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BIOCHEMISTRY 3 > Cellular elements of the haemostatic system. Platelets and von Willebrand factor. > Flashcards

Cellular elements of the haemostatic system. Platelets and von Willebrand factor. Flashcards

1
Q

Platelet Generation

A
  • in bone marrow
  • megakaryoblast ⇒ pro-megakaryocyte ⇒ immature megakaryocyte ⇒ megakaryocyte
  • megakaryocyte undergoes endomitosis
  • cytoplasmic differentiation produces platelets
  • circulates 8-10 days
  • result is anucleated, discoid cell, 2-4 mm diameter
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2
Q

Platelet structure and function

A
  1. Peripheral zone: phospholipid membrane
  2. Sol-gel zone: cytoskeleton, microtubules - maintain shape
  3. Organelle zone: alpha/dense grnaule, lysosomes, mitochondria- stimulate adjacent platelets
  4. Membrane system: calcium storage, enzyme for prostaglandin synthesis
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3
Q

Formation of Hemostatic plug

A
  1. Adhesion
  2. Secretion
  3. Aggregation
  4. Contraction
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4
Q

Adhesion

A
  • attachment of cells on a surface at the site of injury
  • sub endothelial elements are exposed and platelets spread along the surface
  • interaction with sub endothelium, vWF, GPIb
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5
Q

Secretion/ Activation

A
  • shape change when activated
  • release of granular contents and prostaglandin metabolites
  • these interact with receptors on adjacent platelets ⇒ incorporation into evolving aggregate
  • activation by: ADP, collagen, epinephrine ⇒ PLA2 to release arachidoinic acid⇒ PGE2/H2⇒ thromboxane A2⇒ amplification
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6
Q

Dense/delta granules

A

release of: ADP, serotonin, Ca2+

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7
Q

Alpha granules

A

release of: platelet factor 4, b-thromboglobulin, platelet derived growth factor, vWF, factor V, thrombospondin, IgG and fibronectin

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8
Q

Aggregation

A
  • process by which platelets interact with one another to form a hemostatic plug
  • GPIIb-IIIa complex binds vWF, undergoes Ca2+-dependent structural change and acts as receptor for fibrinogen
  • fibrinogen allow bridging of activated platelets
  • fibronectin, thrombospondin stabilize platelet aggregates
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9
Q

Contraction

A
  • initial hemostatic plug stops blood but is unstable and must be followed by fibrin clot
  • platelets undergo contrictile response using actin-myosin apparatus
  • actin binds GPIIb-IIIa, which is bound to fibrin ⇒ clot retraction
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10
Q

Triggers for platelet activation

A 
Thrombin
Collagens
Platelet activating factor
ADP (autocrine/paracrine)
Thromboxane A2 (autocrine/paracrine)
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11
Q

vWF

A
  • multimeric glycoprotein
  • produced as ultra-large vWF in endothelium, megakaryocytes, sub endothelial CT
  • stored in Weibel-Palade body
  • Domains:
  • D’/D3 domain: binds factor VIII
  • A1 domain: binds GPIb-receptor, heparin, collagen
  • A3 domain: binds collagen
  • C1 domain: platelet integrin aiib B3
  • cysteine knot domain: transformes TGFB and B-HCG
  • function: bind to proteins, especially factor VIII, create contact between platelet and collagen + platelets with platelets
  • no catalytic activity
  • platelets have 2 types of vWF receptors: GP1ba, GPIIb/IIIa
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12
Q

Receptors for platelet activation

A
  • PAR1 receptor: thrombin binds, Gq coupled ⇒ initiation of platelet activation via contractile system, surface modification, TXA2 synthesis, granule release
  • Adenosine, PGI2 ⇒ Gs ⇒ cAMP ⇒ inhibit platelet activation
  • ADP ⇒ Gi ⇒ cAMP decrease
  • receptors for collagen, PAF, fibrinogen, vWF, thromospondin, fibronectin, laminin
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13
Q

