week 4- coagulation part 2 Flashcards
what are some regulators of hemostasis:
- anticoagulant proteins
- endothelial cell
- fibrinolysis
what is a major anticoagulant
antithrombin
what does antithrombin degrade
IIa (thrombin) , IXa, Xa
stimulated by heparin and heparin-like proteoglycans
where is antithrombin made
liver
protein C
-made in liver
-vitamin K dependent
-activated when bound by thrombin: thrombomodulin = forms APC complexes
what does protein C inactivate
Va, VIIIa
Tissue factor pathway inhibitor (TFPI)
produced by the endothelial cell and inactivates the tissue factor VIIa complex
healthy endothelial cell is
anti thrombotic
how do endothelial cells prevent platelets from sticking to endothelial cells and limiting secondary hemostasis
- expression of heparin -like molecules that inhibit coagulation
- production of factors that reduce platelet activation
- enzymes that degrade ADP (ADP activates platelets)
- thrombomodulin (binds thrombin and activates protein C)
- Protein S (cofactor for Protein C)
- tissue factor pathway inhibitor
- tissue type plasminogen activator (promotes fibrinolysis)
what is fibrinolysis
removal of clots , set into motion by coagulation
plasmin is formed by cleavage of
plasminogen
active plasmin can
break down fibrin and also inhibits its polymerization
activation of plasminogen occurs via
factor XII dependent pathway
or action of plasminogen activators
2 main types of plasminogen activators
tissue type (t-PA)
urokinase (u-PA)
main source of t PA
endothelial cells
where is u-PA present
plasma
where is tPA most active vs uPA
t-PA most active when bound to fibrin
u-PA can activate plasminogen in fluid phase
fibrinolysis regulators act to limit production of ______
active plasmin
examples of regulators of fibrinolyssi
- plasminogen activator inhibitors (PAI-1, PAI-2)
- antiplasmins
- C1 inhibitor
what is thrombosis
pathologic blood clot formation
thrombosis causes (virchow’s triad)
- endothelial cell activation
- changes in blood composition
- altered blood flow
what might cause endothelial injury/activation of vessel wall?
- inflammation
- infectious agents
- toxins
- trauma
- cancer cells
changes in blood composition is also known as
hypercoagulability
what may change blood composition ?
changes in plasma proteins , accumulation of metabolites that can alter fibrinogen structure
protein losing nephropathy
-glomerulus leaks protein into urine
-antithrombin is about the same size as albumin
-animals lose antithrombin in urine
-at risk of developing blood clot
altered blood flow
-turbulence and stasis
-very turbulent blood flow can mechanically damage the cell
-increases in stress can cause flow induced changes in gene expression
-stasis promotes interaction between platelets and vessel wall
fate of thrombi
- propagation
- embolization
- dissolution
- organization and recanalization
what is a downstream consequence of thrombus
infarts
what is an infarct
-area of ischemic necrosis caused by occulusion or significant reduction in blood flow to tissue
what is immunothrombosis
a blood clot that forms to entrap infectious agents and prevent their dissemination in the body
mechanism of cytokine mediated expression of TF and activation of coagulation proteins
- bacterial infection produces cytokines that stimulate membrane expression or inc. synthesis of TF
* in any disease state with cellular activation or damage, there is potential for activation of coagulation
what is bacterial polyphosphates (polyP) initiation of the contact pathway
-polyp are negatively charged phosphorus polymers that are an important source of energy in prokaryotes
-released by activated platelets and mast cells
-large amounts can activate FXII
-can also generate thrombin independently of FXI activation
thrombin mech:
-thrombin binds to PARs (protease activated receptors)
-signaling pathways triggered by thrombin: PAR promote activation of platelets
- results in all platelet changes associated with coagulation
once a PAR is activated ____
it is endocytosed
______ can activate specific PARs
TF-VIIa complex and Xa
What are NETs
meshes of chromatin and proteins that are spit out onto a cell
-bacteria is trapped in the meshes
DIC: disseminated intravascular coagulation
when inflammation triggers excessive activation of coagulation or dampens fibrinolysis, clots form in an unregulated, disseminated manner
important points of DIC
- always secondary
-animals can be in the state where they are showering their microcirculation with small thrombi or they can be bleeding because they are no longer able to clot
when clots dont form
hemorrhage
hemorrhage defined as
extravasation of blood
petechiae
pinpoint size hemorrhages into skin, MM, or serosal surfaces
ecchymoses
subcutaneous hemorrhage at least 1 cm
hematoma
accumulation of blood within tissue
causes of bleeding
- defects in primary hemostasis
- defects in secondary hemostasis
- trauma
- toxins
- vessel wall
why might animals with liver disease/failure bleed?
-no coagulation factors
-coagulation factors not carboxylated
-secondary to whatever is causing liver disease
severity of infarcts depends on:
-if there are alternative routes to supply tissue
-the needs of the cell population
-if there was advance warning
steps in wound healing:
