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Haemostasis COPY Flashcards

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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

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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

Study These Flashcards
A

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

21
Q

What are the cutaneous features of immune thrombocytopenia

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A

Purpura
Multiple bruises
Ecchymoses

22
Q

Where are clotting factors produced

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A

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

23
Q

Describe the state of clotting factors in the blood

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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

Study These Flashcards
A 
FVII
FX
Prothrombin 
FIX 
FXI 
Protein C
25
Describe serine protease domains
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
Describe the initiation of coagulation
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
What are tissue factors
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
Where are tissue factors highly expressed
``` Lungs Brain Heart Testis Uterus Placenta ```
29
Describe factor VII
``` 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
What do FVII, FIX, FX and PC share
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
Which proteins contain GIa domains
``` FVII FX Prothrombin FIX Protein C Protein S ```
32
Describe the GIa domain
Defines vit K-dependent proteins Contains 9-11 gamme-carboxyglutamic acid residues Binds 6/7 Ca2+ ions -> structural transition
33
What may be the consequence of deficiency in procoagulant factors
Haemophilia Haemophilia A - FVIII Haemophilia B - FIX X-linked
34
Draw a diagram that represents the initiation of coagulation
-
35
Draw a diagram that represents the regulation of coagulation
-
36
Describe how coagulation is regulated
Antithrombin inhibits FXa, FIXa and thrombin TFPI inhibits TF-FVIIa anf FXa APC and protein S inhibits FVa and FVIIIa
37
Describe TFPI
Tissue factor pathway inhibitor TFPI-FXa can bind and inactivated TF-FVIIa Active site = Kunitz domain (K1)
38
Describe the protein C pathway
Protein C is activated by thrombin-TM complex | Activated protein C (APC) inhibits thrombin generation by proteolytically inactivating procoagulants FCA and FVIIIa
39
Describe the process of protein C activation
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
What is the role of protein S
Co-factor for protein C
41
Describe antithrombin
58kDa serine protease inhibitor (SERPIN) Inactivates activated coagulation serine proteases (FXa, thrombin, FIXa, FXIa) Frees serine proteases that escape the vessel damage site
42
Describe fibrinolysis
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
What are the therapeutic uses of tPA
Thrombolysis for: Myocardial infarction Ischaemic stroke
44
Give examples of anticoagulant drugs
Heparin Warfarin DOACs
45
Give examples of anti platelet agents
Aspirin | P2Y12 blockers
46
Which tests are done for haemostat disorders
Coagulation (PT, APTT) platelet function tests d-dimer

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