Lecture 15 Introduction to Normal Hemostasis

Question 1

*What is the definition of Hemostasis?

Answer 1

“Stoppage of blood flow” - Greek.

Mechanism by which bleeding from an injured vessel can be controlled and ultimately stopped.

Question 2

What is primary versus secondary hemostasis?

Answer 2

Primary Hemostasis is composed of vascular and platelet response to injury.

Secondary Hemostasis is composed of the coagulation response (extrinsic and intrinsic pathways) to injury.

Question 3

What are the main series of events in response to when blood vessel injury occurs (start with main headings)?

Answer 3

1. Extravascular Response (bleeding into tissues causes back pressure; collapses injured blood vessels)
2. Vascular Response (Automatic nervous reflex causes vasoconstriction, platelets attracted to site of injury release substances, serotonin, which cause further vasoconstriction.)
3. Platelet Response (Adhesion, aggregation, secretion).
4. Intravascular Response (Substances, TF3, released from damaged vessel wall, activation of 2 pathways of coagulation cascade).
5. Fibrinolytic System (Provides for dissolution of the clot while there is simultaneous tissue repair).

Question 4

What two things can occur if vascular, platelet, coagulation and fibrinolytic systems are not working in balance with each other?

Answer 4

1. Bleeding - poor clot formation or excessive fibrinolysis.
2. Thrombosis - Excessive coagulation or defective fibrinolysis.

Question 5

What role does the blood vessel wall play in general in hemostasis?

Answer 5

The blood vessel wall plays a role in anticoagulation and pro-coagulation.

Question 6

What are the four stages of hemostasis (main headings only)?

Answer 6

1. Vascular Mechanism.
2. Platelet Function.
3. Coagulation (extrinsic and intrinsic pathways)
4. Clot Stabilization (retraction).

Question 7

What are the 3 individual components of the vascular response to Hemostasis?

Answer 7

Vascular Mechanism:
1. Extravascular - mech pressure provided by pooling blood in surrounding tissues results in vasoconstriction preventing further blood loss.
2. Vascular - Neurogenic response causing instantaneous and automatic vasoconstriction. Platelets release serotonin and thromboxane A2 at site of injury causing further vasoconstriction.
3. Intravascular - Coagulation factors in plasma result in the formation of stable fibrin clot.

Question 8

Describe the 3 platelet functions in hemostasis?

Answer 8

1. Adhesion - Exposed collagen from vessel wall injury causes adhesion.
2. Aggregation - Platelets attach to each other. Release of ADP from platelets causes their shape change (discoid to spiney spheres). Thrombin and thromboxanne A2 promotes further aggregation.
3. Secretion - Platelets secrete substances from granules.

Question 9

What role does collagen play in platelet adhesion?

Answer 9

Platelets have receptors for collagen allowing them to bind directly to collagen in areas of low sheer stress (slow blood flood).

Question 10

What is required for platelets to adhere to the blood vessel wall in the main arteries of the body?

Answer 10

Von Willebrand factor (VWF) is required as a bridge between platelets and collagen in areas of high sheer stress (flow).

VWF will bind to exposed collagen and the platelets will bind to VWF

Question 11

Describe the various binding sites (functions) that von Willebrand factor (VWF) has?

Answer 11

1. Binding site for exposed collagen.
2. Binding site for platelet surface membrane GpIb/V/IX promoting platelet adhesion.
3. Binding site for platelet surface membrane GpIIb/IIIa promoting platelet aggregation.
4. Binding site for circulating factor VIII, important coagulation molecule. Binding to VHF helps the factor stabilize for longer term viability as VIII has a short half-life; thereby maintaining proper levels of VIII circulating in the plasma.

Question 12

Does fibrinogen and VWF also bind and what does that do?

Answer 12

Yes fibrinogen and VWF also bind to help support platelet aggregation.

(From the presentation I am not clear on the details here, this is my best interpretation).

Question 13

What granules are involved in these hemostasis roles:
a) Promote coagulation
b) Promotes aggregation
c) Promotes Vaso-constriction
d) Promote vascular repair?

Answer 13

a) Promote coagulation: α - granules
b) Promotes aggregation: dense bodies and α - granules
c) Promotes Vasoconstriction: dense bodies (also membrane phospholipids)
d) Promote vascular repair: α - granules

Question 14

What do the microtubules and microfilaments do when the platelet is activated and why?

Answer 14

Clot Retraction:
When platelets are activated internal microtubules and microfilaments contract to produce a stronger and more stable fibrin clot.

See diagrams on slide 24.

Question 15

Describe the coagulation system in general?

Answer 15

A series of reactions involving coagulation factors known as enzyme precursors (zymogens), active enzymes, non-enzyme co-factors, calcium, phospholipid and the substrate fibrinogen.

Final product is a stable clot that prevents bleeding.

Question 16

What are inactive coagulation factors known as?

Answer 16

Zymogens

Question 17

What are zymogens coagulation factors called when activated?

Answer 17

Proteases, denoted by adding a “a”.

Example:
Zymogen: Factor VII
Protease: Factor VIIa

See table on slide 26.

Question 18

What are the two pathways of coagulation?

Answer 18

Extrinsic pathway
Intrinsic pathway

Question 19

What is the extrinsic pathway testing for?

Answer 19

Tested for using Prothrombin time.

Question 20

What is the intrinsic pathway testing for?

Answer 20

Tested for using Activated Partial Thromboplastin Time

Question 21

What components does the coagulation cascade or “waterfall reaction” involve?

