Achieving Perioperative Hemostasis
Jay Kambam, MD, FACA
Chief, Cardiac Anesthesia
James A. Haley VA Medical Center
Tampa, FL
&
Adjunct Professor of Anesthesiology
USF, Tampa, FL &
Vanderbilt University Medical Center
Nashville, TN
May 15, 2012
PERIOPERATIVE HEMOSTASIS
• Normal hemostasis is a complex interaction between
vessel wall, platelet function, plasmatic coagulation,
and fibrinolysis.
• Causes of perioperative coagulopathy and bleeding are
multifactorial
• Because of PCI and Stents, multiple antiplatelet drugs
and thrombin inhibitors are increasingly being used
• Understanding the details of perioperative hemostasis
and pharmacodynamics of drugs involving hemostasis
is essential
Jay kambam
• Blood must be fluid
• Must coagulate (clot) at appropriate time
– Rapid
– Localized
– Reversible (fibrinolysis)
Thrombosis…inappropriate coagulation
(Examples: DVT, Stent Thrombosis)
Jay kambam
HEMOSTASIS:
3 Major systems involved
• Vessel wall
Endothelin
• Platelets
Adhesion, Activation, Aggregation (AAA)
• Coagulation cascade
Coagulation factors
Plasmin
FSP
Jay kambam
Vessel Injury
Collagen, vWF
Endothelin
Platelet-fibrin clot
FSP
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VESSEL WALL - ENDOTHELIUM
VESSEL WALL - ENDOTHELIUM
Vessel injury or FB/Stent, low flow
Antithrombogenic
(Favors fluid blood)
Anticoagulants
Thrombogenic
(Favors clotting)
Procoagulants
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VESSEL WALL
Endothelin, Collagen, tPAI,
vWF, Factors, PL
Prostacyclin, NO, ADPase, tPA,
Heparin, Thrombomodulin
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Antithrombotic Properties of
Endothelium
 Covers highly thrombogenic basement
membrane
 Uninjured endothelium does not bind platelets
 PGI2 (prostacyclin) and NO from uninjured
endothelium inhibit platelet binding (anti-Txa2)
 ADPase counters the platelet aggregating
effects of ADP
Jay kambam
Antithrombotic Properties of the Endothelium
 Heparin like molecules: activate anti-thrombin III
 Thrombomodulin (glycoprotein) - Antithrombin
– Binds to thrombin
– Decreases ability to produce fibrin
– Increases ability to activate Protein C, which inactivates factors Va
and VIIIa
 Endothelial cells produce tPA which activates fibrinolysis via
plasminogen to plasmin
Jay kambam
Prothrombotic Properties of
Endothelium
 Synthesis of von Willebrand factor (vWF)
 Release of collagen & tissue factor (FIII)
 Production of plasminogen activator inhibitors (tPAI)
 Membrane phospholipids bind and facilitate activation of
++
clotting factors via Ca bridges
VASOCONSTRICTION
Serotonin causes
vasoconstriction
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Dense Granule
Alpha Granule
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Contents of platelet secretary granules and
their physiological activities
Secretary Granules
Physiological activities
Coagulation factors I & V
Platelet specific proteins
Platelet F4
Cofactors for coagulation cascade
Low affinity PF4
Glycoproteins
PF4 potentiates ADP induced aggregation &
antiheparin activity
LA-PF4 possesses antiheparin actvty
Adhesion and cell to cell interaction
ADP and ATP
ADP stimulates aggregation & secretion
Calcium
Serotonin
Promotes coagulation
Vasoconstriction
