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Blood > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

General steps of haemostasis

A

1) Trauma/breach of vascular barrier triggers reflex vascular spasm -> slow down blood flow towards puncture site -> decreased blood loss

2) Primary haemostasis -> formation of platelet plug

3) Secondary haemostasis -> formation of blood clot

4) Clot dissolution

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2
Q

What is thrombopoiesis?

A

Formation of platelets

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3
Q

What does thrombopoietin (TPO) stimulate?

A

Thrombopoiesis

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4
Q

Which organs produce TPO?

A

Liver and kidney

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5
Q

What is a megakaryocyte?

A

Precursor for platelets
- can’t enter circulation directly -> turn into fragments first

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6
Q

What kind of feedback loop does thrombopoiesis utilise?

A

Neg feedback loop

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7
Q

How is TPO removed?

A

Via circulating platelets

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8
Q

What is the lifespan of platelets?

A

~ 10 days

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9
Q

Where are old platelets removed?

A

Spleen

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10
Q

How is a platelet plug formed?

A

1) Platelet adhesion to exposed collagen and subsequent activation (change morphology into ‘spiky’ form)

2) Release of granules containing platelet agonists -> attract more platelet toward puncture site -> encourage further aggregation

3) Platelet aggregates to form plug and release more platelet attracting substances

4) Intact endothelial cells releases NO and prostacyclins that inhibits unintentional platelet activation/aggregation

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11
Q

How does body inhibit uncontrolled platelet formation?

A

Intact endothelial cells releases NO and prostacyclins that inhibits unintentional platelet activation/aggregation

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12
Q

What is Von Willebrand’s factor (vWF)?

A

Plasma protein produced by platelets that mediate platelet adhesion by binding platelets to exposed collagen

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13
Q

How does vWF bind platelets to exposed collagen?

A

Via glycoprotein receptor found on surface of aggregated platelets

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14
Q

What does adhesion do to platelets?

A

Activates platelets -> morphological change; spikes -> greater surface area for attachment of platelet

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15
Q

How does aggregation of platelets occur?

A

Adhesion triggers release of granules containing platelet agonists -> aggregation

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16
Q

Eg of platelet agonists

A

ADP, thromboxane A2 (Tbx A2)

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17
Q

What does ADP do?

A

Attracts and activates more platelets

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18
Q

What does Tbx A2 do?

A

Promote aggregation and further vasoconstriction at puncture site

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19
Q

What does fibrinogen do?

A

Links platelets through glycoprotein receptors

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20
Q

Characteristic of fibrinogen links

A

Weak, temporary -> need further reinforcement via secondary haemostasis

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21
Q

Describe the process of secondary haemostasis

A

Formation of strong and insoluble fibrin mesh -> trap all the blood cells and clotting factors that try to escape from damaged vessel

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22
Q

What does thrombin do?

A

It cleaves and activate fibrinogen as well as factor 13 -> factor 13a

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23
Q

What is fibrinogen?

A

Insoluble protein where fibrin mesh originates from

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24
Q

What does fibrinogen do?

A

Crosslinks platelets tgt

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25
Q

How is a fibrin strand formed?

A

Fibrinogen (soluble) cleaves and activate into fibrin monomer (insoluble) which polymerise into fibrin strand

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26
Q

What is a fibrin mesh?

A

Many fibrin strands crosslinked tgt

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27
Q

What crosslinks fibrin strands?

A

Factor 13a (fibrin stabilising factor)

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28
Q

What is prothrombin?

A

The inactivated form of thrombin that is present in circulation

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29
Q

How is prothrombin activated into thrombin?

A

Factor 10 -> factor 10a which cleaves and activates prothrombin to form thrombin in the presence of Ca2+ and factor 5a

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30
Q

What are the diff pathways of the coagulation cascade?

A

Extrinsic

Intrinsic

Common pathway

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31
Q

How many common coagulation factors are there?

A

12

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32
Q

Which coagulation factors are involved in the extrinsic pathway (exclude the common pathway)?

A

Factor 7

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33
Q

What are the steps to the common pathway?

A

Factor 10 -> factor 10a which cleaves and activate prothrombin to thrombin in the presence of Ca2+ and factor 5a

Thrombin cleave and activate factor 13 -> factor 13a

Thrombin cleave and activate fibrinogen -> fibrin —> fibrin strand -> fibrin mesh (crosslinked by factor 13a)

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34
Q

What are the steps to the extrinsic pathway (exclude common)?

