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Mechanisms of Disease > Lecture 5.1: Haemostasis & Thrombosis > Flashcards

Lecture 5.1: Haemostasis & Thrombosis Flashcards

1
Q

What is Haemostasis?

A

The complex process that stops bleeding

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2
Q

What is Pro-Thrombotic?

A

• Stop skin cuts bleeding
• To heal bone fractures

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3
Q

What is Anti-Thrombotic?

A

• Prevent arteries & capillaries being constantly blocked
• Prevent strokes, heart attacks, and pulmonary thrombo-emboli

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4
Q

Stages of Haemostasis following Vessel Injury (3)

A

1) Primary Haemostasis - formation of unstable
platelet plug
2) Secondary Haemostasis - stabilisation of plug
with fibrin (blood coagulation system)
3) Dissolution of clot and vessel repair (fibrinolysis
& recanalisation)

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5
Q

Formation of Primary Haemostat Plug

A

1) Adhere to subendothelial structures via von
Willebrand factor (VWF)
2) Adhere to each other (aggregation)
3) Form a platelet plug held to together by
insoluble fibrin

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6
Q

What are the 4 Core Components of Haemostasis?

A

1) Vessel Wall - vascular endothelial cells
2) Platelets
3) Coagulation System
4) Fibrinolytic System

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7
Q

Clotting Factors: How to get from Prothrombin to Fibrin?

A

Prothrombin to Thrombin to Fibrinogen to Fibrin

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8
Q

Blood Clotting Cascade: Extrinsic Pathway

A

• Trauma releases Tissue Factor (Factor III)
• Endpoint of Factor X Activation
• Thrombin Activation
• Fibrin Clot Formation

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9
Q

Blood Clotting Cascade: Intrinsic Pathway

A

• Damaged endothelial lining of blood cells
promotes binding of Factor XII
• Endpoint of Factor X Activation
• Thrombin Activation
• Fibrin Clot Formation

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10
Q

Where are most proteins of blood coagulation made?

A

In the Liver

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11
Q

Why is tight regulation of the Coagulation System required?

A

Because 1 ml of blood can generate enough thrombin to convert all the fibrinogen in the body to fibrin

Thus a balance of procoagulant and anticoagulant forces is needed

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12
Q

Turning off the Coagulation System: Antithrombin III

A

• Serine protease inhibitor
• Inhibits thrombin and 10a

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13
Q

Turning off the Coagulation System: Protein C

A

• Vit K dependent zymogen
• Activated into serine protease by thrombin binding to endothelial receptor
thrombomodulin
• Cleaves co factors Va and VIIIa
• Deficiency tends to encourage thrombus formation

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14
Q

What are the most common thrombosis disorders?

A

• Deep Vein Thrombosis (DVT)
• Pulmonary Embolism (PE)
• These are collectively known as Venous
Thromboembolism (VTE)

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15
Q

What are Thrombophilias?

A

Diseases where the blood has an increased tendency to form clots

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16
Q

How do Inherited Disorders of Coagulation and Haemostasis generally occur?

A

• Single gene mutations
• Present as bleeding / thrombosis in an otherwise well patient
• E.g. Factor V Leiden (1 in 20 people), Protein C deficiency

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17
Q

How do Acquired Disorders of Coagulation and Haemostasis generally occur?

A

• Can affect any / all parts of the clotting pathways
• Arise in patients who are already systemically ill,
often with multi-organ failure
• E.g. Liver Damage, Sepsis

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18
Q

What is Fibrinolysis?

A

The breakdown of clots

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19
Q

What is used for Iatrogenic Enhancement of Fibrinolysis?

A

Streptokinase

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20
Q

Process of Fibrinolysis

A

Plasminogen to Plasmin
Plasmin converts Fibrin to Fibrin Fragments

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21
Q

Fibrinolytic Drugs

A

• Streptokinase
• Tissue Plasminogen Activator (t-PA)
• Urokinase

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22
Q

Fibrinolysis Inhibiting Drugs

A

Alpha 2 macroglobulin antiplasmin

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23
Q

What is Haemophilia?

