Prothrombin complex concentrate Octaplex Maude Latulippe, CCFP-EM res Grand Rounds, FMC

Hx CVA in 2007 and A fib on Coumadin CASE 73 year old male Hx CVA in 2007 and A fib on Coumadin Brought in by EMS for right sided weakness and aphasia. Pt unable to walk 73 year old male with Hx CVA in 2007 and A fib on Coumadin brought in by EMS for right sided weakness and aphasia. Last seen normal at 12:30pm by his wife when he left home to go to the casino. At 1500h casino security carried him out of the building for “acting inappropriately” and put him in a taxi. The taxi driver drove him to his home address, but once there the patient could not get out of the car. EMS was called. Upon EMS arrival the patient was completely aphasic and had right sided hemiplegia. He was unable to walk.

Remainder of physical exam is non-contributory. Pt speaks limited English and follows a few commands. No family is present. On exam: Vitals 37.2, 100, 16, 167/98, 98% RA Glucometer 6.8 Eyes open spontaneously. He has a right lower face, arm and leg hemiparesis. He is agitated. EKG: a fib Remainder of physical exam is non-contributory. Patient speaks limited English and follows a few commands. He is not able to supply any history and no family is present.

Chronic venous insufficiency Dyslipidemia Meds: Warfarin Lipitor PMHX: Ischemic CVA in 2007 secondary to A fib and subtherapeutic INR. Was left MCA symptomatology A fib CHF Remote MI HTN PVD Chronic venous insufficiency Dyslipidemia Meds: Warfarin Lipitor Micardis Ramipril Lasix Ischemic CVA in 2007 secondary to A fib and subtherapeutic INR. Was left MCA symptomatology (dysphasia, right arm and face weakness) , no CTA done as some renal insufficiency, deficits improved dramatically and no thrombolytics given at that time. A fib CHF Remote MI HTN PVD Chronic venous insufficiency Dyslipidemia

CT head: left basal ganglia hemorrhage with layering of blood components.

Post CT the patient deteriorates: GCS drops to 7 (E2 M4 V1) Breathing becomes more shallow and appears less effective. Eyes deviate to the left. CBC, lytes, creat unremarkable INR 3.6 PTT N

Should vitamin K be given? How long does FFP take to work? Management: Should vitamin K be given? How long does FFP take to work? What are the other disadvantages of FFP? What new blood product is the best treatment for this patient? What are the other indications for Octaplex- prothrombin complex concentrate? Management: Should vitamin K be given? Yes- IV. Some benefit within 2 hours, maximal benefit by 6-8 hours. Restores physiologic coagulation. How long does FFP take to work? If the INR is normal after vitamin K, is physiologic coagulation necessarily present? Delay to thaw FFP, takes hours to work, does not necessarily restore physiologic coagulation, even if the INR normalizes. What are the other disadvantages of FFP? Large volume Risk of TRALI What new blood product is the best treatment for this patient? Octaplex- prothrombin complex concentrate What are the other indications for Octaplex- prothrombin complex concentrate? A patient on Coumadin with: Intraocular sight threatening bleed Intracranial bleed Compartment syndrome Massive hemorrhage Need for emergent surgery Traditional indication is factor 9 hemophilia

Objectives What is Prothrombin Complex Concentrate (PCC)? Potential risk Advantages: PCC vs Vit K PCC vs FFP How to use it? Indications/Protocol

PROTHROMBIN COMPLEX CONCENTRATE 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 PCC First generation started early 50’s. They were 3 factors products (II, IX, X) used to treat hemophilic B patients because of the lack of single factor products. Coumadin inhibit the maturation of functional vitamin K-dependent coagulation factor (F) II, FVII, FIX, and FX, and hence cause a functional deficiency of these proteins. They also produce a functional deficit of anticoagulant proteins C and S. 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 which consist of a treatment by Solvent-detergent treatment, nanofiltration. There is also a PCR-testing for HIV,HBV,HAV,ParvovirusB19. 1150$ per dose

