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CDL301 Cardiovascular Pharmacology > Lecture 14 Haemostasis and Thrombostasis > Flashcards

Lecture 14 Haemostasis and Thrombostasis Flashcards

1
Q

What are the sub-classifications of bleeding

A

Primary and secondary haemostasis

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2
Q

What are the sub-classifications of clotting

A

Arterial and venous thrombosis

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3
Q

What three fractions are isolated from fresh whole blood following donation

A

Red blood cells platelets and plasma

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4
Q

How long can red blood cells be kept and used for after donation

A

35 days

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5
Q

How long can platelets be kept and used for after donation

A

5-7 days

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6
Q

How long can plasma be kept and used for after donation

A

Can be frozen and stored for quite some time before use

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7
Q

How can fresh frozen plasma be further divided

A

Plasma can be separated into the individual clotting factors

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8
Q

What is the first response to bleeding

A

Localised vasoconstriction

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9
Q

What are the two components to the clotting system

A

Primary haemostasis – platelet activation and adhesion. Secondary haemostasis – activation of the coagulation cascade

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10
Q

What is the role of the coagulation cascade

A

To produce fibrin that fixes the cells together

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11
Q

What are the two causes of platelet bleeding disorders

A

Reduced platelet numbers (thrombocytopenia) or impaired platelet function that is either inherited or acquired

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12
Q

How are patients with platelet bleeding disorders treated

A

Platelet transfusions

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13
Q

How to platelets bind to collagen in the endothelium during clotting

A

Via the binding of von Willebrand factor

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14
Q

What is the inheritance pattern of von Willebrand disease

A

Autosomal dominant

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15
Q

Von Willebrand disease is the most common inherited bleeding disorder with as many as 10% of the population having reduced vWF levels T or F

A

F – whilst it is the most common inherited bleeding disorder its 1% of the population who have reduced vWF levels

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16
Q

Von Willebrand disease is a milder bleeding disorder to haemophilia T or F

A

T

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17
Q

What are the main symptoms of von Willebrand disease

A

Bruising cuts mennohagia epistaxis (nose bleeds) and bleeding of the gums

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18
Q

What are the two approaches in the treatment of von Willebrand disease

A

Desmopressin to stimulate endothelial cell degranulation of the Weibel-Palade bodies that contain vWF. Alternatively intermediate purity/plasma-derived factor VIII is given which contains vWF

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19
Q

What is the name of the granules that contain vWF in the endothelial cells

A

Weibel-Palade bodies

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20
Q

What factor is activated first in the imitation of secondary haemostasis

A

Tissue factor or clotting factor VIIa

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21
Q

What is the main activator of the coagulation cascade in humans

A

Clotting factor VIIa

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22
Q

How is factor VIIa activated during vessel injury

A

Injury to the vessel exposes FVIIa which is underneath the vessel

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23
Q

What are the two effects of activating factor VIIa

A

FVIIa both directly and indirectly leads to the conversion of factor X to factor Xa. It directly stimulates this conversion but also acts via triggering the conversion of factor IX to IXa which then stimulates factor X conversion

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24
Q

Which pathway of factor Xa production is more efficient

A

The indirect pathway

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25
Q

What is the role of factor Xa in the coagulation cascade

A

Factor Xa activates the conversion of factor II to factor IIa. Factor IIa is also known as thrombin and is the enzyme responsible for catalysing the conversion of fibrinogen to fibrin

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26
Q

Below is an outline of the coagulation cascade fill in the missing clotting factors

A

See completed diagram below

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27
Q

What is the inheritance pattern of haemophilia A and B

A

X-linked

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28
Q

Haemophilia A and B have distinct clinical features T or F

A

F – they have identical clinical features

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29
Q

Which clotting factor is deficient in haemophilia A

A

FVIII

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30
Q

Which clotting factor is deficient in haemophilia V

A

FIX

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31
Q

Where is bleeding often seen in haemophilia

A

Joints and muscles

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32
Q

How is haemophilia A severity classified

A

Based on the levels of FVIII present in the blood normal levels are around 50-150%.

