Current Controversies in Selecting Topical Hemostatic Agents

Jeffrey H. Lawson, MD, PhDAssociate Professor of SurgeryDirector, Vascular Surgery Research LabDirector of Clinical Trials in Vascular SurgeryDuke University Medical CenterDurham, North Carolina

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Disclosure Information

Name of Faculty or Presenter Reported Financial Relationship

Jeffrey H. Lawson, MD, PhD Baxter Healthcare, ConsultantZymogentics, ConsultantJohnson and Johnson, ConsultantNovoNordisk, Consultant

Name of Planner or Manager Reported Financial Relationship

PIM Clinical Reviewers: Trace Hutchison, PharmD; 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.

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.

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SurgeryPost-op Recovery

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?

How not to overshoot?Thrombosis

Clotting

Bleeding

Hemorrhage

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The Problem

Most complications are at the dark interface between

• Biology

• Clinical skill

• Medical therapy

• Sick patients

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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

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Hemostasis“Life in the Balance”

Bleedingto Death

TraumaMajor SurgeryHemophilia

Clottingto Death

StrokeMIThrombosis

Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.

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Prevalence of Uncontrolled Bleeding

Surgical Discipline Uncontrolled Bleeding Rate

Cardiovascular 5%–7% Post-op1

General 1.9% Laparoscopic cholecystectomy2

Obstetric 3.9% (vaginal); 6.4% (cesarean)3,4

Orthopedic 2%–6.3% Hip/knee arthroplasty5-7

Urologic 4%–8% TURP8; 3.3%-9.9% URL9

Trauma 30%–40%10,11

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.

Hemostatic Agents for Usein Surgery

• Mechanical tools• Mechanical hemostats• Absorbable hemostatic agents• Biologic hemostatic agents

Mechanical Tools

• Finger

• Gauze sponge

• Cautery

• Laser

• Radiofrequency energy

• Argon beam coagulator

• Clips and suture

• Cavitron ultrasonic suction aspirator (CUSA)

• Harmonic scalpel

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

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

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.

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

Physiologic structure of fibrin strands in a Tisseel clot

Physiologic structure of fibrin strands in a plasma clot

Fibrin Sealants

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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.

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

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Cheng CM, et al. Clin Ther. 2009;31:32-41.

Bovine Thrombin vs Human Thrombin: Who Cares?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:GenTrac Incorporated;2007.

19401940 19501950 19601960 19701970

YearYear

First Clinical Use of Thrombin in Humans

Clinical Reports of Patients with Major Clinical Reports of Patients with Major Complications from AntibodiesComplications from Antibodies

FDA “Grandfathers” Bovine FDA “Grandfathers” Bovine Thrombin for Commercial Thrombin for Commercial ProductionProduction Publications of AEsPublications of AEs

19801980 2000200019901990 20102010

-200

-300

-100

US S

ale

s ($ M

illions)

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 20,000u 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

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

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1. Israels SJ, et al. Am J Pediatr Hematol Oncol. 1994;16:249-254. 2. Streiff MB, et al. Transfusion. 2002;42:18-26.

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

241. 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.

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

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Streiff MB, et al. Transfusion. 2002;42:18-26.

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

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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

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

32Cheng CM, et al. Clin Ther. 2009;31:32-41.

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

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Cheng CM, et al. Clin Ther. 2009;31:32-41.

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

34Cheng CM, et al. Clin Therapeutics. 2009;31:32-41.

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

35Cheng CM, et al. Clin Therapeutics. 2009;31:32-41.

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Keeping on Center

Topical HemostaticsPurified Factors, FFP, Cryo, PLTs

Aminocaproic Acid

Heparin, WarfarinLMWH, Argatroban

t-PA, SK, UPA

NormalHemostasis

ProcoagulantActivity

AnticoagulantActivity

FibrinolyticActivity

AntifibrinolyticActivity

Bleeding

Clotting

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.

Summary

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• 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

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Conclusion

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