Octaplex: Contains FII, FVII, FIX, FX in the ratio of approx. 1:1:1:1 Variation between PCC products All PCC contain factor II, IX, X Standardised on basis of FIX ( more then 0.6IU/Kg) Variation in pro-coagulant content (FII,FX, some contain FVII whereas others don’t) Variation in anti-coag contain Prot C, prot S Heparin PCC undergo different purification/viral inactivation methodology No head to head comparison studies Country to country variation (Octaplex in Ireland, HT-Defix UK, Prothrombinex HT Australia where they recommend to add plasma to replace FVII) Octaplex: Contains FII, FVII, FIX, FX in the ratio of approx. 1:1:1:1

Review of 14 studies involving urgent warfarin reversal with PCCs Role of prothrombin complex concentrates in reversing warfarin anticoagulation: A review of the literature, Cindy A. Leissinger, Am. J. Hematol. 83:137–143, 2008 Review of 14 studies involving urgent warfarin reversal with PCCs 460 patients 7 thrombotic complications = 1.5% … in patient with a pre pro-thrombotic co-morbidity But how effective are the PCC? Role of prothrombin complex concentrates in reversing warfarin was the subject of a literature review The review covered 14 studies involving urgent warfarin reversal with PCCs. Some only analysing the efficacy of PCC, others comparing this treatment with administration vitK or FFP. All studies shows similar results in the efficacy of reversing INR within half a hour or less with very limited thrombotic complication event. Interesting and important to say all those studies taking as primary end point lower INR at a faster manner will decrease amount bleeding, will correct coag factor and will have for result decreased mortality. No study have look at benefit in mortality. In these 14 studies that included 460 patients who received PCCs for warfarin reversal, there was no clinical evidence of disseminated intravascular coagulation (DIC), but 7 thrombotic complications occurred. These adverse events included a thrombotic stroke 48 hr after PCC treatment in a man who had severe sepsis and both cardiac and renal failure, 2 deep vein thromboses and 2 non-Q-wave myocardial infarctions that were not attributed to PCC therapy and 2 patients with extensive comorbidities experienced nonbleeding strokes

Journal of Thrombosis and Haemostasis, 2008 Single-arm prospective study was from Oct 05 to Nov 06 at 15 centers in Austria, Germany, Hungary, Israel, Lithuania, the Netherlands, Poland, andSwitzerland. 43 patients with INR > 2 : 26 requiring interventional procedures 17 acute bleeding This recent article comes from Journal of Thrombosis and Haemostasis. It is a single arm prospective study conducted in 15 different centers. Patients receiving OAT were eligible for this study if their INR exceeded 2 and they required either an emergency surgical or urgent invasive diagnostic intervention or INR normalization due to acute bleeding. Exclusion criteria included: treatment with any other investigational drug within 30 days before study entry; exposure to whole blood, plasma or plasma fractions over the prior 2 weeks; hypersensitivity to PCC constituents; hereditary protein C deficiency; life expectancy <3 months; <2 weeks of stable oral anticoagulation among patients with a recent history of deep vein thrombosis or pulmonary embolism; and acute ischemic cardiovascular disorder, disseminated intravascular coagulation or sepsis. Pregnancy Based on previous clinical studies of Beriplex P/N, a target enrollment of at least 40 patients was selected. This sample size was expected to ensure an exact 95% confidence interval width of <20% around the proportion of patients attaining INR normalization, on the assumption that this proportion would be at least 90%.

