Download Controversies in Selecting Topical Hemostatic Agents

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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Jeffrey H. Lawson, MD, PhD
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Baxter Healthcare, Consultant
Zymogentics, Consultant
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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
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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
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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”
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.
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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.
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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 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
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 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.
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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. 2009;31:32-41.
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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.
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 20,000u 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
1. Israels SJ, et al. Am J Pediatr Hematol Oncol. 1994;16:249-254. 2. Streiff MB, et al. Transfusion.
2002;42:18-26.
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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
 >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.
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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. 2002;42:18-26.
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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
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.
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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. 2009;31:32-41.
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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. 2009;31:32-41.
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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. 2009;31:32-41.
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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.
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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
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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
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