Basic Haemostasis Flashcards Preview

LSS 1- CVS > Basic Haemostasis > Flashcards

Flashcards in Basic Haemostasis Deck (48):
1

what are the functions of the homeostasis?

-Prevention of blood loss from intact vessels
-Arrest of bleeding from injured vessels.

2

What are the two main mechanisms involved in haemostasis?

Platelets and Clotting Cascade

3

What happens in primary and secondary homeostasis?

Primary - platelet activation and aggregation - formation of an unstable platelet plug
Secondary - stabilisation of the plug with fibrin.
Blood coagulation

4

Define coagulation.

The process by which blood is converted from a liquid to a solid.

5

What cells secrete Von Willebrand Factor?

Endothelial cells and platelets

6

What is exposed when the endothelial layer is damaged?

Subendothelial layer - rich in collagen

7

How can the subendothelial layer be recognised?

The Von Willebrand factors bind to the collagen and this attracts platelets- the platelets bind to the Glycoprotein 1b Receptor (GlpIb) on the VWF

OR
Glycoprotein 1a Receptor on the platelets directly binds to the collagen in the sub-endothelial layer.

Indirectly via vWF – occurs in high shear stress vessels such as arteries and microcirculation
Directly to collagen – occurs in low shear stress vessels such as veins

8

how are the platelets activated and what do they release?


Thrombin will then bind, activating platelets
Exocytosis of ADP vesicles and liberation of arachidonic acid
ADP released into blood, and arachidonic acid converted to TXA2 via intracellular COX enzymes


9

what does prostaglandins activate and what does this allow?

Prostaglandins activate other platelets so the platelets aggregate- the glycoproteins IIa and IIb receptors become available which the fibrinogen can bind to.

10

Describe the effect of thrombin on the formation of the primary platelet plug.

Thrombin stimulates the activation of platelets so that they aggregate.

11

Describe the changes in the morphology of the platelets that take place when they are activated.

Change in shape, due to Thrombin binding and subsequent release of Ca++ from calcium stores
The platelets become more speculated.

Change in membrane composition, due to autocrine and paracrine effects of ADP, making platelets more sticky

Expression of GlpIIb/IIIa, due to Thromboxane A2, allowing binding of fibrinogen

Phospholipids that were on the inside of the membrane move to the outside, which is important because they bind to coagulation factors.

12

Where are clotting factors, fibrinolytic factors and inhibitors synthesised?


Liver: Most coagulation proteins

Endothelial Cells: vWF

Platelets: Factor V, vWF (stored inside alpha granules)
Factor V is produced by megakaryocytes

13

what is the intrinsic pathway?

Involves the activation of a ZYMOGEN ( a precursor of a protease)- this is Factor XII.
Factor 12 is converted to Factor 12a which can then convert Factor 11 to Factor 11a and the cascade continues.

14

Which factors are cofactors?

Factor 8 : Factor 8 is co-factor for activated Factor 9. Forms a complex with it in the presence of calcium and phospholipids. This complex cleaves Factor 10 into its active form.


and Factor 5

15

Describe the extrinsic pathway.
What also prevents the secondary haemostasis from going out of control?

When a vessel is damaged, the blood comes into contact with TISSUE FACTOR.
Tissue factor is a potent initator of the clotting cascade.
Factor V and Factor VIII: activated by trace amounts of thrombin
Act as catalysts localised in platelet phospholipid bilayer to increase thrombin production 10,000x

Blood will clot rapidly, minimising blood loss


The extrinsic pathway is activation of factor 10 to 10a by Tissue factor (bound to Factor 7 and calcium.)
10a converts prothrombin to thrombin. Thrombin then activates the platelet- it forms a fibrin clot.This is the normal physiological activation of the clotting cascade.


2 mechanisms to stop secondary haemostasis going out of control and clotting all of the blood:

-ANTITHROMBIN: Circulating in blood, breaks down Factor 2a (and also 9a, 10a, Xia)
-THROMBOMODULIN: Extrinsic protein of endothelial cells, creates enzyme complex to break down catalytic Factors V and VIII
Thrombomodulin is paired to Protein C
Binding of thrombin to thrombomodulin allows Protein S in blood to bind to Protein C and activates Protein C.
Activated Protein C/Protein S complex acts as an enzyme

16

What are factor 1 and factor 2 more commonly called?

