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haem > haemostasis 1: haemostasis > Flashcards

haemostasis 1: haemostasis Flashcards

1
Q

what is haemostasis?

A

the cellular and biochemical processes that enable the specific and regulated cessation of bleeding in resonse to vascular insult

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2
Q

what is the purpose of haemostasis?

A

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

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3
Q

how does a haemostatic plug form?

A

1) vessel constriction - vascular smooth muscle cells contract locally -> limits blood flow to injured vessel
2) formation of unstable platelet plug - platelets adhere + aggregate -> limits blood loss + provides surface for coagulation
3) stabilisation of plug with fibrin (associated with cascade) - blood coagulation -> stops blood loss
4) vessel repair and dissolution of clot - cells migrate + proliferate and fibrinolysis takes place -> restores vessel integrity

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4
Q

what is the structure of a blood vessel (in terms of coagulation properties)?

A

endothelial layer = anticoagulant, subendothelium = procoagulant

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5
Q

what is Von Willebrand factor?

A

glycoprotein that circulates in globular conformation with platelet binding sites ‘hidden’

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6
Q

how does the structure of VWF change in response to vessel injury?

A

globular VWF recognises collagen -> binds -> structural change to linear conformation -> platelet binding sites exposed -> platelets bind to Gp1b

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7
Q

what are some important surface proteins οf platelets?

A

GPVI (interact with collagen), αIIbβ3 integrin that interacts with fibrinogen), α2β1 (integrin that interacts with collagen) GP1b (essential for capture by VWF)

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8
Q

how does a platelet plug form?

A

platelets bind to GP1b on VWF

  • > recruited to site of vessel damage
  • > interact with collagen
  • > collagen acts as stimulator of platelets
  • > platelet activated
  • > change shape + release granules + membrane changes conformation
  • > platelets stick together (αIIbβ3)
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9
Q

when can platelets directly interact with collagen?

A

low shear stress (ie not in arteries & capillaries)

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10
Q

how does the shape of a platelet change upon activation?

A

flowing disc-shape -> ball-shaped on rolling -> hemisphere-shaped (firm but reversible adhesion) -> spreading platelet (like fried egg) - irreversible adhesion

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11
Q

what happens in Von Willebrand disease?

A

not enough / dysfunctional VWF -> initial platelent recruitment step inefficient

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12
Q

what do platelet disorders cause?

A

dysfunctional / not enough platelets -> bleeding phenotype

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13
Q

below what platelet count is spontaneous bleeding common?

A

<40x10^9 (below 10x10^9 is severe)

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14
Q

what is the major function of thrombin?

A

cleaves fibrinogen (soluble) -> fibrin (insoluble)

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15
Q

where are most circulating clotting factors synthesised?

A

liver (endothelial cells + megakaryocytes also produce clotting factors)

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16
Q

what are the main groups of clotting factors?

A

zymogens eg prothrombin, FVII, FX (activated to become serine proteases eg thrombin, FVIIa, FXa), cofactors eg TF, FVa, FVIIIa, inhibitors eg TFPI, protein C

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17
Q

what do serine proteases have in common?

A

homologous serine protease domains

18
Q

what is tissue factor?

A

integral membrane protein that is the primary initiator of coagulation & is cell receptor for FVII - located at extravascular sites + expressed more in certain organs eg lungs, brain, heart
-> provides further haemostatic protection in these organs

19
Q

what is factor VII?

A

serine protease zymogen produced by liver - has Gla domain, 2 EGF-like domains + serine protease domain (1% circulates in active FVIIa form)

20
Q

what features do FVII, FIX, FX & PC share?

A

homologous modular structure (4 domains), Gla domain, EGF domain, all circulate in zymogen form, all activated by proteolysis

21
Q

what does a Gla domain do?

A

allows factors to interact with negatively charged phospholipid layers

22
Q

which factors contain Gla domains?

A

FVII, FX, prothrombin, FIX, protein C, protein S

23
Q

what is warfarin and how does it achieve its function?

A

vitamin K antagonist diminishes response of clotting factors (in Gla domains:
glutamic acid residues post-translationally modified by vitamin K dependent carboxylases
-> additional carboxylic acid added to glutamic acid
-> gives residues affinity to Ca2+
-> domains fold up in such a way that allows binding of phospholipids)

24
Q

what is the first main step of the clotting cascade?

A

FVIIa binds TF (via Gla domain) -> activates FIX or FX (by cleaving activation peptides)

25
Q

what does FXa do in the clotting cascade?

A

FXa liberates thrombin (from ProT) - very inefficient as only small quantities of thrombin are generated

26
Q

what happens when initial thrombin is generated in the clotting cascade?

A

thrombin feedbacks to FVIII & FV -> FVIIIa (cofactor for FIXa) & FVa (cofactor for FXa)

27
Q

what effects do FVIIIa & FIXa then have in the clotting cascade?

A

lots more FXa produced

28
Q

what cofactors in the clotting cascade then result in further thrombin production?

A

FXa + FVa -> 300,000x more thrombin released (compared with FXa alone)

29
Q

what is the overall effect of initial thrombin release in the clotting cascade?

A

small amounts of thrombin positively feedbacks on coagulation cascade to rapidly produce much more thrombin

30
Q

what anticoagulant pathways regulate the clotting cascade?

A

TFPI (tissue factor pathway inhibitor - initiation), APC & PS (FVa + FVIIIa), antithrombin (FXa + FIXa)

31
Q

how does TFPI work?

A

2nd domain binds to FXa -> complex rebinds to TF-FVIIa complex -> 1st TFPI domain binds to FVIIa -> locks all 4 proteins in inactive form

32
Q

what is the TFPI response mainly used for?

A

dampening response to very small injuries (only small amount of circulating TFPI)

33
Q

what happens in the protein C pathway?

A

thrombin binds with high affinity to thrombomodulin on endothelial cell -> becomes anticoagulant -> complex activates protein C -> APC cleaves FVa + FVIIIa at different locations -> cofactors fall apart

34
Q

what overall effect does the protein C pathway have?

A

“fences” clot ie where endothelium is present clot will not form as anticoagulant thrombin-TM complex present

35
Q

what happens to the rest of the thrombin in the clot?

A

antithrombin (a serine protease inhibitor (SERPIN)) inactivates many activated coagulation serine proteases eg Fxa, thrombin, FIXa, FXIa - essentially mops up free serine proteases that escape site of vessel damage

36
Q

how does heparin work?

A

acts as a cofactor for antithrombin: binds to AT -> enhances efficiency with which antithrombin can inhibit thrombin + FXa

37
Q

what happens in fibrinolysis?

A

tPA (tissue plasminogen activator) binds to fibrin -> becomes activated -> plasminogen converted to plasmin -> degrades fibrin clot -> fibrin degradation products removed by liver

38
Q

what drugs can be used to reduce haemostasis?

A

anticoagulants (heparin, warfarin, DOACs) & antiplatelet drugs (aspiring, P2Y12 blockers) - often anticoagulants given for protection against venous thrombi and antiplatelets for arterial thrombi

39
Q

what tests can be used to diagnose abnormal haemostasis?

A

PT & APTT (blood test looking at coagulation of blood), platelet function tests (analysis of platelets), d-dimer (fibrin degradation product)

40
Q

how can tPA be used therapeutically?

A

to treat MI, ischaemic stroke etc

haem (21 decks)

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