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Hematology 2 > Lecture 21 Fibrinolytic System and Inhibitors > Flashcards

Lecture 21 Fibrinolytic System and Inhibitors Flashcards

1
Q

What are the 2 components to the fibrinolytic system?

A
  1. Lyse unwanted clots
  2. Maintain hemostatic balance through inhibition of fibrinolysis
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2
Q

What is the role of plasminogen?

A

Circulating plasma plasminogen is converted to plasmin on the surface of the clot to slowly dissolve the clot.

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3
Q

How is plasminogen kept in check?

A

Any free circulating Plasmin is neutralized by plasmin inhibitors that would otherwise break down fibrinogen and Factors V and VIII which could lead to bleeding

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4
Q

Describe the Fibrinolytic System?

A
  1. Tissue Plasminogen Activator (TPA) is released from endothelial cell during blood vessel injury.
  2. Thrombin bound to thrombomodulin also stimulates release of vascular TPA from endothelial cells.
  3. TPA converts plasma plasminogen to active enzyme Plasmin which breaks down fibrin
  4. Factor XII, XIIa fragments and Kallikrein will lead to conversion of plasminogen to plasmin.

See slide 5 for diagram.

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5
Q

What is plasmin’s effect on Fibrinogen?

A

Plasmin’s effect on Fibrinogen producing Fibrinogen Degradation Products D and E and on cross-linked Fibrin producing D-Dimers.

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6
Q

What does the D-Dimer test indicate?

A

The D-Dimer test in very important in a clinical setting as it proves the presence of stable cross-linked fibrin which can pose very serious health problems for the patient.

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7
Q

What are the three main pathways by which the Fibrinolytic system is activated?

A

1) Extrinsic Activation:
This includes endogenous activations of fibrinolytic system by in-vivo tissues and organs
2) Intrinsic Activation:
This includes the role of the Intrinsic system of coagulation in promoting fibrinolysis
3) Exogenous Activation:
This includes external and therapeutic activation of the fibrinolytic system to treat thrombotic conditions

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8
Q

What pathway provides tissue activators (TPA) and provides the majority of activation for Plasminogen to Plasmin?

A

Extrinsic Activation:
Provides the majority of activation for Plasminogen to Plasmin. Activation from this system includes tissue activators (TPA) from vascular endothelium, organs such as heart, muscle, prostate and uterus. Body fluids also supply activators that keep secretory and urinary passages functioning properly.

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9
Q

Where is Tissue Plasminogen Activator synthesized? How important is this source? What else makes TPA?

A

Primary source of extrinsic activation comes from vascular endothelium which synthesizes vascular Tissue Plasminogen Activator (TPA) and kidney endothelial cell Urokinase.

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10
Q

What factors in the Intrinsic System play a role converting Plasminogen to Plasmin?

A

Intrinsic System of coagulation Factors XIIa, HMWK and Kallikrein play a role in converting Plasminogen to Plasmin

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11
Q

Name the 3 most commonly used exogenous activators used by Doctors to treat abnormal thrombus formations (clots)?

A

The 3 most commonly used are:
1.) Urokinase
2.) Streptokinase
3.) Tissue Plasminogen Activator

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12
Q

What is the purpose of Urokinase in Fibrinolysis?

A

Produced by endothelial cells in the kidney where is dissolves clots formed in the renal tubules

Plays a minimal role in in vivo fibrinolysis compared to TPA

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13
Q

How can Urokinase be produced for therapeutic use? What are two negatives for this product?

A

Can be produced by kidney cell cultures and isolated for therapeutic use
- Expensive
- Lower affinity to fibrin than TPA

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14
Q

What does the Exogenous Activators - Streptokinase do?

A

Is a product of beta-hemolytic Streptococci

Forms a complex with plasminogen exposing plasminogen’s active sites
Complex can convert plasminogen to plasmin.

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15
Q

What is the disadvantage of Streptokinase?

A

Bacterial proteins that body can produce antibodies that would inhibit its function.

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16
Q

How does the doctor deal with Streptokinase resistance?

A
  1. Test for Streptase Resistance
  2. If resistance ↑dose
  3. Repeat administration should be 6-10 months apart
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17
Q

What are the advantages of TPA over Urokinase and Streptokinase?