Vit K given prior to PCC infusion (88% pt) Dose Beriplex by INR Method: Vit K given prior to PCC infusion (88% pt) Dose Beriplex by INR Concomitant tx with blood, plasma hold for 30 min Primary end point: - INR at 30 min INR Dose IU/kg 2-3.9 25 4-6 35 >6 50 Vit K was also given in most of the cases. Forty-three patients, 26 requiring interventional procedures and 17 experiencing acute bleeding, received PCC infusions at a median rate of 7.5 mL min)1 (188 IU/min). Study endpoints included INR normalization (<1.3) by 30 min after PCC infusion. Secondary endpoints were clinical hemostatic efficacy in stopping acute bleeding or preventing major bleeding during interventional procedures and the response and in vivo recovery of FIX, FII, FVII, FX, and proteins C and S.

40/43 INR<1.3 3/43 INR=1.4 At 30 min postinfusion, INR declined to <1.3 in 40 patients (93%), as shown above In the remaining three patients, INR was 1.4 at this time point. Clinical hemostatic efficacy was classified as very good or satisfactory in 42 patients (98%).

INR remain stable at 48h with main value between 1.2-1.3 Markedly increased plasma concentrations of FIX, FII, FVII, and FX were apparent at 30 min following PCC infusion. Normal or nearly normal concentrations of all four coagulation factors persisted throughout the 48 h observation period. Plasma levels of coagulation factors and clotting inhibitors following administration of Beriplex® P/N. F, factor.

the thrombogenicity markers thrombin-antithrombin III complexes (TAT); the fibrin split product, D-dimer; and prothrombin fragments (F1+2) were measured over the 48-hour period following infusion of Beriplex® P/N. Transient rises in TAT and F1 +2 were observed but did not correspond to any clinically observed thromboembolic events, and D-dimer levels remained unchanged. No virus transmission was observed during the 3-month follow-up period for hepatitis A, B and C viruses, HIV or parvovirus B19.

Adverse events Adverse events in 25 pt (58%) Serious : 6 patients 3 died 1 death possibly related to treatment All other serious/non-serious AE not related to treatment In 25 patients (58%) adverse events occurred, including two suspected thromboembolic complications. Serious adverse events were reported in 6 patients. Of those, 3 patients died and one death was possibly related to treatment. However, this patient was already at increased risk of thrombo-embolism as he had metastatic gastric cancer and cardiac arrhythmia as concomitant diseases. On day 4, she had increased SOB and died assuming it was PE. All other serious and non-serious events were considered not related to treatment.

New generation PCC 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 1st generation PCC associated high thrombotic rate 2nd prothrombin overload, the most thrombogenic component), activated coagulation factors in general, active phospholipid content. Now the risk of thromboembolic complication is reduced by a better balance in pro/anticoag factors. There is no more active phospholipid and no activated factor (FVIIa, FIXa) in the product. Often only 1 dose required so the risk of accumulation of thrombotic component if repeated doses is minimal. Pre-treatment PCC decreas risk of viral transmission. PCR is performed on plasma pool.

Treatment options for reversal of oral anticoagulants Vitamin K Application of vitamin K: oral: slow decrease of INR, start within 12-24 h i.v. : slow decrease of INR, start within 6-8 h FIX and FX takes longer Warfarin resistance for 1 week Depending on the their status and what you want to do with them, you have a number of treatment options for your patients who come through your ER on OAT. If you are not in a hurry and the patient does not need emergent surgery, you can withhold your Vitamin K Antagonists If you have some time, 6 – 24 hours you can give Vitamin K If you need to get them to surgery stat, you can replace your patients factors Vit K will take effect in12-24h for oral dose and 6-8h with IV dose. FIX and FX takes longer It is important to remember that, the effects of warfarin on clotting factor synthesis are antagonized for 7 days by a 10-mg dose of vitamin K 19

