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Reversing New and Existing Anticoagulants: What is the Role of Prothrombin Complex Concentrates in Patient Blood Management? Presented by: Dr. Lynn Boshkov,

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Presentation on theme: "Reversing New and Existing Anticoagulants: What is the Role of Prothrombin Complex Concentrates in Patient Blood Management? Presented by: Dr. Lynn Boshkov,"— Presentation transcript:

1 Reversing New and Existing Anticoagulants: What is the Role of Prothrombin Complex Concentrates in Patient Blood Management? Presented by: Dr. Lynn Boshkov, MD Prof. Pathology, Medicine & Pediatrics Director Hemostasis & Thrombosis Associate Director Transfusion Medicine Oregon Health & Science University, Portland Oregon, USA E-mail: boshkovl@ohsu.edu At: SABM Annual Meeting 2012 Pittsburgh, PA Sept 22, 2012 9:15-10:30

2 Structure of this talk: Urgent warfarin reversal issues are complex and product recommendations are evolving tho data is still only grade 2C. Why giving plasma +/- Vit K can be problematicvolume, time, and INR issues An overview of 3- and 4-component PCCs and why we need them for warfarin reversal Why the bloom is off rVIIa for warfarin reversal Concerns re: safety of PCCs?will they clot your patient solid? New anti-IIa and anti-Xa anticoagulants are here as alternatives to warfarin how do we monitor and urgently reverse them? Will PCCs likely be useful here? Anecdotal cases of very off-label use of PCCs as a procoagulant tool in difficult-to-manage non-warfarin clinical scenarios

3 Disclosures: None; confess to bias to 4-component PCCs after seeing them in action as site investigator for the Octaplex trial (Lex-205) Off-label uses (US): Multiple: 3 component PCCs, rVIIa, FEIBA…and, of course, 4 component PCCs (as yet unlicensed in the US)

4 Recommended recent reviews and articles re: reversal of Vit K antagonists and newer anticoagulants: Focus on warfarin: Goodnough LT and Shander A, How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage, 117:6091-6099, Blood 2011. Streiff MB, Prothrombin complex concentrates for reversal of vitamin K antagonists: Assessing the risk, Thromb Haemost 106: 389-390, 2011. Dentali F et al, Safety of prothrombin complex concentrates for rapid anticoagu- lation reversal of vitamin K antagonists, Thromb Haemost 106: 425-438, 2011. Drager WE, Using prothrombin complex concentrates to rapidly reverse oral anticoagulant effects, Ann Pharmacother 45: 1016-20, 2011. Focus on warfarin and the new anti-IIa and anti-Xa agents in clinical practice: Bauer KA, Reversal of antithrombotic agents, Am J Hematol 87:S119- S126, 2012 Dzik W, Reversal of drug-induced anticoagulation: old solutions and new problems, Transfusion 52: 45S-55S, 2012 Ageno W et al, Oral Anticoagulant Therapy in: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest 141 (2 Suppl) Feb 2012.

5 Focus on anticoagulant agents with novel mechanisms of action in pretrials and early trials: Weitz JI et al, New Antithrombotic Drugs in: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest 141 (2 Suppl) Feb 2012. UpToDate articles: Valentine KA et al, Correcting excess anticoagulation after warfarin, www.uptodate.com, Literature review through: Aug 2012. This topic lastwww.uptodate.com updated: Aug 29, 2012 Freeman WD et al, Management of warfarin-associated intracerebral hemorrhage, www.uptodate.com, Literature review through: Aug 2012. Thiswww.uptodate.com topic last updated: April 2, 2012 Leung LLK, Anticoagulants other than heparin and warfarin, www.uptodate.com www.uptodate.com Literature review through: Aug 2012. This topic last updated: Sept 5, 2012

6 Focus of this talk will be the treatment of major bleeding associated first with warfarin and by extension with newer oral anticoagulants with anti-IIa and anti-Xa activity Major Bleeding (ISTH 2005regardless of INR): Fatal bleeding Symptomatic bleeding in a critical area or organ including intracranial, intraspinal, introcular, retroperitoneal, intra- articular, pericardial, or intramuscular with compartment syndrome Drop in Hb level of >/= 2 g/dl (1.24 mmol/l) Need to transfused 2 or more units of whole blood or RBCs

7 Structure of this talk: Urgent warfarin reversal issues are complex and product recommendations are evolving tho data is still only grade 2C. Why giving plasma +/- Vit K can be problematicvolume, time, and INR issues An overview of 3- and 4-component PCCs and why we need them for warfarin reversal Why the bloom is off rVIIa for warfarin reversal Concerns re: safety of PCCs?will they clot your patient solid? New anti-IIa and anti-Xa anticoagulants are here as alternatives to warfarin how do we monitor and urgently reverse them? Will PCCs likely be useful here? Anecdotal cases of very off-label use of PCCs as a procoagulant tool in difficult-to-manage non-warfarin clinical scenarios

8 We subvert almost every step in normal hemostasis to prevent and treat thrombosis: 1-On the venous side: 2-On the arterial side: DVT, PE MI, CVA, afib CVA Anticoagulants Antiplatelet agents (Fibrinolytics) Anticoagulants Fibrinolytics

