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BIOCHEMISTRY 3 > General overview of blood clot formation and elimination. > Flashcards

General overview of blood clot formation and elimination. Flashcards

1
Q

Fibrinogen (Factor I)

A
  • water soluble plasma glycoprotein
  • converted to fibrin by thrombin
  • synthesized in liver by hepatocytes
  • concentration of fibrin: 200-400 mg/dl
  • hexamer (2a, 2B, 2y)
  • 2 D + 1E domain
  • E domain: N-terminal of all peptides + disulfide bonds
  • D domain: b and y polypeptide C-terminals
  • alpha chain folds back ⇒ alphaC domain
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2
Q

Fibrin

A
  • Thrombin proteolyse fibrinogen, cleaves alpha-chain N terminal ⇒ release fibrinopeptide A ⇒ thrombin cleaves beta chains fibrinopeptide B ⇒ fibrin monomers ⇒ polymerize spontaneously to insoluble gel
  • held together by noncovalent and electrostatic forces
  • stabilized by factor XIIIa
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3
Q

Factor XIII

A
  • fibrin stabilizing factor
  • transglutaminase enzyme
  • crosslinks fibrin
  • converted to active XIIIa by thrombin
  • glycoprotein heterotetramer (2a, 2B)
  • also present as homodimer (2a) in platelets
  • alpha-subunit develops in megakaryocytes and monocytes, beta-subunit develops in liver
  • A subunit: transglutaminase part, adds alkyl group to nitrogen on glutamine residue ⇒ bind with lysine ⇒ expel ammonia and create isopeptide bond between LYs and Gln
  • B subunit: no enzymatic activity, carrier for A subunit or regulator subunit
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4
Q

Activation of prothrombin

A

Factor Xa catalyses cleavage of prothrombin at two sites between Arg271-Thr272 and Arg320-Ile321 ⇒ thrombin and single polypeptide strand(binds Ca2+)

  • maximal ROR when complex bound to phospholipid membrane at phosphatidylserine residues
  • Ca2+ must be present
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5
Q

Prothrombinase complex

A
  • consists of: serine protease, Factor Xa, Factor Va
  • assembles on negatively charged phospholipid membranes in presence of Ca2+
  • catalyses: prothrombin (factor II) ⇒ mezothrombin ⇒ thrombin (factor IIa)
  • held together by non-covalent interactions
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6
Q

Factor Va

A
  • composed of heavy and light chain
  • bind to negatively charged phospholipid membranes
  • receptor for membrane bound Factor Xa
  • increases the rate of reaction of prothrombinase complex
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7
Q

Vitamin K

A
  • involved in carboxylation of Glu residues⇒ gamma-carboglutamate residues⇒ involved in binding calcium
  • vital for prothrombin, factors VII, IX and X and proteins C,S and Z
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8
Q

Warfarin

A
  • medication for regular blood clots

- inhibit Vitamin K epoxide reductase (⇒ no vit K reduced ⇒ no Gla)

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9
Q

Common risk factors for clotting

A

Trauma
Family history
Long haul flight
Cancer

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10
Q

Tissue factor pathway (extrinsic)

A
  1. Damage to blood vessel
  2. Factor VII comes in contact with TF ⇒ TF-FVIIa
  3. TF-FVIIa activates Factor IX and X
  4. Factor VII is activated by FXIa, FXII, FXa
  5. Factor X activation immediately inhibited by TFPI
  6. FXa + FVa form prothrombinase complex ⇒ prothrombin to thrombin
  7. Thrombin activates FV, FVIII and activates + released FVIII from vWF
  8. FVIIIa + FIXa form tenase complex ⇒ activate FX
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11
Q

Contact activation pathway (intrinsic)

A
  1. Formation of primary complex by HMWK, prekallikrein and Factor XII
  2. Prekallikrein ⇒ kallikrein, Factor XII ⇒ Factor XIIa
  3. Factor XIIa converts Factor XI⇒Factor XIa
  4. Factor XIa activates Factor IX ⇒ forms tenase complex with Factor VIIIa
  5. Tenase complex activates FX⇒FXa
    - during inflammation, bacteria and neutrophil needed for XII auto activation
    - depending on substrate of kallikrein ⇒ release bradykinin ⇒ release of plasminogen activator ⇒ activate prourokinase
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12
Q

Functions of Thrombin

A
  • converts FXI⇒XIa, VIII⇒VIIIa, V⇒Va, fibrinogen⇒ fibrin, XIII⇒XIIIa
  • thrombin + thrombomodulin activates protein C + inhibits fibrinolysis by cleaving TAFI
  • promotes platelet activation and aggregration
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13
Q

Thrombin inhibitors

A
  1. Antithrombin/ heparin
  2. Heparin co-factor II/ heparin sulphate
  3. alpha-1 protease inhibitor
  4. alpha-2 macroglobulin
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14
Q

