Coagulation Flashcards

1
Q

What is the culminative event of coagulation?

A

The generation of thrombin

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2
Q

What is Thrombin’s function?

A

Turns soluble fibrinogen to Fibrin

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3
Q

What is the function of fibrin?

A

enmeshes the platelet aggregates at the sites of vascular injury and converts the unstable primary plug to firm definitive and stable haemostatic plug

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4
Q

Of all the enzymes of coagulation which is not a serine protease?

A

Factor VIII (8)

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5
Q

What are the three enzyme complexes that thrombin generation is dependent on?

A

1.Extrinsic case (VIIa, TF, PL, Ca2+)
2.Intrinsic case (IXa, VIIIa, PL, Ca2+)
These 2 pathways both generate FXa and the prothrombinase complex (Xa,Va,PL,Ca2+) generating thrombin

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6
Q

How does the generation of thrombin occur after tissue injury?

A

In two waves.

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7
Q

What happens during the initial wave?

A

Small amount generated which prepares the coag cascade for the second larger burst.

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8
Q

How does initiation occur?

A

Occurs by the interaction of membrane bound (TF) which is exposed and activated by an enzyme protein dislphide isomerase after vascular injury, with plasma factor VIIa.

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9
Q

What is TF?

A

The sole initiator of thrombin generation and fibrin formation. It is expressed on fibroblasts of the adventitia and small muscle of the vessel wall, and on non vascular cells.

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10
Q

What does Factor VIIa activate?

A

Activates both both Factor IX and Factor X

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11
Q

What inhibits the extrinsic pathway (extrinsic case)?

A

Tissue factor pathway inhibitor.

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12
Q

What does TFPI form?

A

A complex with VIIa, TF and Xa

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13
Q

What does this inactivation of extrinsic pathway lead to?

A

Dependence of thrombin generation on the intrinsic pathway.

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14
Q

What happens to the small amounts of Thrombin generated by the Extrinsic pathway?

A

It activates Factors VII and V to VIIIa and Va

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15
Q

How is the prothrombinase complex (Xa + Va) formed?

A

Xa is generated by IXa and VIIIa (Intrinsic Xase) in the presence of calcium Ca2+, which then combines with Va PL and Ca2+.

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16
Q

What does generation of prothrombinase yeild?

A

THROMBIN

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17
Q

What is the role of Factor XI?

A
  1. Does not seem to have a role in physiological initiation of coag.
  2. Appears to have a role in activation of Factor IX.
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18
Q

What is the role of Thrombin? How does it work?

A

Hydrolyzes fibrinogen releasing Fibrinipeptides A and B to form Fibrin monomers.

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19
Q

What Happens to The Fibrin monomers?

A

Bound spontaneously by hydrogen bonding to form loose insoluble fibrin polymer.

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20
Q

How is Factor XIII activated?

A

By Thrombin + Ca2+

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21
Q

What is a function of Xllla?

A

Stabilizes the fibrin polymers with formation of covalent cross links

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22
Q

Describe Fibrinogen

A

Heterodimer of 3 dissimilar sub units Alpha, Beta, and Gamma.

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23
Q

Which factors are dependent upon Vitamin K?

A

2, 7, 9, 10

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24
Q

Why is vitamin K important for these factors?

A

Carboxylates some terminal glutamic acid residues on those molecules.

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25
Q

Which 2* factors are not protease enzymes?

A

V and VIII

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26
Q

What 3 molecules produced by Endothelial cells have a inhibitory effect on platelets?

A

NO, CD39, and Prostacyclin

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27
Q

What 2 molecules released by platelets also have vasocontricive activity?

A

TXA2 and Fibrinopeptides.

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28
Q

What facilitates platelet adherence to exposed connective tissue?

A

GPIa and GPIb mediated via VWF

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29
Q

How does platelet aggregation and release accelerate the coagulation process?

A

By providing abundant membrane phospholipid

30
Q

What molecules does TFPI inhibit?

A

Xa. VIIa, and Thrombin

31
Q

How does TFPI work?

A

Forms a quaternary complex

32
Q

What is another direct inactivator of thrombin and other serine proteases?

