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Clinical Perspectives: When Fibrinogen Deficiency Complicates Surgical Hemostasis.

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Presentation on theme: "Clinical Perspectives: When Fibrinogen Deficiency Complicates Surgical Hemostasis."— Presentation transcript:

1 Clinical Perspectives: When Fibrinogen Deficiency Complicates Surgical Hemostasis

2 2 Faculty Mark H. Ereth, MD, MA Professor of Anesthesiology Consultant in Anesthesiology Division of Cardiovascular and Thoracic Anesthesiology Mayo Clinic College of Medicine Mayo Clinic Rochester, Minnesota

3 3 Learning Objectives Describe the pharmacodynamic properties of fibrinogen and its role in the coagulation process Discuss the relationship between plasma fibrinogen level and perioperative hemostasis Explain the advantages and disadvantages of the various types of fibrinogen replacement for the management of surgical hemostasis

4 4 Physiology of Hemostasis Response to traumatic or surgical injury Complex interaction between vascular wall, platelets, coagulation factors, and fibrinolysis Clotting is a complicated process  Platelet-mediated primary hemostasis, explosive thrombin generation  Conversion of fibrinogen to fibrin  Stable fibrin and platelet network or clot produced Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64; Porte J, et al. Drugs. 2002;62:2193-2211; Sauaia A, et al. J Trauma. 1995;38:185-193.

5 5 Overview of Hemostasis Antifibrinolytic agents Plasminogen ThrombinPlasmin APCTAFIa TAFIPC FibrinogenFibrinFDPs –– Adapted from Nesheim M. Chest. 2003;124:33S-39S. Thrombin Thrombomodulin FXIIIa Clot stabilizing factor Coagulation Cascade Fibrinolytic Cascade FDPs=fibrin degradation products.

6 Pharmacodynamics of Fibrinogen Key protein in coagulation cascade 1 Acute phase reactant 2 Primary substrate for plasmatic blood coagulation and fibrinolysis 3 1. Karlsson M, et al. Transfusion. 2008;48:2152-2158; 2. Fenger-Eriksen C, et al. Expert Opin Biol Ther. 2009;9:1325-1333; 3. Danés AF, et al. Vox Sang. 2008;94:221-226. 6

7 Pharmacodynamics of Fibrinogen (cont) Interferes with processes of cellular and matrix interactions, inflammatory response wound healing, and neoplasia 1 Conversion of fibrinogen to fibrin catalysed by thrombin 2  Essential for clot formation Soluble plasma glycoprotein 3  2 identical subunits 3 polypeptide chains 1. Danés AF, et al. Vox Sang. 2008;94:221-226; 2. Weinkove R, et al. Transfus Med. 2008;18:151-157; 3. Fenger-Eriksen C, et al. Expert Opin Biol Ther. 2009;9: 1325-1333. 7

8 Fibrinogen Protein Fenger-Eriksen C, et al. Fibrinogen concentrate  a potential universal hemostatic agent. Expert Opin Biol Ther. 2009;9(10):1325-1333. Reprinted by permission of Taylor & Francis Ltd, http://www.tandf.co.uk/journals. 8

9 Blood Loss During Surgery Inevitable component of surgery 1 Perioperative bleeding, need for blood transfusions associated with 1-3 :  ↑ Morbidity and mortality  ↑ Legal and regulatory exposure  Greater hospital expenditures and length of stay  Risk for transmission of transfusion-mediated infection Surgical or vascular component of blood loss corrected by surgical intervention or embolization 4 Coagulopathic component more difficult to control 4 1. Porte RJ, et al. Drugs. 2002;62:2193-2211; 2. Shander A, et al. Transfusion. 2009;50:753-765; 3. Corwin HL, et al. Crit Care Med. 2004;32:39-52; 4. Vincent J-L, et al. Crit Care. 2006;10:1-12. 9

