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IMS: Biochemistry > Blood Clotting > Flashcards

Blood Clotting Flashcards

1
Q

Blood Clotting

Overview

A

Initiated on the membranes of endothelial cells and platelets:

  1. formation of a fibrin clot
  2. formation of a platelet plug
  3. vasoconstriction (eicosanoids, PGs, Txs)
  4. limits to the process (anticoagulation)
  5. clot dissolution (fibrinolysis)

Wound repair also occurs.

Functions through cascade of proteolytic cleavage or conformational changes.

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2
Q

Effectors of Clotting

A
  • Negatively charged phospholipids (PS, PI)
    • Normally found on inner leaflet
    • Exposure signals injury
  • Ca2+
    • Binds negatively charged γ-carboxyglutamate (Gla) residues on certain clotting proteins
    • Facilitates binding of these proteins to exposed neg-charged phospholipids
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3
Q

Gla Proteins

A
  • Negatively charged γ-carboxyglutamate (Gla) residues on some clotting proteins
  • γ-carboxylation
    • post-translational modification where 9-12 Glu residues at N-terminus gets carboxylated to Gla residues by glutamyl carboxylase
    • Occurs in lumen of RER in hepatocytes
    • Vit K required co-enzyme
      • Gets oxidized in reaction to epoxide
      • Must be reduced back to hydroquinone form to continue, done by Vitamin K epoxide reductase (VKOR)
      • Dicumarol or warfarin inhibits reduction of Vit K
        • Inhibits clotting
        • Slow onset
        • Long half-life
        • Polymorphisms in CP-450 + VKOR isozymes results in different dosing
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4
Q

Extrinsic Pathway

A

Tissue Factor Pathway

  • TF is a transmembrane glycoprotein found in vascular subendothelium = extravascular
  • Extrinsic pathway is quickly shut down by TFPI
  1. Vascular injury exposes extravascular TF (Factor III) to Factor VII.
  2. TF binding causes conformation change of VII activating it to VIIa.
  3. VIIa is a serine protease which activates factor X.
  4. Factor Xa enters common pathway.
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5
Q

Intrinsic Pathway

A

Contact Pathway

All protein factors found in blood = intravascular.

Contact Phase

There are no known bleeding disorders associated with any factor deficiencies of contact phase.

  1. Contact of blood with a negatively charged PL on damaged endothelial surface results in the conformational change and activation of factor XII to XIIa.
    • XII can also be activated by Thrombin from common pathway.
  2. Factor XIIa binds to and cleaves Prekallikrein-HMWK at an anionic surface producing Kallikrein.
  3. Kallikrein can then proteolytically cleave additional Factor XII causing amplification.

X Activation Phase

  1. Factor XIIa proteolytically cleaves XI-HMWK at an anionic surface to produce Factor XIa.
    • Defective Factor XI → Hemophilia C
  2. Factor XIa cleaves Factor IX(Gla) into IXa(protease)
    • Defective Factor IX → Hemophilia B
  3. Factor IXa combines with Factor VIIIa and complex cleaves Factor X into Xa.
    • Factor VIII found in the blood as vWF-VIII complex
      • vWF proteins VIII from degradation
      • VIII dissociates from vWF after proteolytic activation by Thrombin from common pathway.
      • Defective Factor VIII → Hemophilia A
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6
Q

Common Pathway

A

Factor Xa to Fibrin

  1. Factor Xa from both intrinsic and extrinsic paths associates with Factor Va(accessory protein) forming Xa-Va (Prothrombinase complex)
  2. Binding of Ca2+ to Gla residue on Prothrombin (Factor II) facilitates binding of Prothrombin to membrane and to Xa-Va with subsequent cleavage to Thrombin (Factor IIa).
    • Cleavage excises Gla region releasing Thrombin from membrane.
    • Only time Gla excised.
    • Gla-peptide to goes to the liver.
  3. Thrombinplasma cleaves Fibrinogen (Factor I) into Fibrin (Factor Ia).
  4. Fibrin forms the soft fibrin clot.
  5. Thrombin activates Factor XIII to XIIIa.
  6. Factor XIIIa (transglutaminase) cross-links Gln from one fibrin with Lys of another to form an isopeptide bond converting soft clot into an insoluble hard clot.
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7
Q

Fibrin

A
  • Soluble glycoprotein made by liver
  • Dimers of three different polypeptides held together at N-termini by disulfide bonds
  • N-termini of the Aα, Bβ chains form “tufts” on the central three globular domains
  • Thrombin cleaves the negatively charged tufts producing fibrinopeptides:
    • fibrinogen becomes fibrin
    • solubility decreases
    • fibrin monomers associate laterally
    • soft fibrin clot formed
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8
Q

Complete Pathway

Blood Clotting

A

Pathway Interconnections:

  • VIIa – TF of extrinsic path activates IX of intrinsic path.
  • XIIa of intrinsic path activates VII of extrinsic path.
  • IIa of common path activates factors of intrinsic and extrinsic paths.
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9
Q

Clotting Factors

A
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10
Q

Roles of Thrombin

A
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11
Q

Platelet Plug Formation

A

Platelet plug provides primary hemostasis.

Fibrin net provides secondary hemostasis.

