Transcript - Blood CME Center

Strategies for Preventing
and Treating Uncontrolled
Perioperative Bleeding
2
Strategies for Preventing and Treating Uncontrolled
Perioperative Bleeding
CE/CME Visiting Faculty Series
•
Faculty includes renowned surgeons, anesthesiologists, blood
banking specialists, and other experts in operative hemostasis
and transfusion management
•
Combination of didactic, specialty-specific case evaluations and
your interactivity
•
Part of a multicomponent educational initiative that can be
accessed via
www.bloodcmecenter.org
3
Learning Objectives
Upon completion of this activity, participants should be better
able to:
1. Discuss specific patient types who may be at increased risk
for perioperative bleeding and complications from
acquired coagulopathy
2. Explain the essentials of surgical hemostasis and current
guidelines for achieving balance between bleeding and clotting
3. Explain the benefits and risks of blood products as a therapeutic
modality
4. Explain the therapeutic benefits and risks of alternative
hemostatic treatment modalities
5. Explain how to initiate appropriate strategies for achieving
optimal operative hemostasis
4
Bleeding Is a Complication of Many Types of Surgery
•
Surgery is the most common cause of major blood loss in
a medical setting1 and can increase both morbidity
and mortality2,3
•
Unexpected perioperative bleeding is largely caused by impaired
inherited or drug-induced primary hemostasis4
1. Mannucci PM, et al. N Engl J Med. 32007;56:2301-2311; 2. Hall TS, et al. Ann Thorac Cardiovasc Surg. 2001;7:
352-357; 3. D’Amico G, et al. Hepatology. 2003;38:599-612; 4. Pfanner G, et al. Anaesthesist. 2007;56:604-611.
5
Definition of Hemostasis
Hemostasis: “The Arrest of Bleeding”
Stedman’s Medical Dictionary
Bleeding
to Death
Clotting
to Death
Trauma
Major Surgery
Hemophilia
Stroke
MI
Thrombosis
Hemostasis: “Life in the Balance”
Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.
6
Definition of Significant Bleeding
•
>2 L within the first 24 post-op hours1
•
Surgical or vascular component: corrected by surgical
intervention or embolization2
•
Coagulopathic component: more difficult to control due to
several interrelated mechanisms2

Consumption of coagulation factors and platelets

Dilution of coagulation factors

Metabolic disorders (eg, hypothermia, acidosis)
1. Despotis GJ, et al. Ann Thorac Surg. 2000;70(2 suppl):S20-S32;
2. Vincent J-L, et al. Crit Care. 2006;10:1-12.
7
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. Anesth Analg. 1996;82:13-21; 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
Prevalence of Uncontrolled Bleeding (cont)
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. Anesth Analg. 1996;82:13-21; 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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Reasons for Uncontrolled Bleeding
Patient-related
Procedure-related
•
•
•
•
•
•
•
•
•
•
Advanced age
Small body size
Pre-op anemia (low RBC volume)
Antiplatelet or antithrombotic
drugs
Comorbidities:

