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Year 2 - MCD - Haematology > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

What is heamostasis?

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 haemostasis a balance between?

A

Bleeding and Thrombosis

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3
Q

What is the purpose of heamostasis?

A

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

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4
Q

What causes bleeding?

A
  • increased Fibrinolytic factors, Anticoagulant proteins

- decresed coagulant factors and platelets.

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5
Q

What causes thrombosis?

A
  • increased coagulant factors and platelets
  • decreased fibrinolytic factors and anticoagulant proteins.

important, many people die of a haemostatic end-point.

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6
Q

Warfarin

A
  • vitamin K antagonist

- diminishes the function of a number of clotting factors

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7
Q

What are the components of haemostasis?

A
  • platelets
  • vessel wall
  • clotting factors
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8
Q

Virchows Triad

A
  • hypercoaguability
  • stasis of blood flow
  • endothelial injury
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9
Q

What are petechiae a sign of?

A

Thrombocytopenia

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10
Q

What are examples of thrombosis?

A
  • DVT
  • DVT leading to PE
  • MI
  • Stroke

-> most people die due to a haemostatic end-point

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11
Q

What is the broad response to endothelial damage?

A
  1. vessel constriction (VSMC contract locally -> limits BF to injured vessel)
  2. Formation of an unstable platelet plug (primary haemostasis; platelet adhesion, platelet aggregation -> limits blood loss and provides a surface for coagulation)
  3. stabilisation of the platelet plug with fibrin (secondary haemostasis; blood coagulation, stops blood loss)
  4. vessel repair and dissolution of clot (cell migration/proliferation and fibrinolysis -> restores vessel integrity)
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12
Q

What are the layers of an artery?

A
  • lumen
  • tunica intima
  • tunica media
  • tunica adventitia
  • Endothelial Cell layer (1) : anticoagulant
  • sub endothelium: procoagulant basement membrane
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13
Q

What are importnat structures on the surfaces of platelets?

A
  • GPVI: interacts with collagen
  • alpha-IIb-beta-III : this integrin interacts with fibrinogen
  • GpIb: essential for platelet capture via VWF
  • alpha 2 beta 1: another integrin, interacts with collagen
  • thomboxane, thrombin (PAR) and ADP receptors as well
  • contain alpha granules which contain clotting factors, GFs, cytokines -> released when the platelet is activated
  • contain dense granueles (ADP, ATP, phosphates, serotonin, calcium)
  • highly dynamic phospholipid membrane
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14
Q

Platelets

A
  • dynamic function
  • anuclear
  • various receptors
  • life span around 10d
  • derived from megakaryocytes (each one can produce around 4000 platelets)
  • 2-4 micrometers - small!
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15
Q

What happens when platelets are activated?

A
  • release of granules
  • phosphilipid bilayer changes: flip-flop reaction when the neg charged phospholipids on the inner leaflet get exposed to the outer surface ->makes the surface HIGHLY attractive to clotting factors circulating in the blood
  • shape change
  • active microtubules and cytoskeleton -> can rapidly change shape following activation.

=> platelet very rapidly transformed from a quiescent circulating cell to a highly activated procoagulant one/.

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16
Q

What are the roles of platelets?

A
  • haemostasis and thrombosis
  • cancer
  • Inflammation
  • Atherosclerosis
  • Infection (can interact with leukocytes)

=> very dynamic cells -> type of stimulation determines the role they will play.

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17
Q

What are the steps in primary haemostasis?

A
  1. Tissue damage -> sub endothelial collagen is exposed
  2. Exposed sub-endothelial collagen binds globular VWF (via its A3 domain)
  3. Shear forces cause WVF to unravel
  4. WVF unravelling exposes platelet binding sites (GpIb) -> platelets get tethered
  5. Binding of VWF to platelet GpIb recreuits platelets to site of vessel damage
    (Platelets can also bind directly to collagen but only under low shear stress)
  6. platelets become activated and will further recruit platelets. Collagen and thrombin (II) also activate platelets. Platelets bound to collagen / VWF release ADP and thromboxane - activate platelets that are recruited on top
  7. Platelets stick together via integrin alpha-2b-beta-3 (GpIIb/IIIa)
  8. alpha-2b-beta 3 also binds fibrinogen -> platelet plug develops -> helps to stop bleeding nd provides surface for coagulation.
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18
Q

How can platelets bind to collagen?

