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haemostasis Flashcards

1
Q

describe the flow and function of blood under normal conditions.

A

flows within vascular system

transports oxygen, nutrients and hormonal information around the body

removes metabolic waste

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2
Q

the confinement of circulating blood to the blood vessels and maintenance of a fluid state are dependent on which factors?

A

fibrinolytic factors and anticoagulant proteins vs. coagulation factors and platelets

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3
Q

why is the balance of fibrinolytic factors and anticoagulant proteins vs. coagulation factors and platelets important?

A

allows stimulation of blood clotting processes to allow coagulation after injury

limits extent of response to injury area to prevent thrombosis

starts process that eventually leads to fibrinolysis

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4
Q

what is coagulation?

A

blood changes from its liquid state as a result of stimulation of blood clotting processes following injury

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5
Q

what is thrombosis?

A

excessive/generalised blood clotting

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6
Q

what is fibrinolysis?

A

breakdown of a clot as part of the healing process

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7
Q

haemostasis describes what exactly?

A

‘halting of blood’ following trauma to blood vessels

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8
Q

haemostasis results from which 3 intertwined processes?

A

1 - vasoconstriction (contraction of blood vessels)

2- primary haemostasis (formation of an unstable platelet plug at the site of vessel wall damage)

3- secondary haemostasis/coagulation (formation of a stable fibrin clot)

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9
Q

what is vasoconstriction?

A

contraction of blood vessels

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10
Q

what is primary haemostasis?

A

formation of an unstable platelet plug at the site of vessel wall damage

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11
Q

what is secondary haemostasis/coagulation?

A

formation of a stable fibrin clot

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12
Q

what are the 5 reasons why is it important to understand haemostatic mechanisms?

A

1- diagnose and treat bleeding disorders

2- identify risk factors for thrombosis

3- treat thrombotic disorders

4- monitor drugs used to treat bleeding and thrombotic disorders

5- control bleeding in individuals without an underlying bleeding disorder

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13
Q

briefly outline the 4 stages of haemostasis.

A

1- response to injury (vessel constriction)

2- primary haemostasis

  • platelet adhesion
  • platelet aggregation

3- secondary hamostasis
- blood coagulation

4- fibrinolysis (dissolution of clot and vessel repair)

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14
Q

describe platelets.

A

discoid

non nucleated

granule containing cells

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15
Q

where are platelets derived from?

A

myeloid stem cells

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16
Q

where are platelets formed?

A

bone marrow

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17
Q

how are platelets formed?

A

fragmentation of megakaryocyte cytoplasm

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18
Q

what is the circulating lifespan of a platelet?

A

around 10 days

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19
Q

what proteins are present on the platelet plasma membrane that are important for platelet interactions?

A

glycoproteins (GPs)

specifically, GPIa and GPIb

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20
Q

describe direct platelet adhesion.

A

following injury to vessel wall, platelets stick directly to collagen in the damaged endothelium via the GPIa receptor on the platelet plasma membrane.

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21
Q

describe indirect platelet adhesion.

A

following injury to vessel wall, platelets stick indirectly to collagen in the damaged endothelium via von Willebrand factor, which binds to the GPIb receptor on the platelet plasma membrane.

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22
Q

what kind of shape change does platelet adhesion cause in platelets?

A

from discoid to more rounded form with spicules

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23
Q

why is the change in shape of platelets from discoid to more rounded with spicules after platelet adhesion relevant?

A

encourages platelet-platelet interaction

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24
Q

what does platelet adhesion cause?

A

platelet release action

adhesion initiates activation of platelets and release of contents of their storage granules

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25
Q

what are the 2 main types of ultrastructually identifiable storage granules in platelets?

A

α-granules

dense granules

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26
Q

where are most clotting factors synthesised and what are the 2 exceptions?

A

liver

all except VIII and VWF

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27
Q

where are factor VIII and VWF synthesised?

A

endothelial cells

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28
Q

where can VWF also be synthesised aside from the endothelial cells?

A

megakaryocytes

incorporated into platelet granules

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29
Q

what is factor II also known as?

A

prothrombin

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30
Q

factors II, VII, IX and X are dependent on what for their function and why is it essential to their function?

A

vitamin K

needed for carboxylation of glutamic acid residues

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31
Q

what are factors V and VIII?

A

co factors

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32
Q

where are many factors believed to work and why is this important?

A

exposed phospholipid surface of platelets

helps localise and accelerate these reactions

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33
Q

what role do Ca²⁺ ions play in reference to the binding of clotting factors?

A

helps bind activated clotting factors to phospholipid surfaces of platelets

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34
Q

what stabilises the initial platelet plug?

A

fibrin formation

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35
Q

in which cases is the primary platelet plug sufficient?