Studies comparing PCC with Vit K From the same review of literature cited earlier, some articles were directly comparing PCC with vitK. In a prospective, randomized, controlled study, Taberner et al. described 18 patients treated with nicoumalone or warfarin randomized to receive either vitamin K (2.5 mg intravenously) or PCC (16 U/kg) Maximum correction occurred by 30 min after PCC injection, compared with 24 hr after IV vitamin K administration. Furthermore, vitK, even at a low dose of 2.5 mg, resulted in overcorrection in all patients given this treatment. (Prothromplex) Yasaka et al. prospectively compared vitamin K and PCC (7–27 U/kg) alone and in combination in 17 patients with major bleeding The INR significantly decreased (P < 0.01), and plasma levels of coagulation factors II, VII, IX, and X and protein C significantly increased (P < 0.01) 10 min after combination therapy. A similar reduction occurred after the administration of PCC alone, although the INR increased within 12–24 hr after injection. In patients treated with vitamin K alone, the INR decreased after 5–7 hr and dropped further after 12–24 hr. (PPSB-HT)

Treatment, time and INR 21

Fresh frozen plasma (FFP) 15 ml/kg – 1050 ml in 70 kg patient 30-45 min from demand to start infusion Blood group specific Thawed 1-3h for reversal Longer time to infuse TRALI, infection, allergic reaction 200$/unit 15 ml/kg – 1050 ml in 70 kg patient 30-45 min from demand to start infusion Blood group specific Thawed 1-3h for reversal Cannot be infused quickly in some cases If large volume needed, there is a hemodilution effect Longer time to infuse TRALI, infection, allergic reaction 200$/unit standard of an FFP unit is based on its factor VIII content; the actual levels of vitamin K–dependent coagulation factors are not specified and vary considerably

Studies comparing PCC and FFP Those studies show greater INR correction rate and the time of correction significally shorter in patient given PCC compared to FFP. Concomitant use of PCC and FFP didn’t seem to change degree or time of correction.

Retrospective review 55 pts ICH -Group 1 (31pts): PCC +- FFP +- VitK Hematoma Growth and Outcome in Treated Neurocritical Care Patients With Intracerebral Hemorrhage Related to Oral Anticoagulant Therapy Comparison of Acute Treatment Strategies Using Vitamin K, Fresh Frozen Plasma, and Prothrombin Complex Concentrates. Huttner Stroke 2006 Retrospective review 55 pts ICH -Group 1 (31pts): PCC +- FFP +- VitK -Group 2 (18pts): FFP +- VitK -Group 3 (6pts) VitK Outcomes -Reversal of INR -Hematoma growth (CT or MRI>33%) -Neurological outcome (1 year) Another review analised the treatment for reversal of INR in ICH related to OAT. It was published in Stroke in 2006. Retrospective review 55 pts ICH -Group 1 (31pts): PCC +- FFP +- VitK -Group 2 (18pts): FFP +- VitK -Group 3 (6pts) VitK Treatment decision was made by the physician on duty. Parameters such as coronary diseases or chronic heart failure might have influenced initial treatment decisions but were not assessable in this retrospective study Outcomes -Reversal of INR -Hematoma growth (CT or MRI>33%) -Neurological outcome (multivariate regression analysis of risk factors for a poor long-term outcome (12 months))

Frequency of hematoma growth -19.3% vs 33.3% vs 50% (p<0.01) INR reversal (<2h) -84% vs 39% vs 0% (p<0.01) Frequency of hematoma growth -19.3% vs 33.3% vs 50% (p<0.01) Extent of hematoma growth -44% vs 54% vs 59% (NS) Incidence of growth PCC vs No PCC -19.3% vs 37.5% (p<0.01) No difference in outcome INR reversal (<2h) -84% vs 39% vs 0% (p<0.01) Frequency of hematoma growth -19.3% vs 33.3% vs 50% (p<0.01) Extent of hematoma growth -44% vs 54% vs 59% (NS) Incidence of growth PCC vs No PCC -19.3% vs 37.5% (p<0.01) No difference in outcome In the regression analysis on risk factors for long-term outcome, they found: (1) age, (2) GCS (3) glucose, (4) baseline hematoma volume, (5) presence of intraventricular hemorrhage, and (6) occurrence of hematoma growth to be associated with poor outcome No large prospective, randomised, double-blind, head to head comparaison of PCC and FFP demonstrating a definitive clinical benefit of PCC over FFP.

