Homeostasis

Question 1

describe the overview of homeostasis

Answer 1

• immediately following injury, local factors (ENDOTHELIN) trigger localized vasconstriction (reduces blood flow to injured area)
• Vascular damage exposes components of EXTRACELLULAR MATRIX
  
  • platelets adhere and activate –> forms a hemostatic plug
• exposure of TISSUE FACTOR at site of damage sets in motion the coagulation cascade ultimately resulting in activation of THROMBIN
• Thrombin cleaves soluble FIBRINOGEN to yield insoluble FIBRIN
  
  • fibrin network forms, recruiting additional platelets and stabilizing the clot
• Counterregulatory mechanisms activate, limiting SPREAD of the clot (eventual clot ersorption and tissue repair

Question 2

describe Platelet adhesion and activation

Answer 2

1. Vascular damage exposes Extracellular matrix
   
   1. EXPOSES: von Willebrand factor (vWF) and glycoprotein Ib (GpIb)
   2. Platelets adhesion requires both factors
2. vWF links platelets to collage of the ECM aswell as binding COAGULATION FACTOR referred to as Factor VIII
3. integrin alpha2Beta1 binds COLLAGEN
   
   1. helps platelet adhesion to ECM
4. Specific vWF-GpIb interaction required to withstand HIGH SHEAR FORCES
5. ADHESION TRIGGERS Ca2+ signal –> platelets undergo dramatic shape change
   
   1. Spiny and extend long processes

Question 3

What are the secretory granules that platelets release

Answer 3

• Dense granules
  
  • ADP, ATP, Ca2+, histamine, serotonin, Epinephrine
• Alpha-Granules
  
  • fibrinogen, fibronectin, vWF, coagulation factor V, PDGF

Question 4

role of activted platelets

Answer 4

• platelet activation release free ARACHIDONIC ACID
  
  • converted to prostaglandin G2 by COX
    
    • gives rise in thromboxane A2
• Thromboxane A2, serotonin, epinephrine function as VASOCONSTRICTORS which REDUCE BLOOD LOSS at site of injury

Question 5

describe platelet aggreation

Answer 5

• Clot formation requires aggregation of paltelets
  
  • ADP and thromboxane A2 form feed-forward activation effect (stimulate activation of more platelets)
• ADP triggers change in conformation of GpIIb-GpIIIa receptor in platelet membrane
  
  • allows receptor to bind FIBRINOGEN
• aggregated platelets form an initial plug at the site of vascular injury

Question 6

von Willebrand disease

Answer 6

• Patients with Type I von Willebrand disease display…
  
  • lowered vWF protein, reduced vWG function and reduced factor VIII
• Patients usually identified in childhood
  
  • frequent nosebleeds, excessive bleeding following dental tx, excessive bruising
• Managed with DESMOPRESSIN
  
  • induces release of vWF and factor VIII from storage sites within the endothelium

Question 7

Bernard-Soulier syndrome

Answer 7

• Severe, inherited platelet disorder
  
  • Giant platelets, often thrombocytopenia
• Platelets FAIL TO AGGREGATE in response to stimuli
  
  • defect in interaction between vWF and GpIb
• Therapy aims to REDUCE BLEEDING RISK
• platelet transfusion when bleeding or when bleeding is inevitable

Question 8

Glanzmann Thrombasthenia

Answer 8

• inherited bleeding disorder
  
  • quantitative or qualitative defects in GpIIb and/or GpIIIa
  • platelets FAIL TO AGGREGATE in response to various stimuli
    
    • ADP, collagen, epinephrine
  • prolonged bleeding times
• Therapy aims to REDUCE BLEEDING RISK

Question 9

general coagulation cascade

Answer 9

• provides stability to platelet plug through activation of thrombin
• intrinsic and extrinsic pathways
  
  • intrinsic
    
    • blood clots sponatenously in vitro upon exposure to negatively charge surfaces (glass)
      
      • BASIS OF PATIAL THROMBOPLASTIN TIME TEST
  • Extrinsic
    
    • addition of exogenous material (tissue factor) to blood in vitro triggers clotting
      
      • BASIS OF PROTHROMBIN TIME TEST
• Pathways converge upon activation of Factor X
  
  • factor X activation results in activation of thrombin
    
    • key regulator of coagulation

Question 10

Role of vitamin K

Answer 10

• factors X, IX, VII, II (prothrombin) require vitamin K (1972)
• Function to chelate Ca+
• Warfarin prevents regeneration of vitamin K

–> ultimately blocks productio of gama-carboxyglutamate residues

Question 11

Thrombin

Answer 11

• cleaves fibringoen to form fibrin
• enhances clotting via positive feedback
• induces paltelet aggregation
• activates endothelial cells
  
  • wound healing

Question 12

Key points

Answer 12

• Vascular damage
  
  • assembles tissue factor + VIIa + X –> Factor Xa
• Contact with negatively charged membrane surfaces
  
  • assembles IXa + VIIIa + X –> factor Xa
• Factor Xa
  
  • assembles Xa + Va + prothrombin –> to from Thrombin

Question 13

Hemophilia A and B

Answer 13

• Hemophilia A most common
  
  • Deficiency in Factor VIII production
• Hemophilia B
  
  • deficiency in factor IX production
• Now recominant factor VIII or IX administered

Question 14

Thrombin, protein C and protein S

Answer 14

• THROMBIN both drivs and inhibits COAGULATION
  
  • Thombomodulin presents in endothelial cell membrane
    
    • alters susbtrate specificity of thrombin
    • thrombin/thrombomodulin activates PROTEIN C
    • Active protein C binds PROTEIN S
    • Protein C/S complext DEGRADES FACTOR Va and FACTOR IIIa –> BLOCKS CLOTTING

Question 15

Factor V Leiden

Answer 15

• Replaces arginine at amin acid position 506 with glutamine
  
  • generates FACTOR V RESISTANT TO CLEAVAGE BY PROTEIN C
• Leads to HYPERCOAGULATION state
  
  • increases risk of thrombosis

Question 16

Serpins

Answer 16

• family of Serine protease inhibitors
• INHIBIT the activated forms of coagulation factors
• Best example is antithrombin III (ATIII)
  
  • inhibit thrombin
  • binds Heparin
    
    • ATIII-Heparin complexes also inhibits IXa, Xa, XIa and XIIIa

Question 17

Tissue factor pathway inhibitor (TFPI)

Answer 17

• protein produced by endothelial cells
• function as inhibitor of Factor VIIa
  
  • blocks extrinsic pathway
• also inhibits FACTOR Xa

Question 18

REVEW THE SLIDES