal: 4F-PCC 4F-PCC is a lyophilized concentrate containing therapeutic levels of all vitamin K dependent coagulation factors (FII, FVII, FIX, FX) Also contains natural anticoagulants Protein C/S A very small amount of heparin Major advantages: Small volume & high concentration of VK-dependent factors Major disadvantages Possible higher thrombotic risk & cost

15 4F-PCCs: Dosing and Administration In the setting of urgent warfarin reversal, the dosing strategy is based on weight and degree of INR prolongation: INRs 2 to 4 = 25 U / kg (not to exceed 2500 U) INRs 4 to 6 = 35 U / kg (not to exceed 3500 U) INRs >6 = 50 U / kg (not to exceed 5000 U) For surgical/procedural prophylaxis, should be given immediately prior to procedures Sarode R, et al. Circulation 2013;128:

16 FFP v 4F-PCC: Is One Superior? Initial study by Sarode et al found 4F-PCC reversed INRs more rapidly than FFP, but wasn t really powered to examine superiority in setting of bleeding A later study, also by Sarode et al, that was powered for evaluating major bleeding outcomes found: Superiority of 4F-PCC in achieving effective hemostasis vs plasma Again showed a more rapid reduction in INR Sarode R, et al. Circulation 2013;128: Goldstein JN, et al. Lancet 2015;385:

17 FFP vs. 4F-PCC: When to Use? 4F-PCC generally preferred for: Acute, life-threatening bleeds Urgent surgical interventions Volume-overloaded patients who cannot tolerate necessary dosing of FFP FFP generally preferred for: Low-moderate grade bleeds Routine or non-urgent procedural prophylaxis Complex bleeds where more than VK-dependent factors are depleted Pts at high risk for VTE

18 FACTOR INHIBITORS

19 Factor Inhibition: Overview Unlike the factor depletion category where there is essentially one option (warfarin), there are numerous ways to inhibit coagulation factors We ll divide these into categories in the following slides (typically based on the site of action of the anticoagulant)

20 Unfractionated Heparin & Related Anticoagulants

21 Unfractionated Heparin Heparin promotes anticoagulation by enhancing the activity of antithrombin (AT), a natural anticoagulant It acts on multiple coagulation factors via AT, exerting most of its effects on FXa and FIIa Half-life = ~60 min

22 Unfractionated Heparin (UFH) Reversal UFH cannot be effectively reversed by any product issued from the blood bank Plasma infusion may actually may bleeding worse or prolong PTT by providing additional antithrombin Protamine is the preferred antidote to UFH Should be reserved for bleeding due to potential adverse events For bleeding, mg per 100 units of heparin (not to exceed 50 mg)

23 Low molecular weight heparins (LMWHs) LMWHs also work primarily via enhancement of antithrombin (AT) to exert anticoagulant effects on Fxa and FIIa Their effect on FXa >>> FIIa Commonly used LMWHs: Enoxaparin (Lovenox) with half-life of ~4-6 hours Dalteparin (Fragmin) with half-life of ~3-5 hours LMWHs are monitored with the anti-xa assay as they have no impact on PTT

24 LMWH Reversal LMWHs cannot be effectively reversed by any product issued from the blood bank Plasma infusion may actually may bleeding worse by providing additional antithrombin Protamine is the preferred antidote to LMWHs Not as effective as in reversing UFH For bleeding, mg per 100 units for dalteparin or mg per mg of enoxparin

25 Direct Xa Inhibitors

26 Direct Xa inhibitors: Brief background Relatively new class of anticoagulants which inhibit FXa, a potent procoagulant in the common pathway These drugs include: Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Oral with half-lives of ~6-15 hours Fondaparinux (Arixtra) -- Injectable with half-life of hours Dobesh PP, et al. Drug 2015;75:

27 Anti-Xas: Site of action in the coagulation cascade Site of action; inhibits the common coagulation pathway Act primarily by binding FXa active site (exception = fondaparinux, which acts via AT)

28 Bleeding on Anti-Xas Bleeding with these agents is a potentially major issue Relatively long half-life There is no antidote or reversal agent currently available Note that protamine does not work for any of these drugs (including fondaparinux) Because of the problem of major bleeding, Yale has developed a reversal protocol based on available literature

29 Xa Reversal Algorithm

30 Why 4F-PCC for Xa Reversal? Theoretical benefit of providing concentrated doses of FX to overcome the inhibitory effects of these agents Some, limited data to support this practice: An in vitro study where samples from patients on rivaroxaban where mixed with 4F-PCC improved in vitro clot generation An in vivo study of reversal of bleeding associated with edoxaban following a skin punch biopsy Lots of individual case reports! Eerenberg ES, et al. Circulation 2011; 124: Zahir H, et al. Circulation 2015;131: Unold D, Tormey CA. Arch Pathol Lab Med 2015;139:

31 An Antidote to FXa Inhibitors Andexanet alfa It is a modified, recombinant version of FXa Serves as a decoy receptor for FXa inhibitors Has a high affinity for these drugs Should be able to outcompete endogenous FXa Recently reported phase III trial showed in vitro success (via anti-xa measurement) for reversal of apixaban & rivaroxaban Hopefully coming soon clinically Unclear which agent(s) it will be ultimately applicable to Human / animal models thus far suggest efficacy for fondaparinux, apixaban, and rivaroxaban Husted S, et al. Drug Saf 2016;39:5-13. Siegal DM, et al. NEJM 2015;373:

32 Direct Thrombin Inhibitors

33 Direct thrombin inhibitors: Brief background Relatively new class of anticoagulants which bind to thrombin (FIIa), a potent procoagulant in the common pathway One of the earliest label indications for some DTIs was as an alternative to heparin Particularly useful in cases of heparin-induced thrombocytopenia DTIs are now being expanded or proposed for other clinical settings Anticoagulation for atrial fibrillation and prevention of acute coronary syndromes Di Nisio M, et al. NEJM 2005;353: Ganetsky M, et al. J Med Toxicol 2011;7:281-7.

34 DTIs: Site of action in the coagulation cascade Site of action of DTIs; inhibits the common coagulation pathway Act primarily by binding FIIa active site; also exhibit an anti-plt effect (thrombin is a potent PLT agonist) Di Nisio M, et al. NEJM 2005;353: Ganetsky M, et al. J Med Toxicol 2011;7:281-7.

35 DTIs: Facts and figures Commonly used DTIs include: Bivalirudin (Hirulog) IV route; 25 min t 1/2 ; renal excretion and hepatic clearance Argatroban (Novastan) IV route; 45 min t 1/2 ; primarily hepatic clearance Dabigitran (Pradaxa) Oral route; 12 hr t 1/2 ; renal excretion Di Nisio M, et al. NEJM 2005;353: Ganetsky M, et al. J Med Toxicol 2011;7:281-7.

36 DTI: Bleeding an Issue Bleeding in patients on DTIs is a major potential issue For oral variants, relatively long half-life versus IV formulations There is no antidote or reversal agent available for IV formulations However, there is now an effective therapy for the oral DTI, dabigatran! Di Nisio M, et al. NEJM 2005;353: Ganetsky M, et al. J Med Toxicol 2011;7:281-7.

37 Antidote for Oral DTIs As of October, 2015 the FDA has approved a reversal agent for dabigatran Idarucizumab (Praxbind) MOAB fragment which binds and clears unbound dabigatran Drug widely available in most clinical hospitals and pharmacies Tell your clinicians to call pharmacy if they re seeking dabigatran reversal! Praxbind not applicable to other DTIs What can we do for those??? #5

38 IV DTI Reversal Protocol at Yale *Above is applicable to dabigatran & bilvalirudin

39 Summary There are a variety of anticoagulants that work on numerous aspects of the coagulation system Knowledge of their mechanisms / half-lives can help inform reversal and safe times for procedure performance

40 Sickle Cell Disease: Transfusion Support Considerations Jeanne Hendrickson, MD

41 Objectives To assess the indications for transfusion of sickle cell patients To review potential adverse outcomes of transfusion in sickle cell patients

42 NIH 2014

43 Risk/Benefit Ratio of RBC Transfusion in Sickle Cell Disease Any potential benefit of transfusion must be balanced by the risk of serious hazards of transfusion

44

45 in spite of the documented clinical data supporting transfusion therapy, the physiologic and rheologic aspects of this treatment approach are not fully understood Alexy et al, Transfusion 2006

46 Transfusion Options One time vs chronic Simple vs exchange

47 Potential Transfusion Indications: Acute chest syndrome Splenic sequestration Pre-operative transfusion CVA Others

48 Acute Chest Syndrome Defined as a new infiltrate in a patient with sickle cell disease May be accompanied by chest pain, fever, tachypnea, wheezing, or cough A leading cause of death

49 Acute Chest Syndrome: NHLBI, 2014

50 Chronic Transfusion Therapy as Part of the Silent Cerebral Infarct Study Decreased ACS (and VOC and Priapism) DeBaun et al, NEJM 2014

51 Splenic Sequestration Collection of sickled RBCs in splenic sinusoids Often quite acute; minor episodes also occur Precipitating events unclear Peak age 6 months-2 years Occurs at an earlier age in children with low fetal Hb levels Tends to recur Historically a leading cause of death in infants with Hb SS disease

52 NHLBI, 2014

53 Pre-operative transfusion High rates of post-operative complications have been reported in patients with sickle cell disease Including VOC, ACS, other Any type of transfusion decreases postoperative SCD complications Past studies have not reported a difference in outcome between simple and exchange transfusions