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Adhesion, Activation, Aggregation (AAA)
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PLATELET FUNCTION
AGGREGATION
 GPIIb/IIIa - fibrinogen interaction
 Key step for hemostasis, part of final
common pathway
 Therapeutic target of inhibitors
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Platelet Activation Pathways
Arachidonic
acid
TxA2
GP IIb/IIIa
Fibrinogen
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Vessel Injury
Collagen, vWF
Endothelin
Platelet-fibrin clot
FSP
Jay kambam
Factor
Trivial Name(s)
Pathway: Intrinsic/Extrinsic
I
Fibrinogen
Both
II
Prothrombin
Both
III
Tissue Factor
Extrinsic
IV
Calcium
Both
V
Proaccelerin, labile factor, accelerator
(Ac-) globulin
Both
VI (same as Va)
Accelerin
Both
VII
Proconvertin, serum prothrombin
conversion accelerator (SPCA),
cothromboplastin
Extrinsic
VIII
Antihemophiliac factor A,
antihemophilic globulin (AHG)
Intrinsic
IX
Christmas Factor, antihemophilic factor
B,plasma thromboplastin component
(PTC)
Intrinsic
X
Stuart-Prower Factor
Both
XI
Plasma thromboplastin antecedent
(PTA)
Intrinsic
XII
Hageman Factor
Intrinsic
XIII
Protransglutaminase, fibrin stabilizing
factor (FSF), fibrinoligase
Both
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XIIa
XIa
TF IIIa
Prothrombin II
VIII
IXa
VIIIa
VIIa
V
Fibrinogen I
Thrombin IIa
Soft clot
Fibrin
XIIIa
Hard clot
Fibrin
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FINAL STEPS - COAGULATION
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Platelet-Fibrin clot
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Minimum Fibrinogen Levels
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CRYOPRECIPITATE
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Transfusion-associated
Circulatory Overload (TACO)
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FIBRINOLYSIS
Fibrinolysis
Plasminogen
tPA (Tissue Plasminogen Activator)
Fibrin
Plasmin
Fibrin Split Products (FSP)
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FIBRINOLYSIS
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Antifibrinolytics
Lysine Analog
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€
Aminocaproic acid & Tranexamic acid
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(Angiomax)
(Refludan),
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ANTIPLATELET DRUGS - Mechanisms
 Aspirin
-
Thromboxane A2 Inhibitors
 Clopidogrel (Plavix)
 Prasugrel (apagrel)
 Ticlopidine (Ticlid)
Thienopyridines
 Aggrastat (tirofiban)
 ReoPro (abciximab)
 Integrilin (eptifibatide)
GP IIb/IIIa Antagonists
P2Y12/ADP
Receptor Inhibitors
Jay kambam
Antiplatelet Drugs: Inhibition of
activation &/or aggregation
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ASPIRIN
•
•
•
•
•
•
Inhibition of Thromboxane A2 production
Orally administered
Rapidly absorbed from GIT
Peak levels observed in about 30 minutes
Irreversible COX type 1 inhibitor
Chew and do!
Jay kambam
TICLOPIDINE,
CLOPIDOGREL & PRASUGREL
•
Antiplatelet agents are used to treat, prevent arterial
thrombosis.
•
Thienopyridine derivatives, inactive in vitro, requiring
metabolism to achieve in vivo activity.
•
Inhibit binding of ADP to platelet receptor(P2Y12).
