L50 Primary Hemostasis Flashcards
Steps for Prim Hemostasis
1 vessel wall damage 2 platelet adhesion to subendo layer 3. platelet shape change 4. Primary activation 5. shape change and degranulation 6. secondary activation
Step 1- trigger
Vessel wall damage and exposure of subendo layer
- ECM layer exposed with collagen and smooth muscle and TF and other protein components like HMW vWF (normally secreted by endo cells)
- trigger for hemostasis
Step 2 adhesion
Platelet adhesion to subendo layer
a. GP1b (trans membrane platelet protein )
- binds to exposed collagen resulting in a change in three dimensional structure
b. change in shape allows platelet to bind to vWF which then bidns to the subendo collagen
- GP1b-vWF bindng promoted by shear forces
- arterial thrombus will have more platelets than venous
Step three platelet shape change
second adhesion of second step exposes the GpIIb-IIIa (two trans mem prot complex) which thenb binds to fibrinogen and vWF
this is called primary aggregation
Step 4 primary activation
shape change and degranulation
- many platelet agonists (ADP/Thrombin/TXA2) can activate platelets
- each bind againsta specific receptor which is Gq linked
Gq signaling
bind
- increase in calcium concentration
- activation of phospholipase A2
- hydrolysis of membrane PL’s
- arachadonic acid in cytoplasm (20:4 w6)
- formation of thromboxane A2 (using COX1 and thromboxane synthase
- TXA2 secreted
*note: round 1: first activation (adhesion and activation) GP1a and collagen interaction (increase cytosolic CA, release of first ADP and TXA2)
Step five shape change and degranulation
platelet normal flattened out disc shape: activated becomes spiny and spherical, long pseudopods or filapodia
-cyclic endoperoxidases-metabolites of TXA2 biosynth triggers degranulation of both alpha granules (HMV vWF, fibrinogen, serotonin, pDGF) and dense granules (ADP) all released into circulation
drew platelet activation
slide 10
step six secondary activation
autocrine model
ADP is a POTENT activator. binds to ADP receptor on dormant platelets, under secondary activation and shape change
shape change results in two things
- exposure of GIIb-IIIa leads to secondary aggregation
- w/out ADP-NO secondary aggregation
- adp mediated signaling induces swelling of the activated platelet (60% increase in SA) and promotes platelet/platelet contact via fibrinogen
- fibrinogen links 2 platelets with altered shape together - Flipping of PL creating a negatively charged surface
- catalytic surface for fibrin clot
TXA2 secreted from active platelet and activates others
(comp to adp is less potent activator)
why do platelets stay dormant
three ways
- nitric oxide secreted by endo cells
- inhibits platelet aggregation
- promotes vasodilation - endo expresses ADPase (membrane associated) that degrades ADP
- (shuit down) PGI2 (prostacyclin) (PARACRINE) from endo binds PGI2 receptor (on platelet)
- Gs mediated synthesis of cAMP
- cAMP activates Ca on dense tubular system, decreased intracellular calcium
Synthesis and location and function of vWF
synthesis: Endo cells
- secreted in subendo matrix (HMW vWF) for binding to GP1b
- secretedin circulation (cleaved by ADAMTS13-a metalloportease into small vWF) for binding to factor VIII (extending its half life) 2-8 hrs
synthesis: megakaryocytes
- stored in alpha granules of platelets (HMW-vWF) for release into serum on platelet activation, participates in adhesion and primary aggregation
HMW-vWF is more effective at forming complexes with pletelets than small vWF
vWF deficiency
most common inherted bleeding disorder (1-3%)
von WF gene HUGE with 52 exons
multiple mutations of the vWF gene
steps affected:
- platelet adhesion and primary aggregation bc vWF is involved in both
- clotting cascade because factor VIII level are low
presentation:
- varying degrees
- asymptomatic to nosebleeds/bruising/heavier mentaual bleeding and childbirth bleeding``
Drugs that can be used
COX inhibitors
-decreased TXAsv2 synthesis-decreased platelet activation and degran (Aspirin)
ADP receptor inhibitors
-decreased ADP mediated secondary activation; PLAVIX is non competitive inhibitor
GpIIb-IIIa inhibitors
-inhibit GpIIb-IIIa interation- decreased platelet aggregation (such as integrin)
PGI2 agonist
increase platelet cAMP production - decrease cystosolic Ca, decrease platelet activation
thrombotic thrombocytopenic Purpura
Thrombotic Thrombocytopenic Purpura
- metuatino on metalloportease gene resulting in defective metalloprotease
- defective ADAMST13 results in inability to cleave HMW vWF to smaller vWF
affected:
- high levels of HMW vEF
- exaggerated thrombosis (microthrombi)
- thrombocytopenia occurs due to tincreased utilization of platelets to form the microthrombi
presentation
-easy /excessive bruising
microthrombi: formed throughout body
- hemolytic anemia from damage to RBC
- organ damave from vessel damage
90% mortality untreated
Idiopathic Thrombocytopenic Purpura
autoimmune disease
-ab binds to platelet mem protein , change in conf, clearance by spleenmacrophages
affectedL severe thrombocytopenia
-1% cell counts
splenomegalyL in young children more than adults
easy or excessive bruising
superficial bleeding (leaking caps)
gingival bleeding
prolonged bleeding
Bernard soulier syndrome
defective Gp1b gene, resulting in a reduced or abnormal membrane GP1b which is a receptor for vWF
GIANT PLATELET SYNDROME
no adhesion due to defective GP1b
moderate thrombocytopenia
prolonged bleeding time
abnormally large platelets (RBS size)
