week 4- coagulation and hemostasis Flashcards
blood within an animals vessels must be maintained in a _____ state
fluid
flowing blood does what:
- moves platelets along
- doesnt allow platelets to contact the endothelial cells
endothelial cells aid in _________
prevention of blood clot formation
what do endothelial cells secrete
-proteins that help prevent activation of platelets and proteins that participate in blood clot formation
-proteins that break down blood clots
what is hemostasis
process the body utilizes to stop blood from escaping damaged vessels
hemostasis relies on interactions between:
the blood vessel, platelets, and coagulation factors
defects in hemostatic process results in
hemorrhage
what is hemorrhage
the escape/loss of blood from the vascular space
what is physiologic hemostasis?
goes on constantly
thrombosis (pathologic hemostasis)
the same processes can occur in contexts where formation of blood clot is pathologic and detrimental to downstream tissue
when can thrombosis occur
- when factors promoting coagulation are inc.
- actions of inhibitors/fibrinolysis are dec
what is fibrinolysis
enzymatic breakdown of blood clots
when are blood clots pathologic
when they are not localized to a site of injury, form in an uncontrolled manner, or fail to resolve over time
2 types of hemostasis:
primary - provided by platelet
secondary- provided by soluble coagulation factors
major components of hemostasis
- blood vessels
-platelets
-coagulation factors
-inhibitors
general steps of hemostasis:
- vasoconstriction
- primary hemostasis
- secondary hemostasis
what is vasoconstriction the result from?
local sympathetic pain response
what is primary hemostasis
-platelet plug
-physically bridges the defect
-platelets also provide the surface for secondary hemostasis
-secrete cofactors to aid in secondary
what are platelets
anucleate cells that form when megakaryocytes in bone marrow break off pieces of their cytoplasm
what are platelets made of
- alpha granules (adhesion, GFs)
- dense granules (activators, co-factors, GFs)
main steps of platelet plug formation;
-Adhesion
-Shape change
-Secretion
-Aggregation
-Contraction
platelet plug formation detailed:
- injury causes the endothelial cell layer to be unattached and expose vWF and collagen
- platelets bind to vWF and hold them weakly via GPIb
- platelets also bind to collagen via GPVI that activates platelets and change its shape
- form platelet plug and stable adhesion
what is the blood vessel subendothelial matrix rich in
-vWF
-collagen
what are vWF produced by
produced mainly by endothelial cells
what are vWF stored in?
Weibel palade bodies in endothelial cells and platelets
what does vWF do?
coats subendothelial collagen
-facilitates binding of PLT via GPIb
-stabilizes FVIII
-also binds GPIIb-IIIa
what are some platelet activators
- collagen
- thrombin via secondary hemostasis
-PAF
-ADP
glycoproteins vs integrins
-glycoproteins: weaker: tether
-integrins: stronger adhesion
-similar to leukocyte transmigration
what receptor is the most important in platelet aggregation
fibrinogen receptor
what happens when platelets stick to the underlying matrix ?
- conformation change in GPIIb-IIIa
- secrete mediators
- aggregate
- support activation of secondary hemostasis
what forms bridges between platelets
fibrinogen
what does activation of platelets cause
platelets to secrete granules that contain substances that activate additional platelets
first platelet aggregation is
reversible
once thrombin is generated, the platelet plug is
stabilized
platelet plug is stabilized because thrombin:
- binds to receptors on platelets that cause the platelets cytoskeleton to contract
- thrombin leads to fibrin generation which glues platelets together
secondary hemostasis overal goal:
to create the fibrin lattice via coagulation factors, zygomens, and co factors
a series of proteolytic cleavages produces
active thrombin
what does active thrombin do?
cleaves fibrinogen into fibrin
what does fibrin do?
forms the meshwork that holds cells within the clot and gives the clot its tensile strength
proteolytic cleavage can be achieved via
- extrinsic pathway
- intrinsic pathway
- common pathway
which is the primary pathway that activates coagulation in vivo
extrinsic
mechanism of extrinsic pathway:
- TF 3 exposed to factor VIIa
- TF-VIIa complex cleaves factor X to Xa
- starts common pathway
TF/VIIa complex requires
- negatively charged phospholipids and Ca
intrinsic pathway mechanism:
- Factor XII is exposed to thrombogenic surface
- activated to XIIa
- activates XI
- activates IX
- activates X with factor VIIIa
- common pathway
what is the intrinsic pathway known as
amplification pathway
what is the common pathway:
where intrinsic and extrinsic converge
mechanism of common pathway
- X is activated to Xa via intrinsic and extrinsic pathway
- Xa cleaves prothrombin to thrombin
- thrombin cleaves fibrinogen to fibrin
Main activators of the extrinsic pathway:
Tissue factors: via monocytes, endothelial cell damage, and VSMCS
TF VI+ Ca that activates factor X
what are the hemophilia TFs?
VIII and IX
lack of factor XII or XI causes
no bleeding
lack of factor VIII or IX leads to
hemophiliacs
bleeding
which factors are vit K dependent?
IX, X, VII, prothrombin (II)
What does thrombin do?
- cleave fibrinogen
- activates FXIII
- activates FV and VIII
- enhances XI activation
- activates protein C
- activates platelets
coagulation must be ______ to be effective
localized
localization is provided by:
- TF expressing cells
- cell membranes rich in neg charged phospholipids (PS)
cell based model of coagulation steps
- activation
- amplification
- propagation
initiation of Cell based model of coagulation
- TF exposed to VIIa in blood and extrinsic pathway is activated
- generates a little bit of thrombin
activity of Xa is restricted to cell surface
-thrombin acts on platelets which cause their activation/aggregation
-platelets can only interact in injury/endothelial cell compromise/firmly adhered
how does amplification occur ?
-activated platelets flip their membranes and expose large amounts of PS which adds more fuel to coagulation
-thrombin activates more FV, FVIII, FXI
-whole process is amplified as thrombin diffuses from initial site and activates more nearby platelets and coag factors
how is propagation occur?
-critical threshold of activated platelets and coag factors is reached
-large burst of thrombin occurs
-burst is sufficient for cleavage of fibrinogen and formation of fibrin meshwork
thrombin generated during burst ___
can promote clot formation but is a signaling molecule that initiates feedback systems to dampen coagulation and activate fibrinolysis