A

small vessel injury

will fall apart in larger vessels

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36
Q

what do blood coagulation pathways centre on?

A

generation of thrombin

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37
Q

what is the role of thrombin?

A

cleaves fibrinogen to generate fibrin clot that stabilises platelet plug at site of vascular injury

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38
Q

each step in blood coagulation is characterised by what? outline the process.

A

conversion of inactive zymogen (proenzyme) to an active clotting factor

achieved by splitting peptide bonds

this exposes active enzyme site

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39
Q

what is the trigger to initiate coagulation at injury sites?

A

tissue factor (TF)

exposed on surface of endothelial cells. leukocytes and most extravascular cells in areas of tissue damage

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40
Q

why is the presence of TF at injury sites significant?

A

TF present in sites not usually exposed to the blood under normal physiological conditions

therefore blood only encounters TF at sites of vascular injury

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41
Q

what are the 3 phases of secondary haemostasis/coagulation?

A

initiation

amplification

propagation

42
Q

describe the initiation phase of secondary haemostasis/coagulation.

A

TF binds to factor VIIa

leads to activation of factors IX to IXa and X to Xa

leads to activation of prothrombin (factor II)

generates small amount of thrombin (factor IIa)

43
Q

describe the amplification phase of secondary haemostasis/coagulation.

A

small amount of thrombin generated during initiation mediates activation of:

  • co factors V and VIII
  • zymogen factor XI
  • platelets
44
Q

describe the propagation phase of secondary haemostasis/coagulation.

A

factor XI converts more factor IX to IXa

factor IXa works with factor VIIIa to amplify conversion of factor X to Xa

causes rapid burst in thrombin generation

thrombin cleaves fibrinogen to produce insoluble fibrin clot

45
Q

how are the contents of platelet granules released after platelet adhesion?

A

platelet membrane invaginates to form a surace-connected cannalicular system through which contents are released

46
Q

what components (among others) are released by platelet granules after platelet adhesion?

A

ADP

fibrinogen

VWF

47
Q

what is thromboxane A2?

A

a prostaglandin

48
Q

how is thromboxane A2 produced?

A

platelets stimulated to produce it from arachidonic acid derived from the cell membrane

49
Q

what are the roles of thromboxane A2?

A

vasoconstrictor (important during tissue injury and inflammation)

in platelet aggregation

50
Q

describe the process of platelet aggregation.

A

granular release of ADP and thromboxane A2 generation after platelet adhesion

ADP binds to P2Y12 receptor, thromboxane A2 binds to thromboxane A2 receptor

binding has positive feedback effects - further platelet recruitment, activation and aggregation

platelet activation causes conformational changes in the GPIIb/IIIa receptor, providing binding sites for fibrinogen

fibrinogen has a key role in linking platelets together to form the plug

51
Q

fibrinogen has a key role in linking platelets together to form a platelet plug - how are these effects normally counterbalanced?

A

counterbalanced by active flow of blood

counterbalanced by release of prostacyclin (PGI2) from endothelial cells

52
Q

what is prostacyclin?

A

powerful vasodilator

suppresses platelet activation, therefore preventing inappropriate platelet aggregation

53
Q

what are antiplatelet drugs usually used for? give the 2 most commonly used.

A

prevention and treatment of cardiovascular and cerebrovascular disease

e.g aspirin, clopidogrel

54
Q

how does aspirin function as an antiplatelet drug?

A

irreversibly blocks action of cyclo-oxygenase (COX), inhibiting thromboxane A2 production

therefore reduced platelet aggregation

although prostacyclin production is also inhibited by COX, endothelial cells can synthesise more (platelets, being non-nuclear, cannot)

therefore the effects of a dose of aspirin persists for around 7 days until most of the platelets present at the time of ingestion are replaced by new platelets

55
Q

how does clopidogrel function as an antiplatelet drug?

A

irreversibly blocks P2Y12 receptor (ADP) on platelet cell membrane

effects of clopidogrel last around 7 days (until new platelets replaced those present at time of ingestion)

56
Q

what is VWF and how is it synthesised?

A

multimeric glycoprotein

synthesised by endothelial cells and megakaryocytes

circulates in plasma

57
Q

what are the 3 roles of VWF?

A

mediates adhesion of platelets to injury sites

promotes platelet-platelet aggregation

specific carrier for factor VIII in addition to adhesive properties

58
Q

what do inhibitory mechanisms do?

A

prevent blood from clotting completely when clotting is initiated by vessel injury

59
Q

what does the action of inhibitory mechanisms ensure?

A

coagulation is confined to the site of injury

prevents spontaneous activation of coagulation

60
Q

what 3 things does the protein C pathway inhibitory mechanism involve?

A

protein C

protein S

antithrombin

61
Q

describe the protein C pathway inhibitory mechanism.

