Cardio L17 Blood Clotting Flashcards Preview

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Flashcards in Cardio L17 Blood Clotting Deck (55):
1

Blood Clotting
The need →

to avoid blood loss when blood vessels damaged (excessive blood loss produces shock and death).

2

Problems associated with blood clotting →

Inadequate e.g. haemophilia and some venom gives excessive bruising and haemorrhaging.

Inappropriate e.g. deep vein thrombosis, coronary thrombosis, stroke and other venoms.

3

A blood clot consists of a

plug of platelets enmeshed in a network of insoluble fibrin molecules:
2 components:
1. Platelets → are cell fragments made from megakaryocyte (no nucleus).
2. Fibrin

4

Process:
1. Tissue damage activates

a. Conversion of Prothrombin to thrombin via a complex proteolytic cascade
i. Proteolytic cleavage of fibrinogen to fibrin which polymerises to form clot.
b. Activation and aggregation of platelets

5

Platelets aggregation:

Von Willebrand factor
Serotonin

6

Von Willebrand factor

links collagen exposed on damaged blood vessels to platelets.

7

• The activated platelets release factors such as

as ADP and thromboxane to activate more platelets causing aggregation that forms a plug of platelets.

8

Serotonin

is also released causing local vasoconstriction as are other factors that enhance thrombin cleavage.

9

Aggregation of activated platelets: (3)

1. Platelet activation causes changes in the shape of platelets and conformation changes in glycoprotein IIb/IIIa receptors
2. ADP and thromboxane binding lads to a conformation change in IIB/IIIa receptors = active receptors.
3. The activated receptors can be cross-linked by fibrinogen to form bridges between adjacent platelets and facilitate platelet aggregation.

10

Fibrinogen (precursor molecules) structure

3 component chains with globular units and alpha helices with cleavage sites:
1. Gamma
2. Beta → cleaved by thrombin
3. Alpha → cleaved by thrombin

11

Process: of fibrinogen

1. Thrombin cleaves of peptides from alpha and beta subunits.
2. Produces a truncated fibrin which can polymerise as the ends can bind into groves → this polymerisation is the formation of a clot (soft – rapid formation).

12

Hard clot →

Clot is stabilised by cross-linking glutamines with lysines using a transglutaminase (Factor XIIIa)


13


How do we activate the Thrombin:

thrombin is a proteolytic reaction catalysed by a serine protease factor Xa together with a stimulatory protein factor Va.

Cleavage → 2 places (see below) by proteases factor Xa and Va

14

Cleavage two sites:

Kringle domain
Gla domain

15

Kringle domain →

a triple loop structure stabilised by 3 dulsphide bonds → involved in protein interactions between blood clotting factors and mediators.

16

2. Gla domain →

contains 10 gamma-carboxyglutamte.

17

Gla domain cleavage requires

a. This cleavage requires calcium to bind the gamma-carboxyglutamate residues of the Gla region.
b. The calcium binds the prothrombin to the phospholpds of the platelet cell membranes at the damage site.
c. Gamma-carboxyglutamate is formed form glutamate by a vitamin K dependent carboxylation reaction.

18

Enzyme inhibited fibrin Gla domain cleavage

d. This enzyme is inhibited by dicoumarol (found in spoiled sweet clover that cause haemorrhagic disease in cattle) and warfarin (rat poison) used to prevent blood clots in patients prone to DVT.

19

Gamma-carboxyglutamate information:

Found

20

Gamma-carboxyglutamate information: During platelet activation prothrombin is cleaved to thrombin how:

Cleavage requires calcium to bind to the gamma-carboxyglutamate residues in this region.

21

Gamma-carboxyglutamate information: Calcium recruitment

Calcium binds to prothrombin to allow binding to phospholipids on the platelet membrane (damamge site)

22

Gamma-carboxyglutamate information: Gamma-carboxyglutamate formed from

From glutamate by a vitamin K dependent carboxylation reaction.

23

Gamma-carboxyglutamate information: Inhibited by

By dicoumarol which inhibits vit K reductase

24

Thrombin =

Blood clotting therefore control is upstream

25

Thrombin produced by

TF Xa and Va

26

Tissue factors

Serum proteases that cleave

27

Reason for cascade of proteases

To amplify the process

28

Extrinsic pathway: factors involved

(3,7,10)

29

Extrinsic pathway process

1. Trauma causes the release of TF III.
2. TF VIIa is a proteases that causes TF 10 to 10a
3. TF is another serum protease

30

TF III location

Exposed on damaged tissue

31

TF III type

Trans-membrane protein

32

TF III function

Binds and activates factor VII to VIIa

33

Intrinsic pathway: factors involved

(12,11,9,8,10)

34

Intrinsic pathway process

Release Kinogens and Kalikreins
1. Once activated stimulated factor XII to XIIa (12) activated
2. XIIa proteolytic cleaves Xi → Xia
3. Xia converts IX to IXa
4. IXa in conjunction with VIIa cleaves
5. X to Xa

35

Factor IXa interaction with VIIIa →

clinically haemophilia A (X linked).
• Actor 8 stimulates the conversion of factor 10 to 10a by factor 9a
• Factor 10 a activates factor 8 (need a small amount to accelerate the factor 9 function)

36

Haemophilia A →

factor 8a missing.

37

Von Willebrand factor → interacts with

Factor VIII as well as binding platelets to collagen on the damaged blood vessel wall.

38

Controlling the blood clotting cascade:

Clot formation is a balancing act → too much and clost form where they should Not; too little and you bleed to death. Hence an anti-clotting cascade starts almost as soon as vclotting begins.

39

The extrinsic pathway blocked by

• Tissue Factor Pathway Inhibitor (TFPI)
• Antithrombin III (AT3)
• Protein C and S

40

TFPI structure and function

Has three tandem protease inhibitory domains which inhibit Factor Xa and the factor VIIa-Tissue Factor Complex.

41

TFPI circulates in the blood predominantly bound to

To lipproteins (LDL, HDL, lipoprotein a).
In addition, platelets carry about 10% of the TFPI.

42

Antithrombin III: Structure

Is a protein synthesized by hepatocytes and endothelial cells.

43

Antithrombin III: Functions

By inhibiting the serine proteases activity of the clotting factors – especially thrombin and Factor Xa

44

Antithrombin III: Heparin

A highly sulphated oligosaccharide, enhance the inhibitory effect of AT£ by 10000 times! Hence its anticoagulant properties. It is secreted by stimulated mast cells.

45

Proteins C and S: Description

Are Vitamin K-dependent serine proteases synthesized in the liver and circulating in the blood as an inactive form (zymogen)

46

Activation and function of Protein C

Protein C is activated by thrombin complexed to thrombomodulin and its protease activity inhibits the activity of factors Va and VIIIa

47

Function Protein s

Protein S is a cofactor in this process and significantly potentiates the action of Protein C.

48

Thrombomodulin

Is a receptor expressed on the surface of endothelila cells which converts hrombin into a conformation that activates Protein C and hence enhancing its anticoagulant activity.

49

Dissolving blood clots: Involves

Tissue plasminogen Activator

50

TPA Action

Converts plasminogen to Plasmin

51

Plasmin

Capable of breaking down fibrin clots producing fibrin split products which are soluble.

52

TPA

Serine protease normally found on the surface of endothelial cells of veins, capillaries, the pulmonary artery, heart and uterus
Secreted after vascular injury

53

Urokinase

Also aids dissolving the clot by breaking down plasminogen to plasmin

54

TPA clinically

Clot busting – older treatment.

55

Plasminogen Activator-inhibitors

There to control the breakdown

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