Achieving Perioperative Hemostasis

Jay Kambam, MD, FACAChief, Cardiac Anesthesia

James A. Haley VA Medical CenterTampa, FL

&Adjunct Professor of Anesthesiology

USF, Tampa, FL &Vanderbilt University Medical Center

Nashville, TN

May 15, 2012

NO DISCLOSURES

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

Hemostasis

• Blood must be fluid• Must coagulate (clot) at appropriate time

– Rapid– Localized– Reversible (fibrinolysis)

Thrombosis…inappropriate coagulation

(Examples: DVT, Stent Thrombosis)

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HEMOSTASIS:3 Major systems involved

• Vessel wall vasoconstriction Endothelin

• Platelets First Hemostasis Plug

Adhesion, Activation, Aggregation (AAA)

• Coagulation cascade Second Hemostasis Plug

Coagulation factors Plasmin

FSP

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PLATELET ADHESION

VASOCONSTRICTION INITIAL RELEASE REACTION ADP

SEROTONIN PLATELET AGGREGATION

PHOSPHOLIPIDS INCREASED RELEASE REACTION ADP

COAGULATION

SECOND HEMOSTATIC PLUG FIRST HEMOSTATIC PLUG

(FIBRIN PLUG) (PLATELET PLUG)

HemostasisVessel Injury

Platelet-fibrin clot FSP

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EndothelinCollagen, vWF

VESSEL WALL - ENDOTHELIUM

Antithrombogenic Thrombogenic

Vessel injury or FB/Stent, low flow

(Favors fluid blood) (Favors clotting)

Anticoagulants Procoagulants

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VESSEL WALL - ENDOTHELIUM

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VESSEL WALL

Endothelin, Collagen, tPAI, vWF, Factors, PLProstacyclin, NO, ADPase, tPA, Heparin, Thrombomodulin

Antithrombotic Properties of Endothelium

Anti-platelet properties

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

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Antithrombotic Properties of the Endothelium Anticoagulant & Fibrinolytic properties

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

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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

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VASOCONSTRICTION

Serotonin causes vasoconstriction

First Hemostasis Plug

PLATELETS

Alpha Granule

Dense Granule

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Contents of platelet secretary granules and their physiological activities

Secretary Granules Physiological activities1.Alpha Granules

Coagulation factors I & V Cofactors for coagulation cascade

Platelet specific proteins

Platelet F4 PF4 potentiates ADP induced aggregation & antiheparin activity

Low affinity PF4 LA-PF4 possesses antiheparin actvty

Glycoproteins Adhesion and cell to cell interaction

2.Dense Granules

ADP and ATP ADP stimulates aggregation & secretion

Calcium Promotes coagulation

Serotonin Vasoconstriction

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Adhesion, Activation, Aggregation (AAA)

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PLATELET FUNCTION AGGREGATION

GPIIb/IIIa - fibrinogen interactionKey step for hemostasis, part of final

common pathwayTherapeutic target of inhibitors

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Platelet Activation Pathways

Arachidonicacid

TxA2

GP IIb/IIIa

Epine

phrin

e

Collagen ThrombinADP

P2Y12

PAR-4

GP1b

vWF

FibrinogenJay kambam

Jay kambam

Second Hemostasis PlugPLASMATIC COAGULATION

PLATELET ADHESION

VASOCONSTRICTION INITIAL RELEASE REACTION ADP

SEROTONIN PLATELET AGGREGATION

PHOSPHOLIPIDS INCREASED RELEASE REACTION ADP

COAGULATION

SECOND HEMOSTATIC PLUG FIRST HEMOSTATIC PLUG

(FIBRIN PLUG) (PLATELET PLUG)

HemostasisVessel Injury

Platelet-fibrin clot FSP

Jay kambam

EndothelinCollagen, vWF

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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Fibrinogen I FibrinThrombin IIa

Prothrombin II

XaVa

VIIa

TF IIIa

Extrinsic Pathway (PT)

IXa

VIIIa

XIa

XIIa

Intrinsic pathway (PTT)

