Haemostasis Flashcards

1
Q

What is the normal response to injury to the endothelail cell lining?

A

vessel constriction -> formation of unstable platelet plug (platelet adhesion and aggregation) -> stabilisation of plug with fibrin (blood coagulation) -> dissolution of clot and vessel repair

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2
Q

What are the functions of the endothelium?

A

Maintain barrier between blood and tissue factor.

Synthesis – PGI2, thrombomodulin, vWF, plasminogen activators

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3
Q

How are platelets created?

A

stem cell precursors -> megakaryocytes -> megakaryocytes mature and granulate -> megakaryocytes produce ~4000 platelets.

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4
Q

What is the circulating lifespan of a platelet?

A

around 10 days

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5
Q

What are some ultrastructure features of a platelet?

A
Dense granules
alpha-granules
thrombin receptors surface glycoproteins (Glp1a, Glp1b, Glp2b/3a)
phospholipid membrane
microtubules and actomysin
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6
Q

What are the roles of platelets?

A
haemostastis and thrombosis
cancer
atherosclerosis
infection
inflammation
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7
Q

What happens in platelet adhesion?

A
  • vessel damage exposes collagen
  • vWF binds to collagen and undergoes structural change into linear shape exposing binding sides
  • circulating platelets bind to Glp1a on vWF
  • platelets can directly bind to collagen via GPV1 and a2b1 (but only under low shear stress - not arteies/capillaries)
  • interaction of platelts and collagen -> platelet activation -> conformation change and degranulation -> release of ADP and thromboxane
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8
Q

What happens in platelet aggregation?

A
  • activated platelets (a2bB3) recruit additional platelets

- a2bB3 also binds fibrinogen -> platelet plug

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9
Q

What happens during blood coagulation?

A

tissue damage causes tissue factor to bind to factor 7a
factor 7a binds to cell surface (using gla domain)
F12->12a
F11-11a
7a catalyses F9->9a
F10->10a (9a and 7a and Ca2+)
*7a cleaves 9 and 10 - removes activation peptide-> 9a and 10a

factor 10a converts prothrombin (F2)-> thrombin (very inefficient)
thrombin cleaves F8->8a (8a is cofactor for 9a)
F8a/9a complex activates much more factor 10a
F5a (also activated by thrombin) forms complex with 10a produces much more thrombin

fibrinogen -> fibrin

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10
Q

What are Gla domains?

A

vitamin k dependent proteins

contain 9-11 gamma-carboxylic acid residues

bind 6/7 Ca2+ ions -> structural transition which allows it to bind to negatively charged phospholipid cell/ platelet cell

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11
Q

Where are clotting factors, fibrinolytic factors and inhibitors synthesised?

A

Liver - Most coagulation proteins.

Endothelial cells - vWF

Megakaryocytes - vWF, Factor V

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12
Q

What happens once a clot has formed?

A

Tissue factor pathway inhibitor (TFPI) binds/inactivates TF-F7a complex (but very low concentration of TFPI)

Protein C pathway

  • activated by thrombin-thrombomodulin (on endothelial cells) complex
  • chops up F5a and 8a (co factors) -> no more clotting

antithrombin inhibits F9a, 10a and 2a (thrombin)

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13
Q

how do warfarin and heparin work?

A

Warfarin

  • In the liver, vitamin K mediates production of factors II, VII, IX and X which have extra carboxyl groups on
  • The extra carboxyl groups (gamma-carboxyglutamic acid) allow the clotting factors to adhere to platelet membrane PLs
  • Warfarin inhibits vitamin K epoxide reductase and thus reduces creation of secreted clotting factors - reduces the clotting factors that bind to platelet PLs (phospholipids)
  • Thus warfarin inhibits the platelet surface interactions as the clotting factors cannot bind to the surface with Ca2+
  • Warfarin = long-term anticoagulation following venous thrombosis AND treatment of atrial fibrillation

Heparin
- binds t antithrombin and accelerates its actions by 3000x

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14
Q

What laboratory tests can be used to test blood coagulation?

A

APTT – Activated Partial Thromboplastin Time
- Initiates coagulation through F12 and detects abnormalities in INTRINSIC and COMMON pathways.

PT – Prothrombin Time.
- Initiates coagulation through tissue factor and detects abnormalities in EXTRINSIC and COMMON pathways.

TCT/TT – Thrombin Clotting Time.
- Add thrombin -> shows abnormalities in fibrinogen to fibrin conversions.

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