Normal Hemostasis

Definitions

• hemostasis = clot formation at sites of vascular injury

• hemorrhage = insufficient hemostasis

• thrombosis = clot formation outside sites of vascular injury

Steps of Normal Hemostasis

1. arteriolar vasoconstriction

2. primary hemostasis

3. secondary hemostasis

4. regulation & fibrinolysis

Arteriolar Vasoconstriction

• myogenic spasm

• neurogenic pain reflex

• local factors (ie endothelin)

• microvasculature: thromboxane A2

Primary Hemostasis = formation of a weak platelet plug; disorders produce petechia, purpura, mucosal bleeding

1. activation

   • most potent incl. thrombin and subendothelial collagen

   • less potent incl. ADP

2. adhesion: damaged endothelium releases vWF → binds

   • subendothelial collagen

   • platelet GP1b (deficiency = Bernard-Soulier syndrome)

3. secretion: many factors are secreted, most importantly incl.

   • dense granules → ADP

   • alpha granules → P-selectin

   • platelets → thromboxane A₂ (TxA₂)

4. aggregation: fibrinogen/fibrin cross-links platelets

   • binds GP2b/3a (deficiency = Glanzmann thrombasthenia)

   • also binds wWF (retracts clot)

5. pro-coagulation

   • activation exposes phospholipid esp. phosphatidylserine

   • coagulation complexes assemble on platelet surface

Secondary Hemostasis = fibrin deposition onto a platelet plug; disorders produce hematomas and hemarthroses

1. intrinsic pathway: 12 → 11 → 9⁸ → 10

   • initiated by any of: collagen, kallikrein, HMWK

   • monitored by PTT (longer pathway, more letters) or anti-F10 level

   • 8 is a cofactor for 9

   • 8 is the only factor produced outside the liver (by endothelium)

2. extrinsic pathway: 7 → 10

   • initiated by tissue factor aka thromboplastin

   • monitored by PT (shorter pathway, less letters) or INR

3. common pathway: 10⁵ → 2 (thrombin) → 1 (fibrin)

   • 5 is a cofactor for 10

   • thrombin has many roles

     1. pro-coagulation (damaged endothelium)

        • activates fibrinogen → fibrin monomers

        • activates 13 → cross-links fibrin monomers

        • positive feedback to 11, 8, 5

     2. platelet activation: via PAR-1

     3. pro-inflammation: via other PARs

     4. anti-coagulation (healthy endothelium)

Regulation & Fibrinolysis

1. regulation: healthy endothelium is the most important hemostatic agent

   • shields subendothelial collagen, tissue factor, vWF

   • produces a variety of anti-platelets and anti-coagulants

     1. thrombomodulin-epithelial protein C receptor (TM-EPCR): binds thrombin → CS → APC → ↓5 and 8

     2. prostacyclin (PGI2) & nitric oxide (NO): antiplatelet effects, regulated by flow

     3. ADPase: degrades platelet activator ADP

     4. heparins: activate anti-thrombin 3 (ATIII) → ↓thrombin, 10, 9, 11, 12

     5. tissue plasminogen activator (t-PA): activates plasmin

     6. tissue factor pathway inhibitor (TFPI): inhibits tissue factor

     7. α₂-antiplasmin & plasmin activator inhibitor (PAI): inhibit t-PA

2. fibrinolysis = degradation of cross-linked fibrin

   • t-PA → plasmin → fibrin degradation products (FDPs) incl. D-dimer