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Y2 MCD > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

What is haemostasis

A

the cellular and biochemical processes that enables both the specific and regulated cessation of bleeding in response to vascular insult

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2
Q

What is the function of haemostasis

A

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

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3
Q

What are the 4 stages of haemostasis

A
  1. Vessel constriction
  2. Formation of an unstable platelet plug
  3. Stabilisation of the plug with fibrin
  4. Vessel repair and dissolution of clot
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4
Q

Describe the vessel constriction response in haemostasis

A

Vascular smooth muscle cells contract locally
Limits blood flow to the injured vessel
Mainly important in small blood vessels
Local contractile response to injury

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5
Q

What is involved in unstable platelet plug formation and what is the purpose

A

Platelet adhesion and aggregation

Limits blood loss + provides surface for coagulation

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6
Q

What is involved in stabilisation of a platelet plug and what is the purpose

A

Blood coagulation

Stops blood loss

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7
Q

What does vessel repair involve and what is the function

A

Cell migration/proliferation and fibrinolysis

Restores vessel integrity

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8
Q

Describe the normal vessel wall

A 
Endothelial cell - anticoagulant barrier (TM, EPCR, TFPI, GAG)
Subendothelium - procoagulant
Basement membrane - elastin, collagen
VSMC  - TF
Fibroblasts - TF
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9
Q

Which pro-haemostasis factors are carried in the blood

A

FVII, FX, Prothrombin (FII), FV, FVIII, FIX, FXI, Protein C, Protein S etc…

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10
Q

Describe platelets

A 
Small (2-4µm)
Anuclear
Lifespan - 10 days
Platelet count = 150-350 
10^11 produced every day
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11
Q

Describe the megakaryocytic

A

Contains nuclear lobes and a granulated cytoplasm

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12
Q

Describe the development of platelets

A
  1. Haematopoietic stem cell from the bone marrow develops into a promegakaryocyte.
  2. Promegakaryocyte proliferates and forms megakaryocytes
  3. Megakaryocytes mature into platelets (1 MK - 4000 platelets)
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13
Q

Describe the platelet cytoskeleton

A

Important for morphology, shape change, pseudopods, contraction and clot retraction

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14
Q

What are the ultrastructural features of the platelet

A 
On membrane:
Alpha granules 
Dense granules 
Phospholipid membrane
Microtubules and actomyosin
GbIb/V/IX
GPVI
TP, PAR
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15
Q

What is contained in the alpha and dense granules

A

Alpha - growth factors, fibrinogen, FV, VWF

Dense - ADP, ATP, Serotonin, Ca2+

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16
Q

What are the roles of platelets

A 
Haemostasis and thrombosis 
Cancer 
Atherosclerosis 
Infection 
Inflammation
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17
Q

Describe the normal blood vessel

A

Platelets circulate in close contact with the endothelial cell lining of the blood vessel wall
VWF circulates in a globular conformation. Binding sites are hidden from GpIb

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18
Q

Describe what occurs in the blood after injury of the vessel

A
  1. Collagen, fibronectin and laminin become exposed and platelets become recruited via sub-endothelial collagen
  2. VWF binds to collagen via its A3 domain
  3. VWF is unravelled by the shear stress
  4. GPIba binding site of VWF is exposed
  5. Binding of VWF to to platelets recruits other platelets (also Bia GPVI and a2b1 on collagen at low shear)
  6. Activation of platelets
  7. Further recruitment of platelets (also by thrombin and collagen)
  8. Release of platelets bound to collagen/VWF
  9. ADP and thromboxane activates platelets
  10. Aggregation via GpIIb/IIIa + fibrinogen binding
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19
Q

Describe the changes in platelet shape

A

Flowing disc-shaped
Rolling ball-shaped platelet
Hemisphere-shaped platelet
Spreading platelet

20
Q

At what platelet counts will spontaneous bleeding and bleeding occur

A

Severe spontaneous - <10x10^9
spontaneous - <40x10^9
With trauma - 100x10^9

21
Q

What are the cutaneous features of immune thrombocytopenia

A

Purpura
Multiple bruises
Ecchymoses

22
Q

Where are clotting factors produced

A

Liver - most
Endothelial cells - VWF, TM, TFPI
Megakaryocytes - VWF, FV

23
Q

Describe the state of clotting factors in the blood

A

Circulates as inactive precursors
Either serine protease zymogens of cofactors
Activated by specific proteolysis

