Hemostasis - Platelet Function Flashcards
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
canalicular sytstem
provides easy release of granule contentss and excess platelet membrane during shape change
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
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)
agonists that cause platelet activation
ADP, thromboxane A2, collagen, thrombin, epinephrine
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
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.
Thromboxane A2
produced by activated platelets is a potent agonist for platelet activation and aggregation.
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
dense granule contents
ADP
ATP
Serotonin
Pyrophosphate
Calcium
alpha granule contents
Platelet Factor-4
beta-Thromboglobulin
Platelet-Derived Growth Factor
Fibrinogen
Factor V
vWF
High Molecular Weight Kininogen
GP IIb/IIIa receptor
mediates platelet aggregation when activated
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
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
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
clinical manifestations of platelet dysfunction
mucocutaneous bleeding, petechiae, purpura, epistaxis, gingival bleeding, menorrhagia
Bernard-Soulier Syndrome
GP Ib/IX (vWF Receptor) defect
Glanzmann’s Thrombasthenia
GP IIb/IIIa Complex defect
delta-Storage Pool Disease
Dense Body Deficiency
alpha-Storage Pool Disease (Gray Platelet Syndrome)
Alpha Granule Deficiency
Scott Syndrome
Decreased platelet surface acidic phospholipid expression
Quebec Syndrome
Multimerin defect; alpha-granule and procoagulant activity defect
Stimulus-response coupling defects
Heterogeneous; defects of cyclooxygenase, G-couple proteins or calcium response
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
