- Normal coagulation (hemostasis):
- Three initial responses to vascular injury:
- Vasoconstriction:
- Neurohumoral + endothelin
- Platelet adhesion / activation / aggregation:
- Primary hemostasis
- Thrombin generation:
- That leads to fibrin clot formation:
- Secondary hemostasis NCBI+1
- That leads to fibrin clot formation:
- Vasoconstriction:
- Three initial responses to vascular injury:
- Primary hemostasis – what actually happens:
- Adhesion:
- VWF bridges exposed subendothelial collagen to platelet GPIb-IX-V (high shear)
- Collagen also signals via:
- GPVI and α2β1 (GPIa/IIa) NCBI+1
- Activation + secretion:
- Shape change
- Dense granule:
- ADP and TxA₂ amplify recruitment
- Surface phosphatidylserine (PF3) flips out:
- Creating a catalytic platform for coagulation enzymes NCBI
- Aggregation:
- Inside-out signaling activates:
- αIIbβ3 (GPIIb/IIIa)
- Fibrinogen (and later fibrin) bridges adjacent platelets:
- Platelet plug NCBI+1
- Inside-out signaling activates:
- Key receptors to remember:
- ADP → P2Y12 / P2Y1
- TxA₂ → TP
- Thrombin → PAR-1 / PAR-4(and also binds GPIbα) NCBI+2PubMed+2
- Secondary hemostasis – complexes and convergence:
- Tenase complexes:
- Extrinsic:
- Tissue factor (TF) from injured cells – factor VIIa:
- Plus Ca²⁺, membrane:
- Activates factor X
- Plus Ca²⁺, membrane:
- Tissue factor (TF) from injured cells – factor VIIa:
- Intrinsic:
- Exposed collagen + prekallikrein + HMW Kininigen = Factor XII:
- Activate Factor XI:
- Activate factor IXa – then add factor VIIIa:
- Plus Ca²⁺, membrane:
- Powerfully activates factor X (major amplifier)
- Plus Ca²⁺, membrane:
- Activate factor IXa – then add factor VIIIa:
- Activate Factor XI:
- Exposed collagen + prekallikrein + HMW Kininigen = Factor XII:
- Factor X:
- Is the common convergence point NCBI+1
- Prothrombinase complex (correct name for what forms on platelets):
- Factor Xa + factor Va + Ca²⁺ + anionic phospholipid (PF3):
- Converts prothrombin (factor II) to thrombin (factor IIa) NCBI
- Thrombin – central protease (know these):
- Converts fibrinogen → fibrin,
- Thrombin – central protease (know these):
- Converts prothrombin (factor II) to thrombin (factor IIa) NCBI
- Activates factor V, factor VIII, factor XI, factor XIII
- Strongly activates platelets via PAR-1 / PAR-4
- When bound to thrombomodulin:
- Activates protein C (anticoagulant pathway) NCBI+1
- Factor Xa + factor Va + Ca²⁺ + anionic phospholipid (PF3):
- Factor XIII:
- A transglutaminase that crosslinks fibrin and incorporates α2-antiplasmin into the clot:
- Producing stability and resistance to fibrinolysis NCBI
- A transglutaminase that crosslinks fibrin and incorporates α2-antiplasmin into the clot:
- Extrinsic:
- Tenase complexes:
- Adhesion:
- Fibrin’s role with platelets:
- Fibrin(ogen) binds αIIbβ3, linking platelets and stabilizing the plug as fibrin polymerizes and is cross-linked Haematologica
- Normal anticoagulation (checks and balances)
- Antithrombin (AT-III):
- Key serpin that neutralizes:
- Thrombin (IIa), IXa, Xa, XIa, XIIa
- Key serpin that neutralizes:
- Heparin / Heparan sulfate:
- Accelerates AT-III activity dramatically (clinical basis of UFH /LMWH) NCBI+1
- Protein C / Protein S (vitamin K–dependent):
- Thrombin – thrombomodulin on endothelium:
- Activates protein C:
- Which (with protein S cofactor) proteolytically inactivates Va and VIIIa (not fibrinogen)
- Activates protein C:
- Thrombin – thrombomodulin on endothelium:
- TFPI (tissue factor pathway inhibitor):
- Endothelium-derived inhibitor:
- That inactivates factor Xa and, in an factor Xa – dependent manner:
- Shuts down TF – FVIIa:
- The dominant brake on the initiation phase
- Shuts down TF – FVIIa:
- That inactivates factor Xa and, in an factor Xa – dependent manner:
- Protein S enhances TFPIα’s factor Xa inhibition:
- Nuance:
- TFPI does not simply “inhibit factor X”; it inhibits factor Xa and the TF – FVIIa complex NCBI+2ASA Journals+2
- Nuance:
- Endothelium-derived inhibitor:
- Endothelial antithrombotic tone (nice to remember):
- PGI₂, NO, and CD39 (ecto-ADPase) limit platelet activation
- Heparan sulfate potentiates AT
- Antithrombin (AT-III):
- Fibrinolysis (clot removal):
- tPA / uPA (primarily from endothelium) convert plasminogen → plasmin:
- Preferentially on fibrin-rich surfaces
- Plasmin:
- Degrades fibrin and fibrinogen → FDPs (D-dimer reflects cross-linked fibrin breakdown) NCBI+1
- Major inhibitors / regulators:
- PAI-1 (± PAI-2):
- Inhibit tPA / uPA
- α2-antiplasmin:
- Neutralizes plasmin and is cross-linked to fibrin by factor XIII
- TAFI (activated by thrombin – thrombomodulin) trims C-terminal lysines from fibrin, reducing plasminogen / tPA binding and slowing lysis NCBI+2PubMed+2
- PAI-1 (± PAI-2):
- tPA / uPA (primarily from endothelium) convert plasminogen → plasmin:
Rodrigo Arrangoiz MS, MD, FACS, FSSO 