Congestive heart failure

Hypertension

Chronic obstructive
pulmonary disease

Peripheral vascular disease

Diabetes mellitus

Renal failure
Prolonged operation
CABG
Emergency/trauma
Surgical-site bleeding
Surgical skill
RBC=red blood cell; CABG=coronary artery bypass graft.
Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.
10
Types of Uncontrolled Bleeding
•
Surgical bleeding results from failure to control bleeding from
the operative site; signs include expanding hematoma and
saturated dressings (75%-90%)1,2
•
Nonsurgical bleeding is caused by failure of hemostatic
pathways; often manifested as generalized
oozing (10%-25%)1,2
1. Adams GL, et al. Hematol Oncol Clin North Am. 2007;21:13-24;
2. Shander A. Surgery. 2007;142(4 suppl):S20-S25.
11
Costs of Uncontrolled Bleeding
•
Estimating blood costs is a complex undertaking1,2
 Blood costs increase due to shrinking donor availability and
precautions to minimize transfusion risks1
 Great variation among institutions in reoperation and
return-to-operating-room rates2
 Total cost per unit is >$4002
•
“Clinical costs” of sustained bleeding3:
 Consumption of coagulation factors
 Hemodilution, hypothermia, and acidosis
 Compound factor consumption
 More bleeding
1. Shander A, et al. Best Pract Res Clin Anaesthesiol. 2007;21:271-289;
2. Shander A. Surgery. 2007;142:S20-S25;
3. Armand R, et al. Transfus Med Rev. 2003;17:223-231.
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Outcomes of Uncontrolled Bleeding
Clinical
Financial
•
•
•
•
•
•
•
Massive blood loss is associated
with mortality
Transfusion itself may have
independent detrimental effects
Death
Average LOS is 2X to 2.5X
Cost of blood
Costs of transfusion
Costs of adverse outcomes
LOS=length of stay.
Adapted from Shander A. Surgery. 2007;142(4 suppl):S20-S25.
13
Can We Predict Who Will Bleed?
There Is a Difference Between Who Is At Risk and Who Will Bleed
Thrombosis
Clotting
Surgery
Post-op
Recovery
Bleeding
Hemorrhage
1.
2.
3.
4.
Who is likely to bleed or clot too much?
How do we optimize the patient’s physiology?
Which topical agents are effective?
Which biologic agents are effective?
Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.
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Who Bleeds Without Warning?
STS Guidelines: Aspirin…the Dilemma
•
Aspirin causes increased bleeding
•
Amount of bleeding is small (0.5-1 U/patient)
•
Aspirin important for better outcome in acute coronary
syndromes
•
Nothing more important than aspirin, including heparin,
thrombolytics, IIb/IIIa, and PCI
•
STS recommendation: Stop aspirin for a few days in very-lowrisk patients; continue in all others
STS=Society of Thoracic Surgeons; PCI=percutaneous coronary intervention.
Ferraris VA, et al. Ann Thorac Surg. 2005;79:1454-1461.
15
Who Bleeds Without Warning? (cont)
Do Thienopyridines Cause Post-op Bleeding?
•
Evidence is more compelling than for aspirin1
•
11 studies with clopidogrel and CABG1
•
All studies show increased bleeding when clopidogrel given
within 5 days of CABGsome with increased mortality1
•
AHA/ACC and STS guidelines recommend stopping clopidogrel
for 5 days before operation, if possible2
AHA=American Heart Association; ACC=American College of Cardiology.
1. Ferraris VA, et al. Ann Thorac Surg. 2005;79:1454-1461; 2. Braunwald E, et al. J Am Coll
Cardiol. 2002;40:1366-1374.
16
“Cascade” Model of Hemostasis
Intrinsic Pathway
Extrinsic Pathway
factor XII
HMK
PK
factor XI
factor IX
factor XIa
factor IXa
factor VIIIa
PL, Ca+2
factor X
factor VIIa
tissue factor
PL, Ca+2
factor Xa
factor Va
PL, Ca+2
prothrombin
factor X
thrombin
fibrinogen
Adapted from Hoffman M, et al. Thromb Haemost .2001;85:958-965.
fibrin
17
Normal Hemostasis: Pivotal Role of TF/VIIa
II
X
TF
VIIa
VIII/vWF
Xa
IIa
Va
VIIIa
TF-Bearing Cell
TF
VIIa
IXa
IX
Va
Platelet
II
X
Xa
IXa VIIIa
VIIa
V
IX
IIa
Va
Activated Platelet
IXa
VIIIa
Xa
X
Va
II
TF=tissue factor; vWF=von Willebrand factor.
Hoffman M, et al. Blood Coag Fibrinol. 1998;9(suppl 1):S61-S65.
IIa
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Normal Hemostasis Is a Balance
Bleeding
to Death
Clotting
to Death
Trauma
Major Surgery
Hemophilia
Stroke
MI
Thrombosis
•
Blood coagulation
•
Anticoagulation
•
Fibrinolysis
•
Antifibrinolysis
•
Vascular tone and blood flow
•
Endothelial cells and platelets
Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.
19
“Keeping On Center”
Procoagulant
Activity
Bleeding
Clotting
Antifibrinolytic
Activity
Normal
Hemostasis
Fibrinolytic
Activity
Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.
Anticoagulant
Activity
20
“Keeping On Center” (cont)
Factor V falls
IIase increase
Procoagulant
Activity
Bleeding
Clotting
Fibrinolytic
Activity
t-PA increase
t-PA=tissue-type plasminogen
activator; PAI-1=plasminogen
activator inhibitor-1.
TF increase
Antifibrinolytic
Activity
PAI-1 increase
Normal
Hemostasis
Inflammatory
Cytokines
Anticoagulant
Activity
Heparin falls
Adapted from Lawson JH, et al. Semin Hematol.
2004;41(suppl):55-64. 21
“Keeping On Center” (cont)
Topical Hemostatics
Purified Factors, FFP, Cryo, PLTs
Procoagulant
Activity
Bleeding
Clotting
Aminocaproic acid,
Tranexamic acid, Aprotinin
Antifibrinolytic
Activity
Normal
Hemostasis
Fibrinolytic
Activity
t-PA, SK, UPA
FFP=fresh frozen plasma; Cryo=cryoprecipitate; PLTs=platelets; SK=streptokinase;
UPA=urinary-type plasminogen activator; LMWH=low-molecular-weight heparin.
Anticoagulant
Activity
Heparin, Warfarin
LMWH, Argatroban
22
Adapted from Lawson JH, et al. Semin Hematol.
2004;41(suppl):55-64.
Achieving Optimal Operative Hemostasis
Thrombosis
Clotting
Physiology and Good Surgery
Bleeding
Topical Hemostatic Agents
Hemorrhage
Systemic Biologic Therapies
Adapted from Lawson JH, et al. Semin Hematol.
2004;41(suppl):55-64.
23
Treatment Modalities:
Blood Products
Prohemostatic Agents
Blood Products in the Treatment
of Hemorrhage
Transfusion Benefits, Risks, and Trends
Postoperative Blood Transfusion
Benefits:
Risks:
•
•
•
•
•
•
Blood volume replacement
Oxygen-carrying
Clotting factors
•
•
TACO
TRALI
Disease transmission (especially
platelets)
TRIM
Transfusion errors
Evidence: Not enough data about benefits
TACO=transfusion-associated circulatory overload; TRALI=transfusion-related
acute lung injury; TRIM=transfusion-related immunomodulation.
Adapted from Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.
26
Benefits of Blood Transfusion
•
Useful in certain situations−ASA criteria

