Docstoc

Mechanisms of platelet activation and targets for platelet inhibition

Document Sample
Mechanisms of platelet activation and targets for platelet inhibition Powered By Docstoc
					                     Mechanisms of Platelet Activation and Targets for Platelet Inhibition




           Mechanisms of platelet
      activation and targets for platelet
                  inhibition
                                                     Dr Rob Storey

                      Senior Lecturer and Honorary Consultant in Cardiology
                                      University of Sheffield
                                          Sheffield, UK




Slide 1

Robert Storey, MD: Hello, I am Dr Rob Storey from the University of Sheffield in the UK.



               Platelet Activation Mechanisms
                                                                 5HT                      5HT
                               Thromboxane
               Coagulation                           Collagen           ADP               ADP      ADP
                                    A2
                                                                                 ATP      ATP
                   Thrombin                            GPVI     5HT2A   P2Y1
                                           TPα
                                                                                 P2X1
                                   PAR4

                           PAR1
                                                                                      Dense
                                                                                     granule
       Thrombin
                                                    PLATELET                                       P2Y12

       generation                                   ACTIVATION

                Shape                                                          Amplification
                change                        Alpha
                                             granule
                                                                                            Aggregation
                                                                                  αIIb β3
                                                                   αIIb β3                      αIIb β3
                                                                             Fibrinogen
                                Coagulation factors
                                Inflammatory mediators

  Storey RF. Curr Pharm Des. 2006;12:1255-1259.



Slide 2


                                                  This is a transcript of an online program, which may be found at:

                                                    http://www.theheart.org/article/861091.do
                     Mechanisms of Platelet Activation and Targets for Platelet Inhibition


I am going to talk to you about mechanisms of platelet activation and targets for platelet
inhibition. To start off with, I would like to talk about the pathways that lead to platelet activation
and the functional consequences of that. There is a range of receptors on the platelet surface
which are bound by platelet agonists and these lead to platelet activation. The agonists include
thrombin, thromboxane A2, collagen, and ADP which all cause activation via these different
receptors. This leads to shape change of the platelet and also causes conversion of alpha IIb
beta 3 (or glycoprotein IIb/IIIa) from its resting state to its active state where it binds fibrinogen
and allows crosslinking of platelets culminating in platelet aggregation. In addition, platelet
activation leads to the release of granule contents. Alpha granules contain coagulation factors
and very important inflammatory mediators which can drive the process of inflammation
associated with arterial thrombosis. Dense granules contain platelet agonists 5HT and
adenosine diphosphate (ADP), adenosine triphosphate in high concentrations and these are
released and activate the platelet further and recruit other platelets. Also, there is a change in
the amino phospholipid exposure on the surface of the platelet with strong platelet activation
and this allows the assembly of prothrombinase complex -- which catalyzes thrombin
generation and this plays a very important role in thrombin generation and arterial thrombosis.



          Aspirin blocks thromboxane A2 release
                                                         ASPIRIN
                                                                 5HT                      5HT
               Coagulation
                           Thromboxane
                                A2
                                                  x  Collagen           ADP               ADP      ADP
                                                                                 ATP      ATP
                   Thrombin                            GPVI     5HT2A   P2Y1
                                           TPα
                                                                                 P2X1
                                   PAR4

                           PAR1
                                                                                      Dense
                                                                                     granule
       Thrombin
                                                    PLATELET                                       P2Y12

       generation                                   ACTIVATION

                Shape                                                          Amplification
                change                        Alpha
                                             granule
                                                                                            Aggregation
                                                                                  αIIb β3
                                                                   αIIb β3                      αIIb β3
                                                                             Fibrinogen
                                Coagulation factors
                                Inflammatory mediators

  Storey RF. Curr Pharm Des. 2006;12:1255-1259.



Slide 3

Aspirin blocks the release of thromboxane A2 via irreversible acetylation of cyclooxygenase-1
which is in the pathway converting arachidonic acid through to thromboxane A2. Thromboxane
A2 is a strong platelet agonist but as you can see blocking this pathway has a limited overall
effect on the various pathways of platelet activation. Consequently aspirin has a limited effect
on platelet reactivity and platelet reactivity can remain high despite complete blockade of this


                                                  This is a transcript of an online program, which may be found at:

                                                    http://www.theheart.org/article/861091.do
                     Mechanisms of Platelet Activation and Targets for Platelet Inhibition
pathway. The P2Y12 receptor is one of two platelet ADP receptors. P2Y1 is the pathway which
initiates platelet activation whereas P2Y12 plays a role in strongly amplifying the activation
process.