10 Conditions Associated With Coagulopathy Hemophilia Platelet disorders Liver disease Uremia Disseminated intravascular coagulation (DIC) Dilutional coagulopathy Anticoagulant treatment Cardiopulmonary bypass Trauma Blood transfusion Brohi K, et al. J Trauma. 2003;54:1127-1130; Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86. 10

11 11 Prevalence of Excessive Bleeding Surgical DisciplineExcessively Bleeding Patients Cardiovascular5%-9% Post-op 1 General2% Laparoscopic cholecystectomy 2 Obstetric4% (vaginal); 6% (cesarean) 3,4 Orthopedic2%-6% Hip/knee arthroplasty 5-7 Urologic4%-8% TURP 8 ; 3%-10% URL 9 Trauma30%-40% 10,11 1. Despotis GJ, et al. Anesth Analg. 1996;82:13-21; 2. Erol DD, et al. The Internet Journal of Anesthesiology. 2005;9:2; 3. Combs CA, et al. Obstet Gynecol. 1991;77:69-76; 4.Combs CA, et al. Obstet Gynecol. 1991;77:77- 82; 5. Hull R, et al. N Engl J Med. 1993;329:1370-1376; 6. Leclerc JR, et al. Ann Intern Med. 1996;124:619-626; 7. Strebel N, et al. Arch Intern Med. 2002;162:1451-1455; 8. Daniels PR. Nat Clin Pract Urol. 2005;2:343-350; 9. Rosevear HM, et al. J Urol. 2006;176:1458-1462; 10. Holcomb JB. Crit Care. 2004;8(suppl 2):S57-S60; 11. Sauaia A, et al. J Trauma. 1995;38:185-193.

12 12 The Importance of Fibrinogen in Achieving Hemostasis Critical coagulation factor 1 In massive bleeding or trauma, fibrinogen is first coagulation factor to reach critical levels 2 Values  1 g/L can be directly responsible for severe hemorrhage 1,3 Low preoperative levels may be biomarker for excessive postoperative bleeding 4 1. Fenger-Eriksen C, et al. Br J Anaesth. 2008;101:769-773; 2. Brenni M, et al. Acta Anaesthesiol Scand. 2010;54:111-117; 3. Danés AF, et al. Vox Sang. 2008;94:221-226; 4. Ucar HI, et al. Heart Surg Forum. 2007;10:E392-E396. Reprinted from The Heart Surgery Forum, with permission from Forum Multimedia Publishing, LLC, a subsidiary of Carden Jennings Publishing Co., Ltd. Copyright 2010. All rights reserved. 2500.00 2000.00 1500.00 1000.00 500.00 200.00300.00400.00500.00600.00 Postoperative Bleeding, mL Fibrinogen Level, mL

13 Forms of Fibrinogen Replacement I. Fresh frozen plasma (FFP) A mainstay in correction of fibrinogen deficits Risk of volume overload  10-15 mL/kg increases fibrinogen by 40 mg/dL  30 mL/kg increases fibrinogen by 100 mg/dL Risk of transfusion-related infections, immunologic reactions, hypervolemia Rarely do patients receive a 10- to 15-mL/kg dose Danés AF, et al. Vox Sang. 2008;94:221-226; Rahe-Mayer N, et al. Br J Anaesth. 2009;102:785-792. 13

14 Forms of Fibrinogen Replacement II. Cryoprecipitate Conventional hemostatic therapy Rich in fibrinogen  Adult dose = 10 U or 100 mL  One dose increases fibrinogen ≈60 mg/dL Only available source of fibrinogen in some countries Not subject to virus inactivation/elimination Fibrinogen content in cryoprecipitate varies between units Danés AF, et al. Vox Sang. 2008;94:221-226; Fenger-Eriksen C, et al. Br J Anaesth. 2008; 101:769-773; Levy JH, et al. Semin Thromb Hemost. 2008;34:439-444. 14