A

Damaged tissue releases tissue factor/thromboplastin -> bind to and activate factor 7 to form 7a -> cleave and activate factor 10 in the presence of Ca2+ to form factor 10a -> common pathway

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35
Q

Why is it called the extrinsic pathway?

A

Tissue factor comes from external sources

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36
Q

What are the steps to the intrinsic pathway?

A

Exposure to collagen fibres/foreign surface cause factor 12 to undergo conformational change in the presence of platelet phospholipids -> factor 12 activated to factor 12a

Factor 12a cleave and activate factor 11 -> factor 11a

Factor 11a cleaves and activate factor 9 -> factor 9a in the presence of Ca2+

Factor 9a cleaves and activates factor 10 -> factor 10a in the presence of Ca2+ and factor 8a -> common pathway

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37
Q

Why is it called the intrinsic pathway?

A

Factor 12 initiates the pathway and is a circulating plasma protein (endogenous part of circulatory sys)

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38
Q

Why is haemostatic dressing encouraged?

A

It’s a foreign surface -> initiate intrinsic pathway

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39
Q

What happens when Ca2+ is absent and it’s application?

A

Clotting pathway is impaired as many of the pathways req Ca2+

Application: prevent blood in test tube from clotting by adding agent to remove Ca2+

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40
Q

Which factors are not plasma proteins?

A

Factor 3 and Ca2+

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41
Q

Why does liver damage cause bleeding issues?

A

Most of the coagulation factors (except thromboplastin and Ca2+) are produced by the liver

Liver damage -> production of clotting factors impaired -> bleeding

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42
Q

Which factors req Vit K for production?

A

Factors 2, 7, 9 and 10

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43
Q

Consequence of Vit K deficiency

A

Bleeding issues
- Vit K needed to produce some clotting factors
- deficiency -> impaired production of some clotting factors

44
Q

What is factor 1, 2, 3 and 4?

A

Fibrinogen, prothrombin, thromboplastin/tissue factor and Ca2+ respectively

45
Q

Primary vs secondary haemostasis

A

Primary -> rapid but weak

Secondary -> slower but stronger

46
Q

Why does the body need a complicated cascade for haemostasis?

A

Amplification -> speed up process
- cascade expands the no. of fibrin activated

Regulation
- multiple feedback loop

47
Q

Why is there a need for 2 pathways?

A

Stop bleeding -> needs it to be fast
- extrinsic is only 1 step -> extremely fast -> initial clotting

48
Q

How to assess the coagulation sys?

A

Quick screens
- FBC -> platelet count
- prothrombin time (PT)
- partial thromboplastin time (aPTT)
- activator added to trigger test

Specific/confirmatory tests
- coagulation factor assays
- platelet aggregation test (assess fn of platelet in cases whr platelet count is normal)
- vWF antigen assay

49
Q

What does PT measure?

A

Time taken for fibrin clot to form after addition of agents

50
Q

Which pathway does PT evaluate?

A

Extrinsic pathway

51
Q

How is PT time interpreted?

A

Normal -> ~10s
- time&raquo_space; than 10s -> extrinsic pathway is impaired

52
Q

What is International Normalised ratio (INR) and what is the normal range?

A

Corrected ratio of pt’s PT vs normal PT

Normal = 0.8 - 1.2

53
Q

Which pathway does aPTT assess?

A

Intrinsic pathway

54
Q

What is the normal result for aPTT?

A

25-35s

55
Q

Application of aPTT?

A

Screen bleeding disorders

Monitor anti-coagulant therapy
- eg: heparin therapy -> make sure blood doesn’t clot during surgery

56
Q

What do citrated tubes do to the blood collected?

A

Remove Ca2+ via Ca2+ chelators to stop coagulation pathway

57
Q

What agents are added to the citrated plasma during PT and why?

A

Thromboplastin -> activate extrinsic pathway

Ca2+ -> replace Ca2+ that was removed; so that factors can work

58
Q

What agents are added to the citrated plasma during aPTT?

A

Kaolin -> activator; for contact-dependent activation of factor 12

Phospholipids

Ca2+

59
Q

Is Ca2+ deficiency a common cause for bleeding disorders?

A

No, a lot of Ca in the body (eg: bones) -> can’t reach a level that affects coagulation pathway, hence it is ok to remove Ca2+ from the blood during collection.

60
Q

What kind of genetic disorder is hemophilia?

A

X-linked recessive disorder

61
Q

Difference btw hemophilia A vs B

A

A -> factor 8 deficient

B -> factor 9 deficient

62
Q

What test can be used to identify deficiency in a specific coagulation factor?

A

Coagulation factor assay

63
Q

Treatment options for hemophilia

A

Activated prothrombin complex concentrates (APCC) = cryoprecipitate + activated FVII
- not long term treatment as it’s permanently activated

Recombinant coagulation factors
- long term
- replace defective factors

64
Q

Clinical relevance of presence of petechiae

A

Indicated low platelet count

65
Q

What does splenomegaly indicate?

A

Thrombocytopenia
- spleen removes platelet; large spleen -> spleen has been working hard to remove platelets

66
Q

Causes of thrombocytopenia

A

Dengue

Chemotherapy
- stops proliferation of cell

Immune
- attack any step in thrombopoiesis

67
Q

What is Von Willebrand disease?

A

vWF deficiency

Autosomal dominant mutation

68
Q

How is Von Willebrand disease detected?

A

vWF antigen assay

69
Q

Why does Von Willebrand disease prolong aPTT?

A

vWF binds and stabilise factor 8, vWF deficiency -> factor degrade easily -> intrinsic pathway affected

70
Q

Purpose of anti-coagulation system

A

Prevents aberrant clot formation

Removal of clots once they’re no longer needed

71
Q

General steps of anti-haemostasis

A

Plug prevention -> inhibit pri haemostasis

Clot prevention -> inhibit sec haemostasis

Clot removal -> fibrinolysis

72
Q

How is plug formation inhibited?

A

Nitric oxide and prostacyclins inhibit platelet activation and aggregation
- restrict plug formation to damaged wall

73
Q

How is aberrant clot formation inhibited?

A

Tissue factor pathway inhibitor (TFPI)
- binds/inhibits TF-Viia which is needed for activation of extrinsic pathway

74
Q

How is clot formation inhibited via it’s surface receptors?

A

Thrombomodulin and protein C receptor
- sequesters/inactivate thrombin
- activated protein C/S

75
Q

What are the steps to protein C and S activation?

A

1) Thrombomodulin sequesters thrombin -> prevent thrombin from cleaving and activating fibrinogens not at site of wound
- EPCR binds protein C -> bring to thrombin-thrombomodulin complex -> protein C cleaved and activated by thrombin

2) Protein C activated by thrombin-thrombomodulin complex -> binds to circulating protein S -> form APC-PS complex (activated protein C-protein S complex)

3) APC-PS complex is active protease -> cleaves and inactivates factor 5a and 8a -> prevent clotting

76
Q

What are the 3 main players for anti-coagulation and what they inhibit?

A

Tissue factor pathway inhibitor (TFPI)
- inhibit factor 7

Activated protein C and S
- inhibit factor 5a and 8a

Anti-thrombin

77
Q

What produced anti-thrombin (AT)?

A

Liver

78
Q

What is AT?

A

Serine protease inhibitors

79
Q

What does AT do?

A

Sequesters thrombin that leaked from clots -> prevent clotting cascade

Binds/inhibits factor 10a and 9a

Ensures clotting is localised to damaged site

80
Q

What initiates clot removal after wound healing?

A

Degredation of fibrin mesh

81
Q

What mediates fibrinolysis?

A

Plasmin

82
Q

How is plasmin regulated?

A

Circulatory plasminogen = zymogen of plasmin

83
Q

How is plasminogen activated into plasmin?

A

Activated by tissue plasminogen activator (TPA) in presence of fibrin

84
Q

Where does TPA come from?

A

Released from endothelial cells
- hence, if wound is fresh -> endothelial cells absent -> TPA not released -> plasmin not activated

85
Q

What is released into the circulation once fibrin mesh is degraded?

A

Fibrin degradation pdts (FDP)

86
Q

How is fibrinolysis regulated?

A

No TPA from damaged vessels
- not circulating ard damaged vessels

Low TPA affinity to plasminogen in the absence of fibrin
- w/o fibrin -> plasmin can’t be activated -> won’t cleave clot when it is not healed

Presence of circulatory plasmin activator inhibitor (PAI) (TPA inhibitor) and anti-plasmin
- TPA and plasmin that strays into circulation rapidly inhibited/sequestered by PAI and anti-plasmin -> fibrinolysis restricted to clots at wounds that are fully recovered

87
Q

Where are fibrins crosslinked?

