strategies for preventing and treating uncontrolled perioperative bleeding

Strategies for Preventing and Treating UncontrolledPerioperative Bleeding

3

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

4

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

5

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.

6

Definition of Hemostasis

Hemostasis: “The Arrest of Bleeding”Stedman’s Medical Dictionary

Hemostasis: “Life in the Balance”

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

TraumaMajor SurgeryHemophilia

StrokeMIThrombosis

Bleedingto Death

Clottingto Death

7

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.

8

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.

9

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.

10

Reasons for Uncontrolled Bleeding

Patient-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

Procedure-related• Prolonged operation

• CABG

• Emergency/trauma

• Surgical-site bleeding

• Surgical skill

Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.

RBC=red blood cell; CABG=coronary artery bypass graft.

11

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.

12

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.

13

Outcomes of Uncontrolled Bleeding

Clinical• Massive blood loss is associated

with mortality

• Transfusion itself may have independent detrimental effects

Financial• Death

• Average LOS is 2X to 2.5X

• Cost of blood

• Costs of transfusion

• Costs of adverse outcomes

Adapted from Shander A. Surgery. 2007;142(4 suppl):S20-S25.

LOS=length of stay.

14

SurgeryPost-op Recovery

Thrombosis

Clotting

Bleeding

Hemorrhage

Can We Predict Who Will Bleed?

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

1. Who is likely to bleed or clot too much?2. How do we optimize the patient’s physiology?3. Which topical agents are effective?4. Which biologic agents are effective?

There Is a Difference Between Who Is At Risk and Who Will Bleed

15

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-low-

risk patients; continue in all others

Ferraris VA, et al. Ann Thorac Surg. 2005;79:1454-1461.

STS=Society of Thoracic Surgeons; PCI=percutaneous coronary intervention.

16

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 CABGsome with increased mortality1 • AHA/ACC and STS guidelines recommend stopping clopidogrel

for 5 days before operation, if possible2

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.

AHA=American Heart Association; ACC=American College of Cardiology.

17

“Cascade” Model of Hemostasis

Intrinsic Pathway Extrinsic Pathway

factor XIIHMKPK

factor XI factor XIa

factor IXfactor IXa

factor VIIIaPL, Ca+2

factor Xfactor Xafactor VaPL, Ca+2

prothrombin thrombin

fibrinogen fibrin

factor VIIatissue factor

PL, Ca+2

factor X

Adapted from Hoffman M, et al. Thromb Haemost .2001;85:958-965.

18Hoffman M, et al. Blood Coag Fibrinol. 1998;9(suppl 1):S61-S65.

TF-Bearing Cell

Activated Platelet

Platelet

TF

VIIIa Va

VIIIaVa

Va

VIIa

TF VIIa Xa

X II

IIa

IXV Va

II

VIII/vWF

VIIIa

II

IXa

XIX

X

IXa

IXaVIIa

Xa

IIa

IIa

Xa

Normal Hemostasis: Pivotal Role of TF/VIIa

TF=tissue factor; vWF=von Willebrand factor.

19

Normal Hemostasis Is a Balance

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

TraumaMajor SurgeryHemophilia

StrokeMIThrombosis

Bleedingto Death

Clottingto Death

• Blood coagulation• Anticoagulation• Fibrinolysis• Antifibrinolysis• Vascular tone and blood flow• Endothelial cells and platelets

20

“Keeping On Center”

NormalHemostasis

ProcoagulantActivity

AnticoagulantActivity

FibrinolyticActivity

AntifibrinolyticActivity

Bleeding

Clotting

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

21

“Keeping On Center” (cont)

NormalHemostasis

Factor V falls

t-PA increase

IIase increase

TF increase

PAI-1 increase

Heparin falls

InflammatoryCytokines






Bleeding

Clotting

t-PA=tissue-type plasminogen activator; PAI-1=plasminogen activator inhibitor-1.

22

“Keeping On Center” (cont)

Topical HemostaticsPurified Factors, FFP, Cryo, PLTs

Aminocaproic acid,Tranexamic acid, Aprotinin

Heparin, WarfarinLMWH, Argatroban

t-PA, SK, UPA

NormalHemostasis

Bleeding

Clotting

FFP=fresh frozen plasma; Cryo=cryoprecipitate; PLTs=platelets; SK=streptokinase; UPA=urinary-type plasminogen activator; LMWH=low-molecular-weight heparin.