9 And unfortunately patients sometimes bleed….. NY Times on-line: January 5, 2006 Blood Thinners a Danger in Sharon's Treatment The huge stroke suffered by Prime Minister Ariel Sharon of Israel, caused by uncontrolled bleeding into the brain, will probably be devastating and nearly impossible to treat because Mr. Sharon has been on blood thinners…. Before operating, doctors gave Mr. Sharon a drug to counteract the effects of the blood thinner …. Sharon was coumadinized In 2006 the drug to counteract the effects of the blood thinner was almost certainly rVIIa; today it would almost certainly be a PCC

10 Recommendations for reversal of major bleeding on warfarin have been: Relatively rapidly evolving due to emergence of new agents (rVIIs, 4 component PCCs) Controversial due to relatively poor quality of evidence as to benefit, comparative efficacy, and risk/benefit in of these agents esp in heterogenous patient populations (Are valves = DVTs or even other valves??? Are vaculopaths = non-vasculopaths??? Are kids = adults???) Confounded by lack of availability of agents such as 4 component PCCs in the US And even the Bible has been inconstant….

11 Serious Bleeding Vitamin K 10 mg IV FFP or PCC or VIIa Life- threatening Bleeding Vitamin K 10 mg IV FFP or PCC or VIIa August 2008 New in 2008 (Adapted from Tony Giulivi)

12 Although FFP can be given in this situation, immediate and full correction can only be achieved by the use of factor concentrates because the amount of FFP required to fully correct the INR is considerable. CHEST 2008; 133: 175S

13 (From: Goodnough & Shander, Blood, 2011)

14 And the Feb 2012 Chest again revised recommendations…….. Plasma seems condemned rVIIa removed role of 3-component PCCs (and US MDs) left in limbo…..

15 Whats a poor US hematologist to do?? Well, lets look at some basics and try to make our own decision with the materials on hand….

16 Structure of this talk: Urgent warfarin reversal issues are complex and product recommendations are evolving tho data is still only grade 2C. Why giving plasma +/- Vit K can be problematicvolume, time, and INR issues An overview of 3- and 4-component PCCs and why we need them for warfarin reversal Why the bloom is off rVIIa for warfarin reversal Concerns re: safety of PCCs?will they clot your patient solid? New anti-IIa and anti-Xa anticoagulants are here as alternatives to warfarin how do we monitor and urgently reverse them? Will PCCs likely be useful here? Anecdotal cases of very off-label use of PCCs as a procoagulant tool in difficult-to-manage non-warfarin clinical scenarios

17 Basics #1: General tools / interventions for reversal of emergency bleeding on ANY anticoagulant: Direct neutralizing agents: ex. protamine (for standard heparin +/- LMWH) Not available or applicable for VKAs Give/replete missing coagulation factors: plasma, PCCs have II,VII,IX, X so should be useful for VKAs --fibrinogen (cryo, concentrates) not useful for VKAs) Promote synthesis of Vit K dependent factors: give Vit K –but all factors wont respond equally temporally and it will take hrs before any effect and days for full effect Use factor bypass agents off-label: rVIIa, FEIBA

18 Basics #2: Consider clinical issues involved: Urgency : mins? hrs? Volume tolerance: ICH on warfarin + 4 U plasma Optimal dose(s), routes, timing t ½ of the coagulation factors / agents involved Will redosing or a combination of interventions be necessary? How to monitor correction of coagulopathy? Risk of thrombosis? Especially: rVIIa and FEIBA in underlying thrombotic vasculopathy but worries about PCCs tooreason theyre not yet licensed inUS Risk to patient of anticoagulant reversal/interruption? Faced with a choice between bleeding and thrombosis choose bleedingits easier to treat….Dr. Jack Hirsh

19 Some authorities have suggested different target INRs for reversal of VKAs with either plasma or PCCs depending on the degree of bleeding and the thrombotic risk: (Shulman NEJM 349:675, 2003 referenced in UpToDate article on Correcting excess anticoagulation after warfarin) Moderate bleeding and high thrombotic risk: Target INR 2.0-2.1 Serious bleeding and mod thrombotic risk: Target INR 1.5 Serious or life-threatening bleeding and low thrombotic risk: Target INR 1.0

20 Basics #3: Where coumadin works: XI XIa IX X Xa X II IIa Fibrinogen Fibrin X-L Fibrin Va T. F. IXa VIIa VIIIa XIII Coumadin: Vit K antagonist [ II, VII, IX, X = dysfunctional] Tissue Factor Release Extrinsic/ PT Intrinsic/ PTT

21 So ideally for immediate coumadin reversal we would rapidly give a balanced mix of II, VII, IX and X (not forgetting the other Vit K dependent proteins = C and S) Plasma has this mix BUT: 1) At an INR of 2.0-3.0 levels of Vit K dep factors are about 20%--how much plasma do we need to give to bring factor levels to 50-100%? 2)Can we give plasma fast enough esp given the variable t ½s of the different Vit K dep-factors? Factor t ½ (hr) F II 60 F VII 4-6 F IX 22 F X 35

22 Basics #4: Vit K-dep factor levels at an INR of 2.0-3.0 are about 15-25% but there is non-linearity of the INR and the degree of factor defyits much easier to correct the INR from 3.0 to 2.2 with plasma than to go below 2.2: (Adapted from Dzik, Transfusion 2012) ????

