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Haematology > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

Normal haemostasis is a delicate balance between bleeding and thrombosis (formation of a clot). Increases/decreases in what would alter this balance?

A

Increased fibrinolytic factors or anticoagulant proteins, decreased coagulant factors or platelets => more bleeding

Vice versa => more thrombosis

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2
Q

What are the sequential processes associated with haemostat plug formation in response to injury to the endothelial cell lining?

A
  1. Vascular smooth muscle cells contract locally to limit blood flow to injured vessel (mainly important in small blood vessels)
  2. Primary Haemostasis = formation of an unstable platelet plug that limits blood loss + provides surface for coagulation
  3. Secondary haemostasis = initiation of coagulation cascade and stabilisation of the plug with fibrin to stop blood loss
  4. Vessel repair and dissolution of clot to restore vessel integrity
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3
Q

What components of the vessel wall (artery) are procoagulant/anticoagulant?

A

Anticoagulant barrier:

  • Endothelial cells
  • Have TM, EPCR, TFPI, GAG on their surface

Procoagulant:

  • Subendothelial tissue e.g. basement membrane, elastin, collagen
  • Tissue factor (47kDa) expressed by sub-endothelial cells which are not normally exposed to flowing blood e.g. VSMCs and fibroblasts
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4
Q

State the name of the cell from which platelets are derived. How many can each cell produce?

A

Megakaryocytes in bone marrow

~4000 platelets

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5
Q

How do the megakaryocytes release platelets into the blood stream?

A

Haematopoietic stem cell -> promegakaryocyte -> proliferation to megakaryocyte (i.e. becomes polyploid, cytoplasm enlarge) -> maturation (i.e. becomes granular and forms platelets) -> migrate to vessel wall and form proplatelet protrusions that extend into the lumen and release platelets from the tip of these long extensions due to shear forces.

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6
Q

What do 𝛼-granules in the platelets contain?

A

Growth factors
Fibrinogen
Factor V
VWF

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7
Q

What do the dense granules in the platelets contain that is important for platelet function?

A

ADP

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8
Q

Name some of the important receptors on the surface of the platelet, and state what they interact with

A

Integrins:
• 𝛼2b𝛽3 (or GP2b/3a) - interacts with fibrinogen
• 𝛼2𝛽1 - interacts with collagen
• GPVI - interacts with collagen
• GP1b - essential for platelet capture via binding to VWF

GPCRs:
• Thromboxane A2 receptor (TP)
• Protease activated receptor (PAR) - interacts with thrombin
• P2Y12 receptor - interacts with ADP

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9
Q

Why is the platelet cytoskeleton important for platelet function?

A

It enable the platelet to change shape (and have pseudopod extensions) during activation = conversion from a passive/resting cell to an interactive procoagulant cell

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10
Q

Summarise the process of primary haemostasis

A
  • Multimeric VWF circulates in plasma in a globular conformation so binding sites are “hidden” from platelet GP1b receptors
  • Vascular injury damages endothelium and exposes sub-endothelial collagen (and other components)
  • VWF can bind to collagen via its A3 domain
  • The tethered VWF is unravelled by rheological shear forces of flowing blood => exposing platelet binding sites
  • Platelets bind to VWF via GP1b
  • Platelets can also bind directly to collagen, via GPVI and 𝛼2𝛽1, only at low shear forces (i.e. not in arteries/capillaries)
  • Platelets become activated and release VWF to recruit additional platelets, and release ADP + thromboxane to further activate platelets
  • Platelets will bind to each other via fibrinogen on activated 𝛼2b𝛽3 integrin => platelet aggregation => primary platelet plug

Note that platelets are also activated

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11
Q

What are the three changes that occur to activated platelets for aggregation?

A
  • Release of granules
  • Change shape
  • Membrane composition changes = negatively charged ends of outer phospholipids exposed to recruit clotting factors to the site of injury
  • Present new/activated proteins on their surface (e.g. 𝛼2b𝛽3 for fibrinogen)
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12
Q

Describe the platelet shape changes upon adhesion, activation and aggregation

A
  • Flowing disc-shaped
  • Rolling ball-shaped (with pseudopod projections)
  • Hemisphere-shaped
  • Spreading platelets
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13
Q

What is the normal range for platelet count? Below which values do you get spontaneous bleeding?