54 Pre-operative Transfusions: NHLBI, 2014

55 CVA At least 10% of patients with HbSS disease will have a clinical stroke by 20 yo A higher percentage will have a silent stroke

56 Prevention of Stroke Stroke Prevention Trial in Sickle Cell Anemia (STOP): Randomized at risk children with MCA velocity >200 cm/sec by TCD to standard therapy or chronic transfusion therapy (keeping %S <30) Adams et al, NEJM 1998

57 Chronic Transfusion Therapy Decreased Risk of CVA by 92% Adams et al, NEJM 1998

58 STOP 2: Randomized patients from STOP 1 and others with a history of CVA or abnormal TCD who had been on transfusion therapy for 30 months to discontinue chronic transfusion therapy Adams et al, NEJM 2005

59 Events included abnormal TCDs or CVAs Adams et al, NEJM 2005

60 SWiTCH Trial Stroke with transfusion changing to hydroxyurea TWiTCH Trial TCD with transfusions changing to hydroxyurea SIT Trial Silent cerebral infarct multicenter transfusion trial

61 CVA NHLBI, 2014

62 NHLBI, 2014

63 Adverse Effects of RBC Transfusion Iron overload Hyperviscosity RBC Alloimmunization Autoimmunization HLA alloimmunization Other serious hazards of transfusion Transfusion reactions Infectious disease transmission

64 Ferritin Increase After 3 Years on Chronic Transfusion Therapy (Despite Chelation) debaun et al, NEJM 2014

65 RBC Alloimmunization: 1) Increases the risk of immediate as well as delayed hemolytic transfusion reactions A leading cause of transfusion related deaths reported to the FDA each year 2) May increase the risk of RBC autoantibody formation 3) May lead to lengthy and costly blood product delays 4) Increases the risk of hemolytic disease of the newborn

66 Delayed Hemolytic Transfusion Reaction 3-10 days after transfusion of blood that appears compatible Patients previously immunized Antibody not detected pre-transfusion Anamnestic antibody response Intra and/ or extravascular hemolysis Can be severe (ARF, DIC) Rh and Kidd most common offenders

67 Anamnestic Response

68 RBC Alloimmunization Vichinsky et al: NEJM, 1990; 332: % alloimmunization rate in transfused patients with sickle cell disease (5% rate in control, non-sickle patients) 17/32 made multiple alloantibodies 66% of alloantibodies were anti-c, anti-e, or anti-k

69 Responders/Non-Responders Higgins and Sloan, Blood 2008

70 Average Frequencies of the Most Common Antibodies Made by Patients with Sickle Cell Disease Antibody Average Frequency (%) E 21 K 18 C 14 Le a 8 Fy a 7 Jk b 7 D 7 Le b 7 S 6 Fy b 5 M 4 e 2 c 2 Hillyer et al, Blood Banking and Transfusion Medicine

71 Chou and Fasano, Hem Onc Clinics 2016

72 RBC Phenotypic Matching A 2005 CAP survey found that only 37% of laboratories performed a RBC phenotype on non-alloimmunized patients with sickle cell disease Only 75% of these laboratories provided C/E/K phenotypically matched RBCs for such patients Osby M et al, Arch Path Lab Med 2005, and Afenyi-Annan A et al, Immunohematology 2006

73 Alloimmunization to C/E/K Still Occurs in Patients Who Receive the Majority of Their Care at Sites That Provide C/E/K Matched RBCs No. of patients D C c E e K f G o a Vs C w K p a Js a Js b J k a J k b F y a F y b M S Lu a K n a Nickel et al, AJH 2015

74 RBC Genotyping Increasingly being utilized for prediction of phenotype and for troubleshooting particular cases Longitudinal studies are ongoing to determine feasibility (from a donor and recipient perspective) and to determine the cost/benefit ratio compared to RBC phenotyping alone

75 Genotyping May Reveal Blood Group Antigenic Variants in SCD Patients that Phenotyping Cannot Detect Fasano and Chou, TMR 2016

76 NHLBI, 2014

77 In Addition to RBC Alloantibodies, HLA class I antibodies can be induced in SCD patients by Leukoreduced RBCs % of patients Nickel et al, BJH 2015

78 How to prevent adverse transfusion related outcomes? Judicious use of RBCs Obtain accurate transfusion histories Centralize RBC alloimmunization data Provide leukoreduced RBCs Provide phenotypically similar RBCs NIH recommends obtaining a RBC phenotype at 6 months of age and providing antigen matched RBCs C,E,K Fy, Jk, S Consider the role that RBC genotyping may play

79 Objectives To assess the indications for transfusion of sickle cell patients To review potential adverse outcomes of transfusion in sickle cell patients

80 Thank you!