24
Q

What are some serine protease domain-containing proteins/clotting factors

A 
FVII
FX
Prothrombin 
FIX 
FXI 
Protein C
25
Q

Describe serine protease domains

A

Catalyses proteolysis of target substrate
Serin protease contain a catalytic triad of His,Asp,Ser
Serine proteases cleave substrates after specific Arg and Lys residues

26
Q

Describe the initiation of coagulation

A
  1. FVII/FVIIa binds to cell surfaces via GIa domain
  2. TF and FVII form TF-FVIIa
  3. FVIIa becomes more active
  4. Activation of FX and FIX via removal of the activation peptide to yield an active enzyme
  5. Prothrombin activation by FXa (insufficient)
  6. Thrombin activates FV and FVIII
  7. FIXa and FVIIIa activate FX
  8. Enhanced activation of ProT by FXa and FCA
27
Q

What are tissue factors

A

Cellular receptor and cofactor for FVII/VIIa
Only procoagulant factor that does not require proteolytic activation
47kDa integral membrane
Normally locates at extravascular sites (VSMS, fibroblasts)

28
Q

Where are tissue factors highly expressed

A 
Lungs
Brain
Heart Testis
Uterus 
Placenta
29
Q

Describe factor VII

A 
serine protease zymogen 
48kDa plasma glycoprotein 
Expressed/secreted by the liver 
GIa domain, 2xEGF_like domains, serine protease domain 
Circulates in plasma at 10nM 
1% in active form (VIIa)
30
Q

What do FVII, FIX, FX and PC share

A

A homologous modular structure (4 domains)

Gla domain - binding to phospholipid surfaces

EGF domain is involved in protein-protein interactions

all circulate in plasma in zymogen form

activated by proteolysis

31
Q

Which proteins contain GIa domains

A 
FVII
FX
Prothrombin 
FIX
Protein C
Protein S
32
Q

Describe the GIa domain

A

Defines vit K-dependent proteins
Contains 9-11 gamme-carboxyglutamic acid residues
Binds 6/7 Ca2+ ions -> structural transition

33
Q

What may be the consequence of deficiency in procoagulant factors

A

Haemophilia
Haemophilia A - FVIII
Haemophilia B - FIX
X-linked

34
Q

Draw a diagram that represents the initiation of coagulation

A

-

35
Q

Draw a diagram that represents the regulation of coagulation

A

-

36
Q

Describe how coagulation is regulated

A

Antithrombin inhibits FXa, FIXa and thrombin
TFPI inhibits TF-FVIIa anf FXa
APC and protein S inhibits FVa and FVIIIa

37
Q

Describe TFPI

A

Tissue factor pathway inhibitor
TFPI-FXa can bind and inactivated TF-FVIIa
Active site = Kunitz domain (K1)

38
Q

Describe the protein C pathway

A

Protein C is activated by thrombin-TM complex

Activated protein C (APC) inhibits thrombin generation by proteolytically inactivating procoagulants FCA and FVIIIa

39
Q

Describe the process of protein C activation

A

Usually Serine protease cleaves fibrinogen to form fibrin

  1. Thrombin binds to TM with high affinity
  2. Serine protease activates protein C
  3. Protein C becomes localised to endothelial surface
  4. Thrombin cleaves protein C -> activation peptide released
  5. Activates protein C zymogen to APC
  6. release of APC so PC can bind to EPCR
  7. APC down-regulates thrombin generation
40
Q

What is the role of protein S

A

Co-factor for protein C

41
Q

Describe antithrombin

A

58kDa serine protease inhibitor (SERPIN)
Inactivates activated coagulation serine proteases (FXa, thrombin, FIXa, FXIa)
Frees serine proteases that escape the vessel damage site

42
Q

Describe fibrinolysis

A
  1. Plasminogen is converted to plasmin via tissue plasminogen activator (tPa) on the fibrin clot surface
  2. Plasmin breaks down fibrin clot
  3. Fibrin degradation products are produced
43
Q

What are the therapeutic uses of tPA

A

Thrombolysis for:
Myocardial infarction
Ischaemic stroke

44
Q

Give examples of anticoagulant drugs

A

Heparin
Warfarin
DOACs

45
Q

Give examples of anti platelet agents

A

Aspirin

P2Y12 blockers

46
Q

Which tests are done for haemostat disorders

A

Coagulation (PT, APTT)
platelet function tests
d-dimer

Y2 MCD (23 decks)

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