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Barbara Steinlechner Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care Medical University of Vienna Prothrombin Complex Concentrates.

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Presentation on theme: "Barbara Steinlechner Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care Medical University of Vienna Prothrombin Complex Concentrates."— Presentation transcript:

1 Barbara Steinlechner Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care Medical University of Vienna Prothrombin Complex Concentrates

2 http://www.akhwien.at

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4 5/6/2015barbara.steinlechner@meduniwien.ac.at http://www.akhwien.at Key Figures of Medical Care and Adjusted Staff Figures Number of beds.......................................... 2.141 Physicians.................................................. 1.453 Pharmacists, chemists, physicists..............189 Qualified nursing staff............................... 2.941 Medical-technical staff................................ 1.032 Paramedical staff........................................295 Administrative and clerical staff.................. 1.269 Technical/maintenance staff....................... 1.295 Other staff Personal...................................453 Total............................................................ 8.955

5 ANTICOAGULATION Direct thrombin inhibitors

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7 Br J Clin Pharmacol. 2011 Oct;72(4):581-92. Direct thrombin inhibitors. Lee CJ, Ansell JE. Direct thrombin inhibitors

8 Br J Clin Pharmacol 72:4. 581-592. Direct thrombin inhibitors. Catherine J. Leel et al. Parenteral direct thrombin inhibitors: Lepirudin Desirudin Bivalirudin Argatroban

9 ANTICOAGULATION Direct thrombin inhibitors New oral anticoagulant agents

10 New oral anticoagulant agents: Dabigatran Rivaroxaban Apixaban Edoxaban Eur Orthop Traumatol (2011) 2:7–14 The proof for new oral anticoagulants: clinical trial evidence Menno V. Huisman et al.

11 ANTICOAGULATION Direct thrombin inhibitors New oral anticoagulant agents Coumarin vitamin K antagonists

12 WarfarinPhenprocoumonAcenocoumarol Half-life20 - 60 h130 – 160 h9 h Duration of effect 2 – 5 d7 – 10 d3 – 4 d Metabolism:Liver CYP2C isoenzyme Antithrombotic effect: Reduction in F II (Prothrombin) and F X Coumarin vitamin K antagonists

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14 New oral anticoagulant agents: Direct thrombin inhibitors versus Coumarin vitamin K antagonists Eur Orthop Traumatol (2011) 2:7–14. The proof for new oral anticoagulants: clinical trial evidence. Menno V. Huisman et al. Direct thrombin inhibitorsCoumarin vitamin K antagonists Target Thrombin Effect on an established thrombus Functional vitamin K-dependent coagulation factors II, VII, IX and X No direct effect on an established thrombus Prevent clot progression Half life 12 - 179 – 160 h Metabolism Renal clearance 80%Liver metabolism Monitoring Does not require frequent laboratory monitoring INR control Food interaction Reversal FFP would not be expected to help control bleeding. Limited data exist for transfusion of PCC and FVIIa PCC, FFP, Vit K

15 Reversal of coumarin vitamin K antagonists Vitamin K1 Oral vitamin K1 is the treatment of choice unless very rapid reversal of anticoagulation is required 1.0–2.0 mg of oral vitamin K1 is sufficient may be associated with anaphylactic reactions INR can usually be normalised within 24 hours with an IV dose of 5–10 mg of vitamin K1 Med J Aust. 2004 Nov 1;181(9):4 Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Baker RI et al.