23

Thrombosis

Clotting

Bleeding

Hemorrhage

Physiology and Good Surgery

Topical Hemostatic Agents

Systemic Biologic Therapies

Achieving Optimal Operative Hemostasis


Treatment Modalities:Blood ProductsProhemostatic Agents

Blood Products in the Treatment of HemorrhageTransfusion Benefits, Risks, and Trends

26

Postoperative Blood Transfusion

Benefits:• Blood volume replacement

• Oxygen-carrying

• Clotting factors

Risks:• TACO

• TRALI

• Disease transmission (especially platelets)

• TRIM

• Transfusion errors

Evidence: Not enough data about benefits

Adapted from Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.

TACO=transfusion-associated circulatory overload; TRALI=transfusion-related acute lung injury; TRIM=transfusion-related immunomodulation.

27

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

Adapted from Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.

ASA=American Society of Anesthesiologists; CPB=cardiopulmonary bypass; Hb=hemoglobin; CVD=cardiovascular disease.

28

Risks of Blood Transfusion

TACO• 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

1. Popovsky MA. Transfusion Clin Biol. 2001; 8:272-277;2. American Association of Blood Banks. Technical Manual. 1999:577-600;3. Gresens CJ, et al. New York, NY: Marcel Dekker, Inc; 2001:71-86;4. Popovsky MA. Transfus Clin Biol. 2001;8:272-277.

29

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.

30

Risks of Blood Transfusion (cont)

TypeOccurrence in RBC Units Transfused

Infectious:Human immunodeficiency virusHepatitis B Hepatitis C Bacterial infection

1 in 1.4-2.4 x 106

1 in 58,000-149,0001 in 872,000-1.7 x106

1 in 2,000

Immunologic Reactions:Febrile nonhemolytic transfusion reactionsAnaphylactic transfusion reactionsABO mismatchHemolysisDeathLeukocyte-related target organ injuryTransfusion-related acute lung injury Post-transfusion purpura

1 in 1001 in 20,000-50,000

1 in 60,0001 in 600,0001 in 20 to 1 in 501 in 2,000Rare

Transfusion Services Error:Donor screening error (malaria, T cruzi, babesioses, Creutzfeld-Jakob disease)Transfusion services error (other)

1 in 4 x 106

1 in 14,000

Adapted from Ferraris VA, et al. Ann Thorac Surg. 2007;83 S27-S86.

31

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.

32

Pharmacologic Agents in Treatment of Hemorrhage

Prohemostatic Agents

• Antifibrinolytics

Lysine analogues

Aprotinin

• Topical hemostatics

• Protamine

• Desmopressin (DDAVP)

• Recombinant factor VIIa (rVIIa)

AntifibrinolyticsA Brief Review

34

Fibrinolysis

Every rise is followed by a fall.

a The coagulation cascade b Plasmin-mediated fibrinolysis

Summary of the coagulation and fibrinolysis cascades

Expert Reviews in Molecular Medicine © 2002 Cambridge University Press

α-2-APTAFI

PAI-1

Prothrombinasecomplex

+

+

+

+

–

–

Tissue factor FVIIa

FX

FXaFVa

Prothrombin

Thrombin

FibrinogenFibrin

+aggregated

platelets

Thrombus

Plasminogen

Plasmin

tPA

Fibrindegradation

products

35

Fibrinolysis (cont)

There is a balance between formation and degradation of fibrin.

From Nesheim M. Chest. 2003;124(3 suppl):33S-39S.

Prothrombin Plasminogen

Thrombin Plasmin

APC TAFIa

TAFIPC

CoagulationCascade

FibrinolyticCascade

ThrombinThrombomodulin

Fibrinogen Fibrin FDPs

– –

36

Fibrinolysis (cont)

Antifibrinolytic Agents

Tip the balance against fibrinolysis More clot Less bleeding

Prothrombin Plasminogen

Thrombin Plasmin

APC TAFIa

TAFIPC

CoagulationCascade

FibrinolyticCascade

ThrombinThrombomodulin

Fibrinogen Fibrin FDP’s

– –

Adapted from Nesheim M. Chest. 2003;124:33S-39S.

37

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

38

Lysine Analogues

• Block the lysine- binding 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.

39

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.

40

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

41

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)

42

Some Topical Hemostatic Agents

Voils S. Pharmacotherapy. 2007;27:69S-84S.

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

43

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.

44

Some Topical Hemostatic Agents (cont)

Gabay M. Am J Health-Syst Pharm. 2006;63:1244-1253.

