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Bleeding and management of coagulopathy

2011; Elsevier BV; Volume: 142; Issue: 3 Linguagem: Inglês

10.1016/j.jtcvs.2011.03.015

1097-685X

Roman M. Sniecinski, Jerrold H. Levy,

Hemostasis and retained surgical items

Bleeding after cardiac surgery remains a significant problem, increasing both length of stay and mortality, and is caused by multiple factors including dilutional changes, ongoing fibrinolysis, and platelet dysfunction. The evaluation of coagulopathy is problematic because of the long turnaround time of standard coagulation tests. Algorithms involving point of care testing, including thromboelastography and thromboelastometry, have been published; all have the potential to reduce transfusion requirements. Massive transfusion coagulopathy that occurs in trauma can also be seen in complex aortic surgery and other massive bleeding patients and should prompt consideration of a transfusion protocol involving fixed ratios of fresh frozen plasma, platelets, and red blood cells. Pharmacologic agents such as antifibrinolytics are commonly administered, but a multimodal approach to management is important. Recombinant and purified coagulation products are being studied and provide clinicians specific agents to treat targeted deficiencies. A general multi-modal approach is required and recommendations are made for the management of bleeding and coagulopathy in cardiac surgical patients. Bleeding after cardiac surgery remains a significant problem, increasing both length of stay and mortality, and is caused by multiple factors including dilutional changes, ongoing fibrinolysis, and platelet dysfunction. The evaluation of coagulopathy is problematic because of the long turnaround time of standard coagulation tests. Algorithms involving point of care testing, including thromboelastography and thromboelastometry, have been published; all have the potential to reduce transfusion requirements. Massive transfusion coagulopathy that occurs in trauma can also be seen in complex aortic surgery and other massive bleeding patients and should prompt consideration of a transfusion protocol involving fixed ratios of fresh frozen plasma, platelets, and red blood cells. Pharmacologic agents such as antifibrinolytics are commonly administered, but a multimodal approach to management is important. Recombinant and purified coagulation products are being studied and provide clinicians specific agents to treat targeted deficiencies. A general multi-modal approach is required and recommendations are made for the management of bleeding and coagulopathy in cardiac surgical patients. Approximately 5% to 7% of patients undergoing cardiac surgery lose more than 2 L of chest tube drainage during the first 24 hours postoperatively, and up to 5% require reexploration for bleeding, resulting in an increased length of stay and higher mortality.1Hein O.V. Birnbaum J. Wernecke K.D. Konertz W. Jain U. Spies C. Three-year survival after four major post-cardiac operative complications.Crit Care Med. 2006; 34: 2729-2737Crossref PubMed Scopus (64) Google Scholar, 2Moulton M.J. Creswell L.L. Mackey M.E. Cox J.L. Rosenbloom M. Reexploration for bleeding is a risk factor for adverse outcomes after cardiac operations.J Thorac Cardiovasc Surg. 1996; 111: 1037-1046Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 3Christensen M.C. Krapf S. Kempel A. von Heymann C. Costs of excessive postoperative hemorrhage in cardiac surgery.J Thorac Cardiovasc Surg. 2009; 138: 687-693Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Multiple causes, including activation of the coagulation, fibrinolytic, and inflammatory pathways, dilutional changes, hypothermia, and other surgical factors, contribute to this problem. Bleeding may also be further exacerbated by perioperative use of various anticoagulants, including heparin, thrombin inhibitors, and platelet inhibitors. There is a complex equilibrium among red blood cells (RBCs), platelets, coagulation