GP1ba

A
  • platelet receptor for vWF
  • accessed all the time
  • participates in initial adhesion, but weak interactions
  • activated by shear stress when bound to vWF⇒ intracellular Ca2+ signal ⇒ ADP secretion
    ⇒ via ADP purinergic receptor ⇒ Ca2+ signal ampified ⇒ positive feedback (also activates GPIIb/IIIa
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14
Q

GPIIb/IIIa

A
  • belongs to integrin family
  • only bind to vWF when activated (by GP1ba activation)
  • stronger and more sustained adhesion
  • vWF receptor + fibrinogen receptor
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15
Q

P2Y receptor

A
  • purinergic G-protein coupled receptor

- stimulated by ATP, ADP, UTP, UDP and UDP-glucose

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16
Q

Ca2+ signal effects on platelets

A
  1. activates MLCK ⇒ contraction
  2. activates PLA2 ⇒ free arachidonic acid ⇒ TXA2 ⇒ platelet activation
  3. rearrangement of PM ⇒ activate scrambles enzyme ⇒ shuffling phospholipids for more negative outside ⇒ optimal for complexes to bind
  4. initiate secretion of vesicles in platelets
17
Q

Aspirin

A
  • drug to prevent cardiovascular disease

- covalently modifies serine residue in COX1 ⇒ inhibits movement of arachidonic acid ⇒ no TXA2 ⇒ no platelet activation

18
Q

Neutrophils

A
  • kill by NETosis
  • process initiated by PAMP
  • cells keep PM integrity but nucleus disintegrates + chromatin de-coondenses
  • cell releases its DNA ⇒ DNA net in extracellular matrix
  • nuclear + cell granule proteins bind to DNA net
  • NET bind bacteria ⇒ exposed to cytotoxic contents
  • NET DNA has strong negative charge ⇒ activator of FXII
  • NET binds vWF to enhance platelet adhesion
  • NET + fibrin⇒ resistant for fibrinolysis, deoxyribonucleases break down instead
  • Neutrophil elastase: cleave TFPI + antithromin, removes kringle domain from plasminogen, inactivates a2-PI
19
Q

Endothelial cells: anti-coagulation

A
  • platelets release: heparan sulfate, thrombomodulin, EPCR, TFPI
  • endothelium release: NO⇒ s-nitrolates proteins’ free sh-group
20
Q

Endothelial cells: inhibition of platelets

A
  • NO ⇒ soluble guanylyl cyclase ⇒ cGMP ⇒ PKG ⇒ inhibits phosholipase C + TXA2 receptor, activates MLCP
  • cGMP inhibit PDE3 ⇒ increased cAMP ⇒ inhibits platelet activation
  • activation of PGI2 receptor ⇒ cAMP ⇒ arachidonic acid attained ⇒ inhibition of platelet
  • ecto-ADPase⇒ break down ADP ⇒ no positive feedback
21
Q

Endothelial cells: pro-fibrinolytic aspects

A
  • endothelium produces tPA, uPA + prvides co-factor surface for plasminogen activation
  • tPA ⇒ A2.p112 tetramer protein complex
  • uPA receptor co-localise to protect uPA from PAI1
22
Q

Function of liver in hemostasis

A
  1. Hepatocytes: synthesis of proteins + post-translational modifications
  2. Kupffer cells: removal on inactive proteases
  3. Gla domain synthesis
23
Q

Membrane glycoprotein receptors

A
  • GPIb-V-IX: bind to vWF immobilized on collagen
  • GPIa/IIa: bind to collagen
  • GP VI: bind to collagen
  • GPIIb/IIIa: bind to free fibrinogen and vWF
24
Q

vWF binding sites

A
  • collagen
  • GPIb
  • GPIIb/IIIa
  • Factor VIII
  • heparin
25
Q

ADAMTS13

A
  • breaks down vWF

- a disintegrin and metalloprotease with a thrombospondin type 1 motif

BIOCHEMISTRY 3 (17 decks)

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