A

D-domains
- released in this form upon fibrinolysis

88
Q

What is D-dimer?

A

Fibrin fragments consisting 2 D-domains + crosslink

89
Q

What does elevated serum D-dimer indicate?

A

Thrombotic event
- if pt has huge clots w/o fresh wound

90
Q

Concept of homeostasis regarding haemostasis

A

Increased clotting and decreased anti-clotting -> thrombosis

Decreased clotting and increased anti-clotting -> bleeding issues

91
Q

What is thrombosis?

A

Clot formation which results in the occlusion of a blood vessel

92
Q

What are the factors that increase the risk of thrombus formation?

A

Virchow’s Triad
- venous stasis
- endothelial damage
- hypercoagulability

93
Q

How does venous stasis increase risk of thrombus formation? Some eg of risk factors

A

Slow blood flow -> reduce propensity of anti-coagulants to interact w/ coagulation factors

Eg of risk factors:
- post-surgery/immobilisation -> muscle contraction serve as pump to move blood
- trauma -> both endothelial and venous stasis -> clotting to stop bleeding -> block blood vessel -> reduce circulation

94
Q

How does endothelial damage increase risk of thrombus formation? Some eg of risk factors

A

Intact and smooth endothelial wall inhibits plug/clot formation

Eg of risk factors:
- smoking -> pro-inflammatory damage on vascular wall
- high BP -> force of BP on vascular wall cause damage -> endothelial cells damaged (surface receptors affected)
- fatty food/atherosclerosis -> fatty plaque deposited on surface of endothelial cells block surface + calcification causes damage

95
Q

How does hypercoagulabiltiy increase risk of thrombus formation? Eg of some risk factors

A

Thrombophilia -> conditions that increase tendency for clot formation

Eg of risk factors:
- hereditary disorders (i.e: hereditary thrombophilia) -> inherit defect that causes defective anti-coagulation factor/increase coagulation factor
- tumor/cancer -> tilt balance of clotting/anti-clotting factors
- oral contraceptive -> increase pdtn of clotting factors

96
Q

Eg of hereditary thrombophilia

A

Factor V Leiden (most impt)
- significant precedence
- factor 5 become resistant to degradation by APC-PS complex -> continue clotting -> hypercoagulability

Anti-thrombin 3 deficiency

Protein C deficiency

Protein S deficiency

97
Q

What does PTT + activated protein C test for? What are the expected results?

A

Anti-clotting ability

PTT should be prolonged as activated protein C promotes the degradation of activated factor 5 and 8
- if PTT not prolonged -> protein C is not forming well -> factor 5 not responding well to degradation -> factor 5 leiden

98
Q

How should factor 5 leiden diagnosis be validated?

A

Confirm w/ factor 5 leiden assay test

99
Q

What are good physiological targets for anti-coagulation?

A

Inhibit factors that are involved in both intrinsic and extrinsic pathway
- factor 10
- thrombin

100
Q

What are some good drug targets to treat thrombophilia? Eg of drugs

A

Inhibit Vit K -> affect pdtion of several clotting factors
- eg: warfarin

Inhibit factor 10
- eg: rivaroxaban

Inhibit thrombin
- eg: rivaroxaban and dabigatran

Activate anti-clotting factors (eg: AT)
- eg: heparin

101
Q

Eg of anti-platelet therapeutic drugs and their targets

A

Aspirin -> inhibit Tbx A2

Clopidrogel -> inhibit ADP

Abciximab (monoclonal Ab) -> inhibit fibrinogen and vWF

102
Q

What is disseminated intravascular coagulation (DIC)?

A

Serious condition that causes abnormal blood clotting throughout the body’s blood vessels

103
Q

Triggers of DIC

A

Widespread RBC hemolysis

Sepsis -> widespread intro of foreign substances into circulation -> factor 12 activated throughout circulation -> clot form throughout

104
Q

What kind of disorder is DIC and why?

A

Thrombohaemorrhagic
- widespread thrombus -> increased D-dimers -> thrombotic
- depleted platelets and coagulation factors -> prolonged PT and aPTT -> bleeding

105
Q

Treatment for DIC

A

Transfusion of coagulation factors
- replace plasma (plasmaphoresis)

Blood (9 decks)

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