A
  1. Action of TPA said to be clot bound (confined locally to fibrin) therefore minimal depletion of fibrinogen and clotting factors V and VIII resulting in less chance of bleeding. Urokinase and Streptokinase cause plasminogen activation to plasmin in the general circulation increasing chances of bleeding. (re: degradation of factors I,V and VIII by plasmin)
  2. TPA’s other advantage is that it is non-immunogenic and does not suffer from the antibody inhibitory effect experienced by Streptokinase.
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18
Q

What are 6 control and inhibitory substances of the Fibrinolytic System?

A
  1. Thombin-Activatable Fibrinolysis Inhibitor (TAFI)
  2. Plasminogen Activator Inhibitor
  3. Alpha 2 Antiplasmin
  4. Alpha 2 Macroglobulin
  5. Alpha 1 Antitrypsin
  6. Anti-Thrombin

Note: Some of these inhibitors function in both coagulation and fibrinolysis* A defect in these substances can lead to greater degree of fibrinolysis and make the patient prone to bleeding.

19
Q

What are the 4 Fibrinolytic System Inhibitors?

A
  1. Antiplasmins (3 of them)
  2. Thrombin-Activatable Fibrinolysis Inhibitor (TAFI)
  3. Plasminogen Activator Inhibitor (PAI)
  4. Antithrombin
20
Q

Describe the 3 antiplasmins and what do they do?

A
  1. α2-antiplasmin
    Principle inhibitor of fibrinolysis
    1:1 binding with plasmin resulting neutralization
  2. α2-macroglobulin
    Inhibits plasmin after α2-antiplasmin depletion
  3. α1-antitrypsin
    Least significant inhibitor of plasmin
    Only binds when the other two are saturated

These are the three antiplasmins that neutralize freely circulating plasmin that could otherwise cause bleeding.

21
Q

What fibrinolytic inhibitor is activated by the same complex that activates protein C?

A

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI)
1. TAFI is a plasma procarboxypeptidase activated by thrombin:thrombomodulin complex, same complex that activates protein C
2. Two functions are independent
Inhibits fibrinolysis by binding lysine residues on fibrin, preventing binding of plasminogen and TPA

22
Q

What is plasminogen activator inhibitor (PAI)?

A

Plasminogen Activator Inhibitor (PAI)
Inhibits Tissue Plasminogen Activator (TPA) and Urokinase

23
Q

Where in the body is plasminogen activator inhibitor released from and why?

A

Released by endothelium and platelets in response to thrombin formation

24
Q

What does deficiency of plasminogen activator inhibitor (PAI) cause and why?

A

Deficiency causes hemorrhagic disorder due to increased fibrinolysis

25
Q

What chemical in the body inhibits both the coagulation system and fibrinolytic system?

A

Antithrombin plays in inhibiting the coagulation system. It also inhibits the Fibrinolytic System providing a balance to both mechanisms.

26
Q

What are 8 control and inhibitory substances of the Coagulation system?

A
  1. Anti-thrombin
  2. Heparin Cofactor II
  3. Alpha 2 Macroglobulin
  4. Alpha 1 Antitrypsin
  5. C1 Inactivator
  6. Protein C and
  7. Protein S
  8. Tissue Factor Pathway Inhibitor (TFPI)
27
Q

What is anti-thrombin also known as, where is it produced and what is its half life?

A
  1. Known as heparin co-factor is the Most important coagulation inhibitor.
  2. Synthesized in the liver with a half life of 2.7 days.
28
Q

What does anti-thrombin inhibit?

A
  1. Inhibits thrombin, FIX, FX, FXI and FXII. AT acts by forming complexes with factors thereby neutralizing them.
  2. AT also has inhibitory effect on plasmin and kallikrein and thus plays a vital role in monitoring the coagulation, fibrinolytic, kallikrein-kinin and complement system

See slide 23 for effect of Antithrombin on a multitude of coagulation systems.

29
Q

How does heparin sulfate from the body and commercial heparin enhance anti-thrombin activity?

A

In Vivo heparin sulfate (from surface endothelial cell and platelets) and commercial heparin enhance AT activity by causing a conformational change in AT allowing its reactive sites to become more accessible increasing its effectiveness by several thousand times !!!

30
Q

What can be the result of anti-thrombin deficiency?

A

Cases of AT deficiency can cause severe, even fatal thrombotic events.

31
Q

What conditions can result in severe anti-thrombin deficiency?

A
  1. Hereditary deficiencies (both quantitative and qualitative)
  2. Disseminated Intravascular Coagulation (DIC),
  3. Liver disease,
  4. Nephrotic syndrome and
  5. Heