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Y2 MCD Haematology > haemostasis > Flashcards

haemostasis Flashcards

haemostasis: summarise the mechanisms of normal haemostasis including the interactions of vessel wall, platelets and clotting factors

1
Q

define haemostasis

A

cellular and biochemical processes enabling specific and regulated cessation of bleeding in response to vascular insult

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2
Q

purpose of haemostasis

A

prevent blood loss from intact and injured vessels, and to enable tissue repair

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3
Q

balance of normal haemostasis (too little vs too much)

A

too little = bleeding; too much = thrombosis

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4
Q

what is present if too little haemostasis, causing bleeding

A

increase in fibrinolytic factors and anticoagulant proteins, decrease in coagulant factors and platelets

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5
Q

what is present if too much haemostasis, causing thrombosis

A

decrease in fibrinolytic factors and anticoagulant proteins, increase in coagulant factors and platelets

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6
Q

too much haemostasis: consequences of thrombosis

A

deep vein thrombosis -> pulmonary embolism, MI, stroke

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7
Q

haemostatic plug formation in response to injury to endothelial cell lining

A

vessel constriction -> formation of unstable platelet plug -> stabilisation of plug with fibrin (FIa) -> vessel repair and dissolution of clot

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8
Q

haemostatic plug formation in response to injury to endothelial cell lining: how and why is there vessel constriction

A

vascular smooth muscle cells contract locally to limit blood flow to injured vessel

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9
Q

haemostatic plug formation in response to injury to endothelial cell lining: how and why is there formation of unstable platelet plug

A

platelet adhesion and aggregation to limit blood loss and provide surface for coagulation

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10
Q

haemostatic plug formation in response to injury to endothelial cell lining: how and why is there stabilisation of plug with fibrin

A

blood coagulation to stop blood loss

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11
Q

haemostatic plug formation in response to injury to endothelial cell lining: how and why is there vessel repair and dissolution of clot

A

cell migration/proliferation and fibrinolysis to restore vessel integrity

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12
Q

normal artery wall: layers (inside to out)

A

lumen -> tunica intima (anticoagulant endothelial cells) -> tunica media (procoagulant) -> tunica adventida (procoagulant)

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13
Q

normal artery wall: endothelial cell anticoagulant barriers

A

TM, EPCR, TFPI, GAG

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14
Q

normal artery wall: subendothelium procoagulants in basement membrane

A

elastin, collagen

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15
Q

normal artery wall: subendothelium procoagulant in VSMC and fibroblasts

A

TF

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16
Q

normal artery wall: endothelim and blood

A

in tact endothelium, with anticoagulant molecules on surface; in blood, VWF and other plasma proteins (incl. latent form clotting factors)

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17
Q

haemostatic plug formation in response to injury to endothelial cell lining: what vessels is local vessel constriction important

A

small blood vessels

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18
Q

haemostatic plug formation in response to injury to endothelial cell lining: formation of unstable platelet plug

A

primary haemostasis with rapid accumulation of platelets

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19
Q

platelets: size, nucleus?, life span

A

small (2-4um), anuclear, 10 day life span

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20
Q

platelet synthesis bone marrow

A

haematopoietic stem cell -> promegakaryocyte -> megakaryocyte -> maturation as loses ability to divide but replicates DNA (polyloid) so cytoplasm enlarges, becoming granular and forming approx. 4000 platelets

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21
Q

how do platelets enter blood

A

megakaryocytes migrate towards vessel wall in bone marrow, then send out pro-platelet protrusions

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22
Q

ultrastructure of platelet

A

dynamic cells with platelet-specific proteins on surface: GPVI and a2B1 interact with collagen, a2B3 interactis with fibrinogen, GP1b interacts with VWF; receptors receptive to different stimuli and agonists e.g. thromboxane, thrombin, ADP; contain alpha granules which contain growth factors, fibrinogen, FV, VWF; contain dense granules which contain ADP, ATP, serotonin, Ca2+, polyphosphates; contain dynamic phospholipid membrane so attractive to clotting factors when activated