                            P2Y12 receptor blockade
                                                                 5HT                      5HT
                               Thromboxane
               Coagulation
                                    A2
                                                     Collagen           ADP               ADP      ADP TICLOPIDINE
                                                                                                           CLOPIDOGREL
                                                                                 ATP      ATP              PRASUGREL
                   Thrombin                            GPVI     5HT2A   P2Y1
                                           TPα
                                                                                 P2X1
                                   PAR4                                                                    ACTIVE
                                                                                                           METABOLITE
                           PAR1



                                                    PLATELET
                                                                                      Dense
                                                                                     granule        x
                                                                                                   P2Y12
                                                                                                            AZD6140
                                                                                                            CANGRELOR
       Thrombin
       generation                                   ACTIVATION

                Shape                                                          Amplification
                change                        Alpha
                                             granule
                                                                                            Aggregation
                                                                                  αIIb β3
                                                                   αIIb β3                      αIIb β3
                                                                             Fibrinogen
                                Coagulation factors
                                Inflammatory mediators

  Storey RF. Curr Pharm Des. 2006;12:1255-1259.



Slide 4

This amplifies not only platelet aggregation but also amplifies the other functional
consequences of activation, including granule release and platelet procoagulant activity.
Consequently this is a good pathway to target because it inhibits all of these important
processes which contribute to arterial thrombosis. The thienopyridines, ticlopidine, clopidogrel,
and prasugrel are all converted to active metabolites in the liver. These active metabolites are
relatively unstable and bind irreversibly to the P2Y12 receptor. This irreversible binding means
that the effects of the drugs last the life of the platelet -- which is 7-10 days -- and platelet
function is only restored when new platelets are released into the circulation that are not
inhibited by the active metabolite. On the other hand there are reversible antagonists which
bind reversibly to the receptor, this includes AZD6140 which is an oral reversible P2Y12
antagonist and cangrelor, which is an intravenous P2Y12 antagonist that also binds reversibly.
What this means is that when the plasma levels of these drugs fall, the drugs come off the
P2Y12 receptor, the platelet is no longer inhibited, and platelet function is restored.




                                                  This is a transcript of an online program, which may be found at:

                                                    http://www.theheart.org/article/861091.do
                                    Mechanisms of Platelet Activation and Targets for Platelet Inhibition


   Variable Response to Clopidogrel with
    Incomplete P2Y12 Receptor Blockade
        ADP-induced platelet aggregation before and after clopidogrel
      300 mg followed by 75 mg daily for 4-7 days in patients undergoing
        PCI. Cangrelor added in vitro blocks the unblocked receptors.
                                                  100
                    Mean % Platelet Aggregation




                                                  80
                                                                                        Wide interindividual
                                                  60                                    variation in response
                                                                            *
                                                  40

                                                  20
                                                                                               *
                                                   0
                                                        Baseline          Post               Post
  *P<0.05.                                                             Clopidogrel        Clopidogrel
  PCI = percutaneous coronary intervention.                                               + Cangrelor
  Storey RF, et al. Platelets. 2002;13:407-413.



Slide 5

It is widely recognized that the response to standard regimens of clopidogrel is very variable
between individuals and this leads to incomplete P2Y12 receptor blockade; some patients
maintain high platelet reactivity despite administration of clopidogrel. Here we see the
response to ADP measured by platelet aggregation before clopidogrel. On the left the patients
have a high level of platelet aggregation, and then in the middle, the level of platelet
aggregation following clopidogrel administration sufficient to lead to steady state levels of
inhibition. We can see overall, moderate inhibition and wide interindividual variability. If we had
cangrelor in the test tube to block the unblocked P2Y12 receptors we can see we are very
effectively suppressed platelet aggregation and consistently between different individuals.




                                                              This is a transcript of an online program, which may be found at:

                                                                   http://www.theheart.org/article/861091.do
                     Mechanisms of Platelet Activation and Targets for Platelet Inhibition


              Thrombin – anticoagulants and PAR antagonists
HEPARINS
BIVALIRUDIN                                                      5HT                      5HT
                               Thromboxane
               Coagulation                           Collagen           ADP               ADP      ADP
                                    A2
                                                                                 ATP      ATP

SCH530348             x
                   Thrombin
                                           TPα
                                                       GPVI     5HT2A   P2Y1
                                                                                 P2X1
E5555
                       x   PAR1
                                   PAR4


                                                                                      Dense
                                                                                     granule
       Thrombin
                                                    PLATELET                                       P2Y12

       generation                                   ACTIVATION

                Shape                                                          Amplification
                change                        Alpha
                                             granule
                                                                                            Aggregation
                                                                                  αIIb β3
                                                                   αIIb β3                      αIIb β3
                                                                             Fibrinogen
                                Coagulation factors
                                Inflammatory mediators

  Storey RF. Curr Pharm Des. 2006;12:1255-1259.



Slide 6

I now want to talk about thrombin which plays a central role in the process of thrombosis.
Thrombin is the end product of the coagulation cascade, a series of steps in plasma that lead
to the generation of thrombin which then causes the conversion of fibrinogen to fibrin which
binds the clot together. Thrombin also activates platelets via two receptors on the platelet
surface PAR-1 and PAR-4. There is a different class of drugs that will act on different parts of
this process. The anticoagulants, heparins, bivalirudin, as well as factor Xa inhibitors inhibit the
production of thrombin and some also directly inhibit thrombin itself. This inhibits the
coagulation cascade leading to the formation of fibrin and also inhibits platelet activation by
thrombin. On the other hand, there are new antagonists which just block PAR-1, one of the
pathways whereby thrombin leads to thrombosis. These are SCH 530348 and E-5555 which
bind to the PAR-1 receptor on platelets and other cells.