15 Forms of Fibrinogen Replacement III. Human plasma-derived fibrinogen concentrates FDA-approved for congenital afibrinogenemia Not currently FDA-approved for acquired deficiencies Improves clot strength Better viral and prion protein safety than cryoprecipitate More costly than other replacement therapies Fenger-Eriksen C, et al. Br J Anaesth. 2005;94:324-329; Weinkove R, et al. Transfus Med. 2008;18:151-157. 15

16 Fibrinogen and the Treatment of Surgically Acquired Coagulopathy The optimal level of plasma fibrinogen necessary to maintain perioperative hemostasis not fully determined Normal level 175-400 mg/dL Levels ≤80-100 mg/dL can affect PT and aPTT Most transfusion algorithms do not treat levels unless  100-150 mg/dL Boosting fibrinogen level to achieve an upper normal range (mean 3.6 g/L) found to reduce need for allogeneic blood products Rahe-Mayer N, et al. Br J Anaesth. 2009;102:785-792. 16

17 Hemostatic Impairment and Cardiac Surgery Bleeding following cardiac surgery is often multifactorial Hemostatic imbalance often occurs after prolonged CPB  Consumptive loss of coagulation factors  Hemodilution  Hypothermia  Residual anticoagulation  Fibrinolysis Most procoagulant plasma factors reduced by 40%-50% from baseline Reduced platelet count and platelet function Tanaka KA, et al. Anesth Analg. 2008;106:732-738. 17

18 Frequently Encountered Complications of Cardiac Surgery Major bleeding and hemorrhage a major challenge after surgery Surgical reexploration for bleeding occurs after 2%-6% of CABG procedures 1 Associated with prolonged LOS 2 Increased postsurgery costs 3  $12,302 average incremental cost for hemorrhagic complications 1. Dacey LJ, et al. Arch Surg. 1998;133:442-447; 2. Ucar HI, et al. Heart Surg Forum. 2007;10:E392-E396; 3. Brown PP, et al. Ann Thorac Surg. 2008;85:1980-1987. 18

19 Fibrinogen Deficiency and Excessive Bleeding Massive hemorrhage a potential complication Acquired afibrinogenemia responsible for most cases of fibrinogen-related severe bleeding  Consumption and dilutional processes  Consequences of underlying disease  Complex coagulation disturbance Danés AF, et al. Vox Sang. 2008;94:221-226. 19

20 Fibrinogen Deficiency and Excessive Bleeding (cont) Efficacy of fibrinogen concentrate in acquired afibrinogenemia-related bleeding poorly documented* 1 Retrospective clinical surveys suggest potential hemostatic effect of substitution therapy with fibrinogen in bleeding patients 1-3 *Not currently FDA-approved for acquired deficiencies. 1. Danés AF, et al. Vox Sang. 2008;94:221-226; 2. Fenger-Eriksen C, et al. Expert Opin Biol Ther. 2009;9:1325-1333; 3. Weinkove R, et al. Transfus Med. 2008;18:151-157. 20

21 Measurement of Fibrinogen Function aPTT PT TT Serum fibrinogen Clauss assay Thrombelastography Rotational thromboelastometry Brenni M, et al. Acta Anaesthesiol Scand. 2010;54:111-117; Fenger-Eriksen C, et al. Expert Opin Biol Ther. 2009;9:1325-1333; Kalina U, et al. Blood Coagul Fibrinolysis. 2008;19:777-783. 21

22 Issues and Considerations Development of better assays to diagnose fibrinogen deficiencies More research on thrombogenicity of fibrinogen products Development of new fibrinogen preparations, including recombinant fibrinogen Peyvandi F, et al. Clin Adv Hematol Oncol. 2009;7:788-790. 22

23 Discussion Question 23 What are the steps a cardiovascular anesthesiologist takes to improve survival and clinical outcome in a patient with a decreased plasma fibrinogen level due to excessive bleeding?

24 Thank you for participating in this CE activity. To receive credit for this activity, please complete the posttest and evaluation by clicking the “posttest” tab located above and following the instructions. www.BloodCMECenter.org 24


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