factors, natural inhibitors of coagulation, and the fibrinolytic system that is significantly altered in cardiac surgery. Therefore, simple replacement of blood volumes may not always be effective. This review will focus on current therapies to treat bleeding after cardiac surgery. An overview of the coagulation process, with potential sites of intervention, is presented in Figure 1. Most studies demonstrate that transfusion algorithms reduce the need for platelets, fresh-frozen plasma (FFP), or cryoprecipitate. However, any test that prevents empirical administration likely will reduce this need.4Stainsby D. MacLennan S. Thomas D. Isaac J. Hamilton P.J. Guidelines on the management of massive blood loss.Br J Haematol. 2006; 135: 634-641Crossref PubMed Scopus (302) Google Scholar Most algorithms suggest transfusion when bleeding is accompanied by a prothrombin time/activated partial thromboplastin time more than 1.5 times normal, a platelet count less than 50 to 100,000, or fibrinogen concentration less than 100 mg/dL (1 g/L).5Steiner M.E. Despotis G.J. Transfusion algorithms and how they apply to blood conservation: the high-risk cardiac surgical patient.Hematol Oncol Clin North Am. 2007; 21: 177-184Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Measurement of D-dimers or fibrin degradation products is also frequently done to see whether fibrinolysis is occurring. Because most laboratory testing is slow, point of care testing has been the focus of research as recently reviewed.5Steiner M.E. Despotis G.J. Transfusion algorithms and how they apply to blood conservation: the high-risk cardiac surgical patient.Hematol Oncol Clin North Am. 2007; 21: 177-184Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Thromboelastography and rotational thromboelastometry are useful to determine fibrinolysis, and thromboelastography or rotational thromboelastometry-based algorithms have been shown to decrease blood product use. However, the machines require quality-control follow-up and are not available everywhere. Platelet function testing has also been reported but is problematic because most tests need a relatively high platelet count to work and may not be applicable to post-cardiopulmonary bypass (CPB) platelet dysfunction. Volume replacement after cardiac surgery with critical bleeding may require large fluid volumes. RBC transfusions provide oxygen-carrying capacity, but crystalloids, colloids, and RBCs provide neither coagulation factors nor platelets and can exacerbate coagulopathy by dilution. Thrombocytopenia often follows volume replacement, and the inability to evaluate platelet function complicates matters. Severe bleeding requires FFP, platelets, cryoprecipitate, and potentially factor concentrates (eg, fibrinogen and prothrombin complex concentrates [PCCs]) to restore circulating levels of hemostasis factors. After massive transfusion therapy, hypothermia and acidosis frequently occur, further complicating bleeding. Blood temperature and pH must be monitored and corrected during any ongoing transfusion effort. Perioperative blood conservation guidelines in cardiac surgery have been published, recommending institution-specific transfusion algorithms, point-of-care testing, and a multimodal approach to coagulopathy treatment.6Ferraris V.A. Ferraris S.P. Saha S.P. et al.Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline.Ann Thorac Surg. 2007; 83: S27-S86Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar Massive transfusion coagulopathy, generally defined as 10 RBC units or more transfused in a 24-hour period, is best studied from trauma literature. Because several blood volumes may be replaced in these patients by the time results are available, laboratory testing is problematic. As a result, transfusion protocols have been developed where fixed doses of FFP and platelets are administered after a specific number of RBC units have been given, often in a 1:1:1 ratio.4Stainsby D. MacLennan S. Thomas D. Isaac J. Hamilton P.J. Guidelines on the management of massive blood loss.Br J Haematol. 