Jay kambam
CLOPIDOGREL
Prodrug (Thienopyridine)
Administered only orally
No direct antiplatelet activity
Metabolized in the liver
Active metabolite inhibits platelet aggregation
Peak concentration of active metabolite is seen in 1 -2 hrs
Metabolite binds to platelet P2Y12 receptor and
irreversibly inhibits ADP-induced platelet aggregation
Jay kambam
PRASUGREL








Prodrug (Thienopyridine)
Ten to 100 times more potent than clopidogrel
Administered only orally
No direct antiplatelet activity
Metabolized in the liver more rapidly (levels 2 times higher)
Faster activity
Active metabolite inhibits platelet aggregation
Peak concentration of active metabolite is seen in 0.5 hr
 Metabolite binds to platelet P2Y12 receptor and
irreversibly inhibits ADP-induced platelet aggregation
Jay kambam
PLATELET INHIBITORS
 Aspirin
-
Thromboxane A2 Inhibitors
 Clopidogrel (Plavix)
 Prasugrel (apagrel)
 Ticlopidine (Ticlid)
Thienopyridines
 Aggrastat (tirofiban)
 ReoPro (abciximab)
 Integrilin (eptifibatide)
GP IIb/IIIa Antagonists
P2Y12/ADP
Receptor Inhibitors
Jay kambam
Gp IIb/IIIa ANTAGONISTS
• Platelet Gp IIb/IIIa receptors play a
pivotal role in platelet-mediated
thrombus formation, binding to
fibrinogen,vWF & Collagen
• IIb/IIIa antagonists differ in receptor
affinity, reversibility, and specificity
• GpIIb/GpIIIa antagonists more
completely inhibit platelet aggregation
than do ASA and Theinopyridines
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Jay kambam
Platelet Activation Pathways
Arachidonic
acid
TxA2
GP IIb/IIIa
Fibrinogen
Jay kambam
GP IIb/IIIa Antagonists:
Tirofiban (Aggrastat)
Eptifibatide (Integrelin)
Abciximab (ReoPro)
GP IIb/IIIa
antagonist
Inhibition of platelet aggregation
GP IIb/IIIa receptors occupied by antagonists
Agonist
ADP, thrombin,
collagen, epi
Inactive platelet
GP IIb/IIIa
Active Platelet
receptors in
unreceptive state
Aggregating platelets
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Glycoprotein IIb/IIIa inhibitors
Tirofiban (Aggrastat)
• Nonpeptide
• KD 15 nmol/L
• Indication: acute coronary syndrome
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Glycoprotein IIb/IIIa inhibitors
Eptifibatide (Integrelin)
• Cyclic peptide
• KD 120 nmol/L
• Acute coronary syndrome
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Glycoprotein IIb/IIIa inhibitors
Abciximab (ReoPro)
• Human/murine chimeric
monoclonal antibody Fab
• KD 5 nmol/L
• Indication: PCI
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Anticoagulant and Antiplatelet Drugs
• Platelets
Primary Hemostasis Plug
Antiplatelet Drugs:
TxA2 Inhibitors: ASA
Thienopyridines: Clopidogrel, Prasugrel, Ticlopidine;
GP IIb/IIIa Antagonists: Tirofiban (Aggrastat), Eptifbatide (Integrelin), Abciximab
(ReoPro)
Jay kambam
Anticoagulants:
Direct & indirect
antithrombin drugs
Jay kambam
ANTICOAGULANTS
Indirect Thrombin Inhibitor Drugs:
• Vitamin K antagonists, Coumadin (in vivo only)
• Ca++ chelators (in vitro only)
– EDTA, Citrate, Oxalate
• Heparin (in vivo and in vitro)
Direct Thrombin Inhibitor Drugs:
 Bivalirudin (Refludan), Lepirudin (Angiomax), Argatroban (Acova)
 Dabigatran (Pradaxa)*
Jay kambam
Role of vitamin K
Some clotting factors require a post-translational
modification (PTM) before they are active in clotting
These factors are II, VII, IX, X
This PTM involves the addition of a COO- to
certain Glu residues in the clotting factors
This PTM results in the formation of several g-carboxy
glutamates = Gla
This PTM requires vitamin K
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HEPARIN - SOURCES
•
•
•
•
•
Lungs
Liver
Intestinal mucosa
Mast cells of RES
Bovine and Porcine
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HEPARIN - STRUCTURE
 One of the strongest acids
 Heavily sulfated polyanionic mucopolysaccharide
 Mol Wt: 6000-25000 Daltons
