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Year 2 - MCD Haem > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

Define haemostasis

A

Cellular and biochemical processes

that enables both SPECIFIC and REGULATED cessation of bleeding in response to vascular insult

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2
Q

What is haemostasis for?

A

To PREVENT blood loss from intact & injured vessels

Enables tissue repair

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3
Q

What causes the scale to tip towards bleeding?

A
  1. Coagulant factors & Platelets
    DECREASE
  2. Fibrinolytic factors & Anticoagulant proteins
    INCREASE
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4
Q

What causes the scale to tip towards thrombosis?

A
  1. Coagulant factors & Platelets
    INCREASE
  2. Fibrinolytic factors & Anticoagulant proteins
    DECREASE
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5
Q

4 steps towards haemostatic plug formation?

A

Response to injury to endothelial cell lining!

  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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6
Q

Why is vessel constriction (1) important?

A

Limits blood flow to injured vessel!

Does this is 2 ways:

  1. Mainly important in SMALL blood vessels
  2. LOCAL CONTRACTILE RESPONSES i.e. VSMCs contact locally
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7
Q

What is the normal arrangement in a vessel?

A

ONENOTE

Have a SINGLE ENDOTHELIAL layer after the lumen
o this is the ANTICOAGULANT BARRIER

Thereafter, everything UNDER the subendothelium is PROCOAGULANT:
o elastin
o collagen
o TFs

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8
Q

How does haemostasis therefore occur in regards to the vessel structure?

A

Cell line breaks
TFs pour into the lumen
Bring about haemostasis

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9
Q

What are the functions of the endothelium?

A
  1. Maintain barrier betw. blood & TFs
  2. Synthesise important molecule
    - PGI2, thrombomodulin, vWF, plasminogen activators
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10
Q

Difference between LARGE and SMALL blood vessels?

A

SMALL blood vessels lack certain features
e.g. BM
(important as lacks the strong barrier between blood & TFs)

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11
Q

What 2 things make up the Formation of an unstable platelet plug (2)?

A
  1. Platelet ADHESION

2. Platelet AGGREGATION

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12
Q

Why is formation of an unstable platelet plug (2) important?

A

Limits blood loss
&
Provides surface for coagulation

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13
Q

How are platelets created?

A
  1. Bone marrow
  2. Haemtopoietic stem cell (precursor)
  3. Promegakaryocyte
    o proliferate
  4. Maegakaryocyte
    o mature & granulate
  5. Platelet

Each megakaryocyte produces ~4000 platelets

1/3 stored in SPLEEN!

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14
Q

Characteristics of platelets?

A

o Small (2-4um)
o Anuclear
o Lifespan ~10days

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15
Q

Ultrastructure features of platelets?

A

ONENOTE!

Receptors (green):
 o GPIb/V/IX
 o GPVI
 o alpha2b-beta3
 o alpha2-beta1

Granules (blue):
o alpha-granules (GFs, fibrinogen, FV, vWF)
o dense granules (ADP, ATP, Ca2+ etc.)

Phospholipid membrane
o coagulation - the -VE lipids come to the outisde and attract coagulative factors

Microtubles & actomysin
o allows for platelets to rapidly change shape

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16
Q

What are the multiple roles of platelets?

A

o Atherosclerosis

o Infection

o Inflammation

o Cancer

o Haemostasis & thrombosis

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17
Q

vWF receptor on platelets?

A

GIp1b

18
Q

Collagen receptor on platelets?

A

GIp1a

19
Q

Where are vWF normally found?

A

Multimeric vWF circulate in plasma in a globular conformation

Binding sites are ‘hidden’ from platelet GIp1b

20
Q

Explain Platelet Adhesion (2)

A
  1. Vascular injury damages endothelium
    - exposes sub-endothelial collagen
  2. Exposed sub-endothelial collagen BINDS to globular vWF
  3. Tethered vWF (on collagen) is UNRAVELLED by the SHEAR STRESS of blood flow
    - exposes GIp1b binding sites
  4. Platelets bind to exposed vWF binding site
    - this recruits MORE platelets to the area
  5. Platelets become activated
21
Q

Platelets can also bind to something else other than vWF?

A

Collagen!

via. GPVI & a2b1!