16 Active ingredients of four different prothrombin complex concentrates (PCCs) available at our hospital Name of the ingredients Content per vial in IU BeriplexP/N® 500 IU CSL Behring Cofact® 500 IU Biotest GmbH Octaplex® 500 IU Octapharma Pharmaceutics GmbH Prothromplex® 600 IU Baxter GmbH F II 400 – 960 280 - 700600 F VII 200 - 500140 - 400500180 - 480 F IX 400 - 620500600500 F X 440 -1200280 - 700600360 - 600 Protein C 300 - 900-150 - 450140 - 620 Protein S 240 - 760-140 - 260140 – 640 Heparin 4 - 200max. 0.5 IU/ IU F XI80 - 310 Antithrombin 5 - 15000

17 Heparin in prothrombin complex concentrates : Name of the ingredients Content per vial in IU BeriplexP/N® 500 IU CSL Behring Cofact® 500 IU Biotest GmbH Octaplex® 500 IU Octapharma Pharmaceutics GmbH Prothromplex® 600 IU Baxter GmbH Heparin 4 - 200max. 0.5 IU/ IU F XI80 - 310 Risk of HIT (Heparin induced thrombocytopenia) ? Bleeding prolonged ?

18 Incidence of heparin/PF4 antibody formation: 35-65% by days 7 to 10. Chest 2004; 126:311-37 Heparin-induced thrombocytopenia: recognition, treatment, and prevention: Warkentin TE and Greinacher A Incidence of clinical HIT after cardiovascular surgery is less than 2%. Ann Thorac Surg. 2003 Jan;75(1):17-22 Comparison of bovine and porcine heparin in heparin antibody formation after cardiac surgery. Francis JL, Palmer GJ, Moroose R, et al.

19 06.05.2015barbara.steinlechner@meduniwien.ac.at19 4 T Score Prospective evaluation of the „4Ts“ score and particle gel immunoassay specific to heparin/PF4 for the diagnosis of heparin-induced thrombocytopenia. Pouplard C et al. J Thromb Haemost. 2007 Jul;5(7):1373-9.

20 Disseminated intravascular coagulation (DIC) The Subcommittee on DIC of the International Society on Thrombosis and Haemostasis (ISTH) has developed a scoring card for disseminated intravascular coagulation (DIC): 1.Platelet count (more than 100 = 0; less than 100 = 1; less than 50 = 2) 2.Elevated fibrin degradation products (no increase = 0; moderate increase= 2; strong increase= 3) 3.PT upper limit of ref. range ( less than 3 secs = 0; more than 3 secs = 1; more than 6 sec. = 2) 4. Fibrinogen level ( more than 100 mg/dl = 0; less than 100 mg/dl = 1) Score of 5: compatible with overt DIC

21 No PCC in case of... HIT DIC Med J Aust. 2004 Nov 1;181(9):4 Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Baker RI et al.

22 TESTS INR Sensitive to FII, FVII and X (but not FIX). Desirable target INR for most clinical indications is 2.5 (range, 2–3). 50% of major bleeding episodes, which includes intracranial occur while the INR is less than 4.0. Thromboelastography a better test? Records a profile of clot formation in whole blood providing an overall picture of hemostatic function.

23 ROtations- Thromb- Elasto- Metrie (ROTEM)

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30 PLASMA products Virus inactivated pool plasma (z.B. Octaplas®) Collection from volunteer donors Coagulation Factor Activity: 0.5-0.6 U/mL FFP (fresh frozen plasma) (z.B. Quarantan®) Single donor Coagulation Factor Activity: 0.7-1.0 U/mL Plasma proteins: ca. 5 g / 100 mL Indications: Massive bleeding / Polytrauma Liver disease Decrease in F V, F XI, F XIII DIC, Reversal of anticoagulation

31 ----------------PCCFFP DescriptionPlasma collected from voluntary donors. Sterile freeze-dried powder Factors II, IX and X and VII Separated and frozen within 18 hours of collection from volunteer donors. Contains all coagulation factors. ContraindicationsPatients showing signs of thrombosis or disseminated intravascular coagulation. Do not use when coagulopathy can be corrected more effectively with specific therapy, such as vitamin K, cryoprecipitate or other specific factor concentrates. SpecificationsReconstituted in 20 mL of water for injections. Each vial also contains 25 IU of antithrombin and 200 IU of heparin. Available in 150–300 mL sizes. May be stored in blood refrigerator at 2–6 o C for up to 5 days once thawed, and relabelled “thawed plasma”. Thawed plasma has levels of factors II, VII, IX and X adequate for warfarin reversal. AvailabilityNo need to consider ABO group.Should be ABO-group compatible with patient’s red cells (or use AB plasma). Considerations for use Known allergies to prothrombin complex concentrates. Predisposition to venous thrombosis, disseminated intravascular coagulation and myocardial infarction. Allergic reactions and volume overload. Potential for transmission of infections, transfusion-related acute lung injury. Hepatitis B1:50.000 Hepatitis C1:5.000 - 1:20.000 HIV >1:600.000 Parvovirus B19

