Hemostasis and thrombosis

First thing that happens in case of hemorrhage is vasoconstriction
1. Angiotensin
2. Endothelin
Hemostasis
1. Primary
  1. Platelet interaction with subendothelial structures and plaque formation
2. Secondary
  1. Clotting: thrombin and subsequent fibrin generation
Primary hemostasis
1. Main subendothelial structures involved
  1. Collagen
  2. Von Willebrand factor
    1. Synthesized by endothelium and stored in Weibel-Palade bodies
    2. Thrombotic Thrombocytopenic Purpura (TTP)
    3. ADAMTS13 inhibits formation of very high mW forms of vWF
      1. You need 2 main signals
        Presence of Ca2+
        Flow
    4. Synthesized as a dimer with many interactive domains:
      1. A1 is the domain interacting with platelet receptor GpIb
      2. A3 is the domain interacting with collagen
      3. C1 is the domain interacting with IIbIIIa on activated platelets
    5. Very high degree of polymerization
    6. 2 activities:
      1. Activity in primary hemostasis to permit the contact between platelets and the sub endothelium
      2. Carrier of factor VIII within the circulation
2. Platelet granules
  1. Delta granules
    1. Contain ATP and ADP
      1. ADP interacts with additional receptors (P2Y1 and P2Y12)
  2. Alpha granules
3. Platelet receptors
  1. IIbIIIa receptor
    1. It interacts with either vWF or fibrinogen
  2. GpIb is the main receptor that is constitutively expressed on the membrane of resting platelets
    1. Receptor for vWF
      1. First contact that platelets make with the subendothelium
  3. Glycoprotein VI
    1. Constitutive receptor for collagen
Secondary hemostasis
1. Tissue factor
  1. Main receptor for factor VII
    1. Only factor VII bound to tissue factor is pro-coagulant
2. Phospholipids must be expressed on top of the cell membrane and they are crucial for complex formation
3. Vitamin K-dependent clogging proteins
  1. Factor II, VII, IX, X
4. When platelets get activated you have the so-called flip-flop mechanism so the negative charges go towards the circulating blood and the positive charges are moved in
  1. This contributes to the assembly of the clotting complex
5. The substrate of the factor VIIa+TF complex is factor X that is activated to factor Xa
  1. VIIa+TF also leads to factor IX activation (but factor X is preferred just because its concentration is twice the concentration of factor IX)
    1. Factor IX can also activate factor X on a phospholipid surface
  2. Factor IX-VIII+X complex is called tenase
6. Prothrombinase
  1. Composed by factor Xa, prothrombin and factor V
    1. Factor V has to be proteolitically cleaved by thrombin or Xa into an active form
Thrombin
1. Roles of thrombin
  1. It promotes fibrin formation
    1. In order for the fibrin to become insoluble the polymers need to become cross-linked by the activity of factor XIIIa
  2. It starts the fibrinolysis
    1. It induces the release form the epithelium of tPA
      1. this leads to activation of plasminogen to plasmin
        Plasmin degrades fibrin into small pieces called D-dimers
      2. Inhibitors of tPA: Plasminogen activator inhibitor (PAI) 1 and 2
        They also inhibit urokinase (another activator of plasminogen)
  3. It promotes platelet aggregation
  4. It promotes inhibition of fibrinolysis
    1. By promoting the release of PAIs and via the action of procarboxypeptidase, which is transformed in active carboxypeptidase by thrombin itself
  5. It also promotes positive feedback on its own production
    1. In fact it transforms factor V and factor VIII in their active form as cofactors of tenase and prothrombinase complexes
  6. It also has roles in inflammation
  7. Anticoagulant properties (it creates aPC and it induces prostacyclin release from the endothelium
2. It doesn't need the presence of a phospholipid surface to work
Three main natural anticoagulant systems
1. Tissue Factor Pathway Inhibitor
  1. TFPI+glycosaminoglycans complex effectively inhibits factor Xa and complexes with it
    1. In turn this complex inhibits the complex of factor VIIa+tissue factor
2. Antithrombin Heparin System
  1. It targets the enzymes of the clotting system
3. Protein C System
  1. It targets factor VIIIa and factor Va
  2. Protein C is a vitamin K dependent protein
  3. Activated protein C (aPC) forms a complex with another vitamin K-dependent protein, protein S, and the protein C+S complex inactivates the activated forms of factor VIII and factor V by proteolysis
    1. A very common mutation of factor V, called factor V Leiden, renders factor V resistant to inactivation by aPC
4. They act on top of endothelial cells (where they can be more effective)

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	Created by LewisLewis over 10 years ago