Transfuse patients on CPB with Hb ≤6 g/dL

Transfusion justified when Hb ≤7 g/dL in patients older
than 65 years and patients with chronic CVD or
respiratory disease

Benefit unclear for stable patients with Hb between 7 and
10 g/dL

Transfusion recommended for patients with acute blood loss
>1500 mL or >30% of blood volume

Evidence of rapid blood loss without immediate control
warrants transfusion
•
Issue of “triggers”—have come a long way since “10/30” rule,
but still a long way to go
ASA=American Society of Anesthesiologists; CPB=cardiopulmonary bypass;
Hb=hemoglobin; CVD=cardiovascular disease.
Adapted from Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.
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Risks of Blood Transfusion
TACO
1.
2.
3.
4.
•
Common reaction from rapid or massive transfusion of blood1
•
Usually occurs within several hours after start of transfusion
•
Manifested in signs and symptoms that include:
 Dyspnea
 Orthopnea
 Peripheral edema
 Rapid increase in BP
•
Incidence difficult to determine due to underreporting2
•
Patients at risk include3,4:
 Infants and elderly >60/years
 Those with chronic anemia
 Those with cardiac/pulmonary/renal failure
Popovsky MA. Transfusion Clin Biol. 2001; 8:272-277;
American Association of Blood Banks. Technical Manual. 1999:577-600;
Gresens CJ, et al. New York, NY: Marcel Dekker, Inc; 2001:71-86;
Popovsky MA. Transfus Clin Biol. 2001;8:272-277.
28
Risks of Blood Transfusion (cont)
TRALI
•
Rare and life-threatening complication
•
Associated with transfusion of blood components containing
RBCs, platelets, granulocytes, and cryoprecipitates1
•
Usually occurs within 1-2 hours after start of transfusion2
•
Characterized by acute respiratory distress2
•
Symptoms include2:
 Severe bilateral pulmonary edema
 Cyanosis
 Severe hypoxemia
 Tachycardia
 Hypotension
 Fever
•
Incidence varies considerably from 1/5000 to 16/10,0001
•
Fatality rate ranges from 5% to 14%2
1. Kopko PM, et al. Transfusion. 2001;41:1244-1248;
2. Popovsky MA. Transfus Clin Biol. 2001;8:272-277.
29
Risks of Blood Transfusion (cont)
Type
Occurrence in RBC Units
Transfused
Infectious:
Human immunodeficiency virus
Hepatitis B
Hepatitis C
Bacterial infection
1
1
1
1
Immunologic Reactions:
Febrile nonhemolytic transfusion reactions
Anaphylactic transfusion reactions
ABO mismatch
Hemolysis
Death
Leukocyte-related target organ injury
Transfusion-related acute lung injury
Post-transfusion purpura
Transfusion Services Error:
Donor screening error (malaria, T cruzi, babesioses,
Creutzfeld-Jakob disease)
Transfusion services error (other)
Adapted from Ferraris VA, et al. Ann Thorac Surg. 2007;83 S27-S86.
in
in
in
in
1.4-2.4 x 106
58,000-149,000
872,000-1.7 x106
2,000
1 in 100
1 in 20,000-50,000
1 in 60,000
1 in 600,000
1 in 20 to 1 in 50
1 in 2,000
Rare
1 in 4 x 106
1 in 14,000
30
How to Reduce Transfusions?
Blood conservation: general principles
•
Devise an individual plan of care to minimize blood loss
•
Employ multidisciplinary, multimodal treatment approach
•
The lead clinician should provide proactive management
•
Modify routine practices if necessary
•
Screen for, investigate, and treat anemia before and
after surgery
•
Minimize iatrogenic blood loss, including phlebotomies
•
Employ a restrictive transfusion strategy
•
Reassess preoperative/postoperative use of anticoagulant and
antiplatelet agents
•
Consult transfusion experts early
•
Establish in advance a management plan for rapid control of
hemorrhage and transfusion
Shander A, et al. Curr Opin Hematol. 2006;13:462-470.
31
Pharmacologic Agents in Treatment of Hemorrhage
Prohemostatic Agents
•
Antifibrinolytics

