Current Controversies in Selecting Topical Hemostatic Agents

1. Current Controversies in Selecting Topical Hemostatic Agents Jeffrey H. Lawson, MD, PhD Associate Professor of Surgery Director, Vascular Surgery Research Lab Director of Clinical Trials in Vascular Surgery Duke University Medical Center Durham, North Carolina

2. Disclosure Information The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity. 2

3. What Are the Challenges of Hemostasis in Surgery? • Who is likely to bleed or clot too much? • How do we optimize the physiology of the patient? • Which biologic agents are effective? When? How much? • Which topical agents are effective? What are the benefits and risks of available agents? How not to overshoot? Thrombosis Clotting Post-op Recovery Surgery BleedingHemorrhage

4. The Problem Most complications are at the dark interface between • Biology • Clinical skill • Medical therapy • Sick patients

5. Hemostasis “The arrest of bleeding”  Stedman’s Medical Dictionary But is hemostasis more than that? In surgery, hemostasis is… • About bleeding • About clotting • About timing • About balance

6. Hemostasis“Life in the Balance” Bleedingto Death Clottingto Death Trauma Major Surgery Hemophilia Stroke MI Thrombosis Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.

7. Prevalence of Uncontrolled Bleeding 1. Despotis GJ, et al. Ann Thorac Surg. 2000;70:S20-S32; 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.

8. Hemostatic Agents for Usein Surgery • Mechanical tools • Mechanical hemostats • Absorbable hemostatic agents • Biologic hemostatic agents

9. Mechanical Tools • Argon beam coagulator • Clips and suture • Cavitron ultrasonic suction aspirator (CUSA) • Harmonic scalpel • Finger • Gauze sponge • Cautery • Laser • Radiofrequency energy

10. Absorbable Hemostatic Agents • Oxidized cellulose • Surgicel • Low pH • Bactericidal • Gelatin sponge • Gelfoam/Surgifoam • Neutral pH • Good carrier • Microfibrillar collagen • Avitene • Biodegradable matrix • Absorb blood • Activate platelets • Induce coagulation

11. Biologic Hemostatic Agents • Bovine thrombin • Semi-pure cow thrombin • Activates platelets and fibrin • Immunologic effects • FloSeal • Bovine (now human) thrombin-gelatin sponge mix • Easy to use • CoSeal • Polyethylene glycol glue • No obvious biologic effect/immunology

12. Biologic Hemostatic Agents (cont) • Fibrin sealants: Tisseel, Crosseal, Evaseal • Human thrombin fibrinogen mix • Some contain an antifibrinolytic (bovine aprotinin and TMA) • Hard to mix • Better sealant than hemostat • BioGlue • Bovine albumin and gluteraldehyde • Easy to use • Good for aortic dissection • Direct contact harmful to exposed nerves and cardiac conduction tissue1 • Intraluminal fragments of glue may embolize1,2 • Can leak through suture-line needle holes1 • Fatal right ventricular infarction after embolism reported2 1. LeMaire SA, et al. Ann Thorac Surg. 2005;80:106-111. 2. Mahmood Z, et al. J Thorac Cardiovasc Surg. 2004;128:770-771.

13. Fibrin Formation Independent of Patient’s Coagulation • Adheres to exposed collagen on damaged tissue surfaces • Reabsorbed within 7 to 14 days • Does not require any components of the patient’s blood

14. Fibrin Sealants • Physiologic structure of fibrin strands in a plasma clot • Physiologic structure of fibrin strands in a Tisseel clot

15. Topical Hemostatic Agents • Identified by FDA as “a device intended to produce hemostasis by accelerating the clotting process of blood”1 • Used to augment hemostasis in surgery/trauma • Available in a variety of forms (solutions, gels, granules, sprays) and used in conjunction with collagen, gelatin, cellulose matrices • Local thrombin and fibrinogen levels determine the rate of clot formation at wound site • Classification • Tissue/fibrin sealants (contain thrombin, fibrin, etc) • Absorbable hemostatic agents (contain matrices) • Combination products (contain both groups above) • Efficacy: Few RCTs1 • Safety: Bovine formulations associated with numerous adverse events2 1. Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64. 2. Gabay M. Am J Health-Syst Pharm. 2006;63:1244-1253.

