Thrombosis Flashcards

1
Q

What is arterial thrombosis?

A

A blood clot that develops in an artery

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2
Q

How can atherosclerosis lead to thrombosis?

A

Rupturing of fibrous cap around a plaque

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3
Q

When a plaque ruptures what stages follow to lead to thrombosis?

A

Adhesion of platelets to vessel wall

Release of granule contents

Aggregation of platelet to platelet (plug)

Release of co-factors for clotting

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4
Q

Where and how to platelets bind to endothelium?

A

Platelet GP1a binds Collagen

Platelet GP1b binds Von Willebrand factor (vWf)

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5
Q

What types of platelet granules are there and what do they release?

A

Platelets contain two types of storage granule a- granules (PDGF, thrombospondin, platelet factor 4, fibrinogen, fibronectin, vWf etc.) and dense bodies (ATP, ADP, GDP, GTP, serotonin, calcium)

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6
Q

How do platelets bind eachother?

A

Fibrinogen ‘bridges’ stabilise platelet aggregates

Fibrinogen binds platelet surface GPIIb/GPIIIa

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7
Q

What do thrombolytic agents do?

A

Dissolve existing thrombi

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8
Q

What does streptokinase do?

A

Enzyme of b-haemolytic Streptococci

Dissolves blood clots by converting plasminogen into plasmin

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9
Q

How is streptokinase given and what is it used for?

A

Given as iv infusion or via catheter at site of arterial blockage

Used in treatment of acute MI (heart attack) with aspirin

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10
Q

What does recombinant tPA do?

A

Recombinant human tissue Plasminogen Activator protein

Mode of action accelerated plasminogen cleavage to plasmin

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11
Q

How is recombinant tPA given and what is it used for?

A

Given as iv infusion or via catheter at site of arterial blockage

Used in treatment of acute MI (with aspirin and heparin)

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12
Q

How does tPA compare with streptokinase?

A

10x more expensive than streptokinase ($2,200 vs $200)

Clinical trials show slightly increased efficacy compared with Streptokinase

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13
Q

What do antiplatelet agents do?

A

Interfere with platelet activity

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14
Q

How does aspirin work?

A

Non-competitive inhibitor of COX-I and COX-2

Acetylates cyclo-oxygenases COX-I and COX-2 (required for TxA2)

Low dose aspirin blocks platelet TXA2 production

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15
Q

What is TXA2?

A

Thromboxane A2 key mediator of platelet adhesion

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16
Q

What does clopidogrel do?

A

Blocks activity of platelet ADP

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17
Q

What is abciximab? How does it work?

A

Abciximab (c7E3) is a chimeric mouse-human monoclonal antibody directed against the platelet GP IIb/IIIa receptor.

Mechanism thought to be steric hindrance of the receptor.

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18
Q

How does warfarin work?

A

Inhibitor of vitamin K-dependent synthesis of biologically active forms of the clotting factors II, VII, IX and X, as well as the regulatory factors protein C, protein S, and protein Z.

The precursors of these factors require gamma carboxylation of their glutamic acid residues (gamma-glutamyl carboxylase)

This is coupled to the Vitamin K epoxide enzyme (converting reduced vitamin K to vitamin K epoxide)

Warfarin inhibits epoxide reductase (VKORC1) thereby diminishing available reduced vitamin K - which inhibits the carboxylation activity of the glutamyl carboxylase.

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19
Q

What does warfarin inhibit?

A

Epoxide reductase (VKORC1)

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20
Q

What does warfarin do to vitamin K

A

Diminishes available reduced vitamin K

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21
Q

What is a venous thrombosis?

A

Thrombus is a blood clot that forms in situ within a blood vessel that impedes blood flow

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22
Q

What is an embolus?

A

Embolus is an abnormal mass transported in the bloodstream Venous Thromboembolism (VTE) is where a thrombus forms from blood clotting within a deep vein.

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23
Q

What is thrombophlebitis?

A

Thrombophlebitis is inflammation of superficial veins due to a blood clot, less serious than deep vein thrombosis (DVT)

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24
Q

What initiates venous thrombosis?

A

Venous stasis and hypercoagulability - blood clotting in situ

25
Q

What initiates arterial thrombi?

A

Platelet activation

26
Q

What is the most common cause of PE?