Lysine analogues

Aprotinin
•
Topical hemostatics
•
Protamine
•
Desmopressin (DDAVP)
•
Recombinant factor VIIa (rVIIa)
32
Antifibrinolytics
A Brief Review
Fibrinolysis
Summary of the coagulation and fibrinolysis cascades
a The coagulation cascade
b Plasmin-mediated
fibrinolysis
FX
Tissue
factor
FVIIa
+
Prothrombin
FXa
FVa
+
Plasminogen
Prothrombinase
complex
Thrombin
tPA
+
aggregated
platelets
–
+
PAI-1
Fibrinogen
Fibrin
Plasmin
–
Thrombus
+
α-2-AP
TAFI
Fibrin
degradation
products
Every rise is followed by a fall.
Expert Reviews in Molecular Medicine © 2002 Cambridge University Press
34
Fibrinolysis (cont)
Coagulation
Cascade
Fibrinolytic
Cascade
Prothrombin
–
Plasminogen
APC
TAFIa
Thrombin
–
Plasmin
PC
TAFI
Thrombin
Thrombomodulin
Fibrinogen
Fibrin
FDPs
There is a balance between formation and degradation of fibrin.
From Nesheim M. Chest. 2003;124(3 suppl):33S-39S.
35
Fibrinolysis (cont)
Coagulation
Cascade
Fibrinolytic
Cascade
Prothrombin
–
Plasminogen
APC
TAFIa
Thrombin
–
Plasmin
PC
TAFI
Thrombin
Thrombomodulin
Fibrinogen
Fibrin
FDP’s
Antifibrinolytic
Agents
Tip the balance against fibrinolysis  More clot  Less bleeding
Adapted from Nesheim M. Chest. 2003;124:33S-39S.
36
Antifibrinolytics
•
As implied by the name, these agents enhance hemostasis
when fibrinolysis contributes to bleeding
•
•
Lysine analogues

ε-Aminocaproic acid (EACA)

Tranexamic acid (TXA)
Aprotinin: Approved by FDA to reduce blood loss and transfusion
in CABG but marketing suspended 11/5/07
37
Lysine Analogues
•
Block the lysinebinding sites on
plasminogen,
inhibiting the
formation of plasmin
•
TXA is 6-10 times
more potent than
EACA
Mannucci PM, et al. N Engl J Med. 2007;356:2301-2311.
38
Lysine Analogues (cont)
•
Lysine analogues1-3: EACA and TXA

Indicated for enhancing hemostasis when fibrinolysis
contributes to bleeding

Both competitively inhibit plasmin binding to fibrin

Widely used in cardiac surgery, but data supporting
safety and efficacy are limited