A

Normal = 150x10^9 - 400x10^9/L

<40 x 109/L ; Spontaneous bleeding common (e.g. autoimmune thrombocytopenia)

<10 x 109/L ; Severe spontaneous bleeding (e.g. due to treatment of leukemias)

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14
Q

Where are most clotting factors synthesised? Apart from platelets, where else is VWF produced?

A

The liver

Endothelial cells also produce VWF

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15
Q

What do clotting factors circulate as? How are they activated?

A

Inactive precursors => either serine protease zymogens or cofactors

Activated by specific proteolysis

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16
Q

List the serine proteases.

A 
FVII
FX
Prothrombin
FIX
FXI
Protein C
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17
Q

Describe in short how tissue factor interacts with FVII/FVIIa in the initiation of the coagulation cascade (secondary haemostasis)

A
  • FVII/FVIIa bind cell surfaces via Gla domain
  • All domains of FVII/FVIIa interact with TF (which acts as a cellular receptor and cofactor of FVII/FVIIa
  • TF makes FVIIa 2x10^6 times more active
18
Q

Describe in short how tissue factor interacts with FVII/FVIIa in the initiation of the coagulation cascade (secondary haemostasis)

A
  • FVII/FVIIa bind cell surfaces via Gla domain
  • All domains of FVII/FVIIa interact/bind with TF (which acts as a cellular receptor and cofactor of FVII/FVIIa) => form an activated complex
  • TF makes FVIIa 2x10^6 times more active
19
Q

TF is the only procoagulant factor that does not require proteolytic activation. True/False

A

True

20
Q

Describe the domain structure of Factor VII

A

4 domains:

  • Gla Domain
  • 2x EGF-like domains
  • Serine protease domain
21
Q

Describe the domain structure of Factor VII (47kDa)

A

4 domains:

  • Gla Domain
  • 2x EGF-like domains
  • Serine protease domain
22
Q

List the serine proteases that share same overall domain structure as FVII.

A

FIX, FX and PC

23
Q

List the clotting factor proteins that also have a Gla domain

A 
FX
Prothrombin
FIX
Protein C
Protein S
24
Q

How are the Gla domains in those specific proteins formed?

A

Vitamin K Carboxylase converts the glutamic acid residues (in nascent Gla-domain containing proteins) to gamma-carboxyglutamic acid; (R-groups now have two -COOH)

25
Q

How are the Gla domains in those specific proteins formed?

A
  • In post-translational modification, Vitamin K-dependent carboxylation converts the glutamic acid residues (near the N-terminal) to gamma-carboxyglutamic acid; (R-groups now have two -COOH)
  • Gla domains contain
    9 - 11 gamma–carboxyglutamic acid residues

Hence, these proteins are vitamin K dependent

26
Q

What is the resultant function of the Gla domain?

A
  • These modified glutamic acid residues have an affinity for Ca2+.
  • Gla domains bind Ca2+ ions which causes a structural change/folding that allows for binding with negatively-charged
    phospholipids of the endothelial cell or platelet surface
27
Q

What type of drug is warfarin then?

A

Vitamin K antagonist

=> prevents carboxylation => reduces the no. of functional clotting factor proteins => anticoagulant effect

28
Q

State the subsequent steps in secondary haemostasis

A
  • TF-FVIIa complex proteolytically activates FX and FIX (removal of an activation peptide from SP domain)
  • Damping mechanism occurs on the above process, through TFPI, which binds to FXa and the TF-FVIIa complex
  • Initially however, FXa produces trace amounts of thrombin from prothrombin (aka Factor II)
  • Thrombin activates FV and FVIII (as well as FXI to form more FIXa) each then forming their own complex - Ca2+/PL/F9a/F8a and Ca2+/PL/F10a/F5a
  • These two complexes help to produce more thrombin (amplication effect) which cleaves soluble fibrinogen in blood into an insolube fibrin mesh
29
Q

State the other important functions of thrombin

A
  • Activates F13 which cross links fibrin + inhibits fibrinolysis
  • Activates TAF1 (inhibitor of fibrinolysis)
  • Activates platelets
30
Q

What are the intrinsic and extrinsic pathways referring to, regarding the coagulation cascade?

