(MHD) Normal Hemostasis/ Thrombosis I and II

Question 1

Normal vs Abnormal Hemostasis

Answer 1

Normal Hemostasis: the complex process by which ruptured vessels undergo changes which prevent blood loss (i.e. formation of hemostatic plug)

Abnormal Hemostasis: the process by which blood forms a clot within intact blood vessels (aka thrombosis)

Question 2

Hemostasis is dependent upon what three major entities?

Answer 2

1. Blood vesel wall (endothelium and sub endothelial substances)
2. Platelets
3. Coagulation and fibrinolytic systems

Question 3

The (4) main components of the hemastatic response

Answer 3

1. Vasoconstriction
2. Primary hemostasis
3. Secondary hemostasis
4. Formation of platelet-thrombin plug (permanent plug)

Question 4

____________ is released from the endothelial cells in distress

What is this agent and what does it do?

Answer 4

Endothelin

It is a potent vasoconstricting agent

Question 5

The (5) steps of primary hemostasis

Answer 5

1. Platelets adhere to the damaged vessels (bind vWF)
2. Platelets undergo shape change from discoid formation
3. Light and dense granules release important cytokines (ADP, thromboxane A2, serotonin etc.)
4. Activated platelets recruit other platelets
5. Hemostatic plug formation

Question 6

Describe the process of secondary hemostasis

Answer 6

Tissue factor is released from endothelial cells at the site of injury and combines with platelet factors to initiate the plasma coagulation cascade, ultimately causing a thrombin to form.

These coagulation proteins form complexes on the platelet surface utililizing the phospholipids of the platelet membrane.

Question 7

Formed fibrin is polymerized by…

Answer 7

Factor XIIIa

Question 8

During the formation of the platelet-thrombin plug (permanent plug), what are the roles of thrombin (2)

Answer 8

1. Thrombin stimulates recruitment and activation of additional platelets
2. Thrombin enzymatically converts fibrinogen to fibrin

Question 9

The (2) general pathways that the endothelium uses to modulate elements of the hemostasis-coagulation sequence.

Answer 9

1. Anti-thrombotic effect (normal state)
2. Prothrombotic effect (response to injured endothelium)

Question 10

Name the (3) components of the antithrombotic effect of the endothelium

Answer 10

1. Antiplatelet effect
2. Anticoagulant effect
3. Fibrinolytic-effect

Question 11

Describe the antiplatelet effect of the antithrombotic effect

Answer 11

Intact endothelium prevents platelets and coagulation proteins from coming into contact with subendothelial collagen and secretes prostacyclin and NO which prevent platelet aggregation.

Question 12

Describe the role of Heparin-like molecules in the anticoagulant effect of the antithrombotic effect

Answer 12

Heparin-like molecules combine with antithrombin to inactivate factors Xa and IXa

Question 13

Describe the role of Thrombomodulin in the anticoagulant effect of the antithrombotic effect, particularly as it relates to Protein C and its function.

Answer 13

Thrombomodulin combines with thromobin creating a complex that activates protein C. Protein C mediates proteolytic degradation of Factor Va and VIIIa.

Question 14

What is the role of protein S?

Answer 14

It is a cofactor for protein C activation

Question 15

Describe the Fibrinolytic effect of the antithrombotic effect

(describe the role of plasminogen and plasmin)

Answer 15

Among a number of other functions, endothelial cells also secrete plasminogen activators (t-PA). Plasminogen is converted to plasmin which dissolves the clot.

Question 16

What (2) things do endothelial cells secrete to promote the prothrombotic effect?

Answer 16

1. von Willebrand factor
2. Tissue factor

Question 17

von Willebrand factor

Answer 17

A protein which forms a molecular bridge between platelets and sub-endothelial collagen, allowing platelet adhesion to endothelial cells to occur.

Secreted by endothelial cells during Prothrombotic effect.

Question 18

Tissue factor

(what does it do? what can stimulate its secretion?)

Answer 18

Synthesized and secreted by the endothelial cells. Activates the extrinsic sequence of the coagulation cascade, thereby promoting the generation of thrombin and formation of a clot.

Cytokines released by injured endothelial cells can stimulate cells to synthesize more tissue factor

Question 19

What is the key difference between primary and secondary hemostasis?