A

• A rare condition that affects the blood’s ability to
clot
• X-Linked Recessive
• Spontaneous Internal Bleeding
• Painful Haemarthrosis

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24
Q

Laboratory Blood Tests of Haemostasis (3)

A

• Full Blood Count (Platelets)
• Prothrombin Time (PT) aka the INR Test-
measures the Extrinsic Pathway
• Activated Partial Thromboplastin Time (APTT) -
measures Intrinsic Pathway

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25
Q

Why is Vitamin K crucial to the Clotting Cascade/ Haemostasis?

A

• Vitamin K is processed in the liver
• Required to make factors II, VII, IX, Xi ie
extrinsic & intrinsic pathway factors
• Also required to make Proteins C & S
Anticogulant

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26
Q

What is the normal count for platelets?

A

150-450 x 10^9/L

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27
Q

What is Warfarin?

A

• It is a blood thinner
• Vitamin K antagonist
• Inhibits hepatic synthesis of clotting factors II,
VII, IX and X

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28
Q

Problems with Warfarin (4)

A

1) Difficulties in determining dose
2) Narrow Therapeutic Window
3) Drug/diet interactions
4) Delay in efficacy as pre-existing factors is still
available for use

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29
Q

How to calculate dose of Warfarin?

A

This has to be done empirically in each patient with frequent monitoring the INR (measure of prothrombin time)

30
Q

How to overcome bleeding whilst on Warfarin? (2)

A

1) Vitamin K to overcome the vitamin K
antagonism and allow synthesis of vitamin K
dependent clotting factors
2) Prothrombin complex concentrate (PCC – a
mix of factors II, VII, IX and X) if immediate
reversal needed

31
Q

What is DIC?

A

• Disseminated intravascular coagulation
• Condition in which small blood clots develop
throughout the bloodstream
• This blocks small blood vessels

32
Q

What is the Pathophysiology of DIC?

A

• Mechanism of Thrombosis is via the tissue factor (TF)/factor VIIa pathway
• Consumes clotting factors faster than they can be replaced
• Results in subnormal clotting factors
• Then spontaneous bleeding commences in many organs – and can be fatal

33
Q

What is TTP?

A

• Thrombotic Thrombocytopaenia Purpura
• Blood clots form in small blood vessels throughout your body
• Platelet masses (thrombi) in small vessels
• Can limit or block the flow of blood to your organs (brain, kidneys & heart)

34
Q

What is the Pathophysiology of TTP?

A

• Patients have unusually large multimers of von Willebrand factor (vWF) in their
plasma
• They lack a plasma protease responsible for the breakdown of these large
vWF multimers

35
Q

What is Thrombosis?

A

Thrombosis is the formation of a solid mass of blood clot within the circulatory system

36
Q

Virchow’s Triad

A

• Venous Stasis
• Vascular Injury
• Hypercoagulability

37
Q

Risk Factors for Venous Thromboembolism? (11)

A

• Age
• Previous VTE
• Malignancy
• Immobility/bed rest
• Post-operative
• Trauma
• Pregnancy and Puerperium
• Oral Contraceptives / HRT
• Inherited Thrombophilia
• Obesity
• Smoking

38
Q

What is a Thromboembolism?

A

When a blood clot (thrombus) that forms in a blood vessel breaks loose, is carried by the bloodstream, and blocks another blood vessel

39
Q

What is an Embolism?

A

Embolism is the blockage of a blood vessel (artery) by a solid, liquid or gas at a site distant from its origin

40
Q

Risk Factors for Arterial Thrombosis (8)

A

• Age
• Smoking
• Obesity
• Atherosclerosis
• Hypertension
• Hypercholesterolaemia
• Diabetes
• Ethnicity (South Asian Ancestry)

41
Q

What do Arterial Thrombi look like on a Histology slide?

A

• Pale/Red
• Granular
• Lines of Zahn – alternating lines of red cells and
thrombus strands

42
Q

Effects of Arterial Thrombosis

A

• Ischaemia
• Infarction
• Depends on site and Collateral Circulation

43
Q

Effects of Venous Thrombosis

A

• Congestion
• Oedema
• Haemorrhage

44
Q

What does a white/very pale limb mean?