EACA associated with increased incidence of certain
neurologic deficits; concerns about rhabdomyolysis and
renal dysfunction
1. Mannucci PM, et al. N Engl J Med 2007;356:2301-2311;
2. Levy JH. Am J Health-Syst Pharm. 2005;62(suppl 4):S15-S19;
3. Adams GL, et al. Hematol Oncol Clin North Am. 2007;21:13-24.
39
Aprotinin
•
•
A small protein isolated from bovine lung
A non-specific serine protease inhibitor 
inhibits trypsin, plasmin, plasma/tissue
kallikrein, etc
•
Inhibits contact phase activation of
coagulation that both initiates
coagulation and promotes fibrinolysis
•
In CPB, it reduces derangements in
coagulation/fibrinolysis caused by
negatively charged surface of CPB circuit
•
Indirectly preserves platelet function in
extracorporeal circulation
•
Marketing suspended on 11/5/07
following FDA Advisory 2/8/06
40
Topical Hemostatic Agents
•
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
 Many of these topical agents have thrombin or fibrinogen
as their active agent
•
Classification:
 Tissue/fibrin sealants (contain thrombin, fibrin, etc)
 Absorbable hemostatic agents (contain matrices)
 Combination products (contain both groups above)
41
Some Topical Hemostatic Agents
Sealants and Combination Products:
Agent
Topical Application Instructions
Major Drawbacks or Comments
Bovine thrombin
Dry, spray, or mixed with
isotonic saline applied to
bleeding or oozing surfaces;
may also be used with
absorbable gelatin sponge or
with FloSeal NT
Prion disease transmission;
autoantibodies may develop to
impurities, potentially
resulting in coagulopathy
Recombinant human
thrombin
To be released 2008;
presumably will be similar to
bovine thrombin
Potentially less immunogenic
than bovine thrombin
FloSeal Hemostatic
Matrix: bovine gelatin
granules and human
thrombin
Reconstituted mixture is
applied to bleeding or oozing
surfaces
Infectious disease
transmission similar to that
with other human blood
products; bovine sensitization
Virally inactivated
aprotinin-free fibrin
sealant (Crosseal):
thrombin and fibrinogen
(human)
Stored frozen, then thawed and
sprayed
Contains no animal protein
and is virally inactivated and
highly purified; safety
concerns minimized
Voils S. Pharmacotherapy. 2007;27:69S-84S.
42
Some Topical Hemostatic Agents (cont)
Agent
Topical Application Instructions
Major Drawbacks or Comments
CoStasis: microfibrillar
collagen-fibrin (bovine)
Reconstituted mixture forms gel
matrix
Similar to other bovine
preparations
CoSeal Surgical Sealant: 2
synthetic polyethylene
glycols
Reconstituted mixture forms a
hydrogel that is applied to
bleeding or oozing surfaces;
forms mechanical seal
Swells up to 4x its volume;
may cause compression of
anatomic structures
Aprotinin and TXA
Solutions containing 1 MU of
aprotinin or 2.5 g of TXA in
250 mL of saline poured into
pericardial cavity during CPB
Single study with minimal
effectiveness of aprotinin; TXA
was less effective in reducing
blood product usage
Chitosan hemostatic
bandage
Bandage that binds
electrostatically to red blood
cells; considered a device; used
in combat
Floats off wound in severe
hemorrhage
Zeolite
Powder applied to wounded
tissue; considered a device;
used in combat
Local hyperthermia-induced
tissue damage
Voils S. Pharmacotherapy. 2007;27:69S-84S.
43
Some Topical Hemostatic Agents (cont)
Cellulose-, Collagen-, and Gelatin-Based
Topical Hemostatic
Composition
Approval Date
Surgicel (J&J)
Regenerated oxidized
cellulose
October 14, 1960
Gelfoam (Pfizer)
Porcine gelatin molded into
a sponge
Available 1945; approved
July 8, 1983
Surgifoam (J&J)
Porcine gelatin sponge
September 30, 1999
Avitene (Davol)
Bovine collagen
August 26, 1976 (as a drug)
October 24, 1980 (as a
device)
Instat (J&J/Gateway)
Bovine collagen
October 10, 1985
Helistat (Integra LifeSciences)
Bovine collagen
November 8, 1985
Helitene (Integra LifeSciences)
Bovine collagen
November 8, 1985
Gabay M. Am J Health-Syst Pharm. 2006;63:1244-1253.
44
Indications
Hemostatic Agent
Labeled Indication(s)
Surgicel
For use in surgical procedures when conventional methods of
hemostasis, such as pressure and ligature, are ineffective; for
endoscopic procedures, may be used by cutting to size.
Gelfoam
For use in in surgical procedures, including those that may result in
calcellous bone bleeding, when conventional methods of hemostasis are
ineffective or impractical.
Surgifoam
For use in surgical procedures, except urologic and ophthalmic
procedures, when conventional methods of hemostasis are ineffective or
impractical.
Avitene
For use in surgical procedures when conventional methods of
hemostasis are ineffective or impractical.
Instat
For use in surgical procedures, except ophthalmic procedures, when
conventional methods of hemostasis are ineffective or impractical; for
endoscopic procedures, may be used by cutting to size.
Helistat
For use in surgical procedures, except urologic and ophthalmic
procedures, when conventional methods of hemostasis are ineffective or
impractical.
Gabay M. Am J Health-Syst Pharm. 2006;63:1244-1253.
45
Indications (cont)
Hemostatic Agent
Labeled Indication(s)
Helitene
For use in surgical procedures, except urologic and ophthalmic
procedures, when conventional methods of hemostasis are ineffective
or impractical.
CoStasis
For use in surgical procedures, except neurologic,ophthalmic, and
urologic procedures, when conventional methods of hemostasis are
ineffective or impractical.
FloSeal
For use in surgical procedures, except ophthalmic procedures, when
conventional methods of hemostasis are ineffective or impractical.
Thrombin-JMI
For use as an aid to hemostasis whenever oozing blood and minor
bleeding from capillaries and small venules are accessible; may be used
in combination with absorbable gelatin sponge for hemostasis; may be
used in conjunction with any other device that has been approved by
FDA with a specified dosage of topical thrombin.
Gabay M. Am J Health-Syst Pharm. 2006;63:1244-1253.
46
Considerations
•
Efficacy: Few randomized controlled trialsstudies have shown
beneficial effects in controlling capillary bleeding, achieving
hemostasis in vascular surgery, controlling bleeding from
fistula-puncture site in hemodialysis, etc
•
Cost: No published study of cost-effectiveness
•
Safety
47
Adverse Events
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Device failure (continued bleeding observed)
Device deployment failure
Infection
Granuloma
Abscess
Foreign body reaction
Allergic reaction
Interference with wound healing
Respiratory difficulty
Bowel obstruction
Hematoma
Intermittent ischemia
Stroke
Tissue necrosis
Erythema
Edema
www.fda.gov.
48
Adverse Events (cont)
•
In 2004, FDA issued a notification on possible development of
paralysis following use of absorbable hemostatic agents
•
If agent used and left on or near a bony or neural space, when
wetted, the material swelled and exerted pressure on neural
structures, resulting in pain, numbness, or paralysis
•
Recommendations:

Read labels carefully

If used on or near bony/neural spaces, use the minimum
amount necessary to achieve hemostasis and remove as
much of the agent as possible after hemostasis is achieved
www.fda.gov.
49
Protamine
•
Heparin antagonist indicated for heparin overdosage
•
Rapid onset of action
•
Has an anticoagulant effect when used alone; in the presence of
heparin, both drugs lose anticoagulant activity
•
Too-rapid administration can cause severe hypotensive and
anaphylactoid-like reactions
50
DDAVP
•
Originally developed and licensed for the treatment of inherited
defects of hemostasis1,2
•
Several reviews suggest its effect is too small to influence the
need for transfusion and reoperation1,2
•
Most evidence of efficacy is in mild hemophilia A and
von Willebrand’s disease1,2
•
Not indicated for use in cardiac surgery patients1,2

Meta-analysis in cardiac patients: 2-fold increase in MI, a
small decrease in perioperative blood loss, and no added
benefits on clinical outcomes
1. Mannucci PM, et al. N Engl J Med. 2007;356:2301-2311;
2. Levy JH. Am J Health-Syst Pharm. 2005; 62(suppl 4):S15-S19.
51
rVIIa
•
Vitamin K-dependent glycoprotein structurally similar to human
plasma-derived factor VIIa
•
Approved in United States for treatment of bleeding in patients
with hemophilia A or B with inhibitors to factor VIII or IX
•
Multiple reports of off-label use in cardiac surgery, trauma, liver
transplantation to secure hemostasis
•
Promotes hemostasis by activating the coagulation cascade
•
Believed to cause local thrombin generation and platelet
recruitment at sites of vascular and microvascular injury
52
rVIIa (cont)
•
A central factor in coagulation
•
A trypsin-like serine protease (characterized
by a serine residue in the active side of
the enzyme)
•
Initiates coagulation in a complex with TF
•
Once bound to TF, it is activated (FVIIa) by
different proteases
•
Produced in liver; vitamin K–dependent (warfarin)
53
Mechanism of Action
Mannucci PM, et al. N Engl J Med. 2007;356:2301-2311.
54
Approved Indications and Usage
•
Date: March 25, 1999
Indication: Treatment of bleeding episodes in hemophilia A or B
patients with inhibitors to factor VIII or factor IX
•
Date: October 13, 2006
Indication: Treatment of bleeding episodes and for the
prevention of bleeding in surgical interventions or invasive
procedures in patients with acquired hemophilia
http://www.fda.gov/cber/products/novoseven.htm.
55
Approved Indications and Usage (cont)
rVIIa is indicated for:
•
Treatment of bleeding episodes in hemophilia A or B patients
with inhibitors to factor VIII or factor IX and in patients with
acquired hemophilia
•
Prevention of bleeding in surgical interventions or invasive
procedures in hemophilia A or B patients with inhibitors to
factor VIII or factor IX and in patients with acquired hemophilia
•
Treatment of bleeding episodes in patients with congenital
factor VIII deficiency
•
Prevention of bleeding in surgical interventions or invasive
procedures in patients with congenital factor VIII deficiency
NovoSeven [ package insert]. Princeton, NJ: Novo Nordisk Pharmaceuticals;
September 1999.
56
Approved Indications and Usage (cont)
Remember the mechanism…
•
IXa and VIIIa aid VIIa in
activating X
•
If IXa or VIIIa is missing (or
inhibited), rVIIa can replace
their function by converting
more X to Xa
Mannucci PM, et al. N Engl J Med. 2007;356:2301-2311.
57
Monitoring of Treatment
•
Primarily, clinical evaluation of hemostasis
•
Lab testsNo direct correlation to achieving hemostasis:

PT: Shortening to a plateau in hemophilia A/B with inhibitors

aPTT: Shortens the prolonged aPTT in hemophilia A/B with
inhibitors; normalization not usually observed in doses
shown to induce clinical improvement; clinical improvement
is associated with a shortening of aPTT of 15 to 20 seconds

Plasma FVII clotting activity (FVII:C)
58
Adverse Reactions
Seems to be well tolerated (298 hemophilia A or B patients
with inhibitors)
Body System
Event
Body as a whole
Fever
Platelets, Bleeding, and Clotting
Hemorrhage NOS
Fibrinogen plasma decreased
Skin and Musculoskeletal
Hemarthrosis
Cardiovascular
Hypertension
No. of episodes reported
(n=1939 treatments)
No. of unique patients
(n=298)
16
13
15
10
8
5
14
8
9
6
NovoSeven [package insert]. Princeton, NJ: Princeton, NJ: Novo Nordisk Pharmaceuticals;
September 1999.
59
“Off-label” Uses of rVIIa
•
Increasingly being considered for:
 Reversal of oral anticoagulation
 Reversal of heparin, lepirudin, and fondaparinux
 Thrombocytopenia and thrombocytopathy
 Bleeding with impaired liver function
 Gastrointestinal bleeding
 Trauma
 Surgery: Non-traumarelated (hepatic resection,
prostatectomy, cardiac, spinal)
•
These off-label uses are mostly based on anecdotal case reports

Need better evidence
60
“Off-label” Uses of rVIIa (cont)
•
Evidence is lagging behind the rising off-label use of rVIIa
•
Multiple case series/reports:

Benefits in obstetric bleeding, trauma, perioperative bleeding

Beware of perils of case reports: Subjective; no control; bias
(usually only positive experiences are reported)
•
Some concerns: Thrombotic complications (eg,
myocardial/cerebral ischemia, DVT, pulmonary embolism)
•
At a cost of $2000-$8000 per dose, annual costs of such offlabel uses can easily run into millions of dollars in hospitals
•
Only few randomized controlled trials  This is changing
61
Current Ongoing Global Trials
Phase
Total
Enrollment
Expected
Completion
Phase 3
40
June 2008
??
??
December
2010
Randomized, DoubleBlind
(Subject, Caregiver,
Investigator) PlaceboControl, Parallel
Assignment,
Efficacy Study
Phase 3
52
December
2009
Randomized,
Controlled, OpenLabel, InvestigatorBlinded Pilot Study
Phase 2
30
January 2008
Trial Title
Study Design
"Salvage Use" of Recombinant
Activated Factor VII After
Inadequate Haemostatic
Response to Conventional
Therapy in Complex Cardiac
Surgery
Multicenter,
Treatment,
Randomized, DoubleBlind, PlaceboControl,
Parallel Assignment,
Safety/Efficacy Study
Evaluation of the Quality of the
NovoSeven (rFVIIa) Treatment
Practice at Rigs hospital,
Copenhagen University Hospital
Natural History,
Longitudinal,
Defined Population,
Retrospective/
Prospective Study
Effect of Recombinant
Coagulation Factor VIIa on PeriOperative Blood Loss in Patients
Undergoing Major Burn Excision
and Grafting
Efficacy and Safety of Factor VIIa
(Eptacog Alfa) on Rebleeding
After Surgery for Spontaneous
Supratentorial Intracerebral
Hemorrhage.
US National Institutes of Health. ClinicalTrials.gov. Available at:
www.clinicaltrials.gov. Accessed February 10, 2008.
62
Current Ongoing Global Trials (cont)
Phase
Total
Enrollment
Multicenter,
Treatment,
Randomized, DoubleBlind, PlaceboControl,
Parallel Assignment,
Safety/Efficacy Study
Phase 3
40
June 2008
Effect of Recombinant
Coagulation Factor VIIa on PeriOperative Blood Loss in Patients
Undergoing Major Burn Excision
and Grafting
Randomized, DoubleBlind
(Subject, Caregiver,
Investigator) PlaceboControl, Parallel
Assignment,
Efficacy Study
Phase 3
52
December
2009
Efficacy and Safety of Factor VIIa
on Rebleeding After Surgery for
Spontaneous Intracerebral
Hemorrhage (ICH) (PRE-SICH).
Randomized,
Controlled, OpenLabel, InvestigatorBlinded Pilot Study
Phase 2
30
January 2008
Trial Title
Study Design
"Salvage Use" of Recombinant
Activated Factor VII After
Inadequate Haemostatic
Response to Conventional
Therapy in Complex Cardiac
Surgery
US National Institutes of Health. ClinicalTrials.gov. Available at:
www.clinicaltrials.gov. Accessed February 10, 2008.
Expected
Completion
63
Current Ongoing Global Trials (cont)
Phase
Total
Enrollment
Expected
Completion
Randomized, OpenLabel, Active Control,
Parallel Assignment,
Safety/Efficacy Study
Phase 4
84
December
2009
Randomized, Open, Prospective,
Multicenter Pilot Study to
Evaluate the Efficacy and Safety
of Activated Recombinant Factor
VII in Acute Intracerebral
Haemorrhage in Patients Treated
With Oral Anticoagulants or
Antiplatelets Agents.
Randomized, SingleBlind, Active Control,
Parallel Assignment,
Safety/Efficacy Study
Phase 2
32
September
2006
The Use of rFVIIa in Trauma
Patients: A Multi-Center Case
Registry
Natural History,
Cross-Sectional,
Case Control,
Retrospective/
Prospective Study
??
1000
Not recruiting
yet
Assessment of rFVIIa in
Controlling Bleeding in Patients
With Severe Trauma Injuries
Treatment,
Randomized, DoubleBlind,
Placebo Control,
Parallel Assignment,
Safety/Efficacy Study
Phase 3
1502
Recruiting
Trial Title
Study Design
Recombinant Human Activated
Factor VII as Salvage Therapy in
Women With Severe Postpartum
Hemorrhage
US National Institutes of Health. ClinicalTrials.gov. Available at:
www.clinicaltrials.gov. Accessed February 10, 2008.
64
Patient Case: Adam B.
•
Dx: Post-op coagulopathy and uncontrolled bleeding
•
History: 50-year-old male; had antibodies to c and E

Suffered excessive bleeding during surgery and narrowly
avoided transfusion of incompatible blood

Ongoing chest tube drainage in the 2 weeks following
surgery required transfusion of 1 U QOD

