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what is the purpose of hemostasis?
-keep blood fluid and clot-free in healthy vessels
-form a plug in injured vessels to heal and prevent blood loss
what is thrombosis?
inappropriate activation of hemostatic processes
what is thrombus?
solid mass of blood components that forms locally and blocks blood flow
-stays in place
what is embolus?
substance that travels through blood and causes blockage away from site of origin
-when thrombus detaches
what is a thromboembolus?
thrombus breaks free
-most common
what is an arterial thrombosis?
-small to medium vessels
-damaged vessels
-produce platelet-rich clot
what is a venous thrombosis?
-veins and venuoles
-associated with reduced blood flow (hemostasis)
-associated with inappropriate activation of coagulation cascade
-produce fibrin-rich clot
what are considered white clots?
arterial clots
what are arterial clots (contain, cause, treatment)?
-contain many platelets
-caused by atherosclerosis
-treated with antiplatelets
what are considered red clots?
venous clots
what are venous clots (contain, cause, treatment)?
-large size
-mostly fibrin and RBC components
-blood stasis and/or medications
-treated with anticoagulants
what are arterial clots treated with?
antiplatelets
what are venous clots treated with?
anticoagulants
what kind of clot are oral contraceptives associated with?
venous clots
what do antiplatelets prevent?
occurrence or growth of clot
what do anticoagulants prevent?
occurrence or growth of clot
what do thrombolytics do?
bust an existing clot
list the thromboembolic conditions
-DVT
-PE
-stroke
-MI
-disseminated intravascular coagulation
list the bleeding conditions
-vitamin K deficiency
-thrombocytopenia
-stroke
-impaired liver function
-hemophilias
what thromboembolic conditions are associated with venous clots?
-DVT
-PE
what thromboembolic conditions are associated with arterial clots?
-stroke
-MI
list the three predisposing factors of Virchow's Triad
-endothelial injury
-stasis
-hypercoaguable state
what are the three factors of thrombosis called?
Virchow's Triad
what type of thrombosis is endothelial injury usually associated with?
arterial
what type of thrombosis is stasis usually associated with?
venous
what type of thrombosis is hypercoaguable state associated with?
-arterial
-venous
which part of Virchow's triad is inadequate disease management (HTN, HLD, DM) associated with?
endothelial injury
which part of Virchow's triad is afib or atherosclerotic plaques associated with?
stasis
what does stasis do?
-increases endothelial cell activation and platelet proximity
-activated coagulation factors "overstay" their welcome
which part of Virchow's triad may be genetic or acquired?
hypercoaguable state
what are common causes of a hypercoaguable state?
-malignancy
-oral contraceptives
-HIT
what is the sequence of events of coagulation?
-vasoconstriction
-primary hemostasis
-secondary hemostasis (coagulation cascade)
-resolution
which part of coagulation is a reflex mechanism?
vasoconstriction
what does vasoconstriction respond to?
secreted vasoconstrictors (released by damaged cells and platelets)
list the vasoconstrictors
-epinephrine
-serotonin
-endothelin
-thromboxane A2
what rate does vasoconstriction occur?
-immediately
-transient (not permanent)
what is primary hemostasis?
platelets activate and adhere to subendothelial matrix
what is secondary hemostasis?
activation of coagulation cascade leads to formation of fibrin matrix
-recruitment of more platelets
what is resolution?
formation of stable plug
-activation of antithrombotic mechanisms to restrict plug to site of injury
what are the three steps of primary hemostasis?
-adhesion
-granule release and activation
-aggregation
how does platelet adhesion occur?
-damage or injury to vascular endothelium
-subendothelial collagen exposed to blood
-exposed collagen binds VWF and platelets
-binding interactions with glycoproteins
how does granule release and activation occur?
-adhering platelets change shape
-secrete alpha and dense storage granules (ADP)
-phospholipase activation
-increased synthesis and release of TxA2
-ADP AND TxA2 activate platelets
-activation of IP3-DAG pathways
-GPIIb-IIIa converted from resting to activated state (minions--> purple minions)
how does platelet aggregation occur?
-activated GPIIb-IIIa binds to fibrinogen with high affinity
-fibrinogen binds on both sides, cross-links platelets to form a mesh, becomes primary hemostatic plug
what is the purpose of secondary hemostasis?
form a stable fibrin clot at the site of injury
what are the pathways in secondary hemostasis?
-intrinsic
-extrinsic
-merge into common pathway
when does the coagulation cascade occur?
secondary hemostasis
do the two pathways of secondary hemostasis occur at the same time as eachother?
yes
same time as primary hemostasis too
what are activated in the coagulation cascade?
inactive proenzymes
once activated, what do inactive proenzymes serve as?
-cofactors
-enzymes for subsequent reactions
how do you recognize the active form of proenzymes?
a
where are proenzymes synthesized?
liver
where do the reactions that activate proenzymes occur?
phospholipid protein-protein complexes
what is required for proenzymes to be activated?
-phosphatidylserine
-Ca2+
what part of coagulation has amplification and positive feedback?
coagulation cascade (secondary hemostasis)
explain the extrinsic pathway
-initiating factor (TF) is outside of
-tissue factor (TF) is on exposed, damaged endothelium
what is the primary pathway for in vivo coagulation?
extrinsic
what initiates the extrinsic pathway?
TF-calcium complex
what coagulation pathway also plays a role in platelet activation?
extrinsic
explain the intrinsic pathway
factors are contained within blood
what is the primary pathway for in vitro coagulation?
intrinsic
what are the three key functions of thrombin?
-induction of platelet recruitment/activation
-conversion of soluble fibrinogen to insoluble fibrin
-activation of proenzymes --> amplification of coagulation cascade
what drives positive feedback?
thrombin
when does fibrin polymerization occur?
loss of solubility
what is the end result of coagulation?
erythrocytes trapped in fibrin mesh
what is fibrinolysis?
dissolution of clot begins shortly after it is formed
what is plasminogen converted to plasmin by?
tissue-type and urokinase-type plasminogen activators
are the plasminogen activators stable?
no
rapidly inactivated
what does plasmin digest?
-fibrin
-fibrinogen
-factor V
-factor VIII
-prothrombin
-factor XII
what characteristic of plasmin limits its activity to the local clot?
rapidly inactivated
what are the limitations of clot formation?
-pro-coagulant factors are often membrane-bound
-anti-coagulant factors are soluble and secreted
-Five important substances (Antihrombin III, Proteins C and S, t-PA, PGI2, TF pathway inhibitor)
why do pro-coagulant factors limit clot formation?
-membrane-bound
-localized activity
what does antithrombin III do?
inactivates thrombin and other factors
what enhances antithrombin III activity?
heparin-like molecules
what are proteins C and S?
-vitamin K-dependent proteins
-inactivate factors Va and VIIIa
what are treatment strategies for clots?
-inhibit platelet activity
-dissolve clot (clot busters)
-anticoagulants
what treatment strategy prevent clots/enhance endogenous anticlotting system?
anticoagulants
what treatment strategy always has bleeding as an ADR?
anticoagulants