 Similar to nucleic acids (Phosphates)
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HEPARIN - PROPERTIES
Action begins immediately
Peaks in 2 - 5 min
Distribution volume - small (plasma, RES)**
Dose: Adult 3-4mg/kg; Child: 1-3mg/kg
Duration of action - 60-90 min in normothermic
bypass; prolonged with hypothermia
Acute Side effects: vasodilatation
** ideal body weight
Jay kambam
HEPARIN - MECHANISM OF ACTION
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HEPARIN RESISTANCE
Possible causes:
•
•
•
•
•
•
•
•
•
a . ATIII deficiency (congenital or acquired)
b. Arteriosclerotic disease
c. Septicemia
d. Pregnancy
e. Birth control pills
f. Liver disease
g. Prolonged anticoagulant therapy
h.Thrombocytosis
i. Nephrotic Syndrome
Jay kambam
HEPARIN RESISTANCE
• Since the likely cause is ATIII deficiency:
the treatment options are:
– Give ATIII 50 units /kg
– and or 2-4 units of FFP
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Heparin Induced Thrombocytopenia
(HIT Syndrome)
Immune-mediated allergic reaction to heparin/platelet factor 4 complex
Thrombocytopenia:
Platelet count <150,000 or a 30% to 50% drop from baseline during heparin exposure
Onset 5 to 14 days after initiating heparin but can be earlier or later
With or without thrombotic complications at presentation

Diagnosis is clinical
Any type of heparin or route of administration can lead to HIT
Jay kambam
Temporal Patterns of
Thrombocytopenia in HIT
Heparin (re) Exposure
Rapid-onset
HIT
(hours-days)
Day 1
Typical-Onset HIT
Mean day 9
(5-14 days)
Day 5
DelayedOnset HIT
(9-40+ days)
Day 14
Day 30
THROMBOCYTOPENIA (± THROMBOSIS)
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HIT occurs in up to 5% of patients receiving
unfractionated heparin (UFH)
Up to 1% incidence with low molecular weight
heparin (LMWH)
Mortality rate of 22% to 28% has been reported in
patients with HIT associated with thrombosis not
treated with alternative anticoagulation.
Jay kambam
HEPARIN ALTERNATIVES
Direct Thrombin Inhibitors
•
•
•
•
Bivalirudin (Refludan)
Lepirudin (Angiomax)
Argatroban (Acova)
The best choice depends on patient’s
health status (hepatic or renal function)
• Dabigatran (Pradaxa)*
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Diagnosis and Management
Decisions for HIT
• Current or recent heparin exposure with
thrombocytopenia
• Presence of thrombosis or other
characteristic sequelae
• If HIT is suspected, discontinue all forms of
heparin IMMEDIATELY: Initiate alternative
anticoagulant, as indicated
Jay kambam
Dabigatran (Pradaxa)
Direct thrombin inhibitor-oral anticoagulant, Half Life: 13-27hrs,
 Does not require frequent blood tests for International normalized Ratio (INR)
monitoring
 Not highly protein bound, excreted 80% via kidneys & 20% via bile, partially through
hemodialysis
 There is no specific way to reverse the anticoagulant effect of dabigatran in the event of
a major bleeding event, unlike warfarin.
 Dosage upto 150 mg twice daily?
 The (FDA) approved Pradaxa on October 19, 2010, for prevention of stroke in
patients with non-valvular atrial fibrillation
 On February 14, 2011, the ACC & AHA added dabigatran to their guidelines for
managment of non-valvular atrial fibrillation with a class I recommendation
 aPTT (activated partial thromboplastin time), ECT (Ecarin clotting time), TT (Thrombin time)
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Dabigatran Discontinuation before surgery
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Vessel Injury
Collagen, vWF
Endothelin
Platelet-fibrin clot
FSP
Jay kambam
(Angiomax)
(Refludan),
Jay kambam
Perioperative Hemostasis
Optimize coagulation & reduce fibrinolysis
Normal hemostasis is a complex interaction between
vessel wall, platelet function, plasmatic coagulation,
and fibrinolysis.