A

downregulates thrombin generation

1- thrombin binds to thrombomodulin on endothelial cell surface

2- this activates protein C to activated protein C (APC)

3- APC inactivates factors Va and VIIIa in the presence of a co-factor (protein S)

4- thrombin and factor Xa are inactivated by the circulating inhibitor antithrombin
the binding of antithrombin to endothelial cell-associated heparins potentiates the action of antithrombin

62
Q

what are anticoagulant drugs used for?

A

prevention and treatment of thrombosis

63
Q

what are the 3 main anticoagulant drugs?

A

heparin

warfarin

direct oral anticoagulants (DOACs)

64
Q

how does heparin work as an anticoagulant drug?

A

administered intravenously or by subcutaneous injection

works indirectly

potentiates action of antithrombin

factor Xa and IIa (thrombin) inactivated

65
Q

how does warfarin work as an anticoagulant drug?

A

given as an oral tablet, anticoagulant effect needs monitoring by regular blood testing

vitamin K antagonist

interferes with protein carboxylation

reduces synthesis of functional factors II, VII, IX and X by the liver (takes several days to take effect because it is reducing synthesis rather than inhibiting existing molecules)

66
Q

how do DOACs (direct oral anticoagulants) work as anticoagulant drugs?

A

orally available drugs, do not usually require monitoring

directly inhibit either thrombin or factor Xa (i.e without the involvement of antithrombin?

67
Q

describe the process of fibrinolysis.

A

plasminogen is activated by tissue plasminogen activator (tPA) to plasmin (principal fibrinolytic enzyme) when both tPA and plasminogen bind to lysine residues on fibrin

breakdown of fibrin by plasmin leads to generation of fibrin degradation products (FDPs)

68
Q

how is plasmin activated?

A

inactive zymogen form plasminogen circulates in the blood

tissue plasminogen activator (tPA) activates plasminogen to plasmin when both tPA and plasminogen bind to lysine residues on fibrin

69
Q

what can plasmin break down?

A

primarily fibrin, but is not fibrin-specific

also breaks down other protein components of plasma (including fibrinogen, factors Va and VIIIa)

70
Q

how is plasmin inhibited?

A

antiplasmin

circulates in the blood

71
Q

what is the aim of thrombolytic therapy?

A

generates plasmin to lyse clots

used for patients with ischaemic stroke, pulmonary emboli etc

(used to be used in myocardial infarctions but this has been generally replaced with angioplasty and stenting the diseased coronary vessels)

72
Q

how is a thrombolytic agent such as recombinant tPA used in dealing with ischaemic stroke?

A

recombinant tPA generates administered intravenously

benefit is time dependent (needs to be given as quickly as possible, preferably within an hour)

generates plasmin to lyse clots

73
Q

what is the primary risk with using a thrombolytic agent such as recombinant tPA (e.g in dealing with ischaemic stroke?)

A

high risk of bleeding

74
Q

give an example of an antifibrinolytic drug.

A

tranexamic acid

75
Q

what is tranexamic acid?

A

synthetic derivative of lysine

antifibrinolytic drug

76
Q

how does tranexamic acid work as an antifibrinolytic drug?

A

binds to active site on plasminogen

prevents binding of plasminogen to lysine residues on fibrin (competitive inhibition)

plasminogen cannot be activated to plasmin, fibrinolysis cannot occur

77
Q

where is tranexamic acid used?

A

antifibrinolytic drug

used to treat bleeding in trauma and surgical patients

treatment of inherited bleeding disorders

78
Q

what does the intrinsic coagulation cascade model refer to?

A

system where all components are in the plasma (factors IX, X, XI, XII, co-factors V and VIII)

79
Q

what does the extrinsic coagulation cascade model refer to?

A

comprises TF, co-factor V and factors VII and X

80
Q

how does the prothrombin time (PT) work as a test of coagulation?

A

measures integrity of extrinsic pathway

blood combined with sodium citrate (chelates calcium, prevents clotting) and spun to produce platelet-poor plasma

source of TF and phospholipid (usually recombinant thromboplastin) as well as calcium is added to the plasma

time taken to clot is recorded

81
Q

what does a prolonged PT indicated?

A

reduction of activity of factor II (or fibrinogen), V, VII or X

82
Q

when the PT is used to monitor vitamin K antagonist anticoagulant therapy such as warfarin, how are results expressed and why?

A

expressed as international normalised ratio (INR)

involves a correction for different thromboplastin reagents used by different laboratories

therefore all laboratories should obtain the same INR result for a sample irrespective of the thromboplastin source

83
Q

how does the activated partial thromboplastin time (APTT) work as a test of coagulation?