23 Due to this non-linearity: 1. With each ~250 ml unit of plasma increasing factor levels ~ 4% in a 70 kg adult, it should take a lot of plasma (~3-4 L) to take coagulation factors from 20 to 80-100% (INR 2.2 to 1.2-1.0)--if 80-100% is our object. --for minor bleeding 30-40% may be enough but can plasma really do the job for major bleeding? A concentrated source of II, VII, IX and X (i.e. a 4- component PCC) would appear strongly desirable in major bleeding 2. Factor levels are about 30-40% at an INR of 1.4-1.8 and giving 2-4 units of plasma for an INR of 1.3 – 1.8 should do almost nothing for the INR -- exactly what was found by Abdel-Wahab OI, et al. Transfusion 46: 1279-85, 2006.

24 In conclusion: 1.Its hard to give plasma fast enough if you are aiming for 50-80% factor levels to correct major bleeding in a therapeutically coumadinized patient 2.If the INR is >4.0 factor levels are 5-10%--and if the patient is 100 kg--the problem of giving enough plasma fast enough is worse 3. Due to the t ½ of the Vit K dep factors correcting FVII is a real problem 4. PT INR will prolong/correct faster than the PTT and due to the VII problem redosing of factors may be necessary

25 Factor t ½ (hr) F II 60 F VII 4-6 F IX 22 F X 35 Treating bleeding on warfarin: one US approach Problem: Vit K deficiency Isssues to keep in mind: 1. PT INR prolongs/correct faster than PTT target PT INR < 2.0 2. Vit K give IV (over 30-60 min)--SQ absorption erratic adult: INR 2-4.5: 2.5 mg; INR 4.5-10: 5mg; INR>10: 5-10mg [anaphylaxis ~ 3:10,000; can give 2.5-5 mg PO if not emergent] 3. Earliest effect 4-6 hr; 2-3 days to full effect give plasma too [ Large doses needed quickly: 15-20 ml/kg or 4-5 U in an adult] (1 U plasma factor levels ~ 3-5%-- at INR 2.0-3.0 baseline levels 20-30%) 4. In truly emergent situation (ICH) give 3 component PCC and small amount rVIIa or consider FEIBA (but concern re: thrombosis)

26 Caveat if you are using plasma : Youll probably need to give a lot: 15-20 ml/kg minimum One suggested protocol (UpToDate): Determine the target INR: Moderate bleeding and high thrombotic risk: Target INR 2.0-2.1 Serious bleeding and mod thrombotic risk: Target INR 1.5 Serious or life-threatening bleeding and low thrombotic risk: Target INR 1.0 Determine your patients prothrombin complex percentage by the current INR: INR > 4.0: 5 – 10 % of normal INR 1.9-3.2: 15 – 20 % of normal INR 1.4-1.8: 30 – 40 % of normal INR 1.0: 100% of normal Determine the dose of plasma (or PCC) from the following formula: Dose = (target INR level [as %] – present INR level [as %] x body wt (kg) This is the ml of FFP or the IU of PCC needed As an example, in a 70 kg pt with PE 3 mos prior presenting with major GIB and INR of 7.5 (5% of normal activity), the target INR would be 1.5 (40% of normal) and the dose would be: (40-5) x 70 = 2450 of FFP (~10 units) or 2450 IU of PCC And prepare to have a long-drawn out reversal likely complicated by TACO (txn associated circulatory overload)

27 Or if you are in the US reach for the 3-component PCC you can get and use it with a bit of rVIIa: Need 2450 IU of PCC = about 250 ml which can be infused over about 20 mins

28 Structure of this talk: Urgent warfarin reversal issues are complex and product recommendations are evolving tho data is still only grade 2C. Why giving plasma +/- Vit K can be problematicvolume, time, and INR issues An overview of 3- and 4-component PCCs and why we need them for warfarin reversal Why the bloom is off rVIIa for warfarin reversal Concerns re: safety of PCCs?will they clot your patient solid? New anti-IIa and anti-Xa anticoagulants are here as alternatives to warfarin how do we monitor and urgently reverse them? Will PCCs likely be useful here? Anecdotal cases of very off-label use of PCCs as a procoagulant tool in difficult-to-manage non-warfarin clinical scenarios

29 Problem: Currently licensed PCCs (prothrombin complex concentrates) in the US are used to treat hemophilia B = FIX defy and are definitely NOT ideal for warfarin reversal: ProfilnineBebulin VF ManufacturerGrifolsBaxter ContentsVitamin K dependent factors Units/100 units FIX FII FVII FX 148 11 64 120 13 129 SourcePooled human plasma DosingFIX: 75 units/kg May repeat q12hr as needed FIX: 50 units/kg May repeat q24hr as needed Viral attenuationSolvent detergentVapor heat NOTE: Very little FVII (Slide adapted from Michael Recht, MD PhD)

30 So if you give these 3-component PCCs for warfarin reversal you ideally need to give some FVII too…. OHSU has a one-size fits all approach to major bleeding requiring full reversal of coumadin: 1. Give Profilnine 4000 U (or 50 U/kg if patient tiny or hugeaverage American is 100 kg so 4000 U is 40 U/kg) 2. Give 1 mg of rVIIa also to replete FVIIa (this is 10 mcgm/kg if youre 100 kg) 3. To sustain the reversal give Vit K IV 5-10 mg.

