Four-factor prothrombin complex concentrate in adjunct to whole blood in trauma-related hemorrhage : Does whole blood replace the need for factors? Three of the 268 PDI donations (1.1%) tested positive for SARS-CoV-2 ribonucleic acid (RNA). Solomon et als43 pharmacovigilance evaluation of fibrinogen concentrate over a 27-year period specifically analyzed the risk of thromboembolism. Vol 26. A major criticism of these studies is that patients received fibrinogen concentrate without demonstrating low fibrinogen concentration, and in 1 trial, without clinically significant bleeding, because fibrinogen concentrate was given before surgery. Rahe-Meyer N, Levy JH, Mazer CD, et al. Witmer CM, Huang YS, Lynch K, Raffini LJ, Shah SS. Cryoprecipitate also contains factor XIII, von Willebrand factor (vWF), and factor VIII; however, it is not used to replace these factors because factor concentrates and recombinant products with better . The authors found that 67.2% of patients in the treatment arm avoided any allogeneic transfusion (primary outcome) compared to 44.8% in the control group (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.19-0.84). Package insert. Jeppsson A, Waldn K, Roman-Emanuel C, Thimour-Bergstrm L, Karlsson M. Preoperative supplementation with fibrinogen concentrate in cardiac surgery: a randomized controlled study. 49. 2017; 11:3339. National Library of Medicine FIBRYNA. This observation led to the use of cryoprecipitate for treating the patients with hemophilia A and von Willebrand disease (VWD). . When Heyde syndrome patients develop post-CPBacquired hypofibrinogenemia, they may be better served by the treatment with cryoprecipitate, which contains large VWF multimers. Journal of the American College of Cardiology. doi: 10.1002/14651858.CD013551.pub2. Nature. JAMA. Some error has occurred while processing your request. The FIBRES study reported a 2.6% higher thromboembolism rate in patients who received cryoprecipitate at 9.6% compared to 7.0% in patients who received fibrinogen concentrate (Table 1); however, this difference was not statistically different.24, Another randomized controlled trial, which included patients with pseudomyxoma peritonei and cytoreductive surgery, found a higher incidence of thromboembolic events in the cryoprecipitate group at 30.4% (7 of 23) compared to 0% (0 of 22) in the fibrinogen concentrate group.44 In a recent systematic review of randomized controlled trials examining fibrinogen concentrate, the authors concluded that the overall risk of thromboembolism is probably extremely low, and no studies reported a significantly increased risk of thromboembolism in patients receiving fibrinogen concentrate.20, Despite the findings of the FIBRES study, cryoprecipitate may be superior in some cardiac surgical patients.24 In the FIBRES study, the median CPB duration was 130140 minutes, but the CPB duration is often longer in complex aortic surgery with deep hypothermic circulatory arrest or in the other combined cardiac surgery procedures. 48 0 obj <> PCC may also include the natural coagulation inhibitors protein C and protein S. PCC helps replenish these factors.[7]. 2019; 23:98. The proportion of patients assigned to either cryoprecipitate or fibrinogen concentrate as part of the original FIBRES study arm was not different (P = 0.14). Harper PC, Smith MM, Brinkman NJ, Passe MA, Schroeder DR, Said SM, Nuttall GA, Oliver WC, Barbara DW. Vox Sang. 0000005333 00000 n There was 1 vein graft occlusion in the fibrinogen concentrate group, and no vein graft occlusions in the control group. Transfusion. Epub 2018 Jan 13. Blood Transfus. 45 0 obj X@YQLw`J]$aTCPZ-S]T&-m_KX]cIbX^}>u~krM.UleEw Prothrombin complex concentrate ( PCC ), also known as factor IX complex, is a medication made up of blood clotting factors II, IX, and X. 59. 0000002434 00000 n Heparin-induced thrombocytopenia (if the preparation contains heparin). 18. Cryoprecipitate is derived from fresh frozen plasma (FFP), which is frozen within 8 hours of collection. Prothrombin Complex Concentrate Four factor PCC (Kcentra) is dosed on the amount of factor IX. 2015; 4:e002066. 2018 Sep 24 [PubMed PMID: 30244638], Roman M,Biancari F,Ahmed AB,Agarwal S,Hadjinikolaou L,Al-Sarraf A,Tsang G,Oo AY,Field M,Santini F,Mariscalco G, Prothrombin complex concentrate in cardiac surgery: A systematic review and meta-analysis. endobj [Level 5], Hellstern P, Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Another advantage of fibrinogen concentrate is that it can be rapidly reconstituted and administered to patients. Fibrinogen concentrate has multiple potential advantages including rapid reconstitution, greater dose predictability, viral inactivation during processing, and reduced transfusion-related adverse events. 