Answer 21

1.Coagulation factors - zymogens (inactive) converted to serine proteases.
2. Non-enzyme co-factors
3. Calcium
4. Phospholipids
5. Fibrinogen

Question 22

Name the coagulation factors involved in the cascade?

Answer 22

Factors II, VII, IX, X, XI, XII, XIII and prekallikrein.

Question 23

Is factor XIII a serine protease? What is its function?

Answer 23

No, it contains cysteine rather than serine. Builds peptide bonds rather than cleaving them.

Functions as a transglutaminase, transamidase.

Question 24

What is the common name for Factor I and its function?

Answer 24

Factor I is Fibrinogen - Thrombin substrate, polymerizes to form fibrin.

Question 25

What is the common name for Factor II and its function?

Answer 25

Factor II is Prothrombin a serine protease.

Question 26

What is the common name for Factor III and its function?

Answer 26

Factor III is Tissue factor, a cofactor.

Question 27

What factor roman numeral is ionic calcium?

Answer 27

Factor IV, it is a mineral.

Question 28

What factors are serine proteases?

Answer 28

II (Prothrombin), VII, IX, X, XI, XII, and Prekallikrein.

Question 29

What factors are cofactors?

Answer 29

Cofactors are III (Tissue factor), V, VIII and high molecular weight kininogen.

Question 30

What factor functions as a carrier for factor VIII and for platelet adhesion?

Answer 30

von Willebrand Factor.

Question 31

What is the function of platelet factor 3?

Answer 31

Assembly molecule.

(Not to be confused with tissue factor III).

Question 32

Where are the majority of coagulation factors produced?

Answer 32

In the liver.

Note: Uncertain for VIII and XII, see slide 29.

Question 33

Which factors are vitamin K dependent?

Answer 33

Factors II, VII, IX, and X
(2, 7, 9 and 10).

Question 34

Which factors have the shortest have-lives in the body?

Answer 34

Factors V, VII, and VIII (5, 7 and 8)

Question 35

At what % minimum hemostatic level of coagulation factors result in no risk of bleeding? Normal % range for most factors?

Answer 35

General around or mildly below 50% of any patient with a value 50% or over is at no risk of bleeding.

Normal range for most factors is 50% to 150%.

Question 36

What coagulation factors are only in the extrinsic pathway?

Answer 36

Only Factor VII.

Question 37

What coagulation factors are only in the intrinsic pathway?

Answer 37

Factors VIII, IX, XI, XII, Prekallikrein,
HMW Kininogen.

Question 38

What factors are common to both pathways?

Answer 38

Factors I, II, V, X, XIII
(1, 2, 5, 10, and 13).

Question 39

What is the role of factor VII?

Answer 39

In vivo, the VIIa+TF complex in the extrinsic system is the key activator of both the extrinsic and intrinsic pathways as it activates:
1. X to Xa in the common pathway and
2. IX to IXa in the intrinsic pathway.

Question 40

What is the effect of thrombin in the coagulation cascade?

Answer 40

Thrombin converts cofactors V and VIII to Va and VIIIa and XI to XIa which go on to generate large amounts of thrombin which is called the THROMBIN BURST.

Question 41

What factors belong to the contact group? What are they involved with?

Answer 41

HMWK, Prekallikrein, XI, and XII.

Involved in coagulation, fibrinolytic, kinin, and complement systems.

Question 42

What factors belong to the prothrombin group? What is common about them?

Answer 42

Factors II, VII, IX, and X.
These are the vitamin K dependent group.

Question 43

What factors belong to the Fibrinogen Group? What do they do?

Answer 43

Factors I, V, VIII, and XIII.

Acts as substrates for the fibrinolytic system.

Question 44

How is vitamin K important to the coagulation system?

Answer 44

Vitamin K is required to form calcium bridges with the platelet phospholipid surface.

Vitamin K is normally ingested in the diet and produced by the Normal Flora (bacteria) of the gut.

Question 45

What could cause deficiencies in Vitamin K?

Answer 45

Vitamin K may be decreased as a result of dietary deficiency, malabsorption, intake of antibiotics, etc.

Question 46

What anti-coagulation drugs interfere with Vitamin K processing in the body?

Answer 46

Coumadin and Warfarin interfere with Vitamin K carboxylation making these the Vitamin K dependent factors ineffective for coagulation.

Question 47

What is known as the hemophilic factor?

Answer 47

Factor VIII:C, a co-factor in the intrinsic system. Defective in Hemophilia A Disease.

Question 48

What cells produce Von Willebrand Factor (vWF)

Answer 48

Endothelial cells and megakaryocytes.

Large multimeric molecule.

Re

Question 49

What does thrombin do for clot stabilization?

Answer 49

Once Thrombin is generated from Xa and Va, Thrombin will convert Fibrinogen to an unstable Fibrin monomer. To make the clot strong and stable thrombin converts XIII to XIIIa. Factor XIIIa cross links weak fibrin monomers to strong polymers to produce a stable fibrin clot.

Question 50

In what way does thrombin change the chemical bond of the fibrin monomer so it becomes a polymer?

Answer 50

It changes the weak hydrogen bonding to a stronger peptide bonding.

Question 51

How and when are clots dissolved in the body?

Answer 51

Once the stable clot has been formed at the site of injury it has to be slowly dissolved while there is simultaneous underlying tissue repair. This is accomplished by the conversion of an inactive circulating substrate Plasminogen to an active enzyme Plasmin by factors such as Tissue Plasminogen Activator (TPA) and Contact Factors XIa, XIIa, and Kallikrein. Plasmin will slowly break down the fibrin into Fibrin Degradation Products which are removed by monocytes in the blood.