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MoD > Lesson 5 > Flashcards

Lesson 5 Flashcards

1
Q

How many litres of blood to we have circulating in our body?

A

~5L

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2
Q

What is ‘pro-thrombotic’?

A
  • Stop skin cuts bleeding
  • To heal bone fractures
  • To prevent fatal haemorrhage when placenta detaches from the uterus after childbirth
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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

Explain the homeostatic balance regarding blood?

A

Procoagulant factors = anticoagulant factors

Coagulant, coagulation = clotting, thrombosis

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5
Q

What are three stages of haemostasis following vessel injury?

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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6
Q

What are the four components of haemostasis?

A
  1. vessel wall - vascular endothelial cells
  2. platelets
  3. coagulation system
  4. fibrinolytic system

Defects in any of these leads to too much clotting (or little)

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7
Q

Explain the events that follow arterial injury?

A
  1. Vascular spasm - smooth muscle contracts -> vasoconstriction
  2. Platelet plug formation - injury to vessel lining exposes collagen fibres -> platelets adhere, platelets release chemicals (make sticky)
  3. Coagulation - fibrin forms mesh -> traps RBCs/platelets -> clot
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8
Q

What do endothelial cells secrete to initiate platelet plug formation?

A

von Willebrand factor

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9
Q

What normally happens within blood vessels?

A

Endothelial cells of intact vessels produce coagulation inhibitors (heparin-like molecule and thrombomodulin) which prevent clotting, and NO and prostacyclin which prevent platelet aggregation

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10
Q

Provide a description on platelets?

A
  • 2-4 μ diameter
  • anucleate cells
  • lifespan 7-10 days
  • megakaryocytes in marrow
  • intracellular granules
  • normal count = 150-450 x 10^9/l
  • function: maintenance of vascular integrity
  • activated by blood vessel injury
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11
Q

Describe the formation of primary haemostat plug by platelets

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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12
Q

Describe the coagulation system to form clots

A

Series of inactive components (‘factors’) converted to active components

Prothrombin -> THROMBIN -> fibrinogen -> fibrin

Fibrinogen and other clotting factors circulate in the blood

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13
Q

What are the steps in the blood clotting cascade?

A

INTRINSIC PATHWAY - Damaged endothelial lining of blood cells promotes binding of factor XII
EXTRINSIC PATHWAY - Trauma releases tissue factor (factor III)

  • > factor x activation - common endpoint for both pathways
  • > thrombin activation
  • > formation of fibrin clot

Cascade allows formation of a clot from activation of very small amounts of the initial factor

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14
Q

How many factors are apart of proteins of blood coagulation?

A

1-13

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15
Q

Give general facts regarding the coagulation system

A

1 ml of blood can generate enough thrombin to convert all the fibrinogen in the body to fibrin
Tight regulation therefore required
Balance of procoagulant and anticoagulant forces

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16
Q

What are two proteins that aid in turning off the coagulation system?

A

Antithrombin III
Protein C and S
alpha 2 macroglobulin

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17
Q

How does antithrombin III help in turning off the coagulation system?

A
  • serine protease inhibitor

- Inhibits thrombin and 10a

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18
Q

How does protein C help in turning off the coagulation system?

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 i.e. thrombophilia
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19
Q

What are some of the most common thrombosis disorders?

A 
Deep vein thrombosis (DVT) 
Pulmonary embolism (PE)

Collectively known as venous thromboembolism (VTE)

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20
Q

Briefly explain inherited thrombophilias

A
  • Genetically determined disorders of haemostasis
  • Increased risk of VTE

Many single gene defects
Factor V Leiden (1 in 20 people)
Protein C deficiency

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21
Q

What are the general rules regarding disorders of coagulation and haemostasis?

A
  • Inherited disorders are single gene mutations
    present as bleeding thrombosis in an otherwise well patient
  • Acquired bleeding disorders can affect any/all parts of the clotting pathways
    arise in patients who are already systemically ill
    multi-organ failure (liver damage, sepsis etc)
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22
Q

What is fibrinolysis?

A

When clots form, automatically the body starts breaking them down

An example of ‘balance’ - homeostasis

  • Natural local secretion of enzymes
  • Iatrogenic enhancement – ‘clot busting’ – via drugs eg streptokinase
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23
Q

State the steps of fibrinolysis

A 
Plasminogen -> Plasmin 
	3 classes of fibrinolytic drugs: 
		t-PA - tissue plasminogen activator 
		streptokinase
		urokinase

Plasmin proteases fibrin -> clot dissolves (fibrin fragments)

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24
Q

Summarise the 4 phases of haemostasis?