A
  • via GpVI and alpha-2-beta-1

- only at low shear stress - i.e. not in arteries or capillaries

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19
Q

What surface molecule causes platetlets to stick together?

A
  • GpIIb/IIIa

= alpha-2b-beta-3

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20
Q

Reversible vs. irreversible adhesion of platelets

A
  • platelet shape changes upon adhesion, activation and aggregation
  • resting shape
  • rolling ball shaped platelet
  • hemisphere shaped platelet - firm but reversible adhesion
  • spreading platelet - irreversible adhesion -> this spreading process helps seal the site of injury (condom looking)
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21
Q

VWD

A

= Von-Willebrand-Disease

  • individuals that have a mutation in the VWF (not functional enough or not enough production)
  • recruitment of platelets step is not efficient
  • can cause bleeding
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22
Q

Platelet disorders

A
  • problems with receptors e.g. deficiencies
  • problems with platelet production
  • platelets not functional (or destroyed?)

=> not enough platelets OR platelets that areproduced are not functional.

-> Causes bleeding phenotype

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23
Q

What can cause excessive bleeding? (re primary haemostasis)

A
  • VWD

- platelet disorders

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24
Q

Immune thrombocytopenia

A

Leads to:

  • purpura
  • multiple bruises
  • ecchymoses
  • shortage of platelets
  • AI disease which leads to the destructon of platelets.
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25
Q

How do different thrombocyte counts affect the readiness of bleeding?

A
  • normal range
  • <100 x 10^9 /L causes no spontaneous bleeding but bleeding with trauma
  • <40 x 10^9/L spontaneous bleeding is common
  • <10x10^9/L causes severe spontaneous bleeding (e.g. treatment of leukemias)
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26
Q

What type of molecule is thrombin?

A

It is a serine protease -> converts soluble fibrinogen into insoluble strands of fibrin

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27
Q

Where are coagulation molecules from?

A
  1. The liver - most plasma haemostatic proteins
  2. Endothelial cells - WVF. TM, TFPI
  3. Megakaryocytes - WVF. Factor V
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28
Q

How do clotting factros circulate?

A
  • CFs circulate as inactive precursors
  • either serine protease zymogens or co-factors (e.g. contain seirne-roteaes domain)
  • activated by specific proteolysis
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29
Q

What factors are missing in haemophilia?

A

Haemophilia A: FVIII

Haemophilia B: FIX

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30
Q

Which clotting factors have a serine-protease domain?

A
  • FVII
  • FX
  • Prothrombin
  • FIX
  • FXI
  • Protein C

=> they all have a homologous serine protease domain

catalytic triad: His/Asp/Ser -> please substrates after specific Arg and Lys residues

31
Q

Secondary haemostasis - stabilisation of the platelet plug

A
  1. Intact endothelium, anticoagulant endothelial surface, VWF, clotting factors and platelets circulating in the plasma
  2. vessel wall damage -> recruitment of platelets due to VWF and Collagen interactions and also exposure of TF on surface of extravascular cells.
  3. Initiation of clotting cascade (TF and FVII)
  4. Propagation of coagulation
32
Q

What happens in the initiation of the clotting cascade?

A
  • TF interacts with factor 7 via Gla domain -> form complex
  • this activates factor 7 into an active serine protesase
  • TF makes F7a 2x10^6 times more active
33
Q

What is the gla domain?

A
  • this gives CFs the ability to interact with (negatively charged) phospholipid surfaces
  • e.g. found on Factor 7
34
Q

Tissue Factor

A

= FIII

  • primary initiator of coagulation
  • normally located at extravascular sites (-> not usually exposed to blood, VSMC, fibroblasts etc)
  • expressed higher in certain organs (lungs, brain, heart, testis, uterus and placenta)
  • TF in these locations porvides further haemostatic protection
35
Q

Factor 7

A
  • serine protease zymogen
  • expressed/secreted by the liver
  • circulates in plasma (1% of it in its activated form FVIIa)
36
Q

Gla domains

A
  • Gla domains interact with negatively charged phospholipid surfaces that are presented by activated platelets.
  • a number of proteins (coat factors) contain glass domains (e.g. 7, 10, prothrombin, 9, Prot C, Prot S)
37
Q

How are Gla domains activated?