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33
Q

Outline the different severities of haemophilia A and how this relates to the incidence of bleeding

A

Severe Haemophilia A – <1% FVIII (20-40 times a year spontaneous bleeding). Moderate Haemophilia A – 1-5% FVIII (1-2 times a year spontaneous bleeding). Mild Haemophilia A – >5% FVIII (no spontaneous bleeding)

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34
Q

Other than bleeding what are the symptoms of haemophilia

A

Wasted quadriceps due to impaired mobility haemarthrosis causing severe joint damage due to degradation of cartilage

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35
Q

Which is the only clotting factor for which there is not a concentrate for

A

Factor V because it is rarely deficient in patients

36
Q

What is the other name for factor I

A

Fibrinogen

37
Q

What is the other name for factor II

A

Prothrombin

38
Q

Which clotting factors have recombinant concentrates

A

VII VIII IX and XIII

39
Q

Outline how primary and secondary haemostatic disorders are treated

A

Primary haemostatic disorders such as von Willebrand disease are treated with platelet transfusions desmopressin or vWF concentrate. Secondary haemostatic disorders such as haemophilia are treated with the specific clotting factors required

40
Q

Give an example of a primary haemostatic disorder

A

Von Willebrand Disease

41
Q

Give an example of a secondary haemostatic disorder

A

Haemophilia

42
Q

What is meant by thrombosis

A

Inappropriate blood coagulation

43
Q

When is coagulation important

A

Appropriate coagulation occurs when blood escapes from the vessel

44
Q

How do arterial and venous thromboses differ

A

Arterial thromboses occur in high pressure environments and are platelet rich. These often cause myocardial infarctions and thrombotic strokes. Meanwhile venous thromboses occur in low pressure systems and are fibrin rich. These usually case deep vein thromboses and pulmonary embolisms

45
Q

How are arterial and venous thromboses treated differently

A

Arterial thromboses are treated with anti-platelet drugs whereas venous thromboses are treated with anti-coagulant drugs

46
Q

List examples of antiplatelet drugs

A

Aspirin clopidogrel prasugrel ticagrelor cangrelor abciximab eptifibatide and tirofiban

47
Q

What are the three types of delivery of anticoagulant drugs

A

Intravenous subcutaneous and oral

48
Q

Which anticoagulants are administered intravenously

A

Unfractionated heparin

49
Q

Which anticoagulants are administered subcutaneously

A

Low molecular weight heparin (Fragmin)

50
Q

Which anticoagulants are administered orally

A

Warfarin dabigatran rivaroxaban apixaban and edoxaban

51
Q

What class of drugs to warfarin and acenocoumarol belong to

A

Vitamin K antagonists

52
Q

What is the mechanism of action of heparin in thrombosis

A

Heparin binds to and activates the naturally occurring anticoagulant anti-thrombin. Antithrombin inhibits FXIa FXa FIXa and FIIa (thrombin) which in turn prevents fibrin formation and subsequent clot formation

53
Q

What kind of molecules is heparin

A

Glycosaminoglycan

54
Q

Heparin is known as an indirect thrombin inhibitor T or F

A

T

55
Q

What is the APTT test

A

The activated partial thromboplastin time is a test used to monitor the response of a patient to heparin by characterising blood coagulation

56
Q

How is heparin administered

A

By continuous infusion

57
Q

What is the downside to using heparin as an anticoagulant

A

Heparin given to patients consists of a variation of heparin chain lengths from 4kDa to 35kDa. This means that coagulation is less reproducible and controllable in patients

58
Q

What are the main benefits of low molecular weight heparin over standard unfractionated heparin

A

Low molecular weight heparin is only the 7kDa heparin molecule. There is thus much less variation in dose it can be given subcutaneously once a day and it is renally excreted

59
Q

Low molecular weight heparin can only be used for treatment of venous thrombosis T or F

A

F – it can be used for prophylaxis as well

60
Q

What is the benefit of warfarin in terms of its delivery

A

Warfarin can be delivered orally and is completely and rapidly absorbed

61
Q

What is the overall effect of warfarin on clotting factors

A

Warfarin inhibits the production of factors II VII IX X (vitamin K dependent factors)

62
Q

Why is it that warfarin has a slow on and slow off effect

A

This is due to the long half-life of the clotting factors. You have to wait for the already synthesised clotting factors to be degraded