32 In short, why favouring PCC ? Rapid (reversal) No thawing No blood group testing and matching No volume limitation Fast application Highly predictable effect (Antagonism of OAC) No acute lung injury (TRALI)

33 Patient Medical History: Trauma, on Warfarin INR 5 CCT: intracerebral bleeding PCCorFFP ?

34 In short, why favouring PCC ? Rapid (reversal) No thawing No blood group testing and matching No volume limitation Fast application Highly predictable effect (Antagonism of OAC) No acute lung injury (TRALI)

35 Patient Left heart failure, AF, gastrointestinal bleeding, on Phenprocoumon, INR > 5 PCC or FFP ?

36 In short, why favouring PCC ? Rapid (reversal) No thawing No blood group testing and matching No volume limitation Fast application Highly predictable effect (Antagonism of OAC) No acute lung injury (TRALI)

37 Replacement therapies to elevate VWF concentration: VWF concentrates Products that contain FVIII and little or no VWF are generally not useful to treat VWD. Patient: Von Willebrand syndrome induced by Aortic valve stenosis AVR, postoperative bleeding J Cardiothorac Vasc Anesth. 2008 Oct;22(5):719-24. Acquired von Willebrand syndrome in cardiac patients. Velik-Salchner et al. PCC or FFP ?

38 -------------- -- PCCFFP Description Plasma collected from voluntary donors. Sterile freeze- dried powder Contains Factors II, IX, X and VII Separated and frozen within 18 hours of collection from volunteer donors. Contains all coagulation factors. In short, why favouring FFP ?

39 Patient Patient on phenprocoumon, bridged for heart transplantation with a left, ventricular assist device (LVAD), severe gastrointestinal bleeding PCC or FFP ?

40 In short, why favouring PCC ? Rapid (reversal) No thawing No blood group testing and matching No volume limitation Fast application Highly predictable effect (Antagonism of OAC) No acute lung injury (TRALI)

41 HeartMate II LVAS System Components HM II Components: –Implantable titanium blood pump –System Controller Shared Components: –System Monitor –Display Module –Power Sources Power Base Unit Batteries & Clips Emergency Power Pack –Accessories

42 Managing oral anticoagulation during invasive procedures according to risk of thromboembolism TimePatients at relatively low risk Patients at relatively high risk Before surgeryWithhold warfarin therapy 4–5 days before surgery. Night before surgery: If INR > 2, give 1–5 mg vitamin K1 intravenously. Day of surgery: If INR ≤ 1.5 surgery can proceed. If INR > 1.5, defer surgery, or if surgery is urgent, give Prothrombinex-HT (25– 50 IU/kg) plus 150–300 mL fresh frozen plasma or 10–15 mL/kg of fresh frozen plasma if Prothrombinex-HT is not used. Withhold warfarin therapy 4–5 days before surgery. 2–3 days before surgery: Start giving daily or twice- daily treatment doses of unfractionated heparin intravenously or low- molecular-weight heparin (LMWH) subcutaneously. If using LMWH, the last dose (maximum dose of enoxaparin 1mg/kg or dalteparin 100 U/kg) should be at least 24 hours before surgery.