A
  • glutamic acid residues are posttranslationally modified by a vitamin K dependant carboxylase
  • additional carboxylic acid group added onto glutamic acid
  • there are now two COOH residues -> higher affinity to bind Calcium (Ca2+)
  • the ability to bind calcium causes them to have the ability to change their conformation to bind negatively charged phospholipid domains.
38
Q

How does warfarin work?

A
  • warfarin is a vitamin K antagonist
  • it prevents the gamma carboxylation of a number of clotting factors
  • these factors then don’t have a functional Gla domain -> don’t bind to -vely charged phospholipid surfaces

-> anticoagulant

39
Q

Haemophilia A

A
  • recessive
  • X-linked
  • mutation in factor 8 gene
40
Q

Haemophilia B

A
  • recessive
  • X-linked
  • mutation in Factor 9 gene
41
Q

TFPI

A
  • Tissue factor pathway inhibitor
  • ## protein
42
Q

What are inhibitory pathways of coagulation?

A

(i) TFPI (tissue factor pathway inhibitor)
(ii) The protein C anticoagulant pathway (APC & protein S)
(iii) Antithrombin

Deficiencies of antithrombin, protein C and protein S
are important risk factors for thrombosis!

43
Q

Antithrombin

A
  • Serine protease inhibitor (SERPIN)
  • AT inactivates many activated coagulation serine proteases (FXa, thrombin, FIXa, FXIa
  • AT “mops up” and free serine proteases that escape the site of vessel damage.
44
Q

Antithrombin

A
  • Serine protease inhibitor (SERPIN)
  • AT inactivates many activated coagulation serine proteases (FXa, thrombin, FIXa, FXIa
  • AT “mops up” and free serine proteases that escape the site of vessel damage.
45
Q

What happens if you don’t have TFPI?

A
  • these individuals probably die during gestation
46
Q

What are the coagulation properties of the normal vessel wall of an artery?

A
  • EC: anticoagulant barrier (TM, EPCR, TFPI, GAG)
  • Subendothelium: procoagulant BM -> collagen, elastin
  • VSMC: TF
  • Fibroblasts: TF

= surface is anticoagulant the things beneath are pro-coagulant.

47
Q

What is the first step response to endothelial injury?

A

Blood vessel constriction

  • mainly important in small BVs
  • local contractile response to injury. reduce blood flow
48
Q

What is the second step of the response to endothelial injury?

A

Platelet plug formation

49
Q

How are platelets made?

A
  • platelets bleb off from intrusions of the megakaryocytes into the BV
  • each megakaryocyte makes about 4000 platelets
50
Q

What types of granules do platelets. contain?

A
  • alpha granules (growth factor, fibrinogen, FV, VWF)

- dense granules (ADP, ATP. serotonin, Ca2+)

51
Q

How do platelets bind to the damaged vessel part under Norma conditions?

A
  • under high shear stress the VWF binds to collagen and unravels
  • this exposes binding sites e.g. for platelets
  • platelets bind to WVF via Gp1b)
  • platelets can also bind to collagen directly via alpha2beta1 and Gp6 but only under low shear stress)

Collagen activates the platelets -> shape change and release of factors form granules (platelet agonists)
also thrombin from coagulation cascade which is also an important stimulator.

52
Q

How do platelets stick together?

A

Integrin: alpha2b beta 3 (this also binds to fibrinogen)

53
Q

What is needed for the clot to be effecitve?

A

fibrin has to stabilise it

54
Q

Comment on the amount of platelets that we have

A
  • more than we need in normal haemostasis
  • high numbers are for childbirth as well as for trauma
  • even in thrombocytopenia you don’t get spontaneous bleeding
  • below 40 x 10^9/L spontaneous bleeding is common (e.g. AI clearance of platelets)
  • below 10 x 10^9/L -> severe spontaneous blend occurs.
55
Q

Very briefly summarise the coagulation cascade

A

TF and FVII binds

  • multiple steps
  • activation of thrombin (serine protease)
  • this turns soluble fibrib=nogen into insoluble fibrin
56
Q

Name the different groups of clotting factors

A
  • zymogens (prothrombin, 7,9,10,11,12,13)
  • serine proteases (when activated; thrombin, 7a,9a,10a,11a,12a)
  • cofactors (e.g. TF, Va, FVIIa)
  • Inhibitors (TFPI, protein C, protein S, antithrombin)
57
Q

Where is TF expressed higher? Why?

A
  • brain, placenta, lungs, heart, testis, uterus

- > provide further haemostatic protection

58
Q

How does factor 7 circulate?

