31: Hemostasis - Wilson Flashcards
define hemostasis
processes preventing blood loss at sites of vascular injury whilst maintaining the fluid state of circulating blood
tightly controlled to prevent excessive bleeding and hypercoagulability
immediately following injury local factors such as endothelin trigger…
localized vasoconstriction
reduces blood flow to injured area
vascular damage exposes components of extracellular matrix, platelets adhere and activate –>
hemostatic plug forms
exposure of tissue factor at site of damage sets in motion the …
coagulation cascade
ultimately results in activation of thrombin
thrombin cleaves soluble _____ to yield insoluble ___
fibrinogen; fibrin
fibrin network forms, recruiting additional platelets and stabilizing the clot
anucleate cell fragments derived from megakaryocytes in bone marrow
platelets
___________ produce VWF which is secreted into subendothelial extracellular matrix
endothelial cells
vWF links platelets to collagen of the ECM; vWF also binds coagulation factor referred to as factor VIII
efficient platelet adhesion to ECM requires _____ and ________
vWF and glycoprtn Ib on platelet membrane
_______ interaction required to withstand high shear forces
GPIb-vWF
adhesion triggers __ signal and platelets undergo dramatic shape change
calcium
become spiny, extend long processes
activated platelets release mutliple compounds: dense (___________) and a-granules (___________)
ADP, ATP, Ca2_ histamine, 5HT, Epi
fibrinogen, fibronectin, vWF, coagulation factor V, PDFG
platelt activation release free arachidonic acids, which is converted to ______ by COX
prostaglandin G2
ultimately gives rise to thromboxane A2
____, ______, _____ function as vasoconstriction reducing blood loss at site of injury
thromboxane A2
serotonin
epinephrine
feed-forward activation effect of clot formation
ADP and thromboxane A2
____ triggers change in conformation of GpIIb-GPIIIa
ADP
allows receptor to bidn fibrinogen
*most common inherited bleeding disorder
von Willebrand disease
sx: frequent nosebleeds, excessive bleeding following dental treatment, excessive bruising
managed with desmopressin (induces release of vSF and factor VIII form storage sites within the endothelium)
giant platelets fail to aggregate in response to stimuli, defect in interaction between vWF and GpIb
bernard-soulier syndrome
therapy aims to reduce bleeding risk, platelet transfusion
defects in gpIIb and/or GpIIIa causing platelts fail toaggregate in response to various stimuli
glanzmann thrombasthenia
therapy aims to reduce bleeding risk, platelet transfusion
partial thromboplastin time test measures
intrinsic pathway of coagulation cascade
prothrombin time test measures what
extrinsic pathway of coagulation cascade
intrinsic and extrinsic pathways converge upon …
activation of factor X
factor X activation results in activation of thrombin (key regulator of coagulation)
factor = I II III IV VI
fibrinogen prothrombin tissue factor calcium does not exist
most coagulation factors are made…
in the liver
factor VIII is made in endothelial cells
what coagulation factors require vit K?
prothrombin, VII, IX, X
all contain gamma-carboxygluatamate residues, which chelated Ca2+, bound attahces to negatively charged membrane lipids
restricts clot formation to site of injury! !
carboxylase conerting glutamate to gamma-carboxyglutamate requires vit K
warfarin MOA
prevents regeneration of vit K (blocks production of gamma-carboxyglutamate residues)
key regulator of homeostasis
thrombin
does three things
- cleaves fibrinogen to fibrin to make clot
- activates factor V and VII (extrinsic pathway)
- activates factor VIII (intrinsic pathway)
where does the intrinsic pathway work?
on surface of endothelial cells
4 actions of thrombin
- cleaves fibrinogen to form fibrin
- enhances clotting via positive feedback
- induces paltelt aggregation
- activates endothelial cells to promote wound healing
deficiency in factor VIII
hemophilia A
deficiency in factor IX
hemophilia B
endogenous anticoagulant activities
thrombin
prtn C and prtn s
serpins
tissue factor pathway inhibitor
thrombin both _____ and inhibits coagulation
drives
thrombin/thrombodmodulin activates _____
prtn C
active prtn C binds prtn S
prtn c/S complex degrades factor Va and VIIIa –> blocks clotting
factor V resistant to cleavage by prtn C
factor V leiden
hypercoagulation
antithrombin III is an example of…
serpin (serine protease inhibtiors)
inhibits thrombins and binds heparin
inhibitor of factor VIIa that blocks the extrinsic pathway
tissue factor pathway inhibitor TFPI
also inhibits factor Xa
prtn produced by endothelial cells
fibrin is degraded by ______
plasmin
plasmin circulates in blood as plasminogen, has affinity for fibrin and incorporates itself int clot
tPA secreted by endothelial cells (Stimulated by activated prtn C)
how does streptokinase work?
exogenous activator of plasminogen
used to treat PE, DVT