2006; 135: 634-641Crossref PubMed Scopus (302) Google Scholar Whether these fixed ratios prevent coagulopathy is not established in cardiac surgery, but in trauma and in noncardiac surgical battlefield conditions, fixed transfusion ratios improve survival.7Dente C.J. Shaz B.H. Nicholas J.M. et al.Improvements in early mortality and coagulopathy are sustained better in patients with blunt trauma after institution of a massive transfusion protocol in a civilian level I trauma center.J Trauma. 2009; 66: 1616-1624Crossref PubMed Scopus (240) Google Scholar, 8Holcomb J.B. Wade C.E. Michalek J.E. et al.Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients.Ann Surg. 2008; 248: 447-458Crossref PubMed Scopus (795) Google Scholar Thus, with life-threatening hemorrhage, transfusion of fixed ratios of RBCs, FFP, and platelets should be administered when situations analogous to trauma situations are encountered, such as coagulopathy after complex aortic surgery. The lysine analogs epsilon aminocaproic acid and tranexamic acid (TXA) competitively inhibit activation of plasminogen to plasmin, an enzyme that degrades fibrin clots. TXA also inhibits plasmin at higher doses, and most studies reported in cardiac surgery involve TXA. Epsilon aminocaproic acid does not consistently reduce transfusion requirements or surgical reexploration.9Levi M. Cromheecke M.E. de Jonge E. et al.Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints.Lancet. 1999; 354: 1940-1947Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar Multiple meta-analyses of randomized controlled trials consistently report a decrease in bleeding with these agents, but data regarding safety are limited. Postoperative convulsive seizures at one institution were reported to increase from 1.3% to 3.8% after cardiac surgery, temporally coincident with high-dose TXA.10Martin K. Wiesner G. Breuer T. Lange R. Tassani P. The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients.Anesth Analg. 2008; 107: 1783-1790Crossref PubMed Scopus (142) Google Scholar In 24 patients with postoperative seizures, all received high doses of TXA intraoperatively from 61 to 259 mg/kg, mean ages were 70 years, and 21 of 24 had open-chamber procedures.10Martin K. Wiesner G. Breuer T. Lange R. Tassani P. The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients.Anesth Analg. 2008; 107: 1783-1790Crossref PubMed Scopus (142) Google Scholar Although these agents are typically used during CPB, additional use of them should be considered postoperatively with evidence of ongoing fibrinolysis. Aprotinin, a polypeptide serine protease inhibitor, inhibits plasmin and other serine proteases. In cardiac surgery, multiple randomized, placebo-controlled trials reported that aprotinin reduced bleeding and allogeneic transfusions.11Sedrakyan A. Wu A. Sedrakyan G. Diener-West M. Tranquilli M. Elefteriades J. Aprotinin use in thoracic aortic surgery: safety and outcomes.J Thorac Cardiovasc Surg. 2006; 132: 909-917Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar However, recent reports from observational databases and one randomized study questioned the safety of aprotinin.12Mangano D.T. Tudor I.C. Dietzel C. The risk associated with aprotinin in cardiac surgery.N Engl J Med. 2006; 354: 353-365Crossref PubMed Scopus (912) Google Scholar After publication of the BART study,13Fergusson D.A. Hebert P.C. Mazer C.D. et al.A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.N Engl J Med. 2008; 358: 2319-2331Crossref PubMed Scopus (808) Google Scholar Bayer Pharmaceuticals (Montville, NJ) removed the drug from marketing, although it is still available for compassionate use. Karkouti and colleagues14Karkouti K. Wijeysundera D.N. Yau T.M. McCluskey S.A. Tait G. Beattie W.S. The risk-benefit profile of aprotinin versus tranexamic acid in cardiac surgery.Anesth Analg. 