Hemostasis - Platelet Function Flashcards Preview

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Flashcards in Hemostasis - Platelet Function Deck (46):
1

platelet morphology and function

resting platelets are discoid, anucleate cells 2-3 uM in diameter

form by budding or retraction from megakaryocyte proplatelet processes in bone marrow myeloid sinuses and other tissues

microtubule coil helps maintain platelet discoid shape

upon activation, platelet changes shape from discoid to round and then with many projections

2

canalicular sytstem

provides easy release of granule contentss and excess platelet membrane during shape change

3

phases of platelet activation

adhesion - binding to subendothelial matrix

activation - change from quiescent state to promote hemostasis

secretion - release of granule contents

aggregation - binding to other platelets through active GPIIbIIIa

4

process of injury that activates platelets

i) Collagen exposure

ii) Exposure of von Willebrand factor that binds platelet receptors

iii) Thrombin generation

iv) Decreased endothelial production of CD39 ecto-ADPase

v) Endothelin release (vasoconstriction)

5

agonists that cause platelet activation

ADP, thromboxane A2, collagen, thrombin, epinephrine

6

i) Endothelium-dependent platelet inhibitors such as Prostacyclin (PGI2)

stimulates platelet cyclic AMP and Nitric Oxide (Endothelium-Derived Relaxing Factor (EDRF), which stimulates cyclic GMP

7

consequence of platelet activation

a. Platelet shape change

b. Thromboxane A2 generation and release

c. Release of granule contents – recruits and activates additional platelets

d. Inside-out signaling presenting the active fibrinogen binding form of GPIIbIIIa receptors on the platelet surface.

e. Exposure of an anionic phospholipid surface on the outer leaflet of the plasma membrane which promotes the assembly of factor tenase and prothrombinase complexes.

8

Thromboxane A2

produced by activated platelets is a potent agonist for platelet activation and aggregation.

9

Aspirin

acetylates cyclooxygenase and irreversibly inhibits its activity immediately upon exposure within the portal circulation

affects function for the life of the platelet – return to normal requires 7-10 days when a significant number of new platelets appear in the circulation

10

dense granule contents

ADP

ATP

Serotonin

Pyrophosphate

Calcium

11

alpha granule contents

Platelet Factor-4

beta-Thromboglobulin

Platelet-Derived Growth Factor

Fibrinogen

Factor V

vWF

High Molecular Weight Kininogen

12

GP IIb/IIIa receptor

mediates platelet aggregation when activated

13

fibrinogen

the most important multivalent adhesive glycoprotein that can bridge two activated platelets (on a molar basis) but other ligands such as von Willebrand factor can also serve this function

14

platelet function tests

Peripheral smear – count, size, granules

Bleeding time

Point of care instruments:

a. Platelet function analyzer PFA-100® - a screening test for platelet function

b. Accumetrics VerifyNow® - for therapeutic drug monitoring

c. Thromboelastography – aspirin and thienopyridine drug monitoring

d. Other assays

Clot retraction

15

platelet aggregation studies

Optical nephelometry – uses platelet rich plasma
- gold standard assay, but cumbersome for routine screening and clinical monitoring

Electrical impedance - whole blood

agonists: ADP, epinephrine, collagen, arachidonic acid, Ristocetin  

16

clinical manifestations of platelet dysfunction

mucocutaneous bleeding, petechiae, purpura, epistaxis, gingival bleeding, menorrhagia

17

Bernard-Soulier Syndrome

GP Ib/IX  (vWF Receptor) defect

18

Glanzmann's Thrombasthenia

GP IIb/IIIa Complex defect

19

delta-Storage Pool Disease

Dense Body Deficiency

20

alpha-Storage Pool Disease (Gray Platelet Syndrome)

Alpha Granule Deficiency

21

Scott Syndrome

Decreased platelet surface acidic phospholipid expression

22

Quebec Syndrome

Multimerin defect; alpha-granule and procoagulant activity defect

23

Stimulus-response coupling defects

Heterogeneous; defects of cyclooxygenase, G-couple proteins or calcium response

24

acquired disorders of platelet function.

Uremia – metabolic byproducts inhibit platelet function in  Myeloproliferative Disorders

Post-Cardiac Bypass - artificial surfaces activate and cause “spent platelets”

Dysproteinemia – plasma immunoglobulin paraprotein receptor interference

Antiplatelet antibodies – interfere with platelet receptors

Liver disease with fibrin degradation product (fdp) interferes with binding of fibrinogen with platelet receptor

Drugs

25

ecto-ADPase (CD39)

normally expressed by endothelial cells, which removes ADP and ATP nucleotides from the local fluid environment

26

platelet products in atherogenesis

CD40 ligand

interleukin-1beta

P-selectin

platelet factor 4

ROS

F2-isoprostanes

tissue factor

chemokines, cytokines

matrix metalloproteinases

27

CD40 ligand in atherogenesis

endothelial cell expression of chemokines, tissue factor, cell adhesion molecules, and ROS

28

interleukin-1beta in atherogenesis

endothelial cell activation, cell adhesion, chemokine production

29

P-selectin in atherogenesis

adhesion to endothelial cells and monocytes

30

platelet factor 4 in atherogenesis

macrophage differentiation, endothelial cell E-selectin

31

ROS in atherogenesis

scavenges nitric oxide, prevents thrombus disaggregation, lipid peroxidation, F2-isoprostanes

32

F2-isoprostanes in atherogenesis

activates platelets, modulates cell adhesion

33

tissue factor in atherogenesis

promotes thrombosis

34

chemokines and cytokines in atherogenesis

leukocyte recruitment and inflammation

35

matrix metalloproteinases in atherogenesis

plaque destabilization

36

NSAIDs

inhibits cyclooxygenase reversibly, platelet function returns after drug levels fall

use of NSAIDs can interfere with therapeutic antiplatelet aspirin effect

37

Thienopyridines: clopidigrel (Plavix®)

P2Y12 ADP receptor blocking agent which may be used in conjunction with aspirin in patients with stroke and coronary artery disease

the drug must be metabolized to the active form; some persons resistant

38

Ticlopidine (Ticlid®)

ADP receptor blocking agent use associated with increased incidence of Thrombotic Thrombocytopenic Purpura (TTP) in 1:2000-4000 cases

39

Prasugrel, Ticagrelor

efficacious new ADP receptor blocking agents

may be used in patients who have resistance to clopidogrel

40

Abciximab (ReoPro®)

humanized murine monoclonal Fab monoclonal antibody that binds to and inhibits GP IIb/IIIa function

used in cardiovascular catheter interventions

also consider: Eptifibatide, tirofiban

41

Dipyridamole (Persantine®)

inhibits adenosine uptake, acts on PLA2 and causes increased platelet cAMP, which leads to inhibited function

42

GP IIb/IIIa

fibrinogen/vWF (aggregation)

43

GP Ib-V-IX

vWF (adhesion)

44

GP Ia-IIa

collagen (adhesion)

45

GP VI

collagen (activation)

46

isoprostane

bioactive molecule that is formed due to inflammation and increases platelet activation