A

• The limb is bloodless
• Thrombosis of Proximal Artery

45
Q

Outcomes of Thrombosis: Propagation

A

• Progressive spread of thrombosis
• Distally in arteries
• Proximally in veins

46
Q

Outcomes of Thrombosis: Lysis

A

• Complete dissolution of thrombus
• Fibrinolytic system active, clot busted and blood flow re-established
• Therapeutic: DVT signs & symptoms treated with warfarin

47
Q

Outcomes of Thrombosis: Embolism

A

• Part of thrombus breaks off travels through
bloodstream lodging at distant site

48
Q

Outcomes of Thrombosis: Organisation

A

• Reparative process
• Growth of fibroblasts and capillary proliferation (similar to granulation tissue)
• These result in the attachment of the thrombus to the vessel wall

49
Q

Outcomes of Thrombosis: Recanalisation

A

• One or more channels formed through organising thrombus
• Bloodflow re-established but usually incompletely

50
Q

Effects of Major Pulmonary Embolism

A

• Medium sized vessels blocked
• Patients short of breath
• Pleuritic chest pain +/- cough and blood
• Stained sputum (Haemoptysis)

51
Q

Effects of Massive Pulmonary Embolism

A

• >60% Reduction in Bloodflow
• Rapidly Fatal
• Haemodynamic Compromise

52
Q

Effects of Minor Pulmonary Embolism

A

• Small peripheral pulmonary arteries blocked
• Asymptomatic or minor shortness of breath

53
Q

Effects of Recurrent Minor Pulmonary Embolisms

A

• Leads to pulmonary hypertension

54
Q

VTE Prevention (7)

A

• Wearing anti-embolism stockings
• Inflatable sleeves to wear around the legs and
feet
• Blood thinners to reduce the chance of a blood
clot
• Moving and walking where possible when in
hospital
• Drinking plenty of fluid to keep hydrated
• At risk patients must be offered Prophylaxis
• Risk assessment for VTE and bleeding

55
Q

What is Prophylaxis?

A

Treatment given or action taken to prevent disease

56
Q

What is DVT?

A

• Deep Vein Thrombosis
• A blood clot that develops within a deep vein in
the body, usually in the leg

57
Q

Risk Factors for DVT (5)

A

• Being a Frequent Flyer
• Age
• Pregnancy
• Smoking
• Obesity

58
Q

Preventions of DVTs (5)

A

• Anti-Embolism Stockings (AES)
• Intermittent Pneumatic Compression
• Foot Impulse Devices
• Subcutaneous Low Molecular Weight Heparin
(LMWH)
• Direct Oral Anticoagulants

59
Q

Anticoagulants as Treatments for VTE (3)

A

• IV heparin
• Warfarin
• Direct oral anticoagulants (direct Xa inhibitors &
direct thrombin (IIa) inhibitors)

60
Q

Mechanism of Action of Heparin

A

• Naturally occurring anticoagulant
• Potentiates effect of antithrombin III
• Mixture of glycosaminoglycan chains extracted
from porcine mucosa

61
Q

How do you reverse the effects of Heparin?

A

Administer Protamine Sulphate

62
Q

Direct Oral Anticoagulants: Direct Xa Inhibitors

A

• Rivaroxaban
• Apixaban
• Edoxaban

63
Q

Direct Oral Anticoagulants: Direct Thrombin (IIa) Inhibitors

A

• Dabigatran

64
Q

Advantages of Direct Oral Anticoagulants

A

Oral no IV needed
No monitoring
Predictable pharmacokinetics
Rapid onset of action
Minimal drug / food interactions

65
Q

What is the Wells Score?

A

A number that reflects your risk of developing deep vein thrombosis (DVT)

66
Q

How is the Wells Score calculated?

A
67
Q

What is the D-dimer Test?

A

• Used to find out if you have a blood clotting disorder
• D-dimer is a fibrin degradation product
• A small protein fragment present in blood after fibrinolysis of blood clot

68
Q

‘Classic’ Haemophilia

A

• FVIII (‘antihaemophilic factor’) not a protease, but stimulates the activity of
FIXa , a serine protease
• Activity of FVIII increased by proteolysis by thrombin and FXa
• Positive feedback amplifies clotting signal, accelerates clot formation
• Reduced FVIII results in reduced/absent clotting and prolonged bleeding
• Treatment with recombinant FVIII

69
Q

How much blood is there in the body?

A

~5 litres of blood in our body circulation

70
Q

Why is blood essential to the body?

A

For delivering O2, nutrients…etc to tissues

Mechanisms of Disease (11 decks)

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