EXAM #1: HEMOSTASIS Flashcards Preview

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Flashcards in EXAM #1: HEMOSTASIS Deck (34)
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1

Define hemostasis.

Prevention of blood loss at a site of injury.

2

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.

3

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.

4

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

5

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

6

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

7

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.

8

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.

9

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.

10

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.

11

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.

12

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

13

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

14

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.

15

Describe how the prothrombinase complex generates active thrombin

Prothrombinase complex is:
- Factor Xa
- Va
- Ca++

This complex RAPIDLY cleaves prothrombin to thrombin

16

What are the roles of thrombin in generating the insoluble fibrin clot?

Thrombin=
- Cleaves fibrinogen to fibrin that forms the insoluble fibrin clot

17

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

18

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.

19

Outline the pathophysiology of Hemophilia A.

Hemophilia A=
- Most common
- Factor VIII deficiency

20

Outline the pathophysiology of Hemophilia B.

- Less common
- Factor IX deficiency

21

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

22

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

23

What are the consequences for patients with this form of factor V?

Increases the risk for thrombosis

24

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

25

What is ‘tissue factor pathway inhibitor (TFPI)’?

- Protein produce by endothelial cells
- Inhibits VIIa to block the extrinsic pathway
- Also inhibits Factor Xa

26

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

27

What is streptokinase and how does it function?

This is an exogenous activator of plasminogen produced by B-hemolytic streptococci

28

How is vFW treated?

Desmopressin, which induces the release of vWF and Factor VIII from storage sites in the endothelium

29

Outline the entire coagulation cascade.

N/A

30

What is the ultiamte purpose of the coagulation cascade?

Activation of Thrombin