43 CONTRAINDICATION –PCC´s History HIT II Not recommended for* Elective reversal of OAT pre-invasive procedure Elevated INRs without bleed or need for surgical intervention Massive transfusion Coagulopathy associated with liver dysfunction Recent Thrombosis, MCI, recent ischemic stroke or DIC Special population: Pregnant/lactating women, pediatric, congenital factor II and X deficient patients *Evaluation case-by-case basis possible with hematologist/transfusion medicine physician on call

44 CONTRAINDICATION –PCC´s History HIT II Not recommended for* Elective reversal of OAT pre-invasive procedure Elevated INRs without bleed or need for surgical intervention Massive transfusion Coagulopathy associated with liver dysfunction Recent Thrombosis, MCI, recent ischemic stroke or DIC Special population: Pregnant/lactating women, pediatric, congenital factor II and X deficient patients *Evaluation case-by-case basis possible with hematologist/transfusion medicine physician on call

45 Blood 227:6091-99 2011 How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage. Lawrence T et al. In short why favouring PCC ? Rapid (reversal) No thawing No blood group testing and matching No volume limitation Fast application Highly predictable effect (Antagonism of OAC) No acute lung injury (TRALI)

46 2004-2011 Patients (n) PCC (IU) RCP (p) Fib( g) FFP (p) AOAneur88922004.62127.35 HTX27725005.464.3012 LTX68217005.393.369 VAD15020504.733.85 Unpublished data (mean values)

47 Barbara Steinlechner barbara.steinlechner@meduniwien.ac.at Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care Medical University of Vienna

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49 Dosage = Body weight x Target PTZ-Increase Intervall: 1-2 x / d (control) isolated F VII Mangel 4 x / d Ziel PTZDauer kleinere Blutungen30 %1 Tag größere Blutungen Zahnextraktionen, kleinere Operationen30 – 50 %3 – 4 Tage lebensbedrohliche Blutungen große Operationen Frakturen gastrointestinale Blutungen50 – 80 %> 7 Tage

50 Major determinants of oral vitamin K– induced bleeding Specific risk factors > 65 years Uncontrolled hypertension History of active peptic ulcer, hepatic insufficiency Thrombocytopenia (platelet count, < 50 × 109/L), platelet dysfunction, coagulation defect, underlying malignancy, concomitant drugs (eg, acetylsalicylic acid) History of stroke, cognitive or psychological impairment Renal insufficiency Recent trauma, history of falls (> 3 per within previous treatment year, or recurrent, injurious falls) Excessive alcohol intake

51 PROTHROMBINKOMPLEX – KONZENTRATE (PPSB): INDIKATIONEN Angeborener F II, (VII) od. X Mangel Erworbene Gerinnungsstörungen: schwere Lebererkrankungen - CAVE: diss.intravas.Gerinnung Ösophagusvarizenblutungen Überdosierung von Vitamin K Antagonisten Notfallsituationen und dringende Operationen während oraler Antikoagulantienbehandlung Lebensbedrohliche Blutungen und Notfall-Operationen bei Vitamin-K-Mangelzuständen (Verschlußikterus, Gallenwegs- und Pankreas-Erkrankungen, Diarrhöen, Antibiotikatherapie).

52 In short why favouring PCC ? Rapid (reversal) No thawing No blood group testing and matching No volume limitation Fast application Highly predictable effect (Antagonism of OAC) No acute lung injury (TRALI)

53 Guidelines controversies

54 HÄMOSTATISCH WIRKSAME BLUTKOMPONENTEN Antithrombin - concentrate Protein C - concentrate aktivateds Protein C concentrat INHIBITOR- KONZENTRATE PCC´s Activated PCC´s Faktor VIII - concentrate Faktor IX - concentrate (Faktor VII – concentrate) Faktor VIIa - concentrate Faktor XIII - concentrate Fibrinogen Coagulation factors FFP (fresh frozen plasma) virus inactivatetd Poolplasma (Octaplas®) Quarantänegelagertes Einzelspenderplasma (Quarantan®) PLASMA- Products ANDERE Immunglobulin – concentrates