31 FEIBA: $1.3392/iu So for 50 U/kg x 70 kg = 3500 IU x $1.3392 / IU = $ 4, 687 Profilnine: $.4491/iu So for 4000 IU x $0.4491 / IU = $ 1,796---------- NovoSeven RT: (different pricing for each vial size) --- Total cost 4000 Profilnine + 1 mg rVIIa = 1000mcg = $1.1863/mcg = $ 1, 186-------------------------------- ~ $ 3000 2000mcg = $1.1693/mcg 5000mcg = $1.1654/mcg 8000mcg = $1.4579/mcg (though because of the obvious price hike for this vial size, on principle, we do not purchase) Cost of various factors per OHSU Regional Hemophilia Center Giving Profilnine and rVIIa like this is not horribly $$$$

32 Things are much easier outside the US: (From Goodnough & Shander, Blood 2011)

33 Octaplex, a balancedPCC has recently been licensed in Canada for use in warfarin reversal; data being gathered; US trial (Lex-205) has just been completed and is in analysis stage… Beriplex, another 4-componenet balanced PCC has also recently completed their US trial….

34

35 FFP vs Octaplex FFP –Large volume (15 mL/kg; 770-1500 mL) –Risk of TRALI, TACO and anaphylaxis –Requires ABO group –Needs to be thawed –Not virally inactivated PCC –Pooled, virally inactivated –Prion reduction process –Lyophilized –Small volume 40-80 mL – Procoagulant (Slide adapted from Tony Giulivi, MD)

36 In vivo animal model (rat): PCC vs rVIIa; in vitro human plasma….

37 PCC vs rVIIa for reversal of coumadin anticoagulation: PT correction in rats Dickneite G. Thromb Res. 2008;122(1):117-23. Epub 2007 Oct 31 Saline FVIIa PCC (Slide adapted from Tony Giulivi, MD)

38 Dickneite G. Thromb Res. 2008;122(1):117-23. Epub 2007 Oct 31 PCCs vs rVIIa for reversal of coumadin anticoagulation: effect on blood loss in rats (Slide adapted from Tony Giulivi, MD) c Note: PCC but not rVIIa impacted blood loss in the animal model

39

40 PCCs in People: The European Experience J Thromb Haemost 2008; 6: 622-31 15 center in Europe (8 countries) over 1 yr Beriplex P/N Adults, INR>2, needing emergency surgery or bleeding 25 IU/kg (2-4), 35 IU/kg (4-6), 50 IU/kg (>6) Vitamin K a bit diverse (75% IV, 75% 10mg) (Slide from Tony Giulivi, MD)

41 41 The European Experience J Thromb Haemost 2008; 6: 622-31 (Slide adapted from Tony Giulivi, MD)

42 (From: Dzik, Transfusion, 2012)

43 Structure of this talk: Urgent warfarin reversal issues are complex and product recommendations are evolving tho data is still only grade 2C. Why giving plasma +/- Vit K can be problematicvolume, time, and INR issues An overview of 3- and 4-component PCCs and why we need them for warfarin reversal Why the bloom is off rVIIa for warfarin reversal Concerns re: safety of PCCs?will they clot your patient solid? New anti-IIa and anti-Xa anticoagulants are here as alternatives to warfarin how do we monitor and urgently reverse them? Will PCCs likely be useful here? Anecdotal cases of very off-label use of PCCs as a procoagulant tool in difficult-to-manage non-warfarin clinical scenarios

44 That animal data on the rVIIa vs PCC in VKA looked nasty: rVIIa looked like it reversed the INR but not necessarily the bloodwere we treating ourselves in giving it? I didnt think so, because it had seemed to work for me on many occasions, some spectacular And Guy Young had TEG data that it worked….. And various august bodies had recommended it….

45 (From: Goodnough & Shander, Blood, 2011)

46 Case #1: 5 ½ wk boy with severe Vit K deficiency and ICH* Called ~ 5 AM Jan 2, 2006 by PICU Attending Baby had presented with 2 wks loose stools, 1 wk cutaneous bruising, new blood-tinged vomitus and BRBPR Hct 19, platelets 602 PT INR > 15, PTT >200 repeated x 2 CT head: large ICH with major shift urgent correction coagulopathy and neurosurgery needed Had received dose of oral Vit K at birth Shotgun interventions: (after verifying normal fibrinogen) Megadose rVIIa (200 mcgm/kg) Vit K 2 mg IV Plasma and RBCsbut volume tolerance an issue Called in special coag tech to do assays to sort this out… *Flood VH et al, Hemorrhagic Disease of the Newborn Despite Vitamin K Prophylaxis at Birth, Pediatr Blood Cancer 2008 50: 1075-77

