by mtoom


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What is plasma? How is it obtained?
Blood without cells
  • Fibrinogens not removed
It is obtained using an anti-coagulant, and then spitting out the cells in a centrifuge
What is the serum? What is its relationship to plasma?
Serum is blood with cells, fibrinogens removed
  • Fibrinogens removed as fibrin clot after clotting
It is obtained by allowing blood to clot and then centrifuging out the clot and the cells 

Plasma = Serum + Fibrinogens

S
erum Sucks at clotting
What mechanism ensures retention of blood within the vascular system?

What 3 components does it involve?
Hemostasis
  • Endothelial cells lining the blood vessels
  • Platelets
  • Clotting factors (group of blood proteins)
What are the 3 components of Virchow's Triad of Normal Hemostasis?

Vichow's Triad of Normal Hemostasis
  • 1. Normal vascular endothelium
  • 2. Normal blood flow
  • 3. Correct hemostatic balance (pro/anti-coagulant balanced, fibrinolysis)

Classical version of Virchow's Triad
  • 1. Endothelial injury/dysfunction
  • 2. Hemodynamic changes
  • 3. Hypercoagulable state
Platelets
  • What are platelets formed from?
  • Are they nucleated?
  • What is the half-life?
  • What activates them? 
  • Megakaryocytes
  • Non-nucleated
  • t1/2: 5-9 days
  • Activated by thrombin
What happens with platelets when there is an endothelial injury?
  • Plalets adhere to the site of endothelial injury
  • More platelets aggregate forming a plug
  • Fibrin clot is formed, stabilizing the platelet thrombus
What are the 4 challenges of hemostasis?
  • Blood must remain fluid most of the time
  • Blood clotting must occur rapidly
  • Clot must be formed at site of injury in the flowing blood
  • Clot must be readily dissolved
What does plasmin do?
Plasmin does fibrinolysis, which is the conversion of a fibrin polymer into fibrin degradation products (also known as D-dimers)

Plasmin activates:
Fibrin → d-dimers
What is the diagnostic significance of D-dimer?
It is a marker of thrombosis
Describe the structure, shape and domains of fibrinogen
  • Structure: 6 polypeptides (α2β2γ2)
  • Shape: dumbbell
  • Domains: 3 globular, 3 helices
What does Thrombin cause?
Thrombin activates clotting:
fibrinogenfibrin
Are fibrin monomers soluble?
Yes
What happens to fibrin (2)?
  • 1. fibrin (soluble) → fibrin dimers (solube)
     
  • 2. fibrin dimers (soluble) → fibrin polymer (insoluble)

Note: Both steps occur spontaneously
  • 1. What is the function of Factor XIIIa?
  • 2. What activates Factor XIIIa?
  • 3. What is the specific mechanism of Factor XIIIa?
  • 1. Factor XIIIa forms a stable fibrin clot by cross-linking the fibrin polymer
  • 2. Factor XIIIa is activated by thrombin
  • 3. Factor XIIIa introduces a covalent bond between Lys-Gln to cross-link the clot
What is the biological importance of Vitamin K to clotting?
Vitamin K is required to activate clotting factors (by carboxylation)
What does Vitamin K carboxylate?
Vitamin K carboxylates glutamic acid, changing it into γ-carboxyglutamic acid (Gla)

This essentially activates many clotting factors by carboxylating their Glu residues thereby converting them into Gla
What is important about the glutamic acid residues for clotting?
Activated Gla residues will be bound by Ca2+ ions, allowing many clotting factors to bind to the plasma membrane at the site of injury

The carboyxlated form of Glu (i.e. Gla) is essential for membrane binding
What 4 factors are activated by Vitamin K?
7, 9, 10, Prothrombin
What 3 things are allowed for due to the Ca2+-Gla complexes?
  • Cocentration
  • Orientation
  • Localization
of Clotting Factors
What is Warfarin also known as?
Coumadin
Describe the mechanism and effect of Warfarin
Warfarin impairs the reduction of Vitamin K in the liver, thereby reducing its function

Without Gla residues, the clotting factors cannot bind the phopspholipid membrane on activated platelets
Describe 4 mechanisms by which Clotting is Terminated
  • Dilution in flowing blood
     
