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Platelet Function in Cardiothoracic Surgery. Mike Poullis. Overview. Basic science What are they? How do they work? Methods of assessing platelet function Full blood count Microaggregation Macroaggregation Thromboelastography (TEG) Platelet function analyser Bleeding time

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overview
Overview
  • Basic science
    • What are they?
    • How do they work?
  • Methods of assessing platelet function
    • Full blood count
    • Microaggregation
    • Macroaggregation
    • Thromboelastography (TEG)
    • Platelet function analyser
    • Bleeding time
  • Clinical scenarios
    • Drugs
    • Medical conditions
    • Congenital disorders
    • Cardiopulmonary bypass
    • Aprotinin
    • HIT
    • On the ward
basic science
Basic science
  • What are they?
  • How do they work?
coagulation system
Coagulation System
  • Platelets
  • Soluble Factors
  • Red Cells
  • Soluble factors interact with platelets to form a mesh that RBCs stick to
how do platelets work
How Do Platelets Work ?
  • Afferent pathway
  • Inside platelet pathway
  • Efferent pathway

Inside

platelet

pathway

Efferent pathway

Afferent pathway

platelet agonists afferent
Platelet Agonists (Afferent)

Agonist Receptor

Adrenaline alpha

Collagen VLA

ADP ADP

Thrombin PAR I and IV

the platelet
The platelet

Microaggregation and Macroaggregation

mechanism of g protein receptor activation by soluble ligand eg adp
Mechanism of G protein receptor activation by soluble ligand eg ADP

Soluble ligand

(Reversible)

Cell Membrane

G protein

mechanism of g protein receptor activation by protease eg thrombin
Mechanism of G protein receptor activation by protease eg Thrombin

Protease eg thrombin

(Irreversible)

Cell Membrane

G protein

slide15
(cont)

Tethered ligand

(Irreversible)

Peptide

Cell Membrane

G protein

Activation

par activating peptides
PAR activating peptides

PAR activating peptide

(reversible)

Cell Membrane

G protein

Activation

actions proteolytic inhibitors eg aprotinin
Actions proteolytic inhibitors eg Aprotinin

Protease eg thrombin

Aprotinin

Cell Membrane

G protein

par deactivation
PAR deactivation

Protease eg thrombin

Deactivator eg elastase

aa 43/44 & 55/56

aa 41/42

(Irreversible)

NH2

Cell Membrane

G protein

platelet thrombin desensitisation
Platelet Thrombin desensitisation

1

Neutrophil elastase cleaves PAR-1

Specific cleavage inhibits activation

2

Thrombin fragment deactivation theory

efferent
Efferent

Agonist Receptor

GP IIb/IIIa Fibrinogen

GP Ib Von Willebrand Factor

techniques to understand
Techniques to Understand
  • Microaggregation
  • Macroaggregation
  • Platelet function analysers
  • Thrombelastography
  • Calcium fluxes
macroaggregation
Macroaggregation

Increasing

aggregation

Time

what the numbers letters mean
What the Numbers/letters Mean
  • R: Time from initiation to initial fibrin formation
  • k: Time of clot formation until amplitude of 20 mm
  • Alpha angle: Acceleration (kinetics) of fibrin build up and cross-linking
  • MA - Maximum amplitude strength of clot (number function platelets, fibrin)
  • MA60: The rate of amplitude reduction 60 min. after MA (stability) of the clot
tips and tricks
Tips and Tricks
  • Heparinase
  • Adding c7E3 Fab (ReoPro) to the TEG sample will eliminate platelet function from the thromboelastogram.
  • Antifibrinolytic agents such as Epsilon-Aminocaproic Acid, Tranexamic acid and Aprotinin
normal coagulation profile
Normal Coagulation Profile

Heparinase

No Heparinase

heparin effect
Heparin Effect

Heparinase

No Heparinase

calcium flux measurements1
Calcium Flux Measurements

1 Thrombin

2 Adrenaline

A control

B Aprotinin

tests of platelet function
Tests of Platelet Function
  • Full blood count
  • Whole Blood tests
    • Microaggregation
    • Thrombelastography
  • Purified Platelet tests
    • Microaggregation
    • Macroaggregation
    • Platelet function analysers
    • Calcium flux
  • Skin bleeding time
advantages of techniques
Advantages of Techniques
  • Full blood count
    • Quick, easy, reproducible, understandable
  • Whole Blood tests
    • Microaggregation, Thrombelastography Easy