2010; 110: 21-29Crossref PubMed Scopus (71) Google Scholar reported a retrospective single-center cohort study of 15,365 cardiac surgical patients, of whom 1017 received aprotinin and 14,358 received TXA. They noted aprotinin had a better risk-benefit profile than TXA in high-risk, but not low- to moderate-risk, patients and suggested its use in high-risk cases may be warranted. Other synthetic serine protease inhibitors, such as CU-2010, which possess antifibrinolytic activity comparable to aprotinin, are currently under development.15Szabo G. Veres G. Radovits T. et al.The novel synthetic serine protease inhibitor CU-2010 dose-dependently reduces postoperative blood loss and improves postischemic recovery after cardiac surgery in a canine model.J Thorac Cardiovasc Surg. 2010; 139: 732-740Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Protamine is a polypeptide that contains approximately 70% arginine residues and inactivates the acidic unfractionated heparin, but not low-molecular-weight heparin, molecule via a simple acid-base interaction.16Levy J.H. Adkinson Jr., N.F. Anaphylaxis during cardiac surgery: implications for clinicians.Anesth Analg. 2008; 106: 392-403Crossref PubMed Scopus (85) Google Scholar Most patients receive too much protamine for anticoagulation reversal because fixed-dose regimens are based on initial or total heparin dose and do not account for elimination. Excess protamine should be avoided when reversing heparin because it inhibits platelets and proteases, and potentially contributes to coagulopathy.17Mochizuki T. Olson P.J. Szlam F. Ramsay J.G. Levy J.H. Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass.Anesth Analg. 1998; 87: 781-785PubMed Google Scholar Maintaining heparin levels during CPB and administering protamine on the basis of the exact circulating heparin level reduced postoperative bleeding and transfusions and produced the lowest activated clotting time values.18Despotis G.J. Joist J.H. Hogue Jr., C.W. et al.The impact of heparin concentration and activated clotting time monitoring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation.J Thorac Cardiovasc Surg. 1995; 110: 46-54Abstract Full Text PDF PubMed Scopus (148) Google Scholar Heparin rebound can occur after initial reversal and occurs 2 to 3 hours later postoperatively.19Kuitunen A.H. Salmenpera M.T. Heinonen J. Rasi V.P. Myllyla G. Heparin rebound: a comparative study of protamine chloride and protamine sulfate in patients undergoing coronary artery bypass surgery.J Cardiothorac Vasc Anesth. 1991; 5: 221-226Abstract Full Text PDF PubMed Scopus (15) Google Scholar Heparin levels with rebound may range from 0.1 to 0.3 IU/mL, suggesting circulating levels of heparin, based on a 5-L blood volume, of 500 to 1500 units. Protamine doses of 5 to 15 mg may be effective at reversing heparin rebound rather than the 50 mg commonly administered. The activated clotting time is not a sensitive indicator of heparin rebound because platelet counts and fibrinogen levels may also affect values. Protamine can cause adverse reactions, including anaphylaxis, acute pulmonary vasoconstriction, right ventricular failure, and hypotension.16Levy J.H. Adkinson Jr., N.F. Anaphylaxis during cardiac surgery: implications for clinicians.Anesth Analg. 2008; 106: 392-403Crossref PubMed Scopus (85) Google Scholar Patients at an increased risk for adverse reactions are sensitized, often from neutral-protamine-Hagedorn insulin. Protamine reactions occur in 0.6% to 2% of neutral-protamine-Hagedorn insulin–dependent diabetic patients.20Levy J.H. Zaidan J.R. Faraj B. Prospective evaluation of risk of protamine reactions in patients with NPH insulin-dependent diabetes.Anesth Analg. 1986; 65: 739-742Crossref PubMed Scopus (89) Google Scholar, 21Levy J.H. Schwieger I.M. Zaidan J.R. Faraj B.A. Weintraub W.S. Evaluation of patients at risk for protamine reactions.J Thorac Cardiovasc Surg. 1989; 98: 200-204PubMed Google Scholar Other individuals reported at risk for protamine reactions include patients with vasectomy, multiple drug allergies, and prior protamine exposure.16Levy J.H. Adkinson Jr., N.F. Anaphylaxis during cardiac surgery: implications for clinicians.Anesth Analg. 