Factor 1 = Fibrinogen ---> Fibrin
Factor 2 = Prothrombin ---> Thrombin

17

Which factors can be crosslinked?

-Fibrin clot is insoluble.
-The clot can be crosslinked by Factor 13a- crosslinking is covalently crosslinking the fibrin clot so that it is stabilised and can't be broken down by the shear forces

18

What protein breaks down fibrin clots and what is its precursor? How is it activated?

Plasminogen and tPA (produced by endothelial cells) circulate in blood
Only interact on the surface of a fibrin mesh
tPA cleaves the Plasminogen zymogen to Plasmin
Plasmin breaks down fibrin mesh to complete wound healing, this releases Fibrin degradation products.
Plasmin broken down by antiplasmin

19

What is plasmin?

It is a powerful proteolytic enzyme that can break down the fibrin clot.

20

what are the breakdown products of the fibrin clot?

Fibrin Degredation Products (FDP).

21

What products can be given in therapeutic thrombolysis of myocardial infarction?

tPA (tissue plasminogen activator) and bacterial activator streptokinase

22

What are the two main coagulation inhibitory mechanisms?

DIRECT inhibition - antithrombin
Antithrombin – directly inhibits 1) thrombin, 2) FIX, 3) FX and 4) FXI
Tissue factor pathway inhibitor (TFPI) – inhibitor of initiation phase (TF-FVIIa)

INDIRECT inhibition - Protein C inhibition pathway
Activated Protein C/Protein S - inhibits FVa and FVIIIa

23

What factors are inhibited by antithrombin?

-Factor 2a, 9a, 10a and 11a
It is a broad scale clotting factor inhibitor

24

Describe the effect of heparin and when is it used?

-Heparin accelerates the action of antithrombin.
-Heparin is used for immediate anticoagulation in venous thrombosis and pulmonary embolism

25

what happens when there is a reduction in antithrombin?

Higher risk of thrombosis

26

What are factor 8 and factor 5 activated by?

Trace amounts of thrombin

27

Describe the protein C inhibitory pathway.

Thrombin, once produced is usually involved in clot formation, activating platelets and activating factor 8 and factor 5.
Thrombin can bind to thrombomodulin (a protein on the surface of the endothelium) which changes its specification, by redicrecting the activity from fibronogen to protein C.
It then activates Protein C and Protein S, which then inactivate Factor 8 and Factor 5. This is the second anticoagulant mechanism.

28

What are the consequences of Factor V Leiden?

Factor V Leiden is a common polymorphism in the population. Factor V Leiden can't be inactivated as well as wild type Factor V. If protein C can't inactivate the factor V leiden as well, there is increased risk of thrombosis.

29

what are the secondary haemostatic disorder

Genetic:
Haemophilia: Factor VIII (alpha) or Factor IX (beta) deficiency, so no binding

Antithrombin deficiency: No breakdown of Factor IIa, so untempered clotting

Protein C/Protein S deficiency: No breakdown of Factor V and VIII

Factor 5 Leiden: Arg506Gln Polymorphism, so resistant to breakdown by Protein C pathway


Acquired:
Liver Disease: Less liver synthesis, so less coagulation factors produced

Drugs: Heparin (upregulates action of antithrombin) and Warfarin (Factor II, VII, IX, X synthesis inhibitor) will cause too much bleeding

Diluted Blood: Lower concentration of coagulation factors

DIC: Excessive activation of clotting cascade leading to depletion of coagulation factors and fibrinogen, so absolutely no further clotting can occur.
Leads to very easy bleeding (e.g. internal haemorrhage) and organ failure due to fibrin deposition
Can be caused by widespread inflammation (e.g. from sepsis), massive haemorrhage


In secondary haemostasis disorders that cause too much bleeding, primary haemostasis is still functioning, so superficial cuts cause no problems

30

How can the homeostasis system kill you?

-bleeding to death
-kill you with thrombosis

31

What components is in our blood?