47 HCT PT INR PTT (28-42) ( 0.9-1.2) (26.0-36.0) 4 Jan 2006 13:00 21.3 1.15 38.9 3 Jan 2006 10:00 23.5 1.22 39.8 measured FX 0.62 3 Jan 2006 03:50 25.7 1.14 40.2 3 Jan 2006 00:30 25.3 1.07 36.5 2 Jan 2006 19:40 22.9 0.99 33.6 2 Jan 2006 16:15 23.7 0.89 32.2 2 Jan 2006 13:10 19.6 0.83 35.4 return to PICU plasma 15 ml/kg 2 Jan 2006 11:30 18.5 0.98 57.3 to OR ~10:00; IV Vit K ~9:00 2 Jan 2006 07:45 27.2 0.89 39.7 Megadose rVIIa 2 Jan 2006 04:55 19.6 >15 >200** ~ 7:00 ** Final factor assays: Vit K factors: FII, VII, IX: all < 0.01; FX 0.05 Other factors: FV 0.74; FVIII 0.88 Course of correction of coagulopathy: weaning plasma drip / boluses

48

49 However a RCT published in Blood Aug 2010 seems to have settled the issue

50 : (From Dzik, Transfusion, 2012) rVIIa in coumadinized patients corrects the INR and normalizes the TEG and thrombin generation assays in humansbut they still bleedjust like the rats did!!!!!

51 So Chest 2012 seems to have been correct in removing rVIIa as a single warfarin-reversal agent Plus: FDA has added Black Box Warning re: Prothrombotic Risk for off-label use: ~ 4-5% thrombosismostly arterial esp in elderly vasculopaths

52 Structure of this talk: Urgent warfarin reversal issues are complex and product recommendations are evolving tho data is still only grade 2C. Why giving plasma +/- Vit K can be problematicvolume, time, and INR issues An overview of 3- and 4-component PCCs and why we need them for warfarin reversal Why the bloom is off rVIIa for warfarin reversal Concerns re: safety of PCCs?will they clot your patient solid? New anti-IIa and anti-Xa anticoagulants are here as alternatives to warfarin how do we monitor and urgently reverse them? Will PCCs likely be useful here? Anecdotal cases of very off-label use of PCCs as a procoagulant tool in difficult-to-manage non-warfarin clinical scenarios

53 27 studies with 1,032 patients

54

55

56

57 FEIBAActivated PCCsingle article for warfarin reversal Retrospective study of patients receiving either plasma (n=69) or FEIBA (n=72) for warfarin reversal Clinical outcomes not better in FEIBA group and 7% adverse events ? due to FEIBA Survival 88.2% plasma and 77.8% with FEIBA (NS) NO reason to use FEIBA vs PCC for warfarin reversal

58 Structure of this talk: Urgent warfarin reversal issues are complex and product recommendations are evolving tho data is still only grade 2C. Why giving plasma +/- Vit K can be problematicvolume, time, and INR issues An overview of 3- and 4-component PCCs and why we need them for warfarin reversal Why the bloom is off rVIIa for warfarin reversal Concerns re: safety of PCCs?will they clot your patient solid? New anti-IIa and anti-Xa anticoagulants are here as alternatives to warfarin how do we monitor and urgently reverse them? Will PCCs likely be useful here? Anecdotal cases of very off-label use of PCCs as a procoagulant tool in difficult-to-manage non-warfarin clinical scenarios

59 The greatest unmet need in anticoagulation therapy has been the replacement of warfarin with orally active agents that can be given in fixed doses without routine coagulation monitoring. Consequently most of the recent attention has focused on new oral anticoagulants. And Factors IIa and Xa are always attractive targets for anticoagulants….. (Weitz, Chest, 2012)

60 IIa and Xa good targets : XI XIa IX X Xa X II IIa Fibrinogen Fibrin X-L Fibrin Va T. F. IXa VIIa VIIIa XIII Coumadin: Vit K antagonist [ II, VII, IX, X = dysfunctional] Heparins: Bind to antithrombin and accelerate normal inactivation of IIa, Xa, etc 1000x [ LWMHs Xa >>IIa]; fondiparinux (anti-Xa) Argatroban, bivalirudin: Direct thrombin (IIa) inhibitors [inhibit clot-bound thrombin heparins] Tissue Factor Release Extrinsic/ PT Intrinsic/ PTT

61 (Weitz, Chest, 2012)

62 But many other sites are being targeted:

63 (From: Dzik, Transfusion, 2012)

64 (Bauer, Am J Hematol 87:S119, 2012)

65 (Weitz, Am J Hematol, 2012)

66 (Dzik, Transfusion, 2012)

67 Dabigatran Reversal – Animal modes Activated prothrombin complex concentrates Prothrombin complex concentrates – Human PCC did not effect in-vitro tests Dialyzable Specific antibody in development (Slide courtesy of Dr. Tom DeLoughery, Hematology, OHSU)

68 Human study (n=12) of effect of PCC on PT and Endogenous Thrombin Potential after dabigatran. Bleeding not addressed. Different response with rivaroxiban.

69 (Slide courtesy of Dr. Tom DeLoughery, Hematology, OHSU)

70 (Slide courtesy of Dr. Tom DeLoughery, Hematology, OHSU)

71

72 (Bauer, Am J Hematol 87:S119, 2012) Summary of Reversal Agents in Development and their Actions

73 PRT064445 R-antidote Recombinant fXa derivative – Catalytically inactive – Lacks the Gla-domain Reverses both direct and indirect Xa inhibitors In clinical trials (Slide courtesy of Dr. Tom DeLoughery, Hematology, OHSU)

74

75 (Dzik, Transfusion, 2012)

76

77 Structure of this talk: Urgent warfarin reversal issues are complex and product recommendations are evolving tho data is still only grade 2C. Why giving plasma +/- Vit K can be problematicvolume, time, and INR issues An overview of 3- and 4-component PCCs and why we need them for warfarin reversal Why the bloom is off rVIIa for warfarin reversal Concerns re: safety of PCCs?will they clot your patient solid? New anti-IIa and anti-Xa anticoagulants are here as alternatives to warfarin how do we monitor and urgently reverse them? Will PCCs likely be useful here? Anecdotal cases of very off-label use of PCCs as a procoagulant tool in difficult-to-manage non-warfarin clinical scenarios

78 1. Potential role of PCCs in massively bleeding patients on warfarin in the CPB setting??: I confess I have used this 4000 U Profilnine + 1 mg rVIIa combination (or a variant of it) quite a few times to treat: refractory bleeding in the massive transfusion setting in a few patients taken to heart transplant fully coumadinized massively bleeding patients undergoing emergent CPB with coumadin either not reversed or partially reversed…. Jehovahs Witness patients bleeding post CPB (PCCs and factor concentrates=matters of conscience) And, although a series of anecdotes do not data make, it worked like a charm every time I used it…..it secured hemostasis without precipitating thrombosis

79 Reason for consult: Called to 7A at 18:20 on 3/22/11 by Dr. Martin Schreiber of Trauma Surgery re: massive transfusion protocol. Background: 67 yo man lifeflighted to OHSU as level one trauma after being struck by car while bicycling. Extensive injury to L chest with multiple rib and spinous #s, pulmonary contusion, GCS of 12-13 at scene. Hypotensive on arrival. L chest tube placed. Imaging showed #s ribs 1-12 and of spinous processes T1 and T2. CT head showed multiple foci of 2-8 mm ICH c/w axonal shear. Chest tube put out 1300 ml frank blood in 2 hrs following placement with aggressive fluid necessary to sustain bp. Worsening coagulopathy post admission despite administration of aggressive plasma therapy (4 U FFP) with INR > 2, PTT 51.9 and fibrinogen 112 accompanied by fall in hct from 32.9 21.8 and platelets 152 114. 2. Potential role of PCCs in massively bleeding trauma-associated axonal shear hemorrhage to limit blossoming

80 Concern re: Magnitude of coagulopathy and potential for increased bleeding (including progressive ICH) if coagulopathy not rapidly controlled. Also concern that patient might not survive surgery re: ventilatory problems if needed to intubate and ventilate only R lung. Patient appeared between 80-90 kg. Initial interventions: Per discussion with Dr Schreiber decision made to use combination of products with concentrated factors to attempt to rapidly correct hemostasis, control bleeding, and avoid surgery.

81 XI XIa IX X Xa X II IIa Fibrinogen Fibrin X-L Fibrin Va T. F. IXa VIIa VIIIa XIII Tissue Factor Release Extrinsic/ PT Intrinsic/ PTT This is the mix we tried: 1.Cryoprecipitate: fibrinogen, VIII, vWF, XIII 2. Profilnine: II, IX, X +/- VII 3. rVIIa (small replacement dose) 4.Platelets: V (in alpha granules)

82 Products chosen were: 1) Cryoprecipitate 5 pools (to supply concentrated fibrinogen, Von Willebrand factor and FVIII; also supplies FXIII) 2) Profilnine prothrombin complex concentrate (to supply concentrated FIX, FX and FII) 3) A small dose of rVIIa (to supply replacement doses of FVIIa) 4) Platelets (to supply FV--they have it in their alpha granules) The only hemostatically important factor in either the extrinsic or intrinsic left uncovered by this combination is FXI, which is arguably not as important as some of the others in hemostasis and deficiency of which could if necessary be treated with plasma +/- and antifibrinolytic such as tranexamic acid. Given the patient's probable procoagulant drive, and the plan to use aggressive hemostatic factor replacement, our initial sense was not to use tranexamic acid immediately but to keep it in reserve as an option if the above interventions failed.