A

antithrombin-the most potent

33
Q

What drug potentiates the action of antithrombin?

A

Heparin

34
Q

What are some other thrombin and serine protease inhibitor

A

Heparin cofactor II (only thrombin), Alpha 2 macroglobulins, Alpha2-antiplasmin, C1 esterase inhibitor and a1-antitrypsin (only serine proteases)

35
Q

What are proteins C & S?

A

These are inhibitors of Factors V and VIII

36
Q

How is Protein C activated?

A

Thrombin binds to the endothelial cell surface receptor thrombomodulin

37
Q

What other Vitamin K dependent protein enhances the activity of protein C?

A

Protein S.
It binds protein C to the platelet surface, and endothelial protein C receptor localizes protein C to the endothelial cell surface.

38
Q

What else does activated protein C enhance?

A

Fibrinolysis

39
Q

What else does Protein C inhibit?

A

TFPI and thus increases fibrinolysis

40
Q

What is plasminogen?

A

A B-blobulin proenzyme in blood and tissue fluid that is converted to a serine protease plasmin by activating factors of both intrinsic and extrinsic pthwy

41
Q

What is TPA?

A

A serine protease that binds to fibrin, enhancing its capacity to convert thrumbus bound plasminogen to into plasmin

42
Q

How does Protein C affect TPA levels?

A

Protein C destroys plasma inhibitors of TPA

43
Q

How does thrombin inhibit fibrinolysis?

A

By activating TAFI

44
Q

What is the function of Plasmin?

A

Generation of plasmin at the site of injury limits the extent of the evolving thrombus

45
Q

What is one of the functions of the split fibrin products?

A

Competitive inhibitors of thrombin and Fibrin polymerization

46
Q

What inhibits most local free plasmin?

A

Alpha2-antiplasmin

47
Q

What are two well known and characterized fibrin degradation products (used to test for DIC)?

A

Fragments D and E

48
Q

What are the molecules that Plasmin is capable of digesting?

A

Fibrinogen, fibrin, Factors V and VII

49
Q

What inhibits TPA?

A

PAI

50
Q

What inactivates circulating plasmin?

A

Alpha2-antiplasmin and Alpha2-Macroglobulin

51
Q

What does PT measure?

A

Factors VII, X, V, Prothrombin and Fibrinogen

52
Q

PTT measures what?

A

VIII, IX, XI, XII, X, V, Prothrombin and Fibrinogen

53
Q

How is defect of a factor checked?

A

By adding normal plasma to test plasma 50:50

54
Q

If the test fails what is indicated?

A

The presence of an inhibitor of coagulation

55
Q

What interaction intiates the platelets to degranulate?

A

Binding to Collagen

56
Q

What is released on degranulation?

A

ADP TXA2

57
Q

Deficiency of factor XIII leads to?

A

Normal clotting but clots are not stabilized and break down and bleeding continues

58
Q

How does Factor XIII work?

A

It is a transaminase that covalently links fibrin polymers

59
Q

What do haemophilia A patients lack?

A

Factor VIII

60
Q

What do Haemophilia B patients lack?

A

Factor IX

61
Q

What is the difference between serum and plasma?

A

Plasma contains unactivated clotting factors, serum contains used up clotting factors.

62
Q

Factor XII deficiency causes?

A

Long PTT but patients won’t bleed out

63
Q

Cannot fix clotting factor deficiency with?

A

Fresh frozen plasma.

64
Q

Normal PT and PTT but still bleeding suggests?

A

Deficiency of factor XIII

65
Q

What is the ratio of prothrombin 1.2 : thrombin after the cleavage by prothrombinase?

A

1:1

66
Q

How does factor VIII exist in the circulation?

A

Bound to VWF

67
Q

What is Anti-thrombin III?

A

An anti-serine protease, neutralizes the active site on a serine protease

68
Q

How does heparin affect anti-thrombin III?

A

It binds at an allosteric site and makes it a much more effective anti serine protease.

69
Q

What is a naturally occuring analogue of heparin that has the same effect on anti-thrombin III?

A

Haparan sulphate

70
Q

What are D dimers specific for?

A

Cross-linked fibrin.