Causes of perioperative coagulopathy and bleeding are
multifactorial – Not addressed in this lecture
Fibrinogen is in the key position of coagulation
cascade and fibrinolytic pathway.
Understanding the process of perioperative hemostasis
and pharmacodynamics of drugs involving hemostasis
is essential
Jay kambam
Stupid Monkey drinking my coffee
@Kilimanjaro, Kenya
HISTORICAL ACHIEVEMENTS
DATE
ACHIEVEMENT
Miescher - 1868
Kossel - 1896
McClean - 1916
Hagedorn - 1930’s
Jaques, McCutcheon - 1930’s
Chargoff, Olson - 1937-38
Walther - 1939
Jaques - 1949
Hersley - 1966
Jaques - 1973
Discovered protamine in salmon
gonads
Isolated protamines from various
kinds of fish
Discovered heparin’s
anticoagualtion action
Made long-acting insulin with
protamine
Produced heparin-protamine
complex
Discovered heparin’s antidote
Reported protamine’s adverese
effects
Poineered study of protamine’s
toxic effects
Developed ACT test
Developed hep-prot titration test
2. Changes Affecting Platelet
Aggregation:
a) Decreased ability of Platelet
Aggregation to Agonists
b) Platelets are Activated by CPB (2030% Spent)
c) Platelets bind to Monocytes and
Neutrophils
3. Changes Affecting Clot resistance
to Clot lysis by Plasmin:
Preactivation of Platelets Leads to Depletion
of Plasmin Inhibitors (stored in platelets)
which are Critical to protecting the clot from
lysis by the Plasmin
TICOLPIDINE/CLOPIDOGREL
 In CAD stenting, ticlopidine reduces risk for
subacute stent thrombosis
 Clopidogrel reduces ischemic events with recent
MI, stroke, or PVD
 Clopidogrel + aspirin in stenting, is rapidly
growing, given before stenting procedure
 Bleeding variability for cardiac surgery relates to
the duration of therapy
Heparin Manufacturing Process
• Combine 5000 lbs intestines, 200 gallons water, 10 gallons
chloroform, and 5 gallons toluene. Hold at 900 F for 17 hrs.
• Add 30 gallons acetic acid, 35 gallons ammonia, sodium hydroxide
to adjust pH, and 235 gallons water. Bring to a boil then filter.
• Add 200 gallons hot water to filtrate and allow to stand overnight,
then skim off the fat.
• Keep pancreatic extract at 1000F for three days, then bring to boil.
• Filter solids and assay for heparin content.
Heparin source comparison
BOVINE LUNG
Cost
Less
Mol Wt (Daltons)
5000-20,000
Chemical structure
Shorter chains
Platelet aggregation
++
Thrombin inhibition
Less
Factor aX inhibition
More
Post op bleeding
More
Protamine requirement
Less
Delayed thrombocytopenia ++
PORCINE MUCOSAL
More
6000-30,000
Longer chains
+
More
Less
Less
More
+
Bivalirudin (Refludan)
•
•
•
•
•
Half Life 25 min
Reversal: None
Metabolism: Renal > Hepatic
Monitoring ACT, ECT (Ecarin Clotting Time )
Dosage 1.5 mg/kg bolus, then continuous infusion
at 2.5 mg/kg /h
• Other: Titrate ACT > 500
Lepirudin (Angiomax)
•
•
•
•
•
•
Half life: 30 min
Reversal: None
Metabolism: Hepatic > Renal
Monitoring PTT, ACT
Dosage 0.1 mg /kg bolus then 5-10 ug/kg/min
Other: Incidence of Hypercoagulable state after
DC the continuous infusion
Argatroban (Acova)
•
•
•
•
•
•
Half life 80 min
Reversal: None
Metabolism: Renal
Monitoring PTT, ECT (Ecarin Clotting Time)
Dosage 0.25 mg/kg , then 0.5 mg /min infusion
Other: Increase incidence of post-op bleeding.
Incidence of anaphylaxis with the second exposure