                                                  This is a transcript of an online program, which may be found at:

                                                    http://www.theheart.org/article/861091.do
                     Mechanisms of Platelet Activation and Targets for Platelet Inhibition

         GPIIb/IIIa antagonism – the challenge of
              balancing safety and efficacy
                                                                 5HT                      5HT
                               Thromboxane
               Coagulation                           Collagen           ADP               ADP      ADP
                                    A2
                                                                                 ATP      ATP
                   Thrombin                            GPVI     5HT2A   P2Y1
                                           TPα
                                                                                 P2X1
                                   PAR4

                           PAR1
                                                                                      Dense
                                                                                     granule
       Thrombin
                                                    PLATELET                                       P2Y12

       generation                                   ACTIVATION

                Shape                                                          Amplification
                change                        Alpha
                                             granule
                                                                                            Aggregation
                                                                                  αIIb β3
                                                                   αIIb β3                  x   αIIb β3
                                                                             Fibrinogen
                                Coagulation factors
                                Inflammatory mediators
                                                                                    GP IIb/IIIa ANTAGONISTS
  Storey RF. Curr Pharm Des. 2006;12:1255-1259.



Slide 7

Finally I would like to talk about glycoprotein IIb/IIIa antagonists. These antagonists block the
IIb/IIIa receptors and prevent fibrinogen binding to this receptor and thereby block the final
common pathway of platelet aggregation. In addition, they block the outside in signaling which
occurs during platelet aggregation which causes additional amplification of platelet activation.
The problem with these drugs is that you cannot completely block this receptor, otherwise it
leads to intolerable bleeding and severe hemorrhage. On the other hand, low levels of receptor
blockade seem to be clinically ineffective and may even have adverse consequences as was
shown by the problems with oral glycoprotein IIb/IIIa antagonists. Therefore, we have to work
within a particular therapeutic window to maintain the right balance of safety and efficacy. This
has proved quite challenging and, as a consequence, other receptor pathways perhaps which
preferentially inhibit platelet activation are easier to work with and inhibit, to lead to therapeutic
gains.




                                                  This is a transcript of an online program, which may be found at:

                                                    http://www.theheart.org/article/861091.do
             Mechanisms of Platelet Activation and Targets for Platelet Inhibition



                              Conclusions
    •   Aspirin effectively inhibits release of thromboxane A2, an important
        platelet agonist, but this has limited impact on overall platelet
        reactivity
    •   The P2Y12 receptor mediates amplification of platelet activation,
        aggregation, granule secretion, and procoagulant and pro-
        inflammatory responses – this is the target of thienopyridines and
        reversible antagonists
    •   Standard regimens of clopidogrel appear to achieve suboptimal levels
        of P2Y12 receptor blockade in some patients; new strategies that
        achieve consistent levels of receptor blockade may help refine the
        balance of safety and efficacy
    •   Thrombin plays a central role in coagulation and platelet activation –
        anticoagulants target thrombin production ± inhibit formed thrombin;
        PAR1 antagonists block thrombin effects on platelets and other cells
    •   The GPIIb/IIIa receptor (αIIbβ 3) mediates platelet aggregation and
        additional amplification of platelet activation; GPIIb/IIIa antagonists
        have a relatively narrow therapeutic window and are progressively
        being displaced by agents targeting other pathways


Slide 8

In conclusion, aspirin very effectively inhibits the release of thromboxane A2, an important and
strong platelet agonist but this has overall limited impact on platelet reactivity. If we are going
to effectively suppress platelet function, we need to target other pathways. The P2Y12
receptor plays a very important role amplifying platelet activation and all the very important
processes which go along with that. This is the target of thienopyridines and reversible P2Y12
antagonists. Standard regimens of clopidogrel appear to achieve suboptimal levels of P2Y12
receptor blockades in some patients and so we need new strategies that can achieve
consistent levels of receptor blockade in order to refine the balance of safety and efficacy.
Thrombin plays an essential role in coagulation and also platelet activation. Anticoagulants
target thrombin production and in some cases inhibit thrombin; on the other hand, PAR-1
antagonists just block the effects of thrombin on the PAR-1 receptor, on platelets, and other
cells.

Finally the glycoprotein IIb/IIIa receptor mediates platelet aggregation and additional
amplification of platelet activation. Antagonists of this receptor, however, have a relatively
narrow therapeutic window and so are progressively being displaced by agents targeting other
pathways.

Thank you for your time.




                              This is a transcript of an online program, which may be found at:

                                http://www.theheart.org/article/861091.do

				
DOCUMENT INFO