Answer 19

Fibrin is only involved in secondary hemostasis– NOT primary

Question 20

T-PA

Answer 20

Tissue Plasminogen Activator

Also known as fibrinolysis. Functions to dissolve clot after its function has been served. This is important because if it is not broken down you risk thrombosis or embolus.

Question 21

Distinguish between the two types of granules found in platelet cytoplasma

Answer 21

Light granules: aka ALPHA - contain platelet factor 4, fibrinogen and other factors

Dark (dense) granules- aka BETA- contain ADP, calcium, serotonin, etc.

Question 22

Name the 2 most key platelet receptors

Answer 22

• Glycoprotein IIb/IIIa
• Glycoprotein Ib

Question 23

What is von Willebrand factor bound to? (2)

Answer 23

It binds to the surface of exposed subendothelium and to the GpIb receptor of the platelet

Question 24

What is the GpIIb-IIIa receptor bound to and what is its function?

Answer 24

It binds to fibrinogen, which is bound to the GpIIb-IIIa receptor of another platelet, allowing for platelet aggregation

Question 25

Bernard-Soulier syndrome

Answer 25

Deficiency of **GpIb**, which keeps platelet from binding von Willebrand factor (leading to loss of clotting ability)

Question 26

Glanzmann thrombasthenia

Answer 26

Deficiency of **GpIIb-IIIa** complex which leads to a loss of fibrinogen mediated aggregation of the platelets.

Question 27

What are the 3 broad steps that lead to platelets forming a clot

Answer 27

Platelet adhesion, activation and aggregation

Question 28

Activation of platelets is intiated by molecules binding with platelet ______________ receptors.

Answer 28

GP-Ib receptors

Question 29

Upon activation platelets release...

Answer 29

granular content including ADP, calcium, and **thromboxane A2**

Question 30

Thrombin functions to...

Answer 30

...convert fibrinogen to fibrin. **Fibrin** then surrounds and structurally _holds platelets together_ to form the plug.

Question 31

What activates the intrinsic pathway of the coagulation cascade? How is the functioning of this pathway measured?

Answer 31

It is activated by the patients own endogenous activating mechanisms. Measured by the aPTT test

Question 32

What activates the extrinsic pathway of the coagulation cascade? What test is used to measure the state of this pathway? What is are the 2 key factors associated with this pathway

Answer 32

TIssue injury PT/ INR Associated with tissue factor and factor VII (or VIIa)

Question 33

What is the key factor which starts off the common pathway of the coagulation cascade?

Answer 33

Factor X

Question 34

Factors of the coagulation cascade are all ________ proteins, except for factor __________ which is a _________ protein.

Answer 34

* serine * XIIIa (fibrin stabilizing factor) * transaminase

Question 35

What factors make up the prothrombin group of coagulation? All of these proteins contain ____________ which is needed for the binding of \_\_\_\_\_\_\_\_\_.

Answer 35

* Factors II, VII, IX and X * gamma-carboxy glutamic acid * calcium

Question 36

Association between liver and bleeding issues

Answer 36

The liver is key in the production of prothrombin group factors, so liver diseases may result in decreased clotting ability.

Question 37

Name the factors which make up the _contact group_ of the coagulation cascade.

Answer 37

Factors XI, XII, Fletcher factor (Prekallikrein) and Fitzgerald factor (HMW Kininogen) (these last two play a key role in the intrinsic pathway)

Question 38

Name the key inhibitors of the coagulation system

Answer 38

* Antithrombin III (AT) * Tissue factor pathway inhibitor (TFPI)

Question 39

Antithrombin function

Answer 39

A plasma inhibitor which also mediates the anticoagulant actions of heparin.

Question 40

Fibrinolytic system

Answer 40

A network of enzymes that are responsible for the dissolution of a formed clot.

Question 41

What is the key protein which serves to lyse clots?

Answer 41

Plasmin (aka fibrinolysin)

Question 42

Name the key fibrinolytic system inhibitors

Answer 42

1. **Plasminogen activator inhibitor (PAI)** 2. a2-antiplasmin

Question 43

The 3 factors which make up virchow's thrombosis triad

Answer 43

1. endothelial injury 2. hypercoagulability 3. abnormal blood flow

Question 44

Molecular thrombophilias Give an example

Answer 44

Molecular predisposition to thrombosis ex. activated protein C deficiency [APC syndrome]

Question 45

Where does VWF come from?

Answer 45

1. Platelets 2. Endothelial Cell (Weibel-Palade body)