63
Q

What are the side effects of warfarin

A

Bleeding embryopathy

64
Q

What variable is measured to monitor warfarin effectiveness

A

International normalised ratio which is essentially a measure of how quickly a patients’ blood clots compared to control

65
Q

What is meant by a INR of 2.0

A

The patients’ blood will take twice as long to clot as normal

66
Q

What is the INR value of a healthy patient

A

1

67
Q

What is the desired INR for DVT/PE

A

2.0 – 3.0

68
Q

What determines how frequently a patient on warfarin is monitored

A

The frequency of monitoring depends on the stability of the patient’s INR. This varies with the vitamin K levels and hence monitoring can be once per week up to once every 8 weeks

69
Q

The INR of a warfarinised patient must be measured before surgery T or F

A

T

70
Q

What is the average dose of warfarin required

A

5mg

71
Q

Outline the vitamin K cycle and how warfarin interacts with it

A

The liver synthesises factors II VII IX X PC PS and other clotting factors but in order to become functional these factors need to be carboxylated. γ-glutamyl carboxylase (GGCX) is the enzyme that mediates the carboxylation of the clotting factors however GGCX requires vitamin K for its function. Once vitamin K is used by GGCX during carboxylation it becomes oxidised. Vitamin K epoxide Reductase Complex subunit 1 (VKORC1) converts oxidised vitamin K to its reduced form which can then be used by GGCX. Warfarin inhibits VKOR leading to a reduction in reduced vitamin K. This leads to an accumulation of oxidised vitamin K which cannot be used in the carboxylation of clotting factors and hence less active clotting factors are produced

72
Q

Explain how SNPs in VKORC1 can change a patient’s response to warfarin

A

A single nucleotide polymorphism in VKORC1 (1639G>A) results in a decreased activity of the genes’ promoter and subsequently a 44% decreased expression level. This renders patients more sensitive to warfarin as they already have decreased levels of reduced vitamin K and decreased levels of active clotting factors

73
Q

What is the role of CYP2C9 in warfarin activity

A

CYP2C9 is the enzyme responsible for metabolising warfarin to its inactive metabolites

74
Q

Explain how SNPs in CYP2C9 can change a patient’s response to warfarin

A

SNPs in CYP2C9 change its activity in metabolising warfarin. The main SNPs *2 and *3 are reduction-of function (ROF) variants that decrease the ability of the enzyme to metabolise warfarin by 30-40% and 80-90% respectively. This hence renders the patient more sensitive to the drug and with increased plasma concentrations.

75
Q

How can warfarin administration be personalised to individual patients

A

Patients can have the VKORC1 and CYP2C9 genes genotyped to determine their ability to respond to and metabolise warfarin. Their genotype information can then be fed into an algorithm which can calculate the dose of warfarin that is appropriate for that patient

76
Q

What is the major limitation in personalising warfarin doses

A

Genotyping patients prior to warfarin administration takes days and therefore isn’t suitable in treating acute bleeding

77
Q

What are the main benefits of direct oral anticoagulants

A

Orally administered require no monitoring have standard dosing don’t interact with alcohol or food and similarly donkt interact with many other drugs

78
Q

What are the downsides to direct oral anticoagulants(DOACs)

A

They have a short half-life and hence are required daily but are considerably more expensive than warfarin

79
Q

Which DOACs are licenced in the UK

A

Dabigatran rivaroxaban apixaban and edoxaban

80
Q

Which DOACs inhibit factor IIa/thrombin

A

Dabigatran

81
Q

Which DOACs inhibit factor Xa

A

Rivaroxaban edoxaban and apixaban

82
Q

Which thrombotic condititions are DOACs licenced for

A

All are licenced in the treatment of atrial fibrillation DVT and PE. All apart from edoxaban are licenced for thromboprophylaxis

83
Q

What is the main concern when developing a novel anti-coagulant drug

A

The ability to reverse their effects

84
Q

How can the effects of dabigatran be reversed

A

Using the humanised monoclonal antibody against the drug. This is now licenced for the reversal of dabigatran anticoagulation

85
Q

How can the effects of rivaroxaban apixaban and edoxaban be reversed

A

Andexanet is a recombinant modified inactive factor Xa molecule that binds the drug in the circulation and prevents its action on endogenous factor Xa

CDL301 Cardiovascular Pharmacology (17 decks)

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