BUT only at LOW SHEAR i.e. NOT in arteries/capillaries

22
Q

Explain Platelet Activation (2)

A
  1. Platelets become activated following Platelet Adhesion (2)
    - recruit FURTHER platelets
    - Collagen & thrombin also activate platelets
  2. Platelets bound to collagen/vWF RELEASE ADP & thromboxane
    - this activates MORE platelets
  3. Activated platelets recruit MORE platelets
    - via. alphaIIBbeta3 (GpIIb/IIIa) binding site
23
Q

Explain Platelet Aggregation (2)

A
  1. Binding site alphaIIBbeta3 (GpIIb/IIIa) can also bind to FIBRINOGEN
    - platelet plug develops
    - helps slow bleeding
    - provides surface for coagulation
24
Q

What other factor can have an affect on Platelet Adhesion & Aggregation (2)?

A

Thrombin!!

Can amplify the response from its OWN pathway - partially activating the platelets directly

It results in FIBRIN collecting = clot stabilsiation

25
Q

What happens to the platelet shape?

A

Changes upon adhesion, activation & aggregation

Its Hemisphere-shape is firm BUT REVERSIBLE

Its Spreading-shape is IRREVERSIBLE ADHESION

26
Q

What can differing platelet counts allude to?

A

<100x10^9/L
o NO spontaneous bleeding
o BUT bleeding with trauma

<40x10^9/L
o SPONTANEOUS bleeding - common
o Auto-ITP

<10x10^9/L
o SEVERE spontaneous bleeding
o e.g. if are having leukaemia treatment

27
Q

Auto-ITP and how does it present?

A

Auto-Immune Thrombocytopenia (ITP)

Purpura
Multiple bruises
Ecchymoses

28
Q

What occurs during Stablisation of the plug with fibrin (3) and why is it important?

A

Blood coagulation

STOPS blood loss

29
Q

What are the synthesis sites for clotting factors, fibrinolytic factors and inhibitors?

A
  1. LIVER
    o MOST coagulation proteins
  2. Endothelial cells
    o vWF
    o TM & TFPI
  3. Megakaryocytes
    o vWF
    o Factor V
30
Q

How do clotting factors circulate and are activated?

A

Circulate as inactive precursors, either as:
o serine proteases
o zymogens
o cofactors

Activated by specific proteolysis

31
Q

How are serine proteases activated?

A

Once activated, catalyse proteolysis of targer substrate
(Gla domain containing proteins)

Serine proteases contain a catalytic triad His/Asp/Ser
o they cleave substrates after specific Arg (& Lys residues)

32
Q

Where are F8 and F5 found and what can activate it?

A

Phospholipids found on PLATELET surface membrane

Thrombin can activate it
o drives a +VE feedback loop

33
Q

What is the main driver for the extrinsic & intrinsic pathway of haemostasis?

A

TF is the MAIN physiological driver for haemostasis

F12 is used in laboratory tests for the intrinsic pathway (12, 11)

34
Q

Top to bottom, what are the factors?

A

12, 11, 9 and 10

12 and 11 are NOT important for normal haemostasis

35
Q

How do platelets accelerate blood coagulation

A

F5 and F8 are found on the platelet membrane

  1. F9a activates F10
    o F10 –> F10a (found on F8aPI)
  2. F10a then passes to F5aPI
    o this activates F2 (prothrombin –> thrombin)

The thrombin created can then go on to:
o drive MORE platelet activation
o expression of F8aPI & F5aPI

F8aPI and F5aPI accelerate thrombin generation x10,000

36
Q

TF?

A

Cellular receptor & co-factor for F7a

Only procoagulant factor that does NOT require proteolytic activation

Expressed MORE in certain organs (e.g. lungs, brain, heart) so these locations have FURTHER haemostatic protection

37
Q

FVII?

A

F7

Serine protease zymogen - expressed/secreted by the liver

38
Q

What occurs during Vessel repair and dissolution of clot (4) and why is it important?

A

Cell migration/proliferation
&
FIBRINOLYSIS

Restores vessel integrity

39
Q

How is fibrin degraded?

A

NORMALLY there is NO reaction between:
plasminogen (a zymogen)
&
tPA (tissue plasminogen activator)

BUT when in presence of fibrin - PLASMIN in created which degraded fibrin

40
Q

What are the anticoagulation pathways?

A
  1. Antithrombin

Inhibits F9a, F10a and F2a

  1. Protein C (PS)

Inhibits F8aPI and F5aPI
Thrombin binds to platelets to form thrombomodulin –> activates PC –> activates PS

Year 2 - MCD Haem (11 decks)

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