Week 1 hemostasis

Question 1

Describe the coagulation factor pathway in response to injury . Refer to the initiation, amplification, and propagation

Answer 1

1. Initiation of coagulation
   * Takes place when plasma comes into contact with cells outside the endothelial(subendothelial ) bearing TF
   * FVII bind to TF > FVIIa
   * FVII activates FX> FXa and FIX to FXa
   * The complex FVII, TF, and FXa activated FII> FIIa (produces little thrombin)
   * The complex FVII, TF, and FXa is quickly inhibited by Tissue Factor Pathway Inhibitor.

*IXa, FVII, and ca2+ forms a complex on the cell surface to FX into FXa (FVIII is activated by thrombin)
* FIIa activates fibrinogen > fibrin which is stabilized by FXIIIa
*Thrombin function in initiation phase :
Activates FI

2. Amplification ( takes place on platelet surface )
   *Thrombin activates FXI > FXIa
   *FXIa activates FIX > FIXa
   *FIXa , Ca2+ and FVIII activates FX > FXa
   *FXa activates FII into FIIa
   # The activated platelet has a fliped flopped membrane to support the prothrombinase complex and the tenase complex

Thrombin function in the Amplification phase :

• activates FV and FVIII, FXI
• Activates platelets

1.Propagation phase
*This phase includes the formation of the bulk of the fibrin clot through the thrombin burst
*Fibrin is generated at a fast enough pace because a number of inhibitors are activated as soon as coagulation begins therefore fibrin generation must exceed the inhibitor generation rate
*

Question 2

Describe and explain the platelet response and its mechanism in response to hemostasis

Answer 2

1. Platelet adhesion
   * Activated by thrombin following vessel damage
   * Binding of the platelet by means of the GP1b-IXV / vWF interaction to subendothelial tissue results in formation of a layer over this surface .
2. Platelets granule release
   * Platelets undergo a cytoskeleton activation and initaite intracellular signaling to initiate granule ( alpha and dense granules )
3. Aggregration
   * GP IIb /IIIa binds fibrinogenfor platelet to platelet aggregration
4. Procoagulation surface
   * Flipped - Flopped from neutral to negatively charged to allow Ca2+ to anchor the coagulation factors

Question 3

Factors that can cause platelets activation

Answer 3

Thrombin ,collagen ,Epi ,ADP and Thromboxane A2 ( released by activated platelets to activate more platelets

Question 4

List the types of platelet granules and what they contain

Answer 4

Alpha granules ( released for platelet aggregation and thrombin generation )

• Factor XIII
• PAF
• vWF
• Fibrinogen

Dense granules ( Secondary to platelet plug)

• Ca2+
• ATp
• Serotonin

Question 5

List the thrombin function

Answer 5

*Activates FV and FVIII
*Activates FXI
*Activates platelets
*Activates fibrinogen
*Activates TAFI
*Activates more thrombin
*Activates FXIII
*

Question 6

How does the endothelium limit the clot growth

Answer 6

• Prostacyclin is synthesized by the endothelium and it is a vasodilator and has antiplatelet effects
• ADP degradation
• NO is a platelet inhibitor and vasodilator
• Secretes TFPI
• tPA
• Thrombomodulin
• Heparin

Question 7

Natural inhibitors

Answer 7

*TFPI
*Antithrombin synthesized in the liver and inactivates FXa ,FIXa and FXIa in the presence of heparine > antithrombin-thrombin complex is degraded in the liver
*Protein C and co factor Protein S degrade FVa and FVIIIa
When thrombin binds with thrombin modulator it is converted into Protein C activating enzyme
*Prostacyclin ( PGI2)
*NO
*tPa
*ADP degradation

Question 8

Discuss the contact factor pathway

Answer 8

• FXII is activated into FXIIa when it comes into contact with repeating units like glass surface, bacterial cell wall, nucleic acid, etc.
• FXIIa activates prekallikrein > kallikrein which can activate more FXII which can activate FIX
• Kallikrein also acts on molecular weight kininogen resulting in the production of bradykinin which binds on endothelial cells to induce inflammation

People who lack FXII do not bleed

Question 9

Discuss fibrinolysis, its activators, and inhibitors

Answer 9

• Fibrinolysis is dependent on the conversion of inactive plasminogen > plasmin > increase in D dimer levels.
• Plasminogen is synthesized in the liver and can be activated endogenously and exogenously.

1. Endogenous Activators
   * tPa: Largely responsible for initiating intravascular fibrinolysis. Present vascular endothelium and released due to stimuli : thrombin ,adrenaline and strenuous exercise
   * Urokinase: Present in urine, synthesized by GIT and renal tubules and collecting ducts .Largely responsible for fibrinolysis in the extravascular compartment
2. Exogenous Activators
3. Streptokinase: Derived from group C beta-hemolytic streptococci and can be used in the life-threatening thrombotic state, it also downregulates fibrinogen synthesis
4. Recombinant TPA: non-immunogenic and has localised activity
5. Inhibitors of fibrinolysis
6. alpha-2-antiplasmin: Secreted by the liver and found in the platelets, can be cross-linked into clot by FXIIIand can make thrombin resistant to plasmin by competing and binding with plasmin

2.PIA-1: inhibits tPa and it is synthesized by endo cells and platelets . Deficiency can = in excessive bleeding

3. PAI-2: Synthesised by WBC and placenta and levels increase during pregnancy
4. Thrombin -activatable fibrinolysis inhibitor: Thrombin in the presence of thrombin modulator activates TAFI which inhibits fibrinolysis