EXAM #1: HEMOSTASIS Flashcards
Define hemostasis.
Prevention of blood loss at a site of injury.
Describe how platelets adhere to the extracellular matrix exposed at a site of vascular injury.
- Vascular damage exposed ECM
- Platelets adhere to the ECM and activate
Specifically, TF initiates the coagulation cascade.
What is the role of von Willebrand factor and glycoprotein Ib (GPIb)?
- vWF is produced by endothelial cells
- Vascular damage exposes the ECM and vWF
- Platelets contain GPIb that binds vFW
This links the platelet to the damaged ECM. Note that platelets also contain - Integrin a1B1 binds collagen.
What is the importance of von Willebrand factor in the normal function of factor VIII?
vWF also binds Factor VIII, which prolongs the half-life of VIII
Describe the morphological changes that occur upon platelet activation.
- vWF and GP1b binding triggers Ca++ signaling in the platelet
- Morphological change causes the platelet to change from a disc shape to a spherical shape with filopodia
What sorts of compound are secreted by activated platelets?
Dense granules
- ADP
- ATP
- Ca++
- Histamine
- 5-HT
- Epi
alpha-granules
- Fibrinogen
- Fibronectin
- vWF
- Factor V
- PDGF
Vasoconstriction and further platelet activation
Explain the process of platelet aggregation, including the roles of aggregation signals, GpIIb-GpIIa, and fibrinogen
- ADP causes a change in conformation of GpIIb/IIIa receptor, which allows it to bind FIBRINOGEN
- Fibrinogen is the glue that binds platelets together i.e. allows platelets to aggregate
*****At this point the platelt “plug” has been formed.
Outline the pathophysiology of von Willebrand disease?
This is the most common platelet defective clotting disorder
- vWF functions in initial platelet binding and extends the half-life of Factor VIII
- Causes excessive bleeding, bleeding from dental treatment…etc.
What is Bernar-Soulier Syndrome? How is it treated?
Inherited platelet disorder hallmarked by:
- GIANT platelets that fail to aggregate
- Thrombocytopenia
**Generally, there is a defect in the vWF and GpIb interaction; the precise mechanism is unclear.
Treatment includes limiting bleeding risk and platelet transfusion when bleeding is inevitable.
What is Glanzmann thrombasthenia?
This is an inherited bleeding disorder caused by:
- Defect in GpIIb or GpIIIa
- Platelets fail to aggregate b/c they cannot bind fibrinogen i.e. the “platelet glue”
Therapy aims to prevent bleeding and transfusion.
What is the importance of vitamin K in the coagulation cascade? What enzyme is Vitamin K an important cofactor for?
- Vitamin K activates Prothrombin (II), VII, IX, X and Proteins S and C
- Specifically, Vitamin K is a cofactor for Carboxylase, which converts glutamate to y-carboxyglutamate
- y-carboxyglutamate chelates Ca++ and traffics bound Ca++ to negatively charged membrane lipids
Thus, Vitamin K is required to target these clotting factors to the site of injury.
How does warfarin function in the prevention of blood clotting?
- Anticoagulant
- Warfarin inhibits Vitamin K dependent activation of clotting factors
- Specifically, Warfarin inhibits the activation of Vitamin K epoxide to Vitamin K via Vitamin K epoxide reductase
Outline activation of thrombin via the extrinsic pathway.
- Damage to the endothelium exposes Tissue factor
- In the presence of Ca++ Factor VII binds TF and is activated
- Factor X associated with TF/VIIa to form EXTRINSIC XASE COMPLEX
- Factor VII cleaves Factor X to Xa
Include the roles of the various components of the extrinsic Xase complex.
- Generation of Xa via VIIa cleaving X
- Slow cleavage of prothrombin to thrombin
Note that Thrombin activates Factor V.
Describe how the prothrombinase complex generates active thrombin
Prothrombinase complex is:
- Factor Xa
- Va
- Ca++
This complex RAPIDLY cleaves prothrombin to thrombin