55 GERINNUNGSFAKTOREN HALTBARKEIT UND FÜR DIE HÄMOSTASE NOTWENDIGE MINDESTKONZENTRATIONEN Faktor Fibrinogen Prothrombin V VII VIII IX X XI XII XIII AT Mindest- konzentration 70 - 100 mg/dl 20 - 40 % 15 - 25 % 5 - 10 % 25 - 30 % 15 - 25 % 10 - 20 % 10 % 0 % 2 - 3 % 75 % ? Half Life 3 - 5 d 3 d 12 - 36 h 4 - 6 h 11 - 14 h 24 - 32 h 1 - 4 d 2 - 3 d 40 - 50 h 6 - 10 d 18 - 30 h Substitution Fibrinogen-Konz. Prothrombinkomplex FFP F VII Konz, PPSB F VIII-Konz. F IX-Konz. Prothrombinkomplex FFP nicht notwendig FFP, F XIII-Konz. AT -Konz.

56 GERINNUNGSFAKTOREN HALTBARKEIT UND FÜR DIE HÄMOSTASE NOTWENDIGE MINDESTKONZENTRATIONEN Faktor Fibrinogen Prothrombin V VII VIII IX X XI XII XIII AT Mindest- konzentration 70 - 100 mg/dl 20 - 40 % 15 - 25 % 5 - 10 % 25 - 30 % 15 - 25 % 10 - 20 % 10 % 0 % 2 - 3 % 75 % ? Half Life 3 - 5 d 3 d 12 - 36 h 4 - 6 h 11 - 14 h 24 - 32 h 1 - 4 d 2 - 3 d 40 - 50 h 6 - 10 d 18 - 30 h Substitution Fibrinogen-Konz. Prothrombinkomplex FFP F VII Konz, PPSB F VIII-Konz. F IX-Konz. Prothrombinkomplex FFP nicht notwendig FFP, F XIII-Konz. AT -Konz.

57 HÄMOSTATISCH WIRKSAME BLUTKOMPONENTEN: GERINNUNGSFAKTOR - KONZENTRATE Faktorkonzentrate enthalten einen einzelnen (bzw. einige wenige) Gerinnungsfaktoren in hoher Konzentration (spez. Aktivität ca. 50 E/ml) VORTEILE: standardisierte Aktivität geringes Volumen exakt dosierbar standardisierte Produktion virusinaktiviert NACHTEILE: aufwendige Herstellung aus Poolplasma bzw. rekombinant teuer Virussicherheit ? immunogen (Fremdproteine bei rekombinanten Produkten ?) "Anheizen" von prokoagulatorischen Prozessen

58 Thromboembolism risk Better balance pro/anticoag factor No active phospholipid No activated factor (FVIIa, FIXa) Often only 1 dose required Viral transmission 4 cases Parvovirus B19 seroconversions Allergic reaction New generation PCC

59 PROTHROMBINKOMPLEX – KONZENTRATE (PPSB): PRÄPARATE UND INHALTSTOFFE PROTHROMPLEX S-TIM4 ® (Baxter) PROTHROMPLEX Total S- TIM4 ® (Baxter) BERIPLEX P/N ® (Aventis Behring) PREIS (1000E): F II, IX, X Heparin F II, VII, IX, X Heparin, Antithrombin F II, VII, IX, X, Protein C Heparin, Antithrombin 363 – 796 € P rothrombin (F II), P roconvertin (F VII), S tuart-Prower-Faktor (F X), F IX (von Hämophilie B ) separeted from plasma collected from voluntary donors. Sterile freeze-dried powder containing coagulation factors II, IX and X and low levels of factor VII. PPSB =

60 Contains FII, (FVII), FIX, FX, and anticoagulant proteins C, S and heparin Low volume (average 40cc) Administered rapidly, quick onset of action No need for matching blood group Room temperature Prepared using viral inactivation method 1150$ per dose PROTHROMBIN COMPLEX CONCENTRATE

61 ROtations-Thromb-Elasto-Metrie (ROTEM) 06.05.201561barbara.steinlechner@meduniwien.ac.at


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