Physiology - Vickery - Blood and Clotting
Terms
undefined, object
copy deck
- Primary vs. secondary hemostasis
-
pri: platelet plug formation, seconds
sec: plasma coag. system, minutes - platelets: char
-
from megakaryocytes in marrow
some in spleen, most in plasma
no nuclei - platelet action
-
1. adhesion
2. aggregation
3. granule release - adhesion: char
- mediated by memb. receptor proteins = glycoproteins (integrins)
- adhesion receptors on platelets
-
GP IaIIa: for collagen
GP Ib-IX: for for VWF - aggregation receptors
-
GP IIbIIIa: for fibrinogen
to stick platelets to each other - platelet activation
-
release of granules
adhesion->activates (P)lipase A2 enzyme
serotonin: vasoconstr
ADP: activates more platelets - TxA2 char
-
feedback amplification
and
vasoconstrictor: promotes thrombux formation - Aspirin
-
inhibits platelets
blocks COX-1 and COX-2 irreversibly
reduces TxA2 form. and platelet activ.-> bad for ulcers - Endothelial cells: adhesion cascade
- Arach. acid-> (COX-2)-> P-glandin G2-> (PGI synthase)-> PGI2
- PGI2 and TxA2 char
-
opposing
PGI2: vasodilator, causes inflammation
TxA2: vasoconstr., activates platelets, causes clotting
PGI2 inhibits positive feedback action of TxA2 - selective COX inhibitors
- takes brakes off platelet activation-> innapropriate clotting in heart, etc
- thrombosis: treatment/inhibition
-
drugs against platelet receptors
ex. GP IIbIIIa blockers inhibit aggregation - platelet defects
-
thrombocytopenia
membrane receptor defects: Bernard Soulier and Glanzmann's
treatment: platelet xfusions - Bernard Soulier syndromE
-
mut. in VWF receptor
measure adhesion of platelets to endoth. tissue to diagnose - thromobcytopenia
-
v platelet count
-> petachiae (sub-cutan. hemorrhages) - Glanzmann's disease
-
mut in fibrinogen receptor IIbIIIa
affects aggregation - thrombin points of regulation
-
fibrinogen-> fibrin
feedback amplif: XI, V & VII activation
stimulates cross-linking: XIII activation - type B hemophilia
-
spontaneous
Factor IX problem: Christmas Factor - type A hemophilia
-
familial
Cofactor VIII problem: - Factor XIII
-
transglutaminase
cross links fibrin polymers - extrinsic pathway
-
more common
involves Tissue Factor: receptor in memb of epithelial cells - intrinsic pathway
- HMWK complex act. by neg charged surfaces
- Factor V
- enhances Xa activity
- Factor VIII
-
essential for IXa activity, critical for clotting
deficiency-> Hemophilia A - Vitamin K role in clotting
-
necessary to activate coag. factors
bile acid problems-> can't absorb lipid sol. vitamins (like Vit K) - heparin
- stimulates antithrombin/ thrombin interaction
- thrombomodulin
-
thrombin receptor on intact endothelial surfaces
binds and inhibits thrombin
-> therefore, only damaged tissues will not be able to inhibit thrombin - Protein C
-
activated by thrombin/ thrombomodulin complex
cleaves Va and VIIIa-> tones down cascade - Factor V Leiden
-
no cleavable by APC (activated Protein C)
-> ^clotting (inhibits inhibition)
30-40% of famillial thrombosis - Protein S
- binds Protein C, enhances activity
- clot lysis
-
plasmin: protease, hydrolyzes fibrin in clots
TPA: Tissue plasminogen activator makes it (TPA secreted by endothelial cells) - Hemophilia treatment
-
missing factor (VIII or IX prep'n)
can get AIDS and HepB
use recomb. Factor VIII - Von Willebrand's Disease
-
less activity of VWF
more common (pseudohemophilia)
less platelet adhesion - APC resistance
-
Factor V Leiden most common risk factor for thrombosis
resistant to protein C cleavage - Acquired bleeding disorders
-
auto-antibodies
Vitamin K dependent: malabsorbtion, newborns - anticoagulants
-
Rapid: Calcium chelators: citrate, oxalate, heparin (not main activity)
Long Term: Vit K Antagonists (analogs): Warfarin, Dicoumarol