A

Intrinsic pathways refers to the activation of FXI to FXIa (by thrombin) to form more FIXa which goes on to produce more thrombin.

Extrinsic pathway refers to the initial pathway mediated by tissue factor.

31
Q

Haemophilia A and B are cause by deficiencies of what factors? State the type of inheritance.

A

Haemophilia A - FVIII deficiency
Haemophilia B - FIX deficiency

X-linked (i.e. primarily effects boys)

32
Q

State the three inhibitory coagulation mechanisms

A
  1. TFPI (tissue factor pathway inhibitor)
  2. The protein C anticoagulant pathway (indirect mechanism)
  3. Antithrombin
33
Q

How does the tissue factor pathway inhibitor (TFPI) cause the dampening mechanism on the initial step of the coagulation cascade (direct inhibitory mechanism)?

A
  • TFPI binds to FXa via its Kunitz domain 2 (K2) => TFPI-FXa
  • TFPI-FXa can bind/inactivate the TF-FVIIa active site via Kunitz domain 1 (K1)

Note that TFPI has three Kunitz domains (K1, K2 in the middle, K3)

34
Q

Describe the protein C pathway for down regulation of thrombin generation

A
  • Thrombomodulin on the endothelial cell membrane modulates thrombin activity by binding to free thrombin
  • This prevents thrombin from carrying out its functions
  • Instead, the thrombin is directed to cleaving the protein C zymogen into APC (active serine protease) via removal of an activation peptide
  • PC is presented on EPCR
  • APC (in combination with cofactor protein S) breaks down F5a and F8a (into F5ai and F8ai) preventing the amplification cascade
35
Q

What type of molecule is antithrombin? Describe the inhibitory mechanism mediated by antithrombin

A

58kDa serine protease inhibitor (SERPIN)

Antithrombin binds to and neutralises thrombin as well as other activated serine proteases (e.g. 9a, 10a, 11a) that escape the site of vessel damage

36
Q

How does heparin increase antithrombin activity?

A

Heparin increases antithrombin activity by making it more reactive and helping the antithrombin and thrombin come together (like a bridge)

37
Q

Breifly summarise the process of fibrinolysis for vessel repair and dissolution of clot

A
  • Tissue plasminogen activator (tPA) and plasminogen (PA; made in liver) bind to fibrin in the clot and are brought together
  • tPA converts PA into the active form of the enzyme (plasmin)
  • Plasmin breaks down the fibrin into fibrin degradation products (FDPs) (elevated in DIC)
  • Plasmin activity is regulated and localised by antiplasmin
38
Q

How can tPA be used therapeutically?

A

It can be used in therapeutic thrombolysis for Myocardial Infarction, ischaemic stroke etc..

39
Q

Name some anticoagulants and antiplatelet agents. When might you use each type of drug

A

Anticoagulants:

  • Heparin, Warfarin, Direct Oral Anticoagulants (DOACs)
  • Used to protect against venous thrombosis

Antiplatelet agent:

  • Aspirin
  • P2Y12 blockers
  • Used to protect against arterial thrombosis
40
Q

How does Aspirin act as an antiplatelet drug?

A
  • Phospholipids (from lipid bilayer) -> arachidonic acid; catalysed by phospholipase A2
  • Arachidonic acid -> PGH2; catalysed by COX1/COX2
  • In platelets, PGH2 -> Thromboxane A2 (potent inducer of platelet aggregation); catalysed by thromboxane synthase
  • In endothelial cells, PGH2 -> Prostacyclin (important regulator of haemostasis); catalysed by prostacyclin synthase

Aspirin is a COX1 inhibitor

Haematology (11 decks)

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