83 3/22/11 16:10 17:38 18:20 19:45 21:00 Hct 32.9 21.8 17.4 22.7 28.6 Plts 151 114 76 132 107 INR 2.06 1.62 0.87 0.89 PTT 51.9 43.2 38.4 36.5 Fgn 112 142 163 241 ^ ^ Total Blood Product Transfused During Massive RBC -2- + 4 + 2 = 8 RBCs (~350 ml each) A-PLTs 2 = 2 Apheresis platelets (~350 ml each) Plasma 4-- = 4 Plasma (~250 ml each) Cryoppt 2x5 pool + 2x5 pool = 4 x 5 pools cryoprecipitate (~30 ml each) rVIIa 1 mg (at 19:25) = 1 mg rVIIa (~ 1 ml) Profilnine 4000 U (at 19:35) = 4000 U Profilnine PCC (~40 ml) ICH also probably better controlled…. unfortunately patient did not recover neurologically Coagulopathy was rapidly controlled and bleeding

84 3. Use of PCCs in a patient who had gone fully coumadinized (for a mechanical aortic valve) into her liver transplant the previous afternoon and who had continued to bleed ~ 1 unit RBCs every hour overnight despite an FFP drip Initial INR had been 3.5 going into the transplant Had received 6 RBC, 8 plasma, 2 platelets intra-op Post-op INR 1.8 put on plasma drip of 125 cc/hr No Vit K given (I had recommended 2.5 mg but cardiology refused. Bled 8 U overnight with hct 24- 16 following AM INR was 1.5 and she looked like she was headed back to OR Transplant agreed to give Vit K 2 mg IV, Profilnine 30 U/kg, and 1 mg of rVIIa Bleeding stopped and did NOT resume; no thrombosis; OR avoided

85 4.Use of PCCs in massively bleeding patient where bleeding due to inoperable vascular malformation.

86 66 y/o man with history of Loeys-Dietz Marfan variant connective tissue disorder s/p elective AAA repair with R hypogastric bypass 4/17/12. Early post-op course complicated by melanotic stool requiring reexploration (concern ischemic bowel), respiratory failure, metabolic encephalopathy, sepsis. Had ERCP with sphincterotomy and stent 5/1/12. He continued to have complications related to continued melana/GI bleeding, and R common femoral DVT and superficial vein thrombosis. An IVC filter was placed 5/11/12 due to inability to anticoagulate due to ongoing GI Bleeding. Extensive GI work up including EGD, colonoscopy and capsule endoscopy showed multiple AVMs and actively bleeding ulcers throughout the small bowel. Tagged RBC scan showed bleeding, likely from small bowel source. Angio showed multiple aneurysms of celiac and SMA vessels but no obvious signs of active bleeding amenable to embolization. He required daily transfusions for many weeks, and OHSU Hematology Dr. Boshkov, was consulted. He continued to have GI Bleeding and remained in the ICU, requiring massive transfusion of blood products. He was hemodynamically unstable with hypotension due to hemorrhage, and on 5-25-12 he went for Visceral arteriogram with embolization of bleeding vessels, and he had infusion of factors to promote clotting. Tranexamic Acid infusion and Vitamin K IV every 3 days, and daily monitoring of HCT revealed no further bleeding after this intervention, and he has required no blood products transfused since 6/5/12. Tranexamic Acid was transitioned to oral regimen, 1300mg TID, to be given long term to prevent re-bleeding. P.T and O.T therapies were continued, and he will requiring ongoing rehab as he is dependent for mobility at this time. He has improving nutrition, wounds are with small open area at the lower pole of the abdomen which will require a wound nurse consult and surgery followup at Vibra. He should followup with OHSU Vascular Surgery and Hematology clinics when he is discharged from Vibra LTA C.

87 Clinical Hematology/ Transfusion Medicine Staff Consult Note: Massive Transfusion and Urgent Hemostatic Management: Reason for consult: Called formally by PA Amanda Hamilton/ Dr. John Mayberry to 8 CSI re: Massive transfusion protocol at 12:05 PM 5/25/12. Background: Complex and evolving case: 66 y/o man with history of Loeys-Dietz Marfan variant connective tissue disorder s/p elective AAA repair with R hypogastric bypass 4/17/12. Early post-op course complicated by melanotic stool requiring reexploration (concern ischemic bowel), respiratory failure, metabolic encephalopathy, sepsis. Had ERCP with sphincterotomy and stent 5/1/12. His more recent course has been complicated by continued melana/GI bleeding, and R common femoral DVT and superficial vein thrombosis. An IVC filter was placed 5/11/12 due to inability to anticoagulate due to ongoing GIB. Extensive GI work up including EGD, colonoscopy and capsule endoscopy showed multiple AVMs and actively bleeding ulcers throughout the small bowel. Tagged RBC scan showed bleeding, likely from small bowel source. Angio showed multiple aneurysms of celiac and SMA vessels but no obvious signs of active bleeding amenable to embolization. He has been requiring daily transfusions. Bleeding and txn requirement not previously reduced with 4 days of tranexamic acid or estrogen and hematology consulted on 5/17/12 (see their consult note). Fibrinogens lowish--170 and cryoppt advised along with trial of ddAVP given renal dysfunction. Has also received FFP. Not considered a surgical candidate.