2008; 106: 392-403Crossref PubMed Scopus (85) Google Scholar Desmopressin (DDAVP; Sanofi-Aventis, Bridgewater, NJ) is the V2 analog of arginine vasopressin that stimulates von Willebrand factor multimers released from endothelial cells. von Willebrand factor mediates platelet adherence to vascular subendothelium by functioning as a protein bridge between glycoprotein Ib receptors on platelets and subendothelial vascular basement membrane proteins. Desmopressin (DDAVP) shortens the bleeding time of patients with mild forms of hemophilia A or von Willebrand's disease. Desmopressin (DDAVP) is administered intravenously at a dose of 0.3 mg/kg over 15 to 30 minutes to avoid hypotension.22de Prost D. Barbier-Boehm G. Hazebroucq J. et al.Desmopressin has no beneficial effect on excessive postoperative bleeding or blood product requirements associated with cardiopulmonary bypass.Thromb Haemost. 1992; 68: 106-110PubMed Google Scholar Most studies have not confirmed the early reported efficacy during complex cardiac surgery, and a recent review showed only a small effect on perioperative blood loss (median decrease, 115 mL).23Mannucci P.M. Levi M. Prevention and treatment of major blood loss.N Engl J Med. 2007; 356: 2301-2311Crossref PubMed Scopus (345) Google Scholar Because critically ill patients are often receiving vasopressin, which also has V2- and V1-mediated effects, there is little benefit to adding desmopressin (DDAVP). Fibrinogen is an under-recognized coagulation factor critical for producing effective clot in surgical patients, and data support it as a predictor of perioperative bleeding.24Blome M. Isgro F. Kiessling A.H. et al.Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery.Thromb Haemost. 2005; 93: 1101-1107PubMed Google Scholar Normal fibrinogen levels are 200 to 400 mg/dL, although the target fibrinogen level in a bleeding patient is not known. Bleeding increases for each 100 mg/dL decrease in fibrinogen level in parturient patients, who normally have levels more than 400 mg/dL,25Charbit B. Mandelbrot L. Samain E. et al.The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage.J Thromb Haemost. 2007; 5: 266-273Crossref PubMed Scopus (431) Google Scholar and low fibrinogen levels can predict bleeding after prolonged CPB.26Karlsson M. Ternstrom L. Hyllner M. Baghaei F. Nilsson S. Jeppsson A. Plasma fibrinogen level, bleeding, and transfusion after on-pump coronary artery bypass grafting surgery: a prospective observational study.Transfusion. 2008; 48: 2152-2158Crossref PubMed Scopus (175) Google Scholar Most transfusion algorithms recommend therapy when fibrinogen levels are less than 100 mg/dL; however, low fibrinogen levels can increase prothrombin time/partial thromboplastin time that may not correct with FFP. In this situation, cryoprecipitate or fibrinogen concentrates are a better option to restore adequate plasma levels (∼200 mg/dL) because they cause less hemodilution. Fibrinogen can be repleted by cryoprecipitate; 1 unit/10 kg increases fibrinogen by 50 to 70 mg/dL. In Europe, fibrinogen concentrates are available and cryoprecipitate is not used. A fibrinogen concentrate (RiaSTAP; CSL Behring, King of Prussia, Pa) has just been granted licensing as an orphan drug for treating bleeding in patients with congenital afibrinogenemia or hypofibrinogenemia. Recombinant proteins are increasingly available for managing bleeding, topical hemostasis, and other therapeutic interventions. Recombinant proteins also can be modified to alter specific characteristics that may be important in therapeutic effects or provide quantities that can be administered supraphysiologically as a therapeutic agent. Currently, they are used to manage bleeding in patients with hemophilia, von Willebrand's disease, or acquired antibodies/inhibitors. Recombinant activated factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsværd, Denmark) is approved for patients with hemophilia with inhibitors to treat bleeding but is increasingly used off-label as a prohemostatic agent for life-threatening hemorrhage.27Steiner M.E. Key N.S. Levy J.H. Activated recombinant factor VII in cardiac surgery.Curr Opin Anaesthesiol. 