A

DVT

27
Q

Natural Inhibitors of clot formation

A

Antithrombin III, thrombomodulin, activated protein C

28
Q

What is ATIII?

A

Serine protease inhibitor

29
Q

What is thrombomodulin?

A

Endothelial cells produce thrombomodulin which binds to activated thrombin

This complex catalyses the production of activated protein C

30
Q

What is does activated protein C require for its action?

A

Vitamin K

31
Q

How does activated protein C work?

A

Protein C is activated by thrombin cleavage to become Activated Protein C (APC) that cleaves Activated Factor V and Factor VIII

32
Q

What is a pulmonary embolism?

A

DVT travels in the right side of the circulation and becomes trapped in the microvasculature in the pulmonary circulation, reducing perfusion of the lungs.

33
Q

Risk Factors for Venous Thrombosis

A

Age
Venous stasis (especially in the elderly)
Any surgery (especially orthopaedic and prostate)
Pregnancy
Infection
Malignancy (especially adenocarcinomas)
Genetic
AT-III deficiency or Protein C Resistance including Factor V Leiden

34
Q

What is factor V Leiden?

A

Factor V Leiden raises Relative Risk of VTE massively when combined with other factors

35
Q

What is Virchow’s triad?

A

Changes in the intimal surface of the vessel

Changes in the pattern of blood flow

Changes in blood constituents

36
Q

Why does cancer increase risk of VTE?

A

Decreased liver production of anti-coagulants

Direct Factor X activation

Autoantibodies to phospholipids

Cancer cells often express Tissue Factor (TF) or induce TF expression in neighbouring stromal cells
Activation of coagulation cascade induces local and systemic inflammation which induces a pro-thrombotic state

37
Q

What are cardioembolic strokes?

A

Pooling of blood in the fibrillating left atrium leading to clot formation (turbulence) initially adherent to the atrial wall that may later detach and embolise.

38
Q

What is another action of herapin?

A

Heparin stabilises AT III interaction with coagulation enzymes (Factor Xa and Thrombin (IIa))

39
Q

What are examples of novel oral anticoagulants?

A

Rivaroxaban

Dabigatran

40
Q

What is the action of novel oral anticoagulants?

A

Antagonism of the coagulation cascade Factor Xa (e.g. rivaroxaban) and Thrombin (e.g. dabigatran).

41
Q

What is factor V leiden?

A

Mutation in clotting factor that increases risk for blood clots (familial thrombophilia)

42
Q

What are risk factors for abnormal haemostasis?

A

Genetic: ATIII deficiency, APC resistance (familial thrombophilia (incl. Factor V Leiden))

Liver damage: can induce ATIII deficiency

Iatrogenic: warfarin/heparin/tPA

43
Q

Drug used for long term prevention of coronary thrombosis (as distinct from atherosclerosis or
hypertension)

A

Aspirin

Mode of action: blocks platelet TXA2 production - prevents thromboxane formation

44
Q

Drug used for existing coronary thrombus?

A

Streptokinase or tPA

Dissolves blood clots by converting plasminogen into plasmin

Accelerated plasminogen cleavage to plasmin

45
Q

Vein where DVT commonly occurs?

A

Femoral vein

46
Q

In the clotting pathway what is the enzyme that converts fibrinogen to fibrin?

A

Thrombin (IIa)

47
Q

Atherosclerosis is a major cause of venous thrombosis?

A

False

48
Q

Emboli from arterial thrombi are a major cause of strokes?

A

True

49
Q

Plasmin converts fibrinogen to fibrin?

A

False (its thrombin)

50
Q

Streptococcus viridans vegetations on heart valves are a source of arterial emboli

A

True

51
Q

Carotid arteries are uncommon sites for arterial thrombosis

A

True

52
Q

Warfarin is often used to prevent post-operative deep vein thrombosis

A

True

53
Q

In the clotting pathway what is the enzyme which that breaks down fibrin?

A

Plasmin

54
Q

Histology of the embolus would be most likely to show which one of the following?

A

Lines of Zahn (clumped platelet strands arranged in ridges - between ridges fibrin, red cells and leukocytes are deposited)

55
Q

What is the substrate for plasmin?

A

Fibrin

56
Q

Venous thrombi are composed mainly of platelets and fibrin

A

False

57
Q

Major components of venous thrombi

A

RBCs and fibrin fibers

58
Q

Major component of arterial thrombi

A

Fibrin and platelets