16. Stand-Alone Topical Thrombins • May be applied directly to wound via topical spray, used in conjunction with absorbable gelatin or collagen sponges, or included as a component of wound dressings and fibrin and platelet sealants • Bovine plasma-derived thrombin • Antibody formation to bovine thrombin and/or factor V • Subsequent risk of cross-reactivity with human factor V • Hemorrhagic complications associated with factor V deficiencies have been reported • Other impurities may be present in formulation • Human plasma-derived thrombin • Hemostatic efficacy comparable to bovine thrombin • Risk of infectious disease in plasma supply remains • Human recombinant thrombin • Hemostatic efficacy comparable to other thrombins • Good immunologic profile Cheng CM, et al. Clin Ther. 2009;31:32-41.

17. Bovine Thrombin vs Human Thrombin: Who Cares?

18. Bovine Thrombin • Used in a variety of surgical procedures • Cardiovascular surgery • Vascular surgery • Neurologic surgery • Orthopedic surgery • General surgery • Gynecologic surgery • Estimated that >500,000 Americans are exposed each year • >100 reports of adverse events (AEs) in the world’s literature related to bovine thrombin exposure in humans

19. Bovine Thrombin “Black Box” Warning Thrombin, Topical U.S.P. (bovine origin) [package insert]. Middleton, WI:GenTrac Incorporated;2007.

20. First Clinical Use of Thrombin in Humans Clinical Reports of Patients with Major Complications from Antibodies -300 FDA “Grandfathers” Bovine Thrombin for Commercial Production Publications of AEs -200 US Sales ($ Millions) -100 1940 2000 1950 1960 1970 1980 1990 2010 Year

21. Case Study • 76-year-old man admitted for abdominal aortic aneurysm repair • Hx of transient ischemic cerebrovascular attacks; taking coumadin • Surgical hx • 1971 laryngectomy • 1990 coronary artery bypass grafting (4 vessels) • 1996 rotator cuff repair • 1998 left radical nephrectomy • Thrombin spray documented in operative report • 1999 right radical nephrectomy • Patient readmitted for right flank hematoma

22. Case Study (cont) Hospital course • Abdominal aortic aneurysm and bilateral iliac artery aneurysm repair • Intraoperatively received 20,000u thrombin spray and FloSeal (10,000u thrombin) as documented in the perioperative nursing record • Returned to the ICU a few days postoperatively for increased shortness of breath, episodes of epistaxis, and difficulty breathing requiring reintubation and mechanical ventilation • Patient developed profound coagulopathy and was noted as having a factor V inhibitor

23. How Are Antibodies Derived? • Acquired inhibitors to coagulation factors: immunoglobulins bind specifically to these proteins, neutralize their activity, or accelerate their clearance from the circulation1 • Leads to increased risk of severe bleeding1 • Associated with autoimmune diseases, lymphoid malignancies, pregnancy, and with no known risk factors except advanced age1 • Bovine thrombin: the most common contemporary culprit in factor V inhibition2 • Commonly mixed with fibrinogen derived from cryoprecipitate • Contains small amounts of bovine factor V and many other proteins • Can elicit a potent immune response 1. Israels SJ, et al. Am J Pediatr Hematol Oncol. 1994;16:249-254. 2. Streiff MB, et al. Transfusion. 2002;42:18-26.

24. Prevalance of Factor V Inhibitors • Reported prevalence increasing in recent decades • Many cases of factor V inhibitors may go unrecognized or unreported1 • Clinical studies • Bänninger et al2 • 42% of cardiac surgery patients developed factor V inhibitors • 20% of neurosurgery patients • Carroll et al1,3 • 100% of cardiac surgery patients developed factor V inhibitors • Two-thirds of patients developed antibodies to human thrombin and factor V • Ortel et al4 • 95% of cardiac surgery patients developed bovine inhibitors • >50% developed inhibitors to human coagulation factors • Patients with multiple inhibitors to bovine proteins are 5x more likely to have AEs postop 1. Streiff MB, et al. Transfusion. 2002;42:18-26. 2. Bänninger H, et al. Br J Haematol. 1993;85:528-532. 3. Carroll JF, et al. Thromb Haemost. 1996;76:925-931. 4. Ortel TL, et al. Ann Surg. 2001;233:88-96.

25. Current Interventions for Factor Inhibitors • Multimodal therapy including immunosuppression for symptomatic patients • Immunosuppression: mainstay of treatment • Corticosteroids and related compounds • Prednisone, dexamethasone • Adrenocorticotropic hormone • Cyclosporine A • Cytotoxic chemotherapy • IVIG • Reduction of antibody titers with plasmapheresis and immunoabsorption columns • Activated prothrombin complex (or FEIBA) • Recombinant factor VIIa Streiff MB, et al. Transfusion. 2002;42:18-26.