Last night, he developed coagulopathy and dramatically
increased bleeding

Increasing clotting times not corrected by FFP

HCT declined to 19%

Antigen-negative PRBC were not immediately available
HCT=hematocrit; PRBC=packed red blood cells.
65
Patient Case: Adam B.
• First thoughts about continuing to transfuse Adam B.
 What are the risks associated with additional
transfusions?
What Would You Do Next?
66
Take-Away Points
•
Achieving optimal operative hemostasis means maintaining
balance between bleeding and clotting
•
Preoperative risk assessment may predict who will bleed
•
Transfusion concerns include risks, costs, and impact on patient
quality of life
•
Look at patient’s risks for complications and think about the
balance
•
Incorporate blood conservation and prohemostatic therapy into
hemostasis strategy
“Keeping On Center”
67
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
68
Specialty-Specific Clinical Cases
More Opportunities to Decide …
What You Would Do Next!
69
Patient Case: Brian C.
•
Dx: Acute cholecystitis
•
History: 54-year-old male; 5’11,” 240 lb; third ED visit for
same reason
 H/O appendectomy; mild high BP (on BP meds and baby
aspirin) and borderline diabetes mellitus (no meds)
 Labsnormal PT and PTT; HCT 39%, platelets 410,000
 Lap cholecystectomy was performed with difficult
establishment of pneumoperitoneum
 Bleeding began at base of gall bladder
 Cauterization failed to arrest bleeding
 Pressure and topical hemostatics failed to help
 Consult: Agreed to switch to open procedure
 2500 cc blood in abdomen on opening
 HCT 22%, platelets 140,000
 Liver was packed; gall bladder was removed; and after
8 U of PRBC, 1 of cryoprecipitate and 1 of FFP, patient was
still bleeding
What Would You Do Next?
70
Patient Case: Chaney D.
•
Dx: Abdominal crush injury, fracture of both tibias, and closed
head trauma
•
History: Very fit 47-year-old male, no previous surgery, only
med was baby aspirin
 Head-on collision, spun around, and hit head-on from rear
again; air bags deployed after first hit only
 Exploratory lap removed spleen, and liver laceration repaired
 After 2 hours, 12 U PRBC, FFP, cryoprecipitate; bleeding
continued from liver
 Damage control planned and liver tightly packed
 HCT 22%, platelets 85,000
 Plan to re-explore the next day
 Bled through the packing and returned to OR
 HCT 16%, platelets 44,000
What Would You Do Next?
71
Patient Case: Deidre E.
•
Dx: Postpartum hemorrhage
•
History: 38-year-old had C section for failure to progress with
delivery of 8 lb, 11 oz baby with mild preeclampsia
 Pre-op HCT was 31% and EBL was 600 cc
 2 hours postpartum, patient showed signs of volume
depletion, with decreased urine output and low BP

HCT was 20%, fibrinogen <100; FDP elevated and
platelets 75,000

Urine was grossly bloody, glucose 60 and LFT drawn

Repeat platelet count was 30,000 and blood was not clotting

HELLP syndrome was diagnosed and transfusions begun
What Would You Do Next?
72
Patient Case: Elvin F.
•
Dx: Hip replacement from traumatic arthritis
•
History: 54-year-old male with mild hypertension (on meds)

Labs normal; received 5000 U heparin preoperatively

Began bleeding heavily; received third and forth units of
blood, and cell saver used

HCT 24 (37 pre-op), platelets 125,000 and fibrinogen 50

Urine blood tinged; according to patient’s wife, he was
taking 1600 mg ibuprofen and possibly a baby aspirin

FDP was positive and patient developed a coagulopathy

Patient was warmed; acidosis and volume status corrected
What Would You Do Next?
73
Patient Case: Fenton G.
•
Dx: Urgent repeat on-pump CABG due to unstable angina
•
History: 68-year-old male with prior CABG, several MIs, CHF
(on lisinopril)
 3-vessel disease noted with EF 25%; LMWH given in cath lab
 Patient had high BP (on BP meds and clopidogrel) and type 2
diabetes mellitus
 HCT 42%, platelets 220,000
 1 g TXA given after intubation followed by 200 mg/min
 Heparin 10,000 U in CPB reservoir and 400 U/kg
 On separation from bypass, HCT 24%, with 1 L volume in
reservoir
 Intra-aortic balloon pump placed and patient given milrinone
and norepinephrine
 Protamine returns ACT to normal
 Patient oozy at closure
 Patient continues to bleed in PACU at rate of 200 cc per hour
What Would You Do Next?
74
Patient Case: Gavin H.
•
Dx: Trabeculated bladder with UA stones
•
History: 70-year-old male with BPH; taking finasteride
and tamsulosin
 On BP med (amlodipine) and aspirin; PSA 1.2
 Coagulation studies normal and platelets 225,000
 TURP performed under general anesthesia
 Bleeding was encountered; attempts at cautery unsuccessful
 60 cc foley placed on stretch with irrigation, which cleared
but then became bloody again
 Bleeding increased the next day
 HCT was 33% (39 pre-op); resection attempts failed
to arrest bleeding
What Would You Do Next?
75