A
  1. Vascular spasm
  2. Platelet plug formation
  3. Blood clotting (coagulation system)
  4. Clot breakdown (fibrinolytic system)
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25
Q

Clot formation is tightly controlled; clots are formed by ______ ________ of _______ to form _____.

A

Proteolytic cleavage
Fibrinogen
Fibrin

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26
Q

Process reversed by the enzyme ______ causing ________ _______ of fibrin - _________

A

Plasmin
Proteolytic cleavage
Fibrinolysis

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27
Q

________ process can be disrupted in certain genetic diseases. eg __________

A

Clotting

Haemophilia

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28
Q

What are laboratory blood tests of haemostasis?

A

Full blood count (FBC) - platelets

Clotting screening tests:

  1. Prothrombin time (PT) - measures the EXTRINSIC PATHWAY (factors VII, X, V, II and fibrinogen) – also called the INR test
  2. Activated partial thromboplastin time (APTT) - measures the INTRINSIC PATHWAY plus the final common pathways (factors XII, XI, X, IX, VIII, V, II and fibrinogen).
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29
Q

What are two signs of platelet disease?

A
  1. Abnormal numbers
  2. Abnormal function

Or combination of 1 + 2

30
Q

What is the number of platelets during surgical bleeding?

A

surgical bleeding < 50 x 10^9/l

31
Q

What is the number of platelets during spontaneous bleeding?

A

spontaneous bleeding < 20 x 10^9/l

32
Q

What is the number of platelets if there are spontaneous small vessel platelet clots?

A

> 500 x 10^9

33
Q

What is warfarin?

A

“to thin the blood” and prevent thromboses

Vitamin K antagonist
Inhibits hepatic synthesis of clotting factors II, VII, IX and X.

34
Q

What are problems with warfarin?

A
  1. difficulties in determining dose – this has to be done empirically in each patient with frequent monitoring the INR (measure of prothrombin time).
  2. narrow therapeutic window
  3. drug/diet interactions
  4. delay in efficacy as pre-existing factors is still available for use. Therefore, an immediate acting anticoagulant, such as low molecular weight heparin, is needed while warfarin begins to work.
35
Q

What can we do the manage bleeding whilst on warfarin?

A
  1. Vitamin K - overcome the vitamin K antagonism + 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

NOTE: warfarin is cheap but always easy to use.
More recent oral anticoagulants do NOT require therapeutic monitoring (but are more expensive).

36
Q

What does DIC stand for?

A

Disseminated intravascular coagulation

37
Q

What does TTP stand for?

A

Thrombotic thrombocytopaenia purpura

38
Q

Give a brief description of both DIC and TTP?

A

Small vessel thromboses

Paradox – how can intravascular coagulation/thrombosis states lead to excess bleeding [purpura]?

39
Q

What is DIC?

A

Consumption coagulopathy.
Within circulation, clotting is accelerated.
Consumes clotting factors faster than replaced – subnormal clotting factors
Spontaneous bleeding commences in many organs – can be fatal.

Causes: sepsis etc

40
Q

What is TTP?

A

Platelet masses (thrombi) in small vessels
Low blood platelets & normal clotting factors
Abnormal von Willebrand factor
Purpuric bleeding in kidney, skin, brain, gut, and heart

41
Q

What is the definition thrombosis?

A

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

42
Q

Describe Virchow’s triad?

A 
Venous
	• Stasis of flow
	• Blood constituent 
Arterial
	• Blood constituent 
	• Vessel wall intima damage
43
Q

What are the risk factors of venous thromboembolism (VTE)?

A
  • age
  • previous VTE
  • malignancy
  • immobility/bed rest
  • post-operative
  • trauma
  • pregnancy and puerperium
  • oral contraceptives / HRT
  • inherited thrombophilia
  • obesity
  • smoking
44
Q

What are risk factors of arterial thrombosis?

A
  • age
    • smoking
    • obesity
    • atherosclerosis
    • hypertension
    • hypercholesterolaemia
    • diabetes
    • ethnicity - being of south Asian ancestry
45
Q

Describe what arterial thrombi look like on a histology slide?

A
  • Pale/red
  • granular
  • lines of Zahn – alternating lines of red cells and thrombus strands
46
Q

What are the effects of arterial thrombosis?

A
  • ischaemia and infarction
  • depends on site and collateral circulation
    E.g heart muscle necrosis (death of tissue), myocardial infarction
47
Q

What are the effects of venous thrombosis?