We have lots of proteins such as coagulation factors: help form clots to plug any holes
regulatory proteins: to stop from coagulation factors from firing prematurely, which is what causes thrombosis

32

Why do clots not just form all the time?

The don't, because the triggers they need are outside the circulation:
collagen and tissue factor, these are outside the circulation.

33

Von willebrand factor

A big and sticky protein. It has many binding factors.
-it has binding sites for platelets, collagen and factor 8.
Normally it is rolled up, so binding sites is hidden.

-when it binds to collagen, and the flow of blood pushes it it becomes long and thin.
- very big soluble protein, with many binding sites
-Giant adhesive plasma protein

34

platelets

-are fragments of megarkaryocytes.
- don't have nucleus
- made in the bone marrow
- half life of 10 days

35

which receptors can von willibrand bind to?

GP1b-alpha complex and Integrin aIIbeta3 receptor

36

give examples of stimulatory receptors?

-ADP which binds to purine receptors
-thromboxane binds to the thromboxane receptors.

37

what happens when the blood vessel is damaged, give explanation for primary homeostasis/

Blood is going to meet collagen and tissue factor.
Primary homeostasis:
- tissue factor not needed
-von willebrand factor is rolled up so binding sites cannot be seen by platelets, then binds to collagen and has lots of lots binding sites exposed so platelets bind to the von willebrand factor, platelets become activated and the granules will discharge and release more von willebrand factors and therefore form a platelet plug.

38

what happens to the platelet when it is activated?

-Platelet have this property of binding to von willebrand factor, particularly under shear.
-and once they bind they become activated, once they become activated:

1. change shape
2. expose phospholipid
3. present new or activated proteins on their surface ( present negatively charged receptors)

39

How does platelets become activated?

1. Platelets bind to VWF via GpIb allowing secondary binding to collagen & initiates activation
2. then binds to other platelets using fibronogen
3. and these signal to the platelets, causing calcium influx, causing granules to degranulate and releases ADP, fibronogen and more VWF
4. It also takes phospholipids from the surface of the platelet and makes thromboxane, so it can bind to the thromboxane receptor on the platelet and further activate the platelet.

This is a POSITIVE FEEDBACK.

40

what is required for primary homeostasis?

-Collagen
-Platelets
-VWF

This is good in small blood vessels but not in larger vessels.

41

what happens after forming the primary plug?

-To make it more stable we form a fibrin mesh via secondary homeostasis

42

How does secondary homeostasis work?

- do not need collagen
- molecule 7a, it is already activated
- trigger is the 7a tissue complex forming.
- turns zymogen 9 and 10 into their active form so 9a and 10a are formed

43

What happens as soon as the secondary homeostasis is activated?

-It is inhibited by the regulatory factors, which dampen the process, so the pathways is almost instantaneously inhibited.
- however factor 10a produces thrombin which fires away

44

What does thrombin do?

It activates 2 other co-factors.
-co factors 5 and 8 to form 5a and 8a
-this will form 2 complexes
- this produces more thrombin.
-Thrombin cleaves fibronogen, to turn it into fibrin and fibrin is soluble which comes out and forms a mesh

45

what is factor 8a?

Factor 8a is a co-factor for 9a which is a protease.

46

what are the Primary Haemostasis Disorders

GENETIC: vWF disease means fewer platelets will bind to collagen, increasing amount of bleeding
Type 1: Not enough vWF produced
Type 2: Incorrect vWF produced
Type 3: No vWF produced

GENETIC/ACQUIRED: Collagen wall defects means less binding.
3 acquired causes: steroids, age, scurvy

GENETIC/ACQUIRED: Thrombocytopenia
All this means is that platelets are low, doesn’t specify cause
One acquired cause: Aspirin

47

what are the symptoms of primary haemostatic disorder?

Prolonged bleeding
Easily bruised
Prolonged epistaxis
Prolonged menorrhagia

Specific to Thrombocytopenia, you get Petechiae

48

what do fibronlysis disorders cause?§

Fibrinolysis disorders typically cause too activity of fibrinolysis, rather than reduced, so you get too much bleeding