2005; 18: 89-92Crossref PubMed Scopus (21) Google Scholar Only approximately 1% of circulating FVII is activated, and it has no effect until bound with tissue factor. The prohemostatic effects of rFVIIa are produced in part by complexing with tissue factor expressed at the vascular injury site to locally produce thrombin and amplify hemostatic activation. Multiple publications report off-label rFVIIa use after cardiac surgery, although the therapeutic rFVIIa dose in patients without hemophilia has not been established. Thromboembolic complications with rVIIa use have been reported to be 11.1%.28Levi M. Levy J.H. Andersen H.F. Truloff D. Safety of recombinant activated factor VII in randomized clinical trials.N Engl J Med. 2010; 363: 1791-1800Crossref PubMed Scopus (502) Google Scholar However, the drug is typically administered as rescue therapy to patients who have already received multiple transfusions, have impaired coagulation, and are at high risk for adverse events. Only arterial thromboembolic event rates were higher after rFVIIa versus placebo (5.5% vs 3.2%) compared with venous thromboembolic events (5.3% vs 5.7%), and were higher among the elderly, likely reflecting the studies in intracranial hemorrhage.28Levi M. Levy J.H. Andersen H.F. Truloff D. Safety of recombinant activated factor VII in randomized clinical trials.N Engl J Med. 2010; 363: 1791-1800Crossref PubMed Scopus (502) Google Scholar In a recent cardiac surgical study, patients bleeding more than 200 mL/h postoperatively were randomized to placebo (n = 68), 40 μg/kg rFVIIa (n = 35), or 80 μg/kg rFVIIa (n = 69).29Gill R. Herbertson M. Vuylsteke A. et al.Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery.Circulation. 2009; 120: 21-27Crossref PubMed Scopus (200) Google Scholar The primary end points were critical serious adverse events. Secondary end points included reoperation rates, blood loss, and transfusions. Although more adverse events occurred in the rFVIIa groups, they did not reach statistical significance (placebo, 7%; 40 μg/kg, 14%; P = .25; 80 μg/kg,12%; P = .43). However, after randomization, significantly fewer patients in the rFVIIa group underwent a reoperation because of bleeding (P = .03) or required allogeneic transfusions (P = .01).29Gill R. Herbertson M. Vuylsteke A. et al.Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery.Circulation. 2009; 120: 21-27Crossref PubMed Scopus (200) Google Scholar Guidelines for off-label use of rVIIa are given in Table 1.30Sniecinski R.M. Chen E.P. Levy J.H. Szlam F. Tanaka K.A. Coagulopathy after cardiopulmonary bypass in Jehovah's Witness patients: management of two cases using fractionated components and factor VIIa.Anesth Analg. 2007; 104: 763-765Crossref PubMed Scopus (15) Google Scholar, 31Despotis G. Avidan M. Lublin D.M. Off-label use of recombinant factor VIIA concentrates after cardiac surgery.Ann Thorac Surg. 2005; 80: 3-5Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar A clinical protocol for bleeding incorporating the above concepts is presented in Figure 2.Table 1Postoperative rescue therapy with off-label use of recombinant factor VII in patients undergoing cardiac surgery30Sniecinski R.M. Chen E.P. Levy J.H. Szlam F. Tanaka K.A. Coagulopathy after cardiopulmonary bypass in Jehovah's Witness patients: management of two cases using fractionated components and factor VIIa.Anesth Analg. 