A

congestion, oedema, haemorrhage

48
Q

If the limb provides a very white appearance what form of thrombosis is this representative of?

A

Thrombosis of proximal artery

White = bloodless – limb

49
Q

What is propagation? (Outcome of thrombosis)

A
  • progressive spread of thrombosis
  • distally in arteries
  • proximally in veins
50
Q

What is lysis? (Outcomes of thrombosis)

A
  • complete dissolution of thrombus
  • fibrinolytic system active, clot busted and blood flow re-established
  • therapeutic: DVT signs & symptoms treated with warfarin
51
Q

What is embolism? (Outcomes of thrombosis)

A

part of thrombus breaks off travels through bloodstream lodging at distant site

52
Q

What are the effects of pulmonary embolism?

A

massive PE >60% reduction in blood flow rapidly fatal (haemodynamic compromise)

major PE - medium sized vessels blocked. Patients short of breath, pleuritic chest pain +/- cough and blood stained sputum (haemoptysis)

minor PE - small peripheral pulmonary arteries blocked. Asymptomatic or minor shortness of breath

recurrent minor PEs lead to pulmonary hypertension

53
Q

Define embolism

A

Embolism is the blockage of a blood vessel by solid, liquid or gas at a site distant from its origin.
>90% of emboli are thrombo-emboli

54
Q

What does thromboemboli depend on?

A
  1. Venous or arterial

2. Site of origin

55
Q

What is venous thromboemboli?

A

systemic veins -> lungs = PE, pulmonary embolism

56
Q

What is arterial thromboemboli?

A
  • From heart via the aorta -> renal, mesenteric
    • atheromatous carotid arteries -> brain (CVA)
    • atheromatous abdominal aorta -> legs
57
Q

If heart valve thrombi gets into the spleen what can it cause?

A

Splenic infarction

58
Q

If atheromatous aorta gets into leg arteries what can it cause?

A

Foot necrosis (gangrene)

59
Q

Explain what organisation is in relation to outcomes of thrombosis?

A
  • reparative process
  • growth of fibroblasts + capillary proliferation (similar to granulation tissue), which result in attachment of thrombus to vessel wall
60
Q

Explain what recanalisation is in terms of outcomes of thrombosis?

A
  • 1+ channels formed through organising thrombus

* blood flow re-established - usually incompletely

61
Q

What are some causes of embolism?

A

Air
Nitrogen
Fat
Amniotic fluid

62
Q

What are mechanical methods for prevention of VTE?

A

Anti-embolism stockings (AES)
Intermittent pneumatic compression
Foot impulse devices

63
Q

What are pharmacological methods for prevention of VTE?

A 
• Prophylaxis will depend on:
		○ medical condition
		○ suitability for the patient
		○ local policy
• Subcutaneous low molecular weight heparin (LMWH)
• Direct oral anticoagulants
64
Q

What are examples of anticoagulants used in VTE treatment?

A
  • IV heparin
  • Warfarin
  • Direct oral anticoagulants (direct Xa inhibitors and direct thrombin (IIa) inhibitors)
65
Q

What are some indications for the need of anticoagulants?

A
  • VTE (DVT or PE)
  • Atrial fibrillation
  • Mechanical heart valves
66
Q

Provide information on heparin?

A
  • naturally occurring anticoagulant
  • potentiates effect of antithrombin III
  • mixture of glycosaminoglycan chains extracted from porcine mucosa
  • unfractionated heparin (UH)= IV = monitoring by APPT, dose adjusted
  • LMWH = SC = mixture of smaller chains = more predicable anticoagulant effect. dose calculated by body weight
  • Fondaparinux = synthetic

• antidote = protamine sulphate: UH > LMWH > Fondaparinux

67
Q

What are examples of direct oral anticoagulants?

A 
Direct Xa inhibitors e.g. rivaroxaban, apixaban, edoxaban 
Direct thrombin (IIa) inhibitors e.g. dabigatran

Relatively new drugs
Licensed for treatment and prevention of VTE

68
Q

What are advantages of direct oral anticoagulants?

A

Oral, no monitoring, predictable pharmacokinetics, rapid onset of action, minimal drug / food interactions

69
Q

What is platelet function in primary homeostatic plug?

A

Adhesion - surface glycoproteins, vWF
Activation - ADP, thrombin and thromboxane
Release reactions - granule contents
Aggregation - ADP, thromboxane A2

70
Q

What does venous thrombi look like?

A
  • soft
  • gelatinous
  • deep red - deoxygenated
  • higher cell content
71
Q

What is classic haemophilia (defect in factor VII)?

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

MoD (11 decks)

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