0000049787 00000 n Thromb Haemost. Spahn DR, Bouillon B, Cerny V, et al. 23. Introduction. <> There were no differences observed in the number of packed red blood cells (4-factor PCC: 2 units vs. rFVIIa: 2 units), fresh frozen plasma (0 units vs. 1 unit) or platelet (2 units vs. 2 units) transfusions following the administration of 4-factor PCC or rFVIIa. Tanaka KA, Egan K, Szlam F, et al. 57. 91, No. 2007; 21:271289. Itmay beused as a medium to reverse bleeding and improve patient outcomes through interprofessional collaboration between clinicians (MDs, DOs, NPs, PAs), nursing staff, and pharmacists. Ferraris VA, Brown JR, Despotis GJ, et al. In patients where bleeding is related to coagulation factor deficiency, prothrombin complex concentrates (PCC), or fresh frozen plasma (FFP) administration should be considered to reduce bleeding and transfusions (Boer et al. 3rd ed. ; on behalf of the WFH Guidelines for the Management of Hemophilia. Factors affecting the quality of cryoprecipitate. 30. The treatment with fibrinogen concentrate will not replace VWF multimers, and poor platelet adhesion may persist despite normalization of fibrinogen. Results: A total of 252 were included in the analysis [PCC+FFP:63; FFP:189]. Fibrinogen concentrate has several potential advantages over cryoprecipitate, but there are also potential disadvantages. Cho J, Mosher DF. Acquired von Willebrand syndrome and impaired platelet function during venovenous extracorporeal membrane oxygenation: rapid onset and fast recovery. J Cardiothorac Vasc Anesth. Best Pract Res Clin Anaesthesiol. Patients were included if they were at least 18 years of age and had undergone cardiac surgery with bleeding requiring intervention with 4-factor PCC or rFVIIa. In: Cochrane Database Syst Rev. 0000001280 00000 n 3. 26. Oncotarget. Karkouti K, von Heymann C, Jespersen CM, et al. 51. The mechanism of action of PCC in reversing anticoagulation with DOACs remains unestablished. Explain the importance of improving care coordination among the interprofessional team to enhance care delivery for patients who can benefit from therapy with prothrombin complex concentrate. FIBRES - Effect of fibrinogen concentrate vs cryoprecipitate on blood component transfusion after cardiac surgery; 12 FP = frozen plasma; PCC = prothrombin complex concentrate. 60. One donor positive platelet unit was pathogen reduced and transfused 3 days after donation to a patient who remained asymptomatic, and a red blood cell (RBC) unit was given to a SARS-CoV-2positive patient. US Food and Drug Administration. Callum J, Farkouh ME, Scales DC, et al. In the Randomized Evaluation of Fibrinogen Versus Placebo in Complex Cardiovascular Surgery (REPLACE) trial, 152 patients undergoing elective aortic replacement surgery were randomized to receive either fibrinogen concentrate or placebo, depending on whether there was a bleeding mass of 60250 g on surgical packing post-CPB. Crit Care. xref Unauthorized use of these marks is strictly prohibited. Prothrombin complex concentrate (PCC) decreases INR faster than plasma in emergency situations and are the first choice of treatment, but plasma can be used if PCC is not available or if it is contraindicated. American Red Cross, Accessed November 27, 2020. J Am Heart Assoc. 0000003637 00000 n Abbreviations: AVR, aortic valve replacement; CABG, coronary artery bypass grafting; CI, confidence interval; CPB, cardiopulmonary bypass; cryo, cryoprecipitate; CT, computed tomography; FC, fibrinogen concentrate; FFP, fresh frozen plasma; FIBTEM, fibrin-based thromboelastometry test extrinsically activated with tissue factor and containing the platelet inhibitor cytochalasin D; IQR, interquartile range; LIMA, left internal mammary artery; MCF, maximum clot firmness; OR, odds ratio; postop, postoperative; prox, proximal; RBC, red blood cell; TAA, thoracic aortic aneurysm; TAAA, thoracoabdominal aneurysm. In all the indications listed above, 4-factor PCC is the preferredchoice. 2016; 117:4151. Fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC) reverse oral anticoagulants such as Warfarin. Transfusion. In particular, VWF and fibrinogen content can be affected by the amount of plasma that is left for suspension.15 Cryoprecipitate content is also affected by donor variability in factor activity and the type of freezer that is used for storage.16 Most single donor cryoprecipitate units contain at least 250 mg of fibrinogen, which translates to 1.25 g of fibrinogen for a 5 donor pool or 1.5 g of fibrinogen for a 6 donor pool.17 According to the American Red Cross, the mean factor VIII activity of a single donor cryoprecipitate unit is 136 IU and of a pool is 555 IU. Furthermore, when the surgical setting is cardiothoracic, volume overload may promote catastrophic wound or graft dehiscence. In a review of 14 individual studies of the reversal of warfarin anticoagulation, there were five thrombotic events in 308 patients who received 4-factor prothrombin complex concentrates and two in 161 patients who were given 3-factor prothrombin complex concentrates, although none of the adverse events was deemed clinically significant [11].The risk is therefore low, but it ought to be . PCC exists in two varieties: 3-factor PCC and 4-factor PCC. The shelf life is also much longer for fibrinogen concentrate (3 years) compared to cryoprecipitate (1 year), which may be important in smaller, rural hospitals that have a less frequent need for fibrinogen therapy.61 There is also a longer shelf life after reconstitution because fibrinogen concentrate is able to be used for 24 hours after reconstitution versus 6 hours after cryoprecipitate thaws. Individualized dosing is based on the severity of the disorder, extent and location of bleeding, and clinical status of the patient. For the primary end point, the use of allogeneic blood products, the fibrinogen concentrate group was transfused fewer RBC units (0.5 1.1 vs 2.4 1.1), fewer FFP units (0.2 0.6 vs 4.5 2.1), and fewer platelet units (0.0 0.0 vs 1.6 1.7).36. official website and that any information you provide is encrypted The largest randomized multicenter clinical trial of fibrinogen concentrate, the FIBrinogen REplenishment in Surgery (FIBRES) study, enrolled 725 patients at 11 centers in Canada (Table 2).24 This study included adult patients who had significant bleeding related to acquired hypofibrinogenemia after CPB, defined as fibrinogen <200 mg/dL by the Clauss method or the fibrin-based thromboelastometry test extrinsically activated with tissue factor and containing the platelet inhibitor cytochalasin D (FIBTEM) amplitude <10 mm at 10 minutes. Kasper CK. assessment of anti-platelet medication effects. It is now used to replace congenital or acquired vitamin-K deficiency warfarin-induced anticoagulant effect, particularly in the emergent setting. Thromboembolic complicationslike pulmonary embolism, stroke, myocardial infarction, and deep venous thrombosis - today's PCCformulations differ vastly from those used in the 1980s and have a lower thrombosis risk. Karkouti K, Callum J, Crowther MA, et al. Association of off-label drug use and adverse drug events in an adult population. 1964; 203:312. endobj / Khurrum, Muhammad; Ditillo, Michael; Obaid, Omar et al. 2014; 113:922934. 16. Antibodies associated with causingtransfusion-related acute lung injury (TRALI,defined as newacute lung injury that developed during or within 6 hours of transfusion of one or more units, not attributable to another ALI risk factor) - a significant cause of death after transfusion) are removed from PCC during the manufacturing process; therefore, PCC is associated with minimal risk compared to FFP. Fibrinogen concentrate was given based on the rotational thromboelastometry (ROTEM; TEM International, Munich, Germany) parameters.39 Fifteen minutes after fibrinogen concentrate was given, patients could receive prothrombin complex concentrate if ROTEM parameters remained abnormal. Warfarin inhibits vitamin K-dependent synthesis of clotting factors II, VII, IX, and X and anticoagulant factors protein C and protein S. PCC contains factors II, IX, and X, and variable amounts of factor VII concentrate with a final overall clotting factor concentration approximately 25 times higher than in normal plasma. Repeat or subsequent dosing is not recommended. Pro-coagulant haemostatic factors for the prevention and treatment of bleeding in people without haemophilia. Solomon C, Grner A, Ye J, Pendrak I. For several years, FFP and vitamin K were the preferred options for reversing anticoagulation. Name: Michael A. Mazzeffi, MD, MPH, MSc, FASA. For the primary outcome of intraoperative bleeding, there was no difference between the fibrinogen concentrate group (median, 50 mL; IQR, 29100 mL) and the control group (median, 70 mL; IQR, 33145 mL; P = .19) with an absolute difference of 20 mL (95% CI, 1335 mL). Fibrinogen concentrate has many potential advantages including a rapid administration, the predictability of dose response, and a lower risk for viral transmission, which aligns well with the FDAs recommendation to use pathogen-reduced blood products when feasible.62 However, fibrinogen concentrates lack of VWF, factor VIII, factor XIII, and fibronectin may reduce its hemostatic efficacy, particularly in cases with long CPB duration, in aortic stenosis patients, and in ECMO and left ventricular assist device (LVAD) patients. Rahe-Meyer et al36 conducted another small randomized trial in patients undergoing elective aortic valve and ascending aortic replacement surgery. 2006; 54:2633. Please enable it to take advantage of the complete set of features! Transfusion. Fridey JL, ed. [1] [3] It may also be used for reversal of warfarin therapy. Address correspondence to Nadia B. Hensley, MD, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 1800 Orleans Ave, Zayed Tower 6212, Baltimore, MD 21287. CFR-Code of Federal Regulations Title 21. 39. 1. acquired deficiency of prothrombin complex coagulation factors when rapid correction of the deficiency is required 2. congenital deficiency of any of the vitamin K dependant coagulation factors when purified specific coagulation factors are unavailable Prothromplex T Not licensed for use in UK but may be made available on named patient basis. How much factor is in a vial of PCC versus a unit of FFP? 2016 Jul;91(7):705-8. doi: 10.1002/ajh.24384. Conflicts of Interest: See Disclosures at the end of the article. 5. In this Pro-Con commentary article, we discuss the advantages and disadvantages of both products for treating acquired hypofibrinogenemia in the cardiac surgical patients. Activation of the hemostatic system during cardiopulmonary bypass. Acquisition cost is approximately $1000 per 1 g. In comparison, a pooled cryoprecipitate unit (5 donor pool) costs around $300 to acquire, but there are also processing costs and significant costs related to wastage. Br J Anaesth. Conflicts of Interest: N. B. Hensley has served on the scientific advisory board for Octapharma USA (Paramus, NJ) and received royalties from Wolters Kluwer for uptodate.com contributions. 41 0 obj 2014; 64:253257. bleeding; cardiac surgery; critical care; safety. PCC contains significantly higher amounts of the clotting factors compared to FFP; one dose of PCC equals 8 to 16 units of FFP. In patients weighing greater than 100 kg, the recommendation is to exceed the maximum dose. 24. Cryoprecipitate has been available for transfusion since 1964; initially as therapy for haemophilia A, then rapidly becoming first line treatment for von Willebrand's disease and heritable deficiencies of fibrinogen and FXIII 1.With the advent of single-factor concentrate therapy the number of clinical indications for cryoprecipitate has reduced. Bachowski GBD, Brunker PAR, Eder A, et al. 2003; 349:343349. Careers. When frozen cryoprecipitate is thawed for transfusion, it must be used within 6 hours and cannot be refrozen. 25. Whether to use fibrinogen concentrate or cryoprecipitate as a first-line therapy for the treatment of acquired hypofibrinogenemia in the cardiac surgical patients continues to be a subject of intense debate in the United States. Prothrombincomplex concentrates (PCCs) are highly purified concentrates with haemostatic activity pre- paredfrom pooled plasma. We compared the standard dosage of FFP and PCC in terms of efficacy and safety for patients with mechanical heart valves undergoing interventional procedures while receiving Warfarin. Kozek-Langenecker S, Srensen B, Hess JR, Spahn DR. Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review. Hemostatic characteristics of thawed, pooled cryoprecipitate stored for 35days at refrigerated and room temperatures. More recently, fibrinogen concentrate has been used off-label in the United States and is the standard in European countries and Canada to treat the acquired hypofibrinogenemia during cardiac surgery. 0000041494 00000 n 2018; 127:612621. A prospective randomised pilot study. 2022 Feb; [PubMed PMID: 34800389], Owen EJ,Gibson GA,Human T,Wolfe R, Thromboembolic Complications After Receipt of Prothrombin Complex Concentrate. %PDF-1.3 There have been several randomized controlled trials of fibrinogen concentrate in cardiac surgical patients (Table 2).24,3542 One of the first trials conducted by Karlsson et al35 randomized elective coronary artery bypass grafting (CABG) patients who had a preoperative plasma fibrinogen concentration of 380 mg/L. Full size image Patients in the FP group were slightly older, heavier, more likely to be male, and more likely to undergo non-elective surgery. It was developed as a treatment for haemophilia but this use has now been replaced by Factor VIII concentrate. Cushing MM, Haas T, Karkouti K, Callum J. 5J^REMTzP(s7l\wK g trailer Your message has been successfully sent to your colleague. The PCCs are standardized according to their factor IX content. A total of 13 patients (18%) in the PCC group .