Flashcards in Blood Coagulation Deck (26)
What are some possible causes of slow clotting?
hemophilia, liver disease, rat poison
How does liver disease cause slow clotting?
the liver synthesizes many of the clotting proteins including prothrombin, fibrinogen, etc.
How does rat poison cause slow clotting?
they have antagonists of clotting. Causes massive internal bleeding
Specifically, warfarin blocks the conversion of glutamic acid to y-carboxy glutamic acid by acting as an inhibitor to the action of vitamin K (needed for the rxn), so coagulation factors synthesis is inhbitors
What conditions might cause OVERclotting?
What are the three stages of clot formation?
3) Propagation and stabilization
What is the first step in clot formation?
A cut exposes blood to nonvascular cells on the outside of the endothelial lining of vasculature. These nonvascular cells express the integral membrane protein, tissue factor (TF).
What does tissue factor do?
Activates factor VII to VIIa and forms a complex with it- the TF-VIIa complex
What does the TF-VIIa complex do?
activates factor X to Xa
What does factor Xa do?
activates a small amount thrombin from prothrombin. Not enough to make a clot though!
This is the last step of initiation
What does the activated thrombin then do?
activate platelets, which begin to express receptors on their cell surface
activates a protease, XI
and activates two accelerates, V and VIII
What happens next?
XI gets activated to XIa by X, and XIa activates IX to IXa
What does activated IXa do?
combines with an activated accelerator, VIIIa (don't know what activates it) and together they bind to platelet receptors and activate more X to Xa
What happens to the increased amounts of Xa that are made?
Xa will combine with activated Va (don't know what activates it) on platelets via receptors to accelerate (by 1000x) the formation of more thrombin from prothrombin
What do the increased levels of thrombin do?
activates platelets to express surface receptors that facilitate aggregation
activate fibrinogen to fibrin (forms a protein matrix around the platelets plugging the wound)
activated XIIIa from XIII
What does activated XIIIa do?
facilities the cross-linking of fibrin molecules to form a strong clot
What kinds of surface receptors do platelets begin to express when activated by thrombin?
VIIIa, IXa, fibrinogen/FIBRIN binding, collagen binding, fibronectin binding, and a receptor for Va (an accelerator)
How can the initiation step (to produce/activate a small amount of thrombin for amplification) be inhibited?
How does this work?
LACI (lipoprotein associated coagulation inhibitor). LACI inhibits the activation of Xa from the TF-VIIa complex to inhibit thrombin activation
How can the amplifications step of coagulation be inhibited?
anti-thrombin III+ herapin sulfate PG (found on downstream endothelial cells) complex
How does the anti-thrombin III- heparin complex work?
heparin sulfate PG/herapin is a proteoglycan that activates a protein called anti-thrombin III that together form a molecule to limit amplification by inactivating thrombin, factor Xa, and factor IXa if they flow away from the wound site
How can the propagation/stabilization step of coagulation be inhibited?
activated protein C-S complex destroys Va and VIIIa
What does plasmin do?
it is a protease that dissolves clots by digesting fibrin
What is thrombomodulin and what does it do?
It is a transmembrane protein expressed on endothelial cells that bind to activated thrombin and protein C. Protein C is then activated to a C-S complex (protein S is already on the cell surface) that inhibits accelerators Va and VIIIa. The Protein C-S complex is retained on the endothelial cell where it is activated to localize the anti-coagulative nature of it
What is plasmin activated by?
activated protein C and plasminogen activator
Deficiency of protein S, C, or antithrombin III causes what?
What is hemophilia?
genetic disorder causing mutations in the synthesis of coagulation factors