Current Controversies in Selecting Topical Hemostatic Agents

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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

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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 Reported Financial Relationship
Jeffrey H. Lawson, MD, PhD Baxter Healthcare, Consultant Zymogentics, Consultant Johnson and Johnson, Consultant NovoNordisk, 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, 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.
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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
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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
• ? Stedmans Medical Dictionary
• But is hemostasis more than that?

• In surgery, hemostasis is
• About bleeding
• About clotting
• About timing
• About balance

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HemostasisLife in the Balance
Bleedingto Death
Clottingto Death
Trauma Major Surgery Hemophilia
Stroke MI Thrombosis
Lawson JH, et al. Semin Hematol. 200441(suppl
1)55-64.
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Prevalence of Uncontrolled Bleeding
Surgical Discipline Uncontrolled Bleeding Rate
Cardiovascular 57 Post-op1
General 1.9 Laparoscopic cholecystectomy2
Obstetric 3.9 (vaginal) 6.4 (cesarean)3,4
Orthopedic 26.3 Hip/knee arthroplasty5-7
Urologic 48 TURP8 3.3-9.9 URL9
Trauma 304010,11
1. Despotis GJ, et al. Ann Thorac Surg.
200070S20-S32 2. Erol DD, et al. The Internet
Journal of Anesthesiology. 200592 3. Combs
CA, et al. Obstet Gynecol. 19917769-76 4.Combs
CA, et al. Obstet Gynecol. 19917777-82 5. Hull
R, et al. N Engl J Med. 19933291370-1376 6.
Leclerc JR, et al. Ann Intern Med.
1996124619-626 7. Strebel N, et al. Arch
Intern Med. 20021621451-1455 8. Daniels PR.
Nat Clin Pract Urol. 20052343-350 9.Rosevear
HM, et al. J Urol. 20061761458-1462 10.
Holcomb JB. Crit Care. 20048(suppl 2)S57-S60
11. Sauaia A, et al. J Trauma. 199538
185-193.
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Hemostatic Agents for Usein Surgery

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

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Mechanical Tools

• Argon beam coagulator
• Clips and suture
• Cavitron ultrasonic suction aspirator (CUSA)
• Harmonic scalpel

• Finger
• Gauze sponge
• Cautery
• Laser
• Radiofrequency energy

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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

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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

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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.
200580106-111. 2. Mahmood Z, et al. J Thorac
Cardiovasc Surg. 2004128770-771.
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Fibrin Formation Independent of Patients
Coagulation

• Adheres to exposed collagen on damaged tissue
  surfaces
• Reabsorbed within 7 to 14 days
• Does not require any components of the patients
  blood

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

• Identified by FDA as a device intended to
  produce hemostasis by accelerating the clotting
  process of blood1
• 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. 200441(suppl
1)55-64. 2. Gabay M. Am J Health-Syst Pharm.
2006631244-1253.
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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. 20093132-41.
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Bovine Thrombin vs Human Thrombin Who Cares?
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Bovine Thrombin

• Used in a variety of surgical procedures
• Cardiovascular surgery
• Vascular surgery
• Neurologic surgery
• Orthopedic surgery
• General surgery
• Gynecologic surgery
• Estimated that gt500,000 Americans are exposed
  each year
• gt100 reports of adverse events (AEs) in the
  worlds literature related to bovine thrombin
  exposure in humans

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Bovine Thrombin Black Box Warning
Thrombin, Topical U.S.P. (bovine origin)
package insert. Middleton, WIGenTrac
Incorporated2007.
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1940
2000
1950
1960
1970
1980
1990
2010
Year
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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

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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

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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.
199416249-254. 2. Streiff MB, et al.
Transfusion. 20024218-26.
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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
• gt50 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. 20024218-26.
2. Bänninger H, et al. Br J Haematol.
199385528-532. 3. Carroll JF, et al. Thromb
Haemost. 199676925-931. 4. Ortel TL, et al. Ann
Surg. 200123388-96.
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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. 20024218-26.
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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

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Case StudyBovine Antigens Day 5 Postop
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Case StudyHuman Antigens Day 5 Postop
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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

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Case Study Conclusion

• Discharge Diagnosis
• Acquired coagulopathy secondary to factor V
  inhibitor, presumed secondary to topical bovine
  thrombin exposure

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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. 20093132-41.
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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. 20093132-41.
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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. 20093132-41.
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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. 20093132-41.
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Keeping on Center
Topical Hemostatics Purified Factors, FFP, Cryo,
PLTs
Aminocaproic Acid
Antifibrinolytic Activity
Procoagulant Activity
Normal Hemostasis
Bleeding
Clotting
Anticoagulant Activity
Fibrinolytic Activity
Heparin, Warfarin LMWH, Argatroban
t-PA, SK, UPA
FFPfresh frozen plasma Cryocryoprecipitate
PLTsplatelets SKstreptokinase
UPAurinary-type plasminogen activator
LMWHlow-molecular-weight heparin.
Adapted from Lawson JH, et al. Semin Hematol.
200441(suppl)55-64.
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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

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Conclusion

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  subject of operative hemostasis and transfusion
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