2007; 104: 763-765Crossref PubMed Scopus (15) Google Scholar, 31Despotis G. Avidan M. Lublin D.M. Off-label use of recombinant factor VIIA concentrates after cardiac surgery.Ann Thorac Surg. 2005; 80: 3-5Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar•Severe (1 L/h) or life-threatening bleeding without surgical source of bleeding•Marginal response to routine hemostatic therapy (ie, platelets, FFP, cryoprecipitate, desmopressin [DDAVP; Sanofi-Aventis, Bridgewater, NJ])•Administration with appropriate hemostatic factors present•Consider lower doses than used in hemophilia (30–40 μg/kg)•Use in patients with multiple antibodies to platelets; cross-match issues when factors or platelets are not available•Potential use for Jehovah's Witnesses Open table in a new tab Plasma factor XIII (FXIII) is an important final step in clot formation that stabilizes the initial clot. Several investigators have demonstrated reductions in FXIII during CPB and an inverse relationship between postoperative bleeding and FXIII levels. Plasma-derived FXIII (Fibrogammin; CSL Behring, Marburg, Germany) at the end of CPB with concurrent antifibrinolytic therapy reduced postoperative hemorrhage and transfusion requirement in 2 trials32Godje O. Gallmeier U. Schelian M. Grunewald M. Mair H. Coagulation factor XIII reduces postoperative bleeding after coronary surgery with extracorporeal circulation.Thorac Cardiovasc Surg. 2006; 54: 26-33Crossref PubMed Scopus (95) Google Scholar, 33Godje O. Haushofer M. Lamm P. Reichart B. The effect of factor XIII on bleeding in coronary surgery.Thorac Cardiovasc Surg. 1998; 46: 263-267Crossref PubMed Scopus (56) Google Scholar including 22 and 75 patients, respectively. The addition of 2500 U FXIII (Fibrogammin) quickly restored the plasma level of FXIII, as measured by Berichrom, to 70 or greater, and reduced transfusion requirements. A recombinant FXIII has been recently reported in clinical studies, and more studies are under way to evaluate this factor as a therapy to reduce bleeding.34Levy J.H. Gill R. Nussmeier N.A. et al.Repletion of factor XIII following cardiopulmonary bypass using a recombinant A-subunit homodimer. A preliminary report.Thromb Haemost. 2009; 102: 765-771PubMed Google Scholar PCCs are concentrates of coagulation factors that include factors II, VII, IX, and X in variable concentrations.35Levy J.H. Tanaka K.A. Dietrich W. Perioperative hemostatic management of patients treated with vitamin K antagonists.Anesthesiology. 2008; 109: 918-926Crossref PubMed Scopus (120) Google Scholar Two agents (eg, Beriplex P/N [CSL Behring] and Octaplex [Octapharma, Vienna, Austria]) are approved outside the United States for vitamin K antagonist-induced (ie, warfarin) reversal and are being studied currently in the United States. The PCCs available in the United States include FEIBA VH (Baxter, Deerfield, Ill), Profilnine SD (Grifols, Barcelona, Spain), and Bebulin VH (Baxter). They are approved for prevention and control of bleeding in patients with hemophilia B and contain mainly factor IX.35Levy J.H. Tanaka K.A. Dietrich W. Perioperative hemostatic management of patients treated with vitamin K antagonists.Anesthesiology. 2008; 109: 918-926Crossref PubMed Scopus (120) Google Scholar Only FEIBA contains factor VII in an activated form, and Bebulin contains only low levels of factor VII. In general, it is considered preferable to give a PCC containing all 4 vitamin K-dependent coagulation factors and natural anticoagulants antithrombin and activated protein C for anticoagulation reversal. Compared with FFP, PCCs provide quicker international normalized ratio correction, have a small infusion volume, and do not require crossmatching. Although there are historical concerns about potential thrombotic risk with PCCs, present-day PCCs are much improved. Topical hemostatic agents are used intraoperatively to promote hemostasis at the vascular injury site. They are classified on the basis of their mechanism of action and include physical or mechanical agents, caustic agents, biologic physical agents, and physiologic agents.36Achneck H.E. Sileshi B. Jamiolkowski R.M. Albala D.M. Shapiro M.L. Lawson J.H. A comprehensive review of topical hemostatic agents: efficacy and recommendations for use.Ann Surg. 2010; 251: 217-228Crossref PubMed Scopus (305) Google Scholar The agent to use depends on the type of