Factor Xa inhibitors

A
  1. TFPI

2. Protein Z cofactor and inhibitor

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15
Q

Antithrombin

A
  • glycoprotein
  • produced in liver
  • contains 3 disulfide-bonds, 4 glycosylation sites
  • alpha-antithrombin is dominating- has all 4 sites occupied by oligosaccharides
  • beta- antithrombin- 1 site not occupied, activity increases with heparin, enhances binding to FII, FX
  • inhibits: thrombin, VIIa, IXa, Xa, XIa
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16
Q

Heparin

A
  • highly sulfated glycosaminoglycan
  • synthesized in mast cells
  • anticoagulant
  • heparin + AT3 + thrombin
  • heprain + AT3 + Xa
  • increases the ROR of thrombin-antithrombin
  • indirect inhibitor of thrombin
17
Q

Hirudin

A
  • natural peptide in salivary glands of leeches
  • most potent inhibitor of thrombin
  • high affinity to thrombin bc can bind to active site + anion binding site of fibrinogen
  • binds to and inhibits the activity of thrombin
18
Q

Plasma-FXIII

A
  • inactive because b-subunits block alpha-subunit active site
  • thrombin needed for activation
  • Ca2+ helps with beta-subunit dissociation
  • co-factor: Fibrin
19
Q

Platelet-FXIII

A
  • no activation required

- platelet must first be activated ⇒ Ca2+ conc. reaches threshold for FXIII activation

20
Q

FXIII deficiency

A
  • autosomal, recessive
  • umbilical cord bleeding, sbcutaneous bleeding, sub muscular bleeding, intracranial bleeding
  • recombinant A subunit can be given as treatment
21
Q

Characteristics of thrombin

A
  • serine protease family
  • hydrolyses peptide bonds- max 2/protein
  • high specificity
  • consists of 2 polypeptide chains, with disulfide bonds
22
Q

Factors with Gla domain

A 
F II
F VII
F IX
F X
Protein S
Protein Z
APC
23
Q

Positive feedback of Thrombin

A

F VIII
F XI
F V

24
Q

Tissue Factor TF

A
  • transmembrane protein
  • present on membrane surface not in contact with blood
  • results in extrinsic pathway when contact with blood
25
Q

Protein C

A
  • serine protease
  • APC can cleave FV
  • co-factor: protein S
  • contains Gla domain ⇒ bind to phospholipid membrane
  • antithrombotic effects: inactivates FVIII + decreases half-life of prothrombinase
  • thrombin + thrombomodulin needed for activation
26
Q

APC resistance

A
  • mutation in FV and FVIII
  • Arg506⇒ Gln
  • APC cannot cleave this
    ⇒ half-life of prothrombinase increases
27
Q

Significance of gamma-carboxylation

A
  • maintain 3D structure
  • form hydrophobic part ⇒ inserted to membrane + localize protein
  • direct electrostatic interaction with membrane phosphatidylserine + Ca2+
28
Q

Tissue factor inhibitor TFPI

A
  • endogenous inhibitor, can inhibit membrane bound proteases
  • can inhibit both TF-FVIIa + prothrombinase complex
  • produced by endothelial cells and megakaryocytes
  • 2 isoforms, TFPIalpha + TFPIbeta
  • has Kunitz domain (disulfide rich alpha+beta fold)
29
Q

TFPIa

A
  • from endothelial cell ⇒ blood ⇒ bind to heparin sulfate
  • from megakaryocyte⇒ in platelets
  • K3 domain bound to Protein S (anchor FI-FVII with Gla to TFPI)
  • K2 domain bound to FX
  • K1 domain bound to FVIIa⇒ inhibited
30
Q

TFPIb

A
  • connects to endothelial membrane with GPI-anchor
  • K1 domain inhibits FVIIa
  • role: maintain the endothelial surface’s coagulation property
  • cannot inhibit prothrombinase complex ⇒ does not have 3x C-terminal
31
Q

Heparan sulphate

A
  • glycosaminoglycan, covalently attached to protein
  • component of extracellular matrix
  • produced by all cell types
32
Q

Polyphosphate

A
  • source: bacteria, platelet dense granule,
  • short polyP:
    • from platelet
    • activate FV
    • inhibit TFPI
    • activate XI
  • long polyP:
    • from bacteria
    • activate FXII
33
Q

Multicomponent complexes

A
  1. Extrinsic factor tenase:
    * enzyme: VIIIa
    * cofactor: TF
    * substrate: X
  2. Intrinsic factor tenase:
    * enzyme: IXa
    * cofactor: VIIIa
    * substrate: X
  3. Prothrombinase:
    * enzyme: Xa
    * cofactor: Va
    * substrate: prothrombin
  4. Protein C complex:
    * enzyme: thrombin
    * cofactor: TM (protein S)
    * substrate: protein C
34
Q

Prothrombin time PT

A
  • time for fibrin clot to form

- Measures function of Tissue factor pathway, thrombin, fibrinogen, FV, FXIII

35
Q

Activated Partial Thromboplastin time aPTT

A
  • time for fibrin clot to form

- measures function of intrinsic pathway + common pathway

BIOCHEMISTRY 3 (17 decks)

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