A

measures integrity of intrinsic pathway

performed by the contact activator of factor XII by a surface such as glass, or using a contact activator (e.g silica, kaolin)

blood combined with sodium citrate (chelates calcium, prevents clotting) and spun to produce platelet-poor plasma

contact activator, phospholipid and calcium added to the plasma sample

time taken to clot is recorded

84
Q

what 3 things could an isolated prolonged APTT (i.e normal PT) indicate?

A

haemophilia A (factor VIII deficiency)

haemophilia B (factor IX deficiency)

factor XI deficiency

may also be caused by factor XII deficiency, which does not cause bleeding

85
Q

what does a prolonged APTT with an associated prolonged PT indicate?

A

deficiency in multiple clotting factors

86
Q

what 3 things can bleeding be caused by?

A

reduction in platelet number/function (primary haemostasis - platelet plug)

reduction in coagulation factors (secondary haemostasis - fibrin clot)

increased fibrinolysis

87
Q

what 3 things could cause a reduction in platelet number, which could lead to bleeding?

A

failure of platelet production (drugs, viruses, bone marrow infiltration, megaloblastic anaemia resulting from B12 or folate deficiency, hereditary thrombocytopenia)

shortened platelet survival
(immune thrombocytopenia, disseminated intravascular coagulation/DIC)

increased splenic pooling

88
Q

what 2 things could cause a reduction in platelet function, which could lead to bleeding?

A

inherited causes

antiplatelet drugs (e.g aspirin)

89
Q

what are the congenital causes of reduced coagulation factors and how are they inherited?

A

most common bleeding disorder - reduction in level of function of VWF (known as von Willebrand disease) - autosomally inherited, affects males and females

the rest have deficiencies of one of the clotting factors

  • most have haemophilia A (factor VIII deficiency, X-linked)
  • some have haemophilia B (factor IX deficiency, X-linked)
  • a very small percentage have deficiencies of one of the other clotting factors (usually autosomal recessive inheritance, common in areas with high levels of consanguinity)
90
Q

how are congenital causes of reduced coagulation factors treated?

A

replacement of missing clotting factor with specific clotting factor concentrates

91
Q

how is the risk of pathogen transmission eliminated when replacing missing clotting factors due to congenital causes?

A

factor concentrates are recombinant

92
Q

what are the 3 acquired causes of reduced coagulation factors?

A

liver disease

anticoagulant drugs

disseminated intravascular coagulation (DIC)

93
Q

what is disseminated intravascular coagulation (DIC)?

A

process where there is generalised and uncontrolled activation of coagulation, followed by a marked activation of the fibrinolytic system

activation of fibrinolytic system due to TF within the circulation, leading to:

  • generation and dissemination of large amounts of thrombin
  • activation and consumption of platelets
  • widespread formation of thrombi in the small blood vessles (micocirculation)

clotting factors and fibrinogen in plasma become depleted - impairs haemostatic activity, may result in severe bleeding

high levels of fibrin degradation products (FDPs) as a result of fibrinolysis activation

94
Q

what are the causes of increased fibrinolysis, which may lead to bleeding?

A

seen in DIC (disseminated intravascular coagulation)

due to administration of thrombolytic therapy e.g tPA

95
Q

what are some of the causes of DIC (disseminated intravascular coagulation) and how is it controlled/treated?

A

bacterial sepsis

advanced cancer

variety of obstetric emergencies

bleeding can be controlled by replacing missing clotting factors and platelets

underlying cause needs to be addressed in order to switch off the unregulated coagulation activation

96
Q

what is thrombosis?

A

formation of a blood clot within an intact blood vessel

results in obstruction of blood flow with serious consequences

97
Q

what are the 3 contributing factors to thrombosis (Virchow’s triad) and where are they dominant?

A

blood (dominant in venous thrombosis)

vessel wall (dominant in arterial thrombosis)

blood flow (contributes to both arterial and venous thrombosis)

98
Q

what are the 3 changes in blood that may increase the risk of venous thrombosis?

A

reduced level of anticoagulant proteins

reduced fibrinolytic activity

increased levels of clotting factors or platelets

99
Q

what can cause reduced levels of anticoagulant proteins, which may increase the risk of venous thrombosis?

A

usually genetic basis

e.g inherited antithrombin deficiency (inherited thrombophilia)

100
Q

what can cause reduced fibrinolytic activity, which may increase the risk of venous thrombosis?

A

pregnancy

inhibition of plasminogen activation through production of a specific inhibitor by the placenta

101
Q

what can cause increased levels of clotting factors, which may increase the risk of venous thrombosis?

A

factor VIII levels rise when pregnant

factor V activity increased by a point mutation known as factor V Leiden
(makes factor V more resistant to inactivation by protein C)
many people are carriers - most common of inherited thrombophilias

platelets increased in some myeloproliferative disorders

PoM (42 decks)

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