MAJOR ADVANTAGE IS NO SAMPLE PREPERATION

  • Purified Platelet tests
    • Microaggregation Easy
    • Macroaggregation PRECISE DEFECT
    • Platelet function analysers PRECISE DEFECT
    • Calcium flux PRECISE DEFECT
  • Skin bleeding time
    • Whole body answer
limitations of techniques
Limitations of Techniques
  • Full blood count
    • Number not function
  • Whole Blood tests
    • Microaggregation No commercial kit
    • Thrombelastography?sensitivity
  • Purified Platelet tests

YOU HAVE TO PREPARE THE PLATELETS

    • Microaggregation No commercial kit
    • Macroaggregation Experienced technician
    • Platelet function analysers No enzymes available
    • Calcium flux Expensive and experience needed
  • Skin bleeding time
    • Invasive, not specific
clinical scenarios
Clinical Scenarios
  • Drugs
  • Medical conditions
  • Congenital disorders
  • Cardiopulmonary bypass
  • Aprotinin
  • HIT
  • On the ward
effect of drugs on platelet function
Effect of Drugs on Platelet Function
  • Aspirin (Non steroidal anti inflammatory drugs)
  • Clopidogrel, Ticlopidine
  • ReoPro, Tirofiban
  • Prostacyclin
  • Hirudin
  • Ancrod
reopro tirofiban integrilin
ReoPro / Tirofiban / Integrilin

Platelet

Platelet

GP 11b/111a

Fibrin

GP 11b/111a

medical conditions
Medical Conditions
  • Hyperglobulinaemia
    • Multiple myeloma and
    • Waldestrons macroglobulinaemia
  • Renal failure Uraemia
  • Liver disease
  • Myeloproliferative disorders
    • Essential thrombocythaemia
    • Polycytheamia
    • Myelodysplasias
congenital platelet disorders
Congenital Platelet disorders
  • All rare
  • VonWillibrands (commonest)
  • Glanzmann Thrombasthenia (Acquired common)
  • Bernard-Soulier
  • Platelet storage disorders
von willebrands
Von Willebrands

Platelet

Factor V111

vWF

Endothelium

Stabilisation and adhesion

glanzmann thrombasthenia
Glanzmann Thrombasthenia
  • Genetic platelet disorder
  • Gp IIb/IIIa deficient or dysfunctional
  • FACS analysis
bernard soulier
Bernard-Soulier
  • Large platelets
  • Phospholipid not made available
  • GP 1b deficiency

Platelet Storage Disorders

  • ADP or 5-HT release deficiency
  • Defect in dense or alpha granules
how are platelets protected during cpb
How are platelets protected during CPB?
  • Heparin only works on soluble factors!
thrombin
Thrombin

Intrinsic

Extrinsic VII

HEPARIN

CLOT

platelet dysfunction post cpb
Platelet Dysfunction Post CPB
  • Activation decreased numbers and causes clumping
  • Thrombin receptor desensitisation (Neutrophil elastase)
  • Thrombin fragment deactivation theory
  • GP Ib depletion
  • Other
platelets and aprotinin
Platelets and Aprotinin
  • Aprotinin inhibits thrombin induced platelet aggregation but not adrenaline, collagen, and ADP induced aggregation
  • Aprotinin protects GP1b levels
  • Neutrophil enzymes can cleave PAR receptor and make it functionless
hit hitt cpb and aprotinin
HIT, HITT, CPB and Aprotinin
  • PF-4 and heparin antibody
    • Clinical suspicion
    • Immunoassay
    • Bioassay
  • How do you develop HIT?
    • Tissues and blood cell activation
    • Heparin exposure
    • Antibody formation
    • Antibody has to have a functional Fc
drugs to treat hit
Drugs to treat HIT
  • LMW
  • Prostacyclin
  • Ancrod
  • Aprotinin
  • Thrombin antagonists Hirudin
  • Ancrod - aprotinin interaction is important
thrombocytopenia in the well patient on day 5 ready for home
Thrombocytopenia in the well patient on day 5 ready for home
  • Blood film for platelet clumping
  • Repeat in Citrate not EDTA
  • Look at coulter trace
  • ? Need extra dose of aspirin or clopidogrel
interpreting cardiac surgery papers on platelet function
Interpreting Cardiac Surgery Papers on Platelet Function
  • Agonist
  • Technique
  • What is the likely defect?
  • Is it relevant?
  • Methodology quirk “Correcting count for tests”