Coagulation Principles

Primary hemostasis:

  • Platelet plug formation

Secondary hemostasis:

  • Clot formation:
    • If too little clotting → hemorrhage
    • If too much clotting → necrosis, thrombosis, emboli

  • Often at the site of inflammatory cells and injured endothelial cells (exposed plasma).
  • Initiation on any cell expressing tissue factor (TF) and exposed to plasma as mentioned above.
  • Tissue factor (TF)-bearing cells activate factor VIIa.
  • TF-factor VIIa complexes then activate prothrombin to thrombin (factor IIa) and also activate IXa and Xa.
  • Thrombin activates platelets, leading to the propagation phase.
  • Factors II, VII, IX, and X are vitamin K-dependent (as well as protein C and S).

  • Activation of platelets via thrombin (factor IIa) results in exposed platelet phospholipids (phosphatidylserine), which are important for localizing procoagulant complexes.

  • Thrombin also activates the following factors, which create an activated platelet surface ready to amplify thrombin generation:

    • Factor V (released from platelet granules) acts as a cofactor for factor Xa and binds to platelet phospholipids.
    • Factor VIIIa (released from von Willebrand factor) acts as a cofactor for factor IXa and binds to platelet phospholipids.
    • Factor XIa increases the activation of IXa and Xa.

  • The activated platelet surface then amplifies thrombin, leading to the catalysis of fibrinogen to fibrin. This process results in clot formation from fibrin monomers.

  • Formed by high-molecular-weight kininogen (HMWK) and prekallikrein (PK) +/- factor XII that bind on endothelial cell membrane complex receptor (cytokeratin 1 – CK1 & urokinase plasminogen activator receptor)
  • Binding causes:
    • Production of bradykinin (vasodilator)
    • Release tissue plasminogen activator = converts plasminogen to plasmin → fibrinolysis

Interesting facts:

  • C1 esterase inhibitor is important in fibrinolysis
  • C1 esterase inhibitor deficiency recurrent angioedema results from low bradykinin (not reduced inhibition of complement)
  • Contact activation is also an important cause of post-surgical hypotension and fibrinolysis

  • Natural anticoagulants crucial to control extension of clot formation.

  • Tissue factor pathway inhibitor (inactivates Xa & VIIa) and antithrombin III (inactivates IIa, IXa, Xa & XIIa):

    • They are bound to heparan sulfate on endothelial cells close to clot formation and released to inhibit activated clotting factors, preventing their dispersion.

  • Thrombomodulin / protein C / protein S system:

    • Thrombin binds to thrombomodulin on endothelial cells, which leads to the discontinuation of activation of procoagulant factors.
    • Thrombin also binds and activates protein C (vitamin K-dependent anticoagulant).
    • Protein C activity is enhanced by phospholipid, HDL, and protein S (vitamin K-dependent anticoagulant).
    • This system works to inactivate Va and VIIIa, contributing to the regulation of clot formation.

  • Platelet count
  • PT / INR (prothrombin time)
  • aPTT (activated partial thromboplastin time)
  • Platelet function tests (bleeding time or ristocetin-induced platelet aggregation studies)

If there is an increase in PT and normal aPTT:

  • Possible causes include VII deficiency or oral anticoagulant use (e.g., warfarin).

If there is an increase in aPTT and normal PT:

  • Possible causes include deficiencies in VIII, IX, XI, or XII, HMWK or PK deficiency, heparin use, lupus anticoagulant presence, acquired VIII inhibitor, or von Willebrand disease.

If there is an increase in both PT and aPTT:

  • Possible causes include deficiencies in II, V, X, or fibrinogen, or the presence of an inhibitor.