XIIIa

Soft clot

Fibrin

Hard clot

VVIII

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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

Fibrin Fibrin Split Products (FSP)Plasmin

Plasminogen

tPA (Tissue Plasminogen Activator)

Fibrinolysis

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FIBRINOLYSIS

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Antifibrinolytics

Lysine Analog

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€Aminocaproic acid & Tranexamic acid

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Anticoagulant and Antiplatelet Drugs

Anticoagulant and Antiplatelet DrugsMechanism of action

• Platelets Primary Hemostasis Plug

Antiplatelet Drugs:

TxA2 inhibitors: ASA

Thienopyridines (P2Y12/ ADP receptor Inhibitors ): Clopidogrel (plavix), Prasugrel (apagrel),

Ticlopidine (Ticlid)

GP IIb/IIIa Antagonists: Tirofiban (Aggrastat), Eptifibatide (Integrelin), Abciximab (ReoPro)

• Coagulation cascade Secondary Hemostasis Plug

Anticoagulants :

Indirect Thrombin Inhibitors: Coumadin, Heparin

Direct Thrombin Inhibitors: Lepirudin (Angiomax), Argatroban, Bivalirudin (Refludan), Dabigatran

(Pradaxa)Jay kambam

ANTIPLATELET DRUGS - Mechanisms

Aspirin - Thromboxane A2 Inhibitors

Clopidogrel (Plavix)

Prasugrel (apagrel) Thienopyridines

Ticlopidine (Ticlid)

Aggrastat (tirofiban)

ReoPro (abciximab) GP IIb/IIIa Antagonists Integrilin (eptifibatide)

P2Y12/ADPReceptor Inhibitors

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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!

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Thienopyridines: 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).

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CLOPIDOGREL

Prodrug (Thienopyridine)Administered only orallyNo direct antiplatelet activityMetabolized in the liverActive metabolite inhibits platelet aggregationPeak concentration of active metabolite is seen in 1 -2 hrsMetabolite binds to platelet P2Y12 receptor and irreversibly inhibits ADP-induced platelet aggregation

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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

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PLATELET INHIBITORS

Aspirin - Thromboxane A2 Inhibitors

Clopidogrel (Plavix)

Prasugrel (apagrel) Thienopyridines

Ticlopidine (Ticlid)

Aggrastat (tirofiban)

ReoPro (abciximab) GP IIb/IIIa Antagonists Integrilin (eptifibatide)

P2Y12/ADPReceptor Inhibitors

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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

Arachidonicacid

TxA2

GP IIb/IIIa

Epine

phrin

e

Collagen ThrombinADP

P2Y12

PAR-4

GP1b

vWF

FibrinogenJay kambam

Inactive platelet GP IIb/IIIa receptors in

unreceptive state

Inhibition of platelet aggregation

GP IIb/IIIa receptors occupied by antagonists

Agonist

ADP, thrombin, collagen, epi

GP IIb/IIIa antagonist

Fibrinogen

Aggregating platelets

GP IIb/IIIa Antagonists:Tirofiban (Aggrastat) Eptifibatide (Integrelin) Abciximab (ReoPro)

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Active Platelet

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)

• Coagulation cascade Secondary Hemostasis Plug

Anticoagulants: Indirect Thrombin Inhibitors: Coumadin, Heparin

Direct Thrombin Inhibitors: Lepirudin, Argatroban, Bivalirudin, Dabigatran Jay kambam

Anticoagulants:Direct & indirect antithrombin drugs

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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 - PROPERTIESAction begins immediatelyPeaks in 2 - 5 minDistribution volume - small (plasma, RES)**

Dose: Adult 3-4mg/kg; Child: 1-3mg/kgDuration of action - 60-90 min in normothermic

bypass; prolonged with hypothermia

Acute Side effects: vasodilatation

** ideal body weight

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HEPARIN - MECHANISM OF ACTION

• Heparin is not a direct anticoagulant• Heparin activates antithrombin III• Heparin + antithrombin III (Beta Globulin)

Heparin-antithrombin III complex (HATC)• HATC induces anticoagulation by inhibiting four

coagulation activating factors (aII, aIX, aX, and aXI). HATC, in particular, inhibits thrombogenic actions of activated thrombin (aII) and factor X (aX)

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HEPARIN RESISTANCE

• Heparin resistance is usually defined as failure to achieve a target ACT (>450 seconds) after administration of heparin up to 6 mg or 600 units/Kg body weight.