88 This AM became hypotensive --bp 86/42--with increased GI bleeding and massive transfusion called and patient aggressively resuscitated throughout the afternoon with blood products. Tranexamic acid infusion which had been d/c's was begun again. Patient taken to IR where diffuse bleeding blushes and multiple aneurysms noted. Despite aggressive attempts on the part of IR to coil the bleeding lesions, attempts to do this were only partially successful with residual bleeding noted on angio despite the coiling and improvement in coagulation parameters to what should have been hemostatic levels. BP up to126/66 at the end of angio and patient off pressors. Surgery consulted (Drs Ham, Mayberry, Martindale) but patient felt to be unacceptably high surgical risk. Extensive discussion held by me with Drs Ham and Mayberry and thereafter with patient and family, and decision made to try administration of procoagulant agents in an attempt to achieve hemostasis. I accordingly ordered, reconstituted, and personally oversaw administration of Profilnine (prothrombin complex concentrate) and rVIIa. pH was confirmed to be 7.38 prior to administration. The Profilnine and rVIIa were given after infusion of a unit of apheresis platelets and a 5-pool of cryoprecipitate with flushing of the line between administration of each product. It is hoped that administration of these agents will drive sufficient clot formation to stabilize the GI bleeding without provoking life-threatening thrombosis. Patient 's VS remained stable throughout. Post-product 1755 coag parameters as noted.

89 Coagulation parameters and administration of blood products and hemostatic adjuvants as indicated: <--8CSI---- 0133 1015 1140 1230 1345 1510 1755 Hct 19.2 21.1 22.3 20.2 28.5 26.1 Platelets 155 167 136 101 99 99 INR 1.52 1.54 1.54 1.75 1.38 0.65 PTT 24.2 27.3 27.3 >200 29.6 26.7 Fibrinogen 180 177 183 161 215 218 Hep level 0.08 ^ ^ ^ ^ Total blood products during massive RBCs 4 + 2 + 3 + = 9 'U' RBCs FFP 2 + 3 + 1 + = 6 'U' Plasma Apheresis platelets 1 + 1 = 2 'U' Apheresis platelets Cryoprecipitate (5 pool) 1 + 1 = 2 x 5-pools cryo Profilnine* 3000 'U' rVIIa** 5 mg TA# <--------------------------ongoing---------- * Profilnine ~ 20 U/kg given around 1700 over 10 mins ** rVIIa ~ 40 mcgm/kg Given around 1710 over 10 mins # Tranexamic acid --ongoing

90 Suggest: To maximize hemostasis and attempt to compenstate for effects of pathological vasculature suggest: 1) Continue to monitor CBC and coagulation parameters: A) Transfuse RBCs to keep hct > 28 to assist platelet margination given renal dysfunction. B) Transfuse plasma to keep INR < 1.5 C) Transfuse platelets to keep platelets > 100 D) Transfuse cryoprecipitate to keep fibrinogen > 200 2) Maintain tranexamic acid drip--antifibrinolytics are often effective in control of bleeding in patients with vascular malformations. Would be very slow to d/c this and would consider bridging to oral tranexamic acid if survives. 3) I am on call over long weekend and will continue to follow with you. Please page with ?s/concerns. Would possibly consider repeating Profilnine and rVIIa dosing tomorrow if evidence of ongoing slow bleeding. Total time I spent in assessment and treatment of the coagulopathy during the massive transfusion and its aftermath (>50% in coordination of care): 6 hours

91 Summary: 1. Urgent warfarin reversal issues are complex and product recommendations are evolving and tho data is only grade 2C my recommendation is consistent with the 2012 Chest: Give a 3-component PCC + small dose rVIIa either as a one size fits all protocol or according to calculations until we have 4-component PCCs licensed in the US then give a 4- component PCC instead Give Vit K 10 mg IV 2.Giving plasma if you havent got PCCs is OKbut: you will need to give large volumes quickly FVII and INR issues will bedevil you and your likely elderly patient will be at high risk for TACO 3.Both 3- and 4-component PCCs are somewhat prothrombotic (? 2% incidence) and should be used with caution in the elderly, in vasculopaths, and in patients with liver disease 3

92 4.Avoid both rVIIa and FEIBA for warfarin reversal 5. Lets hope the FDA gets us a 4-component PCCs soon 6. New anti-IIa and anti-Xa anticoagulants are here as alternatives to warfarin reversing these agents is difficult and PCCs will probably have a limited role here, although Id use them in, say, a patient with ICH and renal failure. Remember outside of renal failure their t ½ is relatively short, and your patient has been placed on them for usually pretty sound procoagulant reasons; also if you give PCCs you will be giving goodly levels of other factors in addition to the II and X you want to replete. 7. PCCs are a new hemostatic tool in the armamentarium and desperate hematologists and others will use them creatively as part of the hemostatic last rites Randomized trials would be lovely but numbers of patients and funding will be a problem (industry has got to be even more leery after the NovoSeven fiascoes)

93 8.I find myself using more PCCs, cryoprecipitate (I long for fibrinogen concentrate), mini-dose rVIIa, and tranexamic acid to control hard-to-manage bleeding diatheses. 9.We need better ways to monitor coagulation than the traditional PT INR, PTT, fibrinogen and platelet count esp in patients with complex disorders and on new agents including anti-platelet agents. Im using increasing numbers of TEGs and platelet- mapping TEGs and would like other things like the Ecarin time and thrombin generation assays to be available. Worrisomely Holcomb just published in the Sept 2012 Annals of Surgery 256 (3): 476-86. Annals of Surgery 256 (3): 476-486:

94 Of the 1974 trauma patients in this study 17 were on OACs :

95 Questions?


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