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

45

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.

46

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.


Indications (cont)

47

Considerations

• Efficacy: Few randomized controlled trialsstudies 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

48

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.

49

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.

50

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

51

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.

52

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

53

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)

54

Mechanism of Action


55

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.

56

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.

57

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


58

Monitoring of Treatment

• Primarily, clinical evaluation of hemostasis

• Lab testsNo 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)

59

Adverse Reactions

Seems to be well tolerated (298 hemophilia A or B patientswith inhibitors)

Body System Event

No. of episodes reported(n=1939 treatments)

No. of unique patients(n=298)

Body as a whole FeverPlatelets, Bleeding, and Clotting Hemorrhage NOS Fibrinogen plasma decreasedSkin and Musculoskeletal HemarthrosisCardiovascular Hypertension

16

1510

14

9

13

85

8

6

NovoSeven [package insert]. Princeton, NJ: Princeton, NJ: Novo Nordisk Pharmaceuticals; September 1999.

60

“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-traumarelated (hepatic resection,

prostatectomy, cardiac, spinal)

• These off-label uses are mostly based on anecdotal case reports Need better evidence

61

“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 off-label

uses can easily run into millions of dollars in hospitals

• Only few randomized controlled trials This is changing

62

Trial Title Study Design Phase

Total Enrollmen

tExpected

Completion

"Salvage Use" of Recombinant Activated Factor VII After Inadequate Haemostatic Response to Conventional Therapy in Complex Cardiac Surgery

Multicenter, Treatment, Randomized, Double-Blind, Placebo-Control, Parallel Assignment, Safety/Efficacy Study

Phase 3 40 June 2008

Evaluation of the Quality of the NovoSeven (rFVIIa) Treatment Practice at Rigs hospital, Copenhagen University Hospital

Natural History, Longitudinal, Defined Population, Retrospective/ Prospective Study

?? ?? December 2010

Effect of Recombinant Coagulation Factor VIIa on Peri-Operative Blood Loss in Patients Undergoing Major Burn Excision and Grafting

Randomized, Double-Blind (Subject, Caregiver,Investigator) Placebo-Control, Parallel Assignment, Efficacy Study

Phase 3 52 December 2009

Efficacy and Safety of Factor VIIa (Eptacog Alfa) on Rebleeding After Surgery for Spontaneous Supratentorial Intracerebral Hemorrhage.

Randomized, Controlled, Open-Label, Investigator-Blinded Pilot Study

Phase 2 30 January 2008

US National Institutes of Health. ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed February 10, 2008.

Current Ongoing Global Trials

63

Trial Title Study Design Phase

Total Enrollmen

tExpected

Completion

"Salvage Use" of Recombinant Activated Factor VII After Inadequate Haemostatic Response to Conventional Therapy in Complex Cardiac Surgery

Multicenter, Treatment, Randomized, Double-Blind, Placebo-Control, Parallel Assignment, Safety/Efficacy Study

Phase 3 40 June 2008

Effect of Recombinant Coagulation Factor VIIa on Peri-Operative Blood Loss in Patients Undergoing Major Burn Excision and Grafting

Randomized, Double-Blind (Subject, Caregiver, Investigator) Placebo-Control, Parallel Assignment, Efficacy Study


Efficacy and Safety of Factor VIIa on Rebleeding After Surgery for Spontaneous Intracerebral Hemorrhage (ICH) (PRE-SICH).

Randomized, Controlled, Open-Label, Investigator-Blinded Pilot Study

Phase 2 30 January 2008

Current Ongoing Global Trials (cont)


64

Trial Title Study Design PhaseTotal

EnrollmentExpected

Completion

Recombinant Human Activated Factor VII as Salvage Therapy in Women With Severe Postpartum Hemorrhage

Randomized, Open-Label, Active Control, Parallel Assignment, Safety/Efficacy Study


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, Single-Blind, 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, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Phase 3 1502 Recruiting


Current Ongoing Global Trials (cont)

65

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.

66

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?

67

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”

68

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

69

Specialty-Specific Clinical Cases

More Opportunities to Decide …

What You Would Do Next!

70

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) Labsnormal 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


71

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


72

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


73

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


74

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


75

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


strategies for preventing and treating uncontrolled perioperative bleeding

Documents

death slide

primary hemostasis

n engl j

types of surgery surgery

surgical intervention

ann intern

vincent j

death clotting