Transcript Document

Hemostasis & Thrombosis: Platelet Disorders
Beth A. Bouchard
BIOC 212: Biochemistry of Human Disease
Spring 2005
HEMOSTASIS
Hemorrhage
Thrombosis
Hemostasis
HEMOSTASIS (CONT.)
1). INITIATION
Vessel wall – endothelial cells and subendothelial components
2). LOCALIZATION
Platelets – circulating cellular elements
3). PROPAGATION/AMPLIFICATION
Plasma coagulation proteins (factors)
4). TERMINATION
Plasma coagulation protein inhibitors
5). ELIMINATION
Fibrinolytic system
Vessel Wall: Endothelial cells
•
Physically separate platelets from
subendothelial proteins that can
induce platelet activation
•
Produce 2 potent vasodilators and
inhibitors of platelet function:
prostacyclin (prostaglandin I2, PGI2)
and nitric oxide
Increase the
concentration of the
cyclic nucleotides cGMP
and cAMP in platelets,
which down regulate the
signalling pathways that
support platelet activation
•
Express CD39 on their surface,
which enzymatically hydrolzes ADP,
a potent platelet agonist release by
activated platelets
Vessel Wall (cont.)
Response to Vessel Wall Injury:
Platelet adhesion and activation
• Exposure of flowing blood and platelets to subendothelial
components
• Platelets bind to the subendothelial collagen bound to von
Willebrand factor (vWF), which is secreted from endothelial
cells directly into the subendothelial space or adsorbed from
plasma following endothelial cell secretion
• vWf also binds directly to platelets via glycoprotein Ib-IX
• Platelet interactions with collagen (via a specific platelet
membrane receptor) and platelet activating factor (PAF),
from the vessel wall, leads to their activation
Platelets adhered to damaged endothelium
Response to Vessel Wall Injury:
Vasoconstriction
• Temporarily reduces local blood flow and hence,
blood loss
• Mediated in part by serotonin and thromboxane A2
(TXA2) from activated platelets
Serotonin is released from platelet dense granules
TXA2 is a product of platelet prostaglandin metabolism
PLATELETS
PLATELETS (CONT.)
Platelet plug
Platelet Plug Formation = 1° hemostasis
Platelet Plug Formation: Platelet activation
• Bind to subendothelial proteins and associated
vWF subsequent to blood vessel injury
• Activated via their interaction with collagen and
PAF
•
Additional platelet agonists include ADP,
epinephrine, thrombin, immune complexes, and high
shear stress – all of the compounds interact with
specific platelet membrane receptors
• Several platelet activation pathways are initiated
Platelet Plug Formation: Platelet
activation events
• Platelet shape change: extend
pseudopodia, which facilitates aggregation
and coagulant activity
• Release of alpha and dense granule
contents including a number of compounds
involved in hemostasis
• Aggregation
Activated platelets
Platelet Plug Formation: Platelet
aggregation
• Platelet activation results in the functional
expression of membrane receptors normally
expressed in a non-functional state (glycoprotein
IIb-IIIa)
• Fibrinogen from the plasma or released from
activated platelet alpha-granules binds to
activated glycoprotein IIb-IIIa membrane
receptors effectively bridging platelets to each
other
Platelets adhered to and aggregated upon
collagen
Platelet Plug Formation
Platelet Plug Formation
• Measured clinically as the bleeding time
• Normal bleeding time is from 2 – 10 min
• Usually the bleeding time is sufficient to
detect defects of platelet adhesion and
aggregation, in which it is prolonged
Disorders of Platelet Adhesion or
Aggregation
• Affecting constituents of the vessel wall
• Affecting the ability of the platelet to
interact with the subendothelium at sites
of blood vessel injury
• Affecting the ability of the platelet to
interact with other platelets
Vessel Wall Defects
• von Willebrand’s disease: a group of autosomal
dominant disorders that result in reduced or
abnormal synthesis of vWF
• Defects in collagen synthesis
Ehlers-Danlos Syndrome: congenital defect in
collagen synthesis
Scurvy: results from vitamin C (ascorbic acid)
deficiency, which is involved in collagen synthesis
Excess exogenous or endogenous corticosteroids: also
leads to acquired deficiency in collagen synthesis
Platelet Defects
• Bernard-Soulier Syndrome: expression of
low levels of or defective glycoprotein IbIX on the platelet surface
• Glanzmann’s thrombasthenia: expression
of low levels of or defective glycoprotein
IIb-IIIa on the platelet surface
Other Defects
• Fibrinogen: deficiency or production of
abnormal protein
• Acquired disorders include low platelet
count (thrombocytopenia) as a result of
defective formation of platelets by the
bone marrow or excessive destruction of
platelets
Antiplatelet Drugs