No blood group testing and matching No volume limitation PCC vs FFP Favouring PCC Rapid No thawing No blood group testing and matching No volume limitation fast application Highly predictable effect (Antagonism of OAC) No acute lung injury (TRALI) Favouring PCC Rapid No thawing No blood group testing and matching No volume limitation fast application Highly predictable effect (Antagonism of OAC) No acute lung injury (TRALI) High virus safety: 2 viral reduction steps Inactivation: S/D-treatment Removal: Nanofiltration TRALI transfusion related acute lung injury: acute lung injury related to infusion donor anti-granulocyte antibodies which react with AG of the recipient. PCC pooled from >1000 pt and treated with many step/procedure. 26

Is INR a good test? Sensitive to FII, FVII and X (but not FIX) Thromboelastography a better test? Profile of clot formation in whole blood PT-INR is routinely used for regulating OAT as well as monitoring the reversal of its anticoagulant effect. The test is sensitive to decreased levels of factor VII and factor X, and prothrombin, but not to decreased levels of factor IX. Because FFP contains variable amounts of factor IX, the correction of the INR with FFP may not be accompanied by a correction of factor IX levels. Thus, the INR may be normalized but the patient remains at risk of further bleeding. The use of the INR for monitoring patients treated with rFVIIa is also problematic. Pharmacological doses of rFVIIa will always lower the INR regardless of the levels of other coagulation factors. Hence, when monitoring the reversal of anticoagulant effect, INR values should be interpreted with caution as they might not reflect the actual status of all vitamin K–dependent coagulation factors Thromboelastography may provide a more meaningful measure of coagulation status. This system records a profile of clot formation in whole blood providing an overall picture of hemostatic function. Nevertheless, more data are needed to prove the clinical utility of the measure.

Guidelines controversies Guidelines to reverse coumadin anticoagulation in major bleeding patients

Indications for use (AHR) 1) For Warfarin reversal only in cases of Urgent surgical procedure required or Massive bleeding – CNS, GI 2) INR >1.5

Elective reversal of OAT pre-invasive procedure CONTRAINDICATION: History HIT Not recommended for* Elective reversal of OAT pre-invasive procedure Tx of elevated INRs without bleed or need for surgical intervention Massive transfusion Coagulopathy associated with liver dysfonction Recent Hx thrombosis, MI, 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 Contains a small amount of heparin therefore should not be given to patients with HIT or with known allergies to heparin 30

PCC Dosage (Regional guidelines): (less than the manufacturer’s recommended dose) 40mL (1000IU Factor IX activity) and Vit K 10mg IV (Higher dose may be needed in extremes of INR or weight) Max 120mL (3000 IU) Administration: Initial rate 1mL/min x 10 min max rate 3 mL/min F-U: PT/INR 15 min post dose Dosing recommendation by company is dependant baseline INR and weight. Because of of good response to lower concentration and easier preparation, easier access with treatment with unique dosing, Calgary transfusion committee decided to use unique dosage for protocol. 40mL (1000IU Factor IX activity) and Vit K 10mg IV (Higher dose may be needed in extremes of INR or weight) 2nd dose may be given 15 min after 1st dose if bleed persist (after collection of an PT/INR) 3rd dose if INR>1.5. Need hematopatho approval Monitor allergic/anaphylactic reaction and all most be reported to Transfusion Medicine. No report so far in clinical studies Need to be reconstitued and given IV 30-60 min after reconstitution. Should not be mixed with other meds or NS in the same infusion set A single dose cost 1150 CAN$ Current ED stock is 2 doses (4 vials) at PLC and RGH ED 5 doses (10 vials) at FMC

Availability Octaplex available at FMC, PLC and RGH Any physicians who follow the protocol can order Octaplex. An Octaplex request form must be completed and faxed to the transfusion Medicine department. Octaplex available very rapidly