A
  • in plasma at around 10nm
  • around 1% circulates in its activated form - we don’t know why but without this activated part the haemostatic system would not work.
59
Q

Homologous serine protease protein structure

A
  • FVII, FIX, FX and PC share
  • a homologous modular structure with 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 prteolysis
60
Q

What does TF+FVII do?

A

Activates:

  • FX -> Xa
  • FIX -> IXa
61
Q

Summarise the coagulation cascade

A
  • TF + FVI -> TF-FVIIa
  • this activates FX -> FXa and FIX -> FIXa
  • FXa turns ProT -> thrombin (inefficient)
  • a small amount of thrombin further primes coagulation to greatly enhance the generation of more thrombin
  • Thrombin activates Co-factors FV -> FVa and FVIII -> FVIIIa
  • FXa + FVa -> 300 000 x more efficient at making ProT -> Thrombin
  • FVIIIa + FIXa enhance FX -> FXa
  • Thrombin cleaves fibrinogen into fibrin.
62
Q

APC

A

activated protein C

63
Q

Regulation of coagulation

A

TFPI: TF-FVIIa (tissue factor pathway inhibitor)

AT: FXa, FIXa, thrombin (serine proteases)

APC and protein S: FVa and FVIIIa (cofactors)

Has to be regulated to prevent thrombotic effects

64
Q

How does TFPI work?

A
  • F10 binds to TF and F7 complex
  • this activates F10a and it is released
  • TFPI binds to F10a voa 2nd Kunitz domain
  • TPFI-F10a complex binds to F7a of the TF-F7a complex and inactivates it.
  • there are only small quantities of TFPI circulation so it is not enough to shut down coagulation before it started, only dampens in small injuries.
65
Q

Protein C Pathway

A
  • can cleave FVa and FVIIIa at different parts
  • activated by thrombin-TM complex on EC
  • F2/thrombin binds to TM, it is made anticoagulant
  • cleaves protein C (removes activation peptide) to make it APC
  • APC with cofactor protein S regulates
  • regulates the propagation of coagulation by down-regulating thrombin generation, it does not inhibit thrombin
66
Q

Factor 5 Leiden

A
  • FVa cannot be inactivated as efficiently
  • increased risk of thrombosis
  • Protein C pathway cannot shut down coagulation as efficiently.
67
Q

WHERE is protein C activated?

A

at the edge of the slot where thrombin meets the endothelial surface. of an intact endothelial cell (TM on endothelial surface)

68
Q

Antithrombin

A

= serpin (serine protease inhibitor)

inactivates a number of serine proteases incl. FXa and thrombin, as well as FIX and FXI

  • also mops up free serine proteases that escape the site of vessel damage.
69
Q

Problems with deactivation of coagulation

A

Deficiencies of antithrombin, protein C and protein S
are important risk factors for thrombosis!

  • probably death in gestation without TFPI
70
Q

How does Heparin work?

A
  • not a direct anticoagulant
  • binds to AT and enhances its efficiency (cofactor)
  • at AT inhibiting thrombin and Xa
71
Q

Fibrinolysis

A
  • removal of clot via fibrinolysis
  • plasminogen -> plasmin via tPA
  • plasminogen made in the liver
  • tPA is activated by binding to fibrin and then is activated and can then make plasmin from plasminogen
  • plasmin is a permiscous and active serine protease that chops up the fibrin fibres in the clot and gives rise to fibrin degradation products that circulate and are broken down in the liver.
72
Q

Therapeutical use of tPA

A
  • in MI (less frequently), ischaemic stroke etc.
  • > clot busters
  • promotes lysis of the clot and will promote better blood flow
73
Q

Clinical drugs re haemostasis

A

Drugs

- anticoagulants - heparin, warfarin, DOACs (direct oral anticoagulants: small molecule inhibitors of Xa to thrombin, increasing use)
- antiplatelet agents – aspirin, P2Y12 blockers (to reduce responsiveness)

you would generally protect the people at risk of venous thrombosis with anticoagulants and the people at risk of arterial thrombosis with anti platelet agents.

Tests

- coagulation (PT, APTT) -> global readout of someone's haemostatic potential
- platelet function tests - in abnormal bleeding.
- d-dimer -> one of the FDPs from fibrinolysis; how much clotting has been going on in the recent past?

Year 2 - MCD - Haematology (11 decks)

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