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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
Q

5 roles of platelets

A

haemostasis and thrombosis, cancer, atherosclerosis, infection, inflammation

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26
Q

normal blood vessel: normal VWF in uninjured vessel

A

multimeric VWF circulates in plasma in globular confromation, with binding sites hidden from platelet Gplb

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27
Q

normal blood vessel haemostasis: platelet adhesion

A

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
Q

normal blood vessel haemostasis: platelet activation

A

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
Q

normal blood vessel haemostasis: platelet aggregation

A

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
Q

normal blood vessel haemostasis: platelet activation enhancing coagulation

A

coagulation causes production of thrombin -> catalyses fibrin deposition -> clot stabilisation simultaneously, so no further bleeding

31
Q

platelet shape change: flow, adhesion, activation, aggregation; whether reversible or irreversible

A

disc-shaped -> rolling ball-shaped -> hemisphere-shaped (firm but reversible adhesion) -> spreading platelet (irreversible adhesion)

32
Q

2 disorders of initial platelet recruitment

A

VW disease and platelet disorders: mutations in VWF or platelets (receptors/production, so not enough or ones produced are disordered)

33
Q

platelet count and thrombocytopenia: normal, trauma, common spontaneous

A

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
Q

3 symptoms of thrombocytopenia

A

purpura, multiple bruises, ecchymoses

35
Q

what happes at platelet count of <10x10^9

A

severe spontaneous bleeding, e.g. treatment of leukaemias

36
Q

blood coagulation for stable fibrin plug: extrinsic (tissue factor) and intrinsic pathways

A

diagram

37
Q

3 physiological locations of coagulants

A

liver, endothelial cells, megakaryocytes

38
Q

coagulants in liver

A

most plasma haemostatic proteins

39
Q

coagulants in endothelial cells

A

VWF, TM (thrombomodulin), TFPI

40
Q

coagulants in megakaryocytes

A

VWF, FV

41
Q

what do clotting factors circulate as and how are they activated

A

cofactors or inactive precursors (zymogens), which are then activated by specific proteolysis to serine proteases; can be inhibited

42
Q

process of proteolysis of inactive zymogens to active serine proteases

A

domain catalyses proteolysis by using catalytic triad His/Asp/Ser, which cleave substrates after specific Arg (and Lys) residues

43
Q

initiation of coagulation: tissue factor - location in vessels, receptors, serine proteases it activates, activation?

A

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
Q

initiation of coagulation: which organs contain higher [tissue factor] and why

A

lungs, brain, heart, testis, uterus, placenta, so further haemostatic protection

45
Q

initiation of coagulation: FVII - what is it, where secreted, structure, plasma circulation and active form

A

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
Q

coagulation serine protease protein structure: what 5 things do FVII, FIX, FX and PC share

A

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
Q

what does Gla domain define and bind to

A

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
Q

initiation of coagulation: what does TF-FVIIa proteolytically activate and how

A

FX and FIX (removes activation peptide to yield active enzyme), forming FXa and FIXa

49
Q

initiation of coagulation: what can FXa cleave and produce; feature of activation

A

prothrombin to generate thrombin; inefficient as only small quantities generated

50
Q

due to small amount of thrombin generate by FXa, what does thrombin do to greatly enhance thrombin production

A

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
Q

what does thrombin do

A

cleaves fibrinogen into fibrin

52
Q

what can patients deficient in procoagulant factors develop, and what is the inheritance

A

haemophilia, X-linked

53
Q

what is deficient in haemophilia A

A

FVIII

54
Q

what is deficient in haemophilia B

A

FIX

55
Q

regulation of coagulation diagram

A

diagram

56
Q

what does TFPI (tissue factor pathway inhibitor) bind to and what can this do; hence what does it regulate

A

binds to FXa to inactivate TF-FVIIa active site via K1; regulates initiation of coagulation; dampens coagulation response to very small injuries

57
Q

what is protein C activated by

A

thrombin-TM complex on EC

58
Q

what does activated protein C (APC) down-regulate (DOES NOT INHIBIT) and how; hence what does it regulate

A

thrombin generation by proteolytically inactivating procoagulant cofactors FVa and FVIIIa; regulates propagation phase of coagulation

59
Q

FV leiden mutation and effect

A

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
Q

pathway of protein C activated

A

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
Q

what acts as a co-factor for protein C

A

protein-S

62
Q

what does protein C ensure

A

haemostatic plug prevented from spreading beyond site of injury

63
Q

what happens to thrombin generated after APC to prevent coagulation occuring elsewhere (antithrombin)

A

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
Q

process of fibrinolysis to remove fibrin clot

A

plasminogen (liver) -> plasmin (by tPA - tissue plasminogen activator), as plasmin degrades fibrin to fibrin degradation products

65
Q

when are fibrin degradation products elevated

A

in DIC

66
Q

what can tissue plasminogen factor be used in clinically

A

therapeutic thrombolysis for MI, ischaemic stroke etc (clot buster)

Y2 MCD Haematology (20 decks)

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