Current Controversies in Selecting Topical Hemostatic Agents Jeffrey

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

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: Name of Faculty or Presenter Jeffrey H. Lawson, MD, Ph. D Reported Financial Relationship Baxter Healthcare, Consultant Zymogentics, Consultant Johnson and Johnson, Consultant Novo. Nordisk, Consultant 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. Name of Planner or Manager Reported Financial Relationship PIM Clinical Reviewers: Trace Hutchison, Pharm. D; Jan Hixon, RN, BSN, MSN; Linda Graham, RN, BSN; Jan Schultz, RN, BSN, MSN Have no real or apparent conflicts of interest to report. ECM: Bart Zoni, Executive Director; Patrick Crowley, Senior Director of Operations; Kathleen Krafton, Senior Editor Have no real or apparent conflicts of interest to report. 2

What Are the Challenges of Hemostasis in Surgery? 1. Who is likely to bleed or clot too much? 2. How do we optimize the physiology of the patient? 3. Which biologic agents are effective? When? How much? 4. Which topical agents are effective? What are the benefits and risks of available agents? Thrombosis How not to overshoot? Clotting Surgery Post-op Recovery Bleeding Hemorrhage 3

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

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 5

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

Prevalence of Uncontrolled Bleeding Surgical Discipline Uncontrolled Bleeding Rate Cardiovascular 5%– 7% Post-op 1 General 1. 9% Laparoscopic cholecystectomy 2 Obstetric 3. 9% (vaginal); 6. 4% (cesarean)3, 4 Orthopedic 2%– 6. 3% Hip/knee arthroplasty 5 -7 Urologic 4%– 8% TURP 8; 3. 3%-9. 9% URL 9 Trauma 30%– 40%10, 11 1. Despotis GJ, et al. Ann Thorac Surg. 2000; 70: S 20 -S 32; 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): S 57 -S 60; 11. Sauaia A, et al. J Trauma. 1995; 38: 185 -193. 7

Hemostatic Agents for Use in Surgery • • Mechanical tools Mechanical hemostats Absorbable hemostatic agents Biologic hemostatic agents

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

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

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

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 • Bio. Glue – Bovine albumin and gluteraldehyde – Easy to use – Good for aortic dissection – Direct contact harmful to exposed nerves and cardiac conduction tissue 1 – Intraluminal fragments of glue may embolize 1, 2 – Can leak through suture-line needle holes 1 – Fatal right ventricular infarction after embolism reported 2 1. Le. Maire SA, et al. Ann Thorac Surg. 2005; 80: 106 -111. 2. Mahmood Z, et al. J Thorac Cardiovasc Surg. 2004; 128: 770 -771.

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

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

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 RCTs 1 Safety: Bovine formulations associated with numerous adverse events 2 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. 15

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. 16

Bovine Thrombin vs Human Thrombin: Who Cares?

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

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

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

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

Case Study (cont) Hospital course • Abdominal aortic aneurysm and bilateral iliac artery aneurysm repair • Intraoperatively received 20, 000 u thrombin spray and Flo. Seal (10, 000 u 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

How Are Antibodies Derived? • Acquired inhibitors to coagulation factors: immunoglobulins bind specifically to these proteins, neutralize their activity, or accelerate their clearance from the circulation 1 • Leads to increased risk of severe bleeding 1 • Associated with autoimmune diseases, lymphoid malignancies, pregnancy, and with no known risk factors except advanced age 1 • Bovine thrombin: the most common contemporary culprit in factor V inhibition 2 § § § 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. 23

Prevalance of Factor V Inhibitors • • • Reported prevalence increasing in recent decades Many cases of factor V inhibitors may go unrecognized or unreported 1 Clinical studies § Bänninger et al 2 § 42% of cardiac surgery patients developed factor V inhibitors § 20% of neurosurgery patients § Carroll et al 1, 3 § 100% of cardiac surgery patients developed factor V inhibitors § Two-thirds of patients developed antibodies to human thrombin and factor V § Ortel et al 4 § 95% of cardiac surgery patients developed bovine inhibitors § >50% developed inhibitors to human coagulation factors § Patients with multiple inhibitors to bovine proteins are 5 x 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. 24

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. 25

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 26

Case Study Hospital course • Abdominal aortic aneurysm and bilateral iliac artery aneurysm repair • Intraoperatively received 20, 000 u thrombin spray and Flo. Seal (10, 000 u 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

Case Study: Bovine Antigens Day 5 Postop

Case Study: Human Antigens Day 5 Postop

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

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

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. 32

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 B 19 • 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. 33

Human Recombinant Thrombin • • • Approved for use in the United States in 2008 • Identical in amino acid sequence to naturally occurring human thrombin Minimizes risk of immunogenic cross-reactivity and infection transmission • 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 Cheng CM, et al. Clin Therapeutics. 2009; 31: 32 -41. 34

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. 35

Keeping on Center Topical Hemostatics Purified Factors, FFP, Cryo, PLTs Antifibrinolytic Activity Procoagulant Activity Bleeding Clotting Aminocaproic Acid Normal Hemostasis Fibrinolytic Activity Anticoagulant 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. 36 Adapted from Lawson JH, et al. Semin Hematol. 2004; 41(suppl): 55 -64.

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 37

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 38