26. Current Interventions for Factor Inhibitors (cont) • Because of variable nature of presentation, treatment should be flexible and guided by severity of symptoms • Asymptomatic patients • No treatment, close monitoring • Patients with mild to moderate bleeding • Initial trial of steroid with supportive transfusion therapy • If unsuccessful, additional agents should be employed • Patients with severe or life-threatening bleeding • Multimodal treatment • Transfer to a medical center with advanced critical care and hematology support

27. Case Study Hospital course • Abdominal aortic aneurysm and bilateral iliac artery aneurysm repair • Intraoperatively received 20,000u thrombin spray and FloSeal (10,000u thrombin) as documented in the perioperative nursing record • Returned to the ICU a few days postoperatively for increased shortness of breath, episodes of epistaxis, and difficulty breathing requiring re-intubation and mechanical ventilation • Patient developed profound coagulopathy and was noted as having a factor V inhibitor

28. Case Study:Bovine Antigens Day 5 Postop

29. Case Study:Human Antigens Day 5 Postop

30. Case Study: Treatment • Copious amounts of blood and factor replacement • Patient continued to have increasing abdominal distension; hemodynamically unstable • CT scan suggestive of intraperitoneal bleed • Received immune globulin 10% (Gamimune N)-IVIG • Exploratory laparotomy; 3 liters of blood removed • Prolonged ICU course with ventilator dependence • Discharged to nursing facility that accommodates ventilator-dependent patients

31. Case Study: Conclusion Discharge Diagnosis Acquired coagulopathy secondary to factor V inhibitor, presumed secondary to topical bovine thrombin exposure

32. Human Plasma-Derived Thrombin • Approved for use in the United States in 2007 • Not associated with the risk of antibovine factor V development • Not associated with potential for factor V antibody formation • Identical indications as for bovine thrombin • Derived from human plasma from FDA-licensed plasmapheresis centers in the United States Cheng CM, et al. Clin Ther. 2009;31:32-41.

33. Human Plasma-Derived Thrombin (cont) • Plasma screened and tested for • Hepatitis B surface antigen • Human immunodeficiency virus antibodies • Hepatitis A, B, and C viruses • Parvovirus B19 • Some risk of transmitting infectious disease remains, including Cruetzfeldt-Jakob disease • Contraindicated in patients with hx of severe systemic reactions or anaphylaxis to human blood products • As with all thrombin products, contraindicated for injection into the circulatory system • Risk of thrombosis • Do not use to treat severe or brisk arterial bleeding Cheng CM, et al. Clin Ther. 2009;31:32-41.

34. Human Recombinant Thrombin • Approved for use in the United States in 2008 • Not associated with the risk of antibovine factor V development • Not associated with potential for factor V antibody formation • Identical indications as bovine thrombin • Produced via recombinant DNA technology from genetically modified Chinese hamster ovary cells • Cells produce human thrombin precursors • Enzymes derived from snake venom used to activate precursors to human thrombin • Thrombin purified in a chromatographic process • Identical in amino acid sequence to naturally occurring human thrombin • Minimizes risk of immunogenic cross-reactivity and infection transmission Cheng CM, et al. Clin Therapeutics. 2009;31:32-41.

35. Human Recombinant Thrombin (cont) • Contraindicated in patients with known hypersensitivity to hamster proteins, snake proteins, or any component of human recombinant thrombin • Risk of allergic reaction • Safety of repeated applications unknown • Like all thrombin products, contraindicated for injection into the circulatory system • Risk of thrombosis • Do not use to treat severe or brisk arterial bleeding • More experience and randomized clinical trials are needed to determine efficacy, safety, or economic differences between topical thrombins Cheng CM, et al. Clin Therapeutics. 2009;31:32-41.

36. Keeping on Center Topical Hemostatics Purified Factors, FFP, Cryo, PLTs Aminocaproic Acid Antifibrinolytic Activity Procoagulant Activity Normal Hemostasis Bleeding Clotting Anticoagulant Activity Fibrinolytic Activity t-PA, SK, UPA Heparin, Warfarin LMWH, Argatroban FFP=fresh frozen plasma; Cryo=cryoprecipitate; PLTs=platelets; SK=streptokinase; UPA=urinary-type plasminogen activator; LMWH=low-molecular-weight heparin. Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.

37. Summary • Multiple topical agents are available to aid in intraoperative hemostasis • Agents have important varying safety and efficacy profiles • Immunogenic effects of bovine preparations can lead to serious AEs in surgical patients • Accept known risks and benefits and implement current intraoperative protocols when making treatment decisions for surgical patients

38. Conclusion For more CE/CME educational programs on the subject of operative hemostasis and transfusion medicine, including uniquely progressive learning designed for each clinical discipline, log on to: www.bloodcmecenter.org