T3 L4: Haemostasis

• What are the functions of the endothelium?

  • Control blood fluidity and flow
  • Signals inflammatory cells to areas needing defence / repair
  • Gate-keeper between blood and tissues (control extravasation)
• What is von Willebrand factor?

  a blood protein that is an important trigger for many aspects of clotting

  secreted by endothelium when injured
• What does the endothelium do regarding haemostasis when healthy?

  secretes inhibitors of haemostasis to prevent blood clots
• What is the opposite of haemostasis?

  haemorrhage
• What are the 3 platelet-based pathways to repair blood vessels via haemostasis?

  1. Forming primary haemostatic plug: adhesion, activation, aggregation
  2. Meshwork on clot via coagulation: enzyme cascade
  3. Slow blood flow via vasoconstriction: secrete serotonin, ADP, thromboxane A2
• What is Virchow's Triad?

  3 factors that are critically important in development of venous thrombosis:

  1. Hypercoagulability
  2. Endothelial damage
  3. Stasis of blood flow

  pregnancy and obesity activate all three.
• How are platelets (thrombocytes) formed via haematopoiesis?

  myeloid linkage

  megakaryocytes in bone marrow produce platelets

  
• What is thrombocytopaenia?

  low platelet count in blood
• What is platelet activation?

  events in the platelet that occur when a platelet is stimulated to create a clot. Includes:

  • secrete dense granules: vasoconstrictors, coagulation factors
  • change shape
  • increase respiratory rate (as all above requires energy)

  Platelet Phospholipid - a necessary component of several steps in the coagulation cascade

  
• What is Prasugrel?

  platelet inhibitor

  used for reduction of thrombotic CVS events
• What is the very BASIC mechanism of how a clot is made?

  extrinsic pathway OR intrinsic pathway → common pathway → clot
• How can thrombosis occur spontaneously?

  where blood flow is slow

  eg Atrial fibrillation → thrombosis → travel via BVs (embolism)→ stroke
• What is the difference between plasma and serum?

  Plasma: fluid portion of blood

  Serum: fluid left after clotting
• How do labs stop clotting of blood?

  use citrate / heparin
• What are the two coagulation cascades?

  Extrinsic (Tissue factor) Pathway

  • requires secretion of tissue factor
  • initiation of coagulation

  Intrinsic (Contact Activation) Pathway

  • all factors / proenzymes already in place
  • amplification of process through positive feedback
• How is thrombin activated?

  Factor 10a + Factor 5a

  three pathways:

  1. Extrinsic 10ase
  2. Intrinsic 10ase
  3. Thrombin (positive feedback)
• What is the difference between Extrinsic Xase and Intrinsic Xase?

  Extrinsic Xase: Tissue factor + Factor 7a

  Intrinsic Xase: Factor 8a + Factor 9a
• What are Factor X, Factor Xa and Xase?

  Factor X: Factor 10

  Factor Xa: Activated Factor 10

  Xase: enzyme that converts X → Xa
• How does the intrinsic pathway go?

  1. Inactive F8
  2. thrombin
  3. F8a
  4. F9a
  5. Intrinsic 10ase
  6. Inactive F10
  7. F10a
  8. F5a
  9. prothrombin
  10. thrombin

  
• What are the 2 groups of coagulation factors?

  Prothrombin group: 2, 7, 9, 10

  Thrombin group: 1, 5, 8
• What are the Prothrombin group coagulation factors and what are their properties?

  Factors 2, 7, 9, 10

  Enzymes

  Vitamin K needed for synthesis

  Require Ca2+ activation

  Stable
• What are the Thrombin group coagulation factors and what are their properties?

  Factors 1, 5, 8

  Activated by thrombin

  5 and 8 are co-factors

  1 is fibrinogen

  increased in: inflammation, pregnancy, oral contraceptives
• What is the other name for thrombin?

  Factor 2a
• Coagulation is based on a positive feedback loop, where thrombin activates upstream clotting factors.
• Where are clotting factors made in the body?

  liver
• What is the significance of Vitamin K?

  class of related fat soluble vitamins

  essential for gamma carboxylation of clotting enzymes

  required to synthesise enzyme coagulation factors:

  2, 7, 9, 10
• What can too much fibrinolysis / inhibition of coagulation result in?

  BV accumulating damage

  haemorrhage
• What is Plasmin?

  Enzyme that lyses fibrin (destroys clots)

  starts as inactive plasminogen (made by liver)

  requires tissue Plasminogen Activator (tPA) to mature

  *tPA on the surface of endothelial cells
• What is Protein C?

  Anticoagulant

  (Starts as inactive made my liver; Activated on surface of endothelium)

  Inactivates F5a and F8a

  works with Protein S to inactivate
• What is Antithrombin III?

  peptide (by liver)

  blocks activity of thrombin, 9a, 10a

  HEPARIN - massively increases ATIII activity
• What can Antithrombin 3 deficiency increase the risk of?

  thrombotic disease
• What is Vitamin K deficiency?

  pathology

  Vitamin K required for synthesis of prothrombin coagulation factors

  result in clotting insufficiency

  rare as made by gut microbiome

  caused by: GI disease / no fat absorption

  Warfarin - prevents recycling of vitamin K; depletes after a few days
• What is Haemophilia A?

  clotting disorder

  congenital lack of F8

  X linked - only males have symptoms

  treatment: purified F8 (expensive, rare)

  Haemophilia B: F9
• Inflammation and haemostasis have synergistic effects on each other.
• When endothelium is lost, what underneath is exposed and stimulates coagulation?

  collagen
• What are the types of pharmacological control of blood clotting?

  Anti-platelet agents: block platelet action (arterial disease)

  Anti-coagulants: block coagulation factors (venous disease)

  Fibrinolytics: anti-thrombotics (clot-busting)
• What are Anti-platelet agents?

  prevent clotting in arteries

  example:

  • Aspirin
  • ADP receptor inhibitors: Prasugrel
• What are Anti-coagulants?

  prevent clotting in veins

  Examples:

  Heparins: inhibit F10a

  Novel Oral Anti-Coagulants (NOACs): Rivaroxaban (F10a)

  Warfarin: Vitamin K antagonist
• What are Fibrinolytics?

  aka thrombolytic drugs

  Clot-busting medications

  Example:

  • Tissue plasminogen activator (tPA)
  • Streptokinase