  1. vWF binds exposed collagen on endothelial surface.
  2. Platelets bind:
    • To vWF via GP1b which is a component of the membrane receptor complex (GP1b/V/IX).
      • vWF made by endothelial cells and megakaryocytes.
    • Directly to collagen via GPVI
  3. Binding stops forward movement of platelets causing adherence.
  4. Platelet activation causes degranulation.
    • Thrombin most potent activator.
  5. Conformation change following activation leads to aggregation.
  6. Conf. Δ in GPIIb/IIIa receptor exposes fibrinogen binding sites.
  7. Fibrinogen binds & link activated platelets to one another.
    • Fibrinogen → Fibrin by IIa
    • Cross linkage by XIIIa from plasma and platelets.
    • Fibrin net strengthens platelet plug to resist shear forces.
  8. Activation also exposes anionic PL which allows formation of tenase on surface of platelets.
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12
Q

Platelet Activation

A
  1. Thrombin binds to and activates protease-activated receptors (PARs) on the surface of platelets & endothelial cells.
    1. Type of GQPCR
  2. Receptor activates PLC which cleaves PIP2 into DAG and IP3
  3. DAG activates PKC leading to degranulation.
  4. IP3 causes release of calcium from delta granules.
  5. Calcium causes activation of PLA2
    • Shape changes in platelet​
      • Ca2+ activates MLCK which phosphorylates MLC
      • Favors association with actin
    • Synthesis of TXA2
      • Platelet degranulation
      • Vasoconstriction
      • Binds to platelet membrane GPCR causing activation of additional platelets
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13
Q

Platelet Activation

Regulation

A

(1) the vascular wall is separated from blood by a monolayer of endothelial cells
(2) endothelial cells synthesize the vasodilators PGI2 and NO
(3) endothelial cells have a cell surface ADPase that converts ADP to AMP

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14
Q

Platelet Degranulation

A

Degranulation releases:

  • Delta granules:
    • Serotonin: causes vasocontriction
    • ADP: activations additional platelets
      • Plavix blocks ADP receptors preventing ability to activate platelets
  • Alpha granules:
    • PDGF: helps in wound healing
    • Factor Va
    • vWF
    • Fibrinogen
    • Many more
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15
Q

vonWillebrand’s Disease

A
  • Caused by deficiency in vWF
  • Most common inherited coagulopathy
  • AR
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16
Q

Bernard-Soulier Syndrome

A

Deficiency in platelet receptor for vWF.

17
Q

Glanzmann’s Thrombasthenia

A

Rare defect in platelet receptor for fibrinogen.

18
Q

Immune thrombocytopenia

A

Autoimmune disorder caused by autoantibodies to platelet receptor for fibrinogen.

19
Q

Pathways of Coagulation

Interrelationships

A
  1. TF—VIIa of extrinsic path activates IX of intrinsic path.
  2. XIIa of intrinsic path activates VII of extrinsic path.
  3. Thrombin (IIa) of common path activates components of both the intrinsic and extrinsic paths; also activates platelets.
  4. Tenase of intrinsic path forms on the surface of activated platelets and damaged endothelium.
  5. One fifth of total Va is released by activated platelets.
  6. XIIIa and VWF present in plasma and platelets.
20
Q

Antithrombin III

(ATIII)

A
  • Made by liver
  • Serine protease inhibitor (serpin)
  • ATIII binds to:
    • Thrombin (most important)
    • Factor IXa through XIIa (inactivation of X is key)
    • VIIa-TF complex
  • Binding makes catalytic domain of thrombin inacessible
  • Complexes removed by liver
  • Binding greatly increased by Heparin
    • Released in response to injury by mast cells
21
Q

APC

A

Protein C - Protein S complex

  • Protein C(Gla) activated by thrombin-thrombomodulin complex.
    • Thrombomodulin expressed on the surface of undamaged endothelial cells.
      • Binds thrombin.
      • Decreases thrombin’s affinity for fibrinogen.
      • Increases affinity for Protein C.
  • Protein C complexes with Protein S to form the activated Protein C complex (APC).
  • APC cleaves Va and VIIIa.
    • S helps achor C to the clot.
22
Q

Factor V Leiden

A
  • Mutant form of factor V which is resistant to APC cleavage.
  • Most commonly inherited thrombophilic condition
23
Q

Plasmin

A
  • Serine protease which degrades fibrin
  • Plasminogen is made by the liver & released into the blood
  • Binds to fibrin and is incorportated into clots as they are formed
24
Q

Fibrinolysis

A
  • Plasminogen incorporated into clots during formation.
  • Physiological activators of plasminogen bind and cleave it to plasmin.
    • Tissue plasminogen activator (TPA)
      • Made by endothelial cells
      • Secreted in inactive form in response to thrombin
      • Becomes active when bound to fibrin-plasminogen
    • Urokinase (u-pa)
      • Made in the kidney
  • Plasmin cleaves fibrin clot.
  • Bound Plasmin and TPA protected from inhibitors. When fibrin clot is dissolved they are exposed and inactivated.
    • α-2 antiplasmin
    • PAI (plasminogen activator inhibitor)

IMS: Biochemistry (10 decks)

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