Antifibrinolytic Therapy for

Y2K+1
Ray Tople, M.D.
Anesthesia and Operative Service
BAMC
 Introduction

• Hemostasis
• Bleeding complications with CT surgery
• Antifibrinolytic therapy
Hemostasis
• How does this work
again?
– Surgical hemostasis
– Vascular reactivity
– Platelet activity
– Coagulation
– Fibrinolysis
Surgical Hemostasis
• Repair vascular
trespass with suture
• Electrocautery
Vascular Reactivity
• Local vasoconstriction
• Adjacent arteriole
dilation
Platelet Activity
• Platelet adherence to
endothelium
• Platelet transformation
• Release reaction
• Platelet aggregation
• Contact activation
Platelet Activity
 Coagulation Cascade
• Proenzymes
• Activation
• Chain reaction of
serine proteases
• Formation of fibrin
from fibrinogen
• Organization of fibrin
Coagulation Cascade
 Fibrinolysis
• Conversion of
plasminogen to
plasmin
• Plasmin degradation
of fibrin clot
• Inactivation of
plasmin by alpha-2
antiplasmin
 Fibrinolysis
• Extrinsic
– t-PA, u-PA (from
endothelial cells)
– activity magnifies in
presence of fibrin
– released by epi,
bradykinin, thrombin,
factor Xa, CPB
 Fibrinolysis
• Intrinsic
– Factor XIIa cleaves
plasminogen to
plasmin
– Kallikrein may also
activate plasminogen
 Fibrinolysis
• Exogenous Activation
– Streptokinase
(bacteria)
– Urokinase (human
urine)
– Activate plasminogen
with low fibrin affinity
so systemic fibrinolysis
ensues
Fibrinolytic Pathway
Cardiothoracic Surgery

The Bleeding Patient

or
“A day in OR 7”
 Excessive Bleeding
• Chest tube drainage of:
– > 10 cc/kg in first hour or
– > 20 cc/kg in first 3 hours postoperatively or
– any increase of 300 cc/hr or more following
minimal output
• Indicates anatomic disruption warranting
surgical intervention
Causes of Postoperative Bleeding
• Patient factors
• CPB insult
• Hypothermia
• Inadequate repair of
vascular trespass
 Patient Factors
• Inherited disorders of coagulation
• Systemic disease
– Hepatic/Renal/Splenic
• Medication induced
– Platelet inhibitors, anticoagulants,
thrombolytics
 Insult of Cardiopulmonary
Bypass
• Platelet dysfunction
• Clotting factors
• Hypothermia
• Fibrinolysis
 Platelet Dysfunction
• Hemodilution
• Hypothermia-induced sequestration
• Platelet destruction from CPB (suction,
filters, oxygenators)
• Partial activation by fibrinogen/fibrin along
circuit
 Clotting Factors
• Denaturation of plasma proteins
(cardiotomy suction, oxygenators)
• Hemodilution
 Hypothermia
• Sequestration of platelets
• Platelet dysfunction (shape, inhib ADP dep
adhesiveness)
• Increased activity of a heparin-like inhibitor
of factor Xa
• Slows cleavage of coagulation factors
• Accentuates fibrinolysis
 Fibrinolysis
• Thrombin activation of fibrinolysis
secondary to thrombogenic surface of CPB
• Plasminogen activators increase
• Mostly occurs extravascularly
• Usually has little clinical impact
• If fibrin degradation products accumulate,
they may impair systemic hemostasis
Antifibrinolytics
• Synthetic lysine
analogs
– epsilon aminocaproic
acid (EACA)
– tranexamic acid (TA)
• Naturally occurring
protease inhibitor
– Aprotinin
 Lysine Analogs
• Bind to plasminogen
and plasmin, blocking
ability of fibrinolytic
enzymes to bind to
lysine residues of
fibrinogen
• Excreted renally
• Half-life of 80 min
Aprotinin
• Inhibits plasminogen,
plasmin, and kallikrein
• Derived from bovine
lung
• Incid of anaphylaxis
1/1000
• Prolongs celite-ACT,
use kaolin-ACT
Antifibrinolytics
 Efficacy
• After Bypass
– EACA/TA found to decr bleeding by 15%,
however no data in “bleeding” patients
– Aprotinin - no role in “bleeding” patient
• Before Bypass
– EACA/TA - decr bleeding by 30-40%
– Aprotinin - decr bleeding by 40-50%
Antifibrinolytic Comparisons
 Whole Blood Harvest + TA vs.
TA vs. Aprotinin
• Pre-bypass harvest of whole blood provides
unaffected platelets (“platelet sparing”)
• Prospective, randomized, partially blinded
study shows equivalent effectiveness as full
dose aprotinin with greatly reduced cost
(decr EBL and transfusion requirements)
 Safety of Antifibrinolytics
• Prospective studies regarding risk of
thrombotic complications have shown all
three to be safe
• Most avoid in patients with demonstrated
consumptive coagulopathy or high urinary
tract bleeding
• Infusion rates should be adjusted for renal
insufficiency
 Cost of Antifibrinolytics at
BAMC as of Jan 2000
• Amicar
– Approximately $15/case
• Transexamic acid
– Approximately $35/case
• Aprotinin
– Full dose approximately $650/case
 Summary
• No significant difference in requirement of
transfusions between TA/EACA/Aprotinin
• Less bleeding with aprotinin, has anti-
inflammatory effect
• Cost aprotinin >> TA > EACA
• So…EACA is drug of choice for most CABG’s
(esp if primary CABG)
• Consider alternative if higher risk patient
Questions or comments?