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

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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 complexThrombocytopenia:

Platelet count <150,000 or a 30% to 50% drop from baseline during heparin exposureOnset 5 to 14 days after initiating heparin but can be earlier or laterWith or without thrombotic complications at presentation

Diagnosis is clinicalAny type of heparin or route of administration can lead to HIT

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Temporal Patterns of Thrombocytopenia in HIT

Day 1 Day 5 Day 14 Day 30

Delayed-Onset HIT

(9-40+ days)

Rapid-onset HIT

(hours-days)

Typical-Onset HITMean day 9(5-14 days)

Heparin (re) Exposure

THROMBOCYTOPENIA (± THROMBOSIS)

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Incidence of HIT

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.

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HEPARIN ALTERNATIVESDirect 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

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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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PLATELET ADHESION

VASOCONSTRICTION INITIAL RELEASE REACTION ADP

SEROTONIN PLATELET AGGREGATION

PHOSPHOLIPIDS INCREASED RELEASE REACTION ADP

COAGULATION

SECOND HEMOSTATIC PLUG FIRST HEMOSTATIC PLUG

(FIBRIN PLUG) (PLATELET PLUG)

HemostasisVessel Injury

Platelet-fibrin clot FSP

Jay kambam

EndothelinCollagen, vWF

Anticoagulant and Antiplatelet DrugsMechanism of action

• Platelets Primary Hemostasis Plug

Antiplatelet Drugs:

TxA2 inhibitors: ASA

Thienopyridines (P2Y12/ ADP receptor Inhibitors ): Clopidogrel (plavix), Prasugrel (apagrel),

Ticlopidine (Ticlid)

GP IIb/IIIa Antagonists: Tirofiban (Aggrastat), Eptifibatide (Integrelin), Abciximab (ReoPro)

• Coagulation cascade Secondary Hemostasis Plug

Anticoagulants :

Indirect Thrombin Inhibitors: Coumadin, Heparin

Direct Thrombin Inhibitors: Lepirudin (Angiomax), Argatroban, Bivalirudin (Refludan), Dabigatran

(Pradaxa)Jay kambam

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

Perioperative HemostasisOptimize coagulation & reduce fibrinolysis

Stupid Monkey drinking my coffee@Kilimanjaro, Kenya

HISTORICAL ACHIEVEMENTSDATE ACHIEVEMENT Miescher - 1868 Discovered protamine in salmon

gonads Kossel - 1896 Isolated protamines from various

kinds of fish McClean - 1916 Discovered heparin’s

anticoagualtion action Hagedorn - 1930’s Made long-acting insulin with

protamine Jaques, McCutcheon - 1930’s Produced heparin-protamine

complex Chargoff, Olson - 1937-38 Discovered heparin’s antidote Walther - 1939 Reported protamine’s adverese

effects Jaques - 1949 Poineered study of protamine’s

toxic effects Hersley - 1966 Developed ACT test Jaques - 1973 Developed hep-prot titration test

Platelet Alterations During & After CPB

2. Changes Affecting Platelet Aggregation:

a) Decreased ability of Platelet Aggregation to Agonists

b) Platelets are Activated by CPB (20-30% Spent)

c) Platelets bind to Monocytes and Neutrophils

Platelet Alterations During & After CPB

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 PORCINE MUCOSAL

Cost Less More

Mol Wt (Daltons) 5000-20,000 6000-30,000

Chemical structure Shorter chains Longer chains

Platelet aggregation ++ +

Thrombin inhibition Less More

Factor aX inhibition More Less

Post op bleeding More Less

Protamine requirement Less More

Delayed thrombocytopenia ++ +

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