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23
Q

cytoskeleton of platelets and significance

A

microtubules and actomyosin so rapidly change shape

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24
Q

what does platelet activation involve

A

conversion from passive to interactive cell

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25
5 roles of platelets
haemostasis and thrombosis, cancer, atherosclerosis, infection, inflammation
26
normal blood vessel: normal VWF in uninjured vessel
multimeric VWF circulates in plasma in globular confromation, with binding sites hidden from platelet Gplb
27
normal blood vessel haemostasis: platelet adhesion
vascular injury damages endothelium and exposes sub-endothelial collagen, which binds globular VWF; tethered VWF unravelled by rheological sheer forces of flowing blood, exposing Gplb so that platelets get tethered; binding recruits platelets to site of vessel damage (can also bind directly to collagen via GPVI and a2B1 at low shear), and platelets become activated
28
normal blood vessel haemostasis: platelet activation
binding to VWF binding sites activates platelets, as do collagen and thrombin; platelets bound to collagen / VWF release ADP and thromboxane which are agonists and further activate and recruit platelets; platelets change shape
29
normal blood vessel haemostasis: platelet aggregation
platelets will bind to each other via fibrinogen on activated aIIbB3 integrin; aIIbB3 also binds fibrinogen, causing a platelet plug to develop to help stop bleeding and providing surface for coagulation
30
normal blood vessel haemostasis: platelet activation enhancing coagulation
coagulation causes production of thrombin -> catalyses fibrin deposition -> clot stabilisation simultaneously, so no further bleeding
31
platelet shape change: flow, adhesion, activation, aggregation; whether reversible or irreversible
disc-shaped -> rolling ball-shaped -> hemisphere-shaped (firm but reversible adhesion) -> spreading platelet (irreversible adhesion)
32
2 disorders of initial platelet recruitment
VW disease and platelet disorders: mutations in VWF or platelets (receptors/production, so not enough or ones produced are disordered)
33
platelet count and thrombocytopenia: normal, trauma, common spontaneous
100-400x10^9 is normal (high in case of trauma or childbirth); 40-100x10^9 is no spontaneous bleeding but with trauma; <40x10^9 is spontaneous bleeding common (immune thrombocytopenia)
34
3 symptoms of thrombocytopenia
purpura, multiple bruises, ecchymoses
35
what happes at platelet count of <10x10^9
severe spontaneous bleeding, e.g. treatment of leukaemias
36
blood coagulation for stable fibrin plug: extrinsic (tissue factor) and intrinsic pathways
diagram
37
3 physiological locations of coagulants
liver, endothelial cells, megakaryocytes
38
coagulants in liver
most plasma haemostatic proteins
39
coagulants in endothelial cells
VWF, TM (thrombomodulin), TFPI
40
coagulants in megakaryocytes
VWF, FV
41
what do clotting factors circulate as and how are they activated
cofactors or inactive precursors (zymogens), which are then activated by specific proteolysis to serine proteases; can be inhibited
42
process of proteolysis of inactive zymogens to active serine proteases
domain catalyses proteolysis by using catalytic triad His/Asp/Ser, which cleave substrates after specific Arg (and Lys) residues
43
initiation of coagulation: tissue factor - location in vessels, receptors, serine proteases it activates, activation?
tissue factor at extravascular sites is exposed; contains cellular receptor and cofactor for FVII/VIIa (via Gla domain), making it more active; tissue factor is primary initiator and does not require proteolytic activation
44
initiation of coagulation: which organs contain higher [tissue factor] and why
lungs, brain, heart, testis, uterus, placenta, so further haemostatic protection
45
initiation of coagulation: FVII - what is it, where secreted, structure, plasma circulation and active form
serine protease zymogen; expressed and secreted by liver; domain structure: Gla domain 2x EGF-like domains, serine protease domain; 1% of plasma FVII circulates in active form (FVIIa); made active by tissue factor binding
46
coagulation serine protease protein structure: what 5 things do FVII, FIX, FX and PC share
homologous 4 domain modular structure, Gla domain (binds to phospholipid surfaces), EGF domain (protein-protein interactions), circulate in plasma as zymogens, activated by proteolysis
47
what does Gla domain define and bind to
vitamin K-dependent proteins; binds to Ca2+ ions so undergoes structural transition so can bind to -ve phospholipid cell or platelet surface; warfarin is a Gla domain antagonist, so diminishes number of clotting factors
48
initiation of coagulation: what does TF-FVIIa proteolytically activate and how
FX and FIX (removes activation peptide to yield active enzyme), forming FXa and FIXa
49
initiation of coagulation: what can FXa cleave and produce; feature of activation
prothrombin to generate thrombin; inefficient as only small quantities generated
50
due to small amount of thrombin generate by FXa, what does thrombin do to greatly enhance thrombin production
cleaves FVIII and FV to FVIIIa (cofactor for FIXa, with complex producing more FXa) and FVa (FXa and FVa complex cleaves prothrombin to thrombin)
51
what does thrombin do
cleaves fibrinogen into fibrin
52
what can patients deficient in procoagulant factors develop, and what is the inheritance
haemophilia, X-linked
53
what is deficient in haemophilia A
FVIII
54
what is deficient in haemophilia B
FIX
55
regulation of coagulation diagram
diagram
56
what does TFPI (tissue factor pathway inhibitor) bind to and what can this do; hence what does it regulate
binds to FXa to inactivate TF-FVIIa active site via K1; regulates initiation of coagulation; dampens coagulation response to very small injuries
57
what is protein C activated by
thrombin-TM complex on EC
58
what does activated protein C (APC) down-regulate (DOES NOT INHIBIT) and how; hence what does it regulate
thrombin generation by proteolytically inactivating procoagulant cofactors FVa and FVIIIa; regulates propagation phase of coagulation
59
FV leiden mutation and effect
Arg subsitituted for Glu, so FVa cannot be deactivated as efficiently, so at increased risk of thrombosis as protein C pathway cannot shut coagulation down as efficiently
60
pathway of protein C activated
thrombin is procoagulant and converts fibinogen to fibrin; upon thrombin (FIIa) binding to thrombomodulin with high affinity, becomes anticoagulant -> thrombin cleaves protein C to release activation peptide, which converts protein C zymogen to activated protein C (APC, localised to endothelial surface)
61
what acts as a co-factor for protein C
protein-S
62
what does protein C ensure
haemostatic plug prevented from spreading beyond site of injury
63
what happens to thrombin generated after APC to prevent coagulation occuring elsewhere (antithrombin)
antithrombin (SERPIN: serine protease inhibitor) inactivates many activated coagulation serine proteases (FXa, thrombin (FIIa), FIXa, FXIa), so mops up any free serine proteases that escape site of damage
64
process of fibrinolysis to remove fibrin clot
plasminogen (liver) -> plasmin (by tPA - tissue plasminogen activator), as plasmin degrades fibrin to fibrin degradation products
65
when are fibrin degradation products elevated
in DIC
66
what can tissue plasminogen factor be used in clinically
therapeutic thrombolysis for MI, ischaemic stroke etc (clot buster)

Y2 MCD Haematology (20 decks)

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