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
What are the roles of thrombin in generating the insoluble fibrin clot?
Thrombin=
- Cleaves fibrinogen to fibrin that forms the insoluble fibrin clot
What is the role of thrombin in and sustaining and accelerating the extrinsic and intrinsic coagulation pathways?
- Activates Factor V and VII of the extrinsic pathway
- Activates Factor VIII of the intrinsic pathway
Outline the activation of thrombin via the intrinsic pathway as it is thought to occur in the body.
1) Kallikrein= XII to XIIa
2) XI
3) IX
4) IXa activates Factor X
5) Factor Xa generates low levels of thrombin
6) Thrombin activates Factor VIII
Factor VIIIa and Ca++ form the intrinsic Xase complex with Factor X that rapidly activates Factor X to Xa. Xa rapidly activates thrombin.
Outline the pathophysiology of Hemophilia A.
Hemophilia A=
- Most common
- Factor VIII deficiency
Outline the pathophysiology of Hemophilia B.
- Less common
- Factor IX deficiency
How does thrombin, via thrombomodulin, protein C, and protein S function in anticoagulation?
1) Thrombin + thrombomodulin activates Protein C
2) Protein C and Protein S complex
3) Protein C/S complex inhibits Factor VIIIa and Va to block clotting
Thus, thrombomodulin changes the specificity of Thrombin
What is ‘factor V Leiden’ deficiency?
- Arginine in amino acid position 506 is changed swapped with glutamine in Factor V
- This mutation makes Factor V resistant to cleavage by protein C
What are the consequences for patients with this form of factor V?
Increases the risk for thrombosis
What is meant by the term ‘serpins’ ?
This is a family of serine protease inhibitors that INHIBIT the activated forms of coagulation factors
- ANTITHROMBIN III is the most important of the serpins
What is ‘tissue factor pathway inhibitor (TFPI)’?
- Protein produce by endothelial cells
- Inhibits VIIa to block the extrinsic pathway
- Also inhibits Factor Xa
How is fibrinolysis achieved?
- Fibrin is degraded by the serine protease plasmin
- Plasmin circulates as the inactivated plasminogen
- Plasminogen is activated to plasmin by TISSUE PLASMINOGEN ACTIVATOR i.e. t-PA
What is streptokinase and how does it function?
This is an exogenous activator of plasminogen produced by B-hemolytic streptococci
How is vFW treated?
Desmopressin, which induces the release of vWF and Factor VIII from storage sites in the endothelium
Outline the entire coagulation cascade.
N/A
What is the ultiamte purpose of the coagulation cascade?
Activation of Thrombin
What blood test measures the intrinsic pathway?
PTT i.e. “Partial Thromboplastin Time”
What is the blood test to measure the extrinsic/ common pathway of the coagulation cascade?
PT i.e. Prothrombin Time
Where does the common pathway start?
Factor X
What is the difference between the soft and hard clots?
Soft clot= clot held together by Fibrinogen and GpIIb/IIIa
Hard= thrombin activation of XIII, which catalyzes amide linkages between fibrin