  • Trapping of proteases in growing fibrin clot
     
  • Serine protease inhibitors (Serpins) such as antithrombin
     
  • Thrombomodulin, Protein C, Protein S pathway
What does antithrombin do?
It binds to the active site of thrombin and forms an inactive complex

How does heparin work?
Heparin binds antithrombin making it more effective at binding and inactivating thrombin
How does thrombomodulin function?
It literally changes thrombin from being a coagulant to being an anti-coagulant

Due to thrombomodulin, acts as a cofactor for thrombin to activate Protein C
How does Protein C function? What is its effect?
Protein C proteolytically inactivates Va and VIIIa

Protein C
has an anti-coagulation effect
How does Protein S function? What is its effect?
Protein S functions as a co-factor to Protein C

Protein S has an anti-coagulation effect
What does thrombomodulin require to exert its effects? (2)
Protein C, Protein S
Name 4 anticoagulants
  • EDTA, citrate
  • Warfarin
  • Heparin
  • "New" oral anticoagulants
How do EDTA and Citrate work?
They work in the same pathway as Heparin

They strip Ca2+ from proteins, inactivating the Ca2+-Gla complex and this prevents Vitamin K dependent factors from binding phospholipid membranes
What is the primary action of Warfarin?
To inhibit reduction of Vitamin K
What is the primary action of Heparin?
Heparin activates antithrombin (an enzyme inhibitor)
What is Tissue Plasminogen Activator (TPA)?
It is a medication that converts plasminogen (inactive) to plasmin (enzyme)

This has the effect of breaking down clots.  Thus, it is a fibrinolytic
What is the difference between a fibrinolytic and an anti-coagulant and an anti-platelet?
  • Fibrinolytic: Breaks down clot
  • Anti-coagulant: Stops clot from getting bigger but doesn't break it down
  • Anti-platelet: Inhibits platelets so that they are less active in creating a plug that starts a clot
What exactly are d-dimers?
Breakdown products of fibrinolysis
Are d-dimers soluble?
Yes
What is the significance of a positive or negative d-dimer test?
  • Positive: Inconclusive
  • Negative: Rule out a PE
Considering the blood must remain fluid without clotting, how is this challenge met?
Clotting factors are kept in an inactive form unless clotting is required
Considering that blood clotting must occur rapidly, how is this challenge met?
Inactive zymogens (clotting factors) are immediately activated after cleavage of 1-2 peptide bonds
Considering that clotting can only occur at the site of the injury, how is this challenge met? (2)
  • Clotting occurs where tissue factor (TF) is released from damaged tissue
  • Clotting factor complexes assemble on platelet plug membrane
Considering that a clot must be readily dissolved, how is this hemostasis challenge met?
Plasmin cleaves a few bonds and the insoluble fibrin polymer is cleaved into d-dimers (which are soluble)
  • The aPTT test (or PTT test) activates which pathway?
  • It involves incubation with what? 
  • Intrinsic (and common)
  • Incubation of plasma with thromboplastinkaolin
Note: Kaolin artificially starts the intrinsic pathway for the purposes of the PTT test.
How is the intrinsic pathway activated physiologically?
Normally the intrinsic pathway is activated to amplify the effects of the extrinsic pathway, which is activated by vascular injury.

The intrinsic pathway is also activated by exposure to collagen which also occurs in injury.
How is the extrinsic pathway activated physiologically?
The extrinsic pathway is kicked off by tissue factor inside the cells of damaged tissue.

It serves as a "spark" to start clotting whereas the intrinsic pathway serves as "gas" to accelerate the fire.
  • The PT (INR) test activates which pathway?
  • It involves incubation with what?
  • Activates and measures the extrinsic (and common) pathways
  • Involves incubation with thromboplastin and Tissue Factor

Note:
  • INR is the internationally standardized PT test
  • Tissue factor is what starts the extrinsic pathway
What does thromboplastin do?
It activates thrombin to cause clotting
Warfarin does what to the following tests?
  • PT (ie. INR)
  • PTT (ie. aPTT)
Increases both, less effect on PTT
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