Progress of case: FFP is ordered. 10mg IV Vitamin K given. Transfusion medicine is called to release Octaplex from the blood bank. Octaplex 40cc (2 vials) given

INR is reversed from 3.8 to 1.3 within 15 minutes of administration of Octaplex. The patient does not appear to worsen clinically and does not require intubation. He is admitted to the Stroke Team. A CT scan the next day unfortunately shows significant progression of the bleed. The patient has very poor neurological function. Goals of care are changed to comfort measures and he dies on the 10th day after admission.

Take home point Octaplex is a Prothrombin Complex Concentrate available in Calgary through blood bank Contains FII, FVII, FIX, FX, protein C, protein S and heparin Use if INR>1.5 + Massive bleeding (GI/ICH) or Urgent surgical procedure needed C-I: HIT Give 2 vials (40cc) + vit K 10 mg IV Should be effective in less then 30 min, recheck INR Very sick patients with poor outcomes, mortality/morbidity benefit still unproven

Special thanks Thanks to Dr Carey, Dr Dorrington, Dr Shelagh Coutts (neuro) and Dr Rad (hemato) Thanks to Carolyn Jursa, Octapharma representant and to the department of blood product FMC

The use of PCC in Intensive Care Medicine, symposium Oct 2009, UK Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital, David Bruce,Tim JC Nokes, Department of Haematology, Derriford Hospital, UK, critical care,2008 Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial., PABINGER, B. BRENNER J, Thromb Haemost 2008, Warfarin-reversal: results of a phase III study with pasteurised, nanofiltrated prothrombin complex concentrate, Ingrid Pabinger-Fasching , Medical University of Vienna, Austria Role of prothrombin complex concentrates in reversing warfarin anticoagulation: A review of the literature, Cindy A. Leissinger, Philip M. Blatt, American Journal of Hematology, 2008 Current Practices and Unresolved Questions Intracerebral Hemorrhage Associated With Oral Anticoagulant Therapy, Steiner, Stroke 2006 Hematoma Growth and Outcome in Treated Neurocritical Care Patients With Intracerebral Hemorrhage Related to Oral Anticoagulant Therapy Comparison of Acute Treatment Strategies Using Vitamin K, Fresh Frozen Plasma, and Prothrombin Complex Concentrates, Huttner, Stroke 2006 The use of PCC in Intensive Care Medicine, symposium Oct 2009, UK Up to date 115 pts retrospective data of all patients who have been administered Octaplex from March 2008 to Feb 2009. Response to Octaplex was rapid with decline of INR within 10 min after Octaplex administration (from 3.8 ± 2.3 to 1.6 ± 0.8). The desired clinical response based on post-infusion INR (<1.6)was achieved in most patients (74%) and a moderate correction of INR in the rest (26%). Activated Factor VII (Niastase)  contains only factor VII and could shortcut the classical intrinsic coagulation pathway (in higher doses) in hemophilia patients with Factor VIII inhibitors (Dysfunction intrinsic pathway). It is also used as last shot in non-surgical bleeding patients with no obvious laboratory coagulopathy or bleeding patients not responding to FFP transfusion. it is thought it can help to creat platelet aggregates in small vessels in patient with refractory bleeding. Expensive 4000$ per dose Very small litterature covering its use for OAT bleeding pts Our local data collected as of January showed a 90% success rate in reversing INR to normal with a single dose of octaplex.  Numbers in Ontario were lower and this was thought to be because the product was being prepared in a minibag and perhaps was binding to the plastic.  Reasoning for concurrent Vit K administration is that INR alone is likely not a completely accurate way to assess if coag factor levels are adequate.  Giving Vit K will additionally support raising levels of these factors.  Current ED stock is 2 doses (4 vials) at PLC and RGH ED 5 doses (10 vials) at FMC.