Transcript Perioperative Hemostasis
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
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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 FSP Plasmin Jay kambam
Vessel Injury Collagen, vWF Endothelin Platelet-fibrin clot FSP Jay kambam
VESSEL WALL - ENDOTHELIUM
VESSEL WALL - ENDOTHELIUM
Antithrombogenic ( Favors fluid blood ) Vessel injury or FB/Stent, low flow Thrombogenic
(
Favors clotting
)
Anticoagulants Procoagulants Jay kambam
VESSEL WALL Endothelin, Collagen, tPAI, vWF, Factors, PL Prostacyclin, NO, ADPase, tPA, Heparin, Thrombomodulin Jay kambam
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
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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 Jay kambam
Dense Granule Alpha Granule Jay kambam
Contents of platelet secretary granules and their physiological activities Secretary Granules Physiological activities
Cofactors for coagulation cascade
Coagulation factors I & V Platelet specific proteins
Platelet F4 Low affinity PF4
Glycoproteins
PF4 potentiates ADP induced aggregation & antiheparin activity LA-PF4 possesses antiheparin actvty
A
dhesion and cell to cell interaction
ADP and ATP Calcium Serotonin ADP stimulates aggregation & secretion Promotes coagulation Vasoconstriction Jay kambam
Adhesion, Activation, Aggregation (AAA) Jay kambam
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
TxA 2
GP IIb/IIIa Fibrinogen Jay kambam
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Vessel Injury Collagen, vWF Endothelin Platelet-fibrin clot FSP Jay kambam
Factor I II III IV V VI (same as Va) VII VIII IX X XI XII XIII Trivial Name(s) Fibrinogen Prothrombin Tissue Factor Calcium Proaccelerin, labile factor, accelerator (Ac-) globulin Accelerin Proconvertin, serum prothrombin conversion accelerator (SPCA), cothromboplastin Antihemophiliac factor A, antihemophilic globulin (AHG) Christmas Factor, antihemophilic factor B,plasma thromboplastin component (PTC) Stuart-Prower Factor Plasma thromboplastin antecedent (PTA) Hageman Factor Protransglutaminase, fibrin stabilizing factor (FSF), fibrinoligase Pathway: Intrinsic/Extrinsic Both Both Extrinsic Both Both Both Extrinsic Intrinsic Intrinsic Both Intrinsic Intrinsic Both Jay kambam
XIIa XIa TF IIIa VIII IXa VIIIa Prothrombin II 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) Jay kambam
FIBRINOLYSIS
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Antifibrinolytics
Lysine Analog Jay kambam
€ Aminocaproic acid & Tranexamic acid Jay kambam
(Angiomax) (Refludan), Jay kambam
ANTIPLATELET DRUGS - Mechanisms
Aspirin
Clopidogrel (Plavix) Prasugrel (apagrel) Ticlopidine (Ticlid
)
Thromboxane A2 Inhibitors Thienopyridines P2Y12/ADP Receptor Inhibitors
Aggrastat (tirofiban) ReoPro (abciximab) Integrilin (eptifibatide) GP IIb/IIIa Antagonists Jay kambam
Antiplatelet Drugs: Inhibition of activation &/or aggregation Jay kambam
Jay kambam
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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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( P2Y 12 ) .
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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 Clopidogrel (Plavix) Prasugrel (apagrel) Ticlopidine (Ticlid) Thromboxane A2 Inhibitors Thienopyridines P2Y12/ADP Receptor Inhibitors
Aggrastat (tirofiban) ReoPro (abciximab) Integrilin (eptifibatide) GP IIb/IIIa Antagonists 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 Jay kambam
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Platelet Activation Pathways
Arachidonic acid
TxA 2
GP IIb/IIIa Fibrinogen Jay kambam
GP IIb/IIIa Antagonists: Tirofiban (Aggrastat) Eptifibatide (Integrelin) Abciximab (ReoPro) GP IIb/IIIa antagonist Agonist Inactive platelet GP IIb/IIIa
receptors in unreceptive state
ADP, thrombin, collagen, epi Active Platelet Inhibition of platelet aggregation GP IIb/IIIa receptors occupied by antagonists Aggregating platelets Jay kambam
Glycoprotein IIb/IIIa inhibitors Tirofiban (Aggrastat)
• Nonpeptide • K
D
15 nmol/L • Indication: acute coronary syndrome
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Glycoprotein IIb/IIIa inhibitors Eptifibatide (Integrelin)
• Cyclic peptide • K
D
120 nmol/L • Acute coronary syndrome
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Glycoprotein IIb/IIIa inhibitors Abciximab (ReoPro
)
• Human/murine chimeric monoclonal antibody Fab • K
D
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 Jay kambam
HEPARIN - SOURCES
• • • • •
Lungs Liver Intestinal mucosa Mast cells of RES Bovine and Porcine Jay kambam
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 Jay kambam
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 Jay kambam
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) Typical-Onset HIT Mean day 9 (5-14 days) Delayed Onset HIT (9-40+ days)
Day 1 Day 5 Day 14 THROMBOCYTOPENIA (± THROMBOSIS) Day 30
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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)* Jay kambam
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-o ral 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.
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
Dosage upto 150 mg twice daily?
aPTT (activated partial thromboplastin time), ECT (Ecarin clotting time), TT (Thrombin time) Jay kambam
Dabigatran Discontinuation before surgery Jay kambam
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 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 ACHIEVEMENT 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 (20 30% 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
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Combine 5000 lbs intestines, 200 gallons water, 10 gallons chloroform, and 5 gallons toluene. Hold at 90 0 F for 17 hrs.
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Add 30 gallons acetic acid, 35 gallons ammonia, sodium hydroxide to adjust pH, and 235 gallons water. Bring to a boil then filter.
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Add 200 gallons hot water to filtrate and allow to stand overnight, then skim off the fat.
•
Keep pancreatic extract at 100 0 F 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 Factor aX inhibition Less More Post op bleeding Protamine requirement More 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