bleeding, the agent's specific mechanism of action, its interaction with the environment, and the underlying coagulopathy.36Achneck H.E. Sileshi B. Jamiolkowski R.M. Albala D.M. Shapiro M.L. Lawson J.H. A comprehensive review of topical hemostatic agents: efficacy and recommendations for use.Ann Surg. 2010; 251: 217-228Crossref PubMed Scopus (305) Google Scholar Absorbable agents include gelatin sponges (Gelfoam; Pfizer, New York, NY), derived from purified pork skin gelatin that increase contact activation to help create topical clot. Surgicel (Ethicon, Somerville, NJ) or Oxycel (Becton Dickinson Infusion Therapy Systems, Sandy, Utah) is oxidized regenerated cellulose that works like Gelfoam. Avitene (Davol, Warwick, RI) is microfibrillar collagen derived from bovine skin. Collagen sponges are available in different commercial forms and are derived from bovine Achilles tendon or bovine skin. Gelatin foam should not be used near nerves or in confined spaces but can be administered topically with thrombin. CoSeal (Baxter) is used where swelling and expansion are not a concern. BioGlue (Bioform Medical, San Mateo, Calif) has been used in cardiac surgery, but it contains a glutaraldehyde component that cross-links proteins and fixes the tissues to which it is applied. Topically applied thrombin preparations are also used extensively. The first available thrombin was derived from bovine plasma (Thrombin-JMI, King Pharmaceuticals, Bristol, Tenn). Bovine thrombin currently should be avoided because of its potential for antibovine thrombin antibody formation and immune-mediated coagulopathy.37Lawson J.H. The clinical use and immunologic impact of thrombin in surgery.Semin Thromb Hemost. 2006; 32: 98-110Crossref PubMed Scopus (108) Google Scholar Currently, there are 2 human thrombins available for clinical use, including plasma-derived thrombin (Evithrom; Omrix, Somerville, NJ, and Johnson & Johnson, New Brunswick, NJ) and recombinant human thrombin RECOTHROM (ZymoGenetics, Inc, Seattle, Wash). Fibrin sealants, also referred to as biological glue or fibrin tissue adhesives, are component products that combine thrombin (mostly human) and fibrinogen (usually plasma derived). The first commercial fibrin sealant, Tisseel (Baxter), was approved in 1989. Additional fibrin sealants are currently in use, including Crosseal (Ethicon), Evicel (Ethicon), and FloSeal (Baxter). They are packaged with a dual-syringe delivery system that combines the components to form a fibrin clot.36Achneck H.E. Sileshi B. Jamiolkowski R.M. Albala D.M. Shapiro M.L. Lawson J.H. A comprehensive review of topical hemostatic agents: efficacy and recommendations for use.Ann Surg. 2010; 251: 217-228Crossref PubMed Scopus (305) Google Scholar The thrombin concentration determines the onset and the tensile strength of the fibrin seal.36Achneck H.E. Sileshi B. Jamiolkowski R.M. Albala D.M. Shapiro M.L. Lawson J.H. A comprehensive review of topical hemostatic agents: efficacy and recommendations for use.Ann Surg. 2010; 251: 217-228Crossref PubMed Scopus (305) Google Scholar Crosseal contains human fibrinogen, human thrombin, and TXA. Evicel does not contain any fibrinolytic inhibitors. Agents studied in cardiac surgery, including FloSeal, are the subject of a recent review.38Barnard J. Millner R. A review of topical hemostatic agents for use in cardiac surgery.Ann Thorac Surg. 2009; 88: 1377-1383Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar The potential for bleeding in patients undergoing cardiac surgery represents an ongoing problem for clinicians. The increasing use of anticoagulation agents creates a need for multiple pharmacologic approaches. The growing use of clopidogrel, prasugrel, and newer oral anticoagulants will continue to pose new paradigms and potential problems in managing surgical patients. Newer therapies, including recombinant therapies, provide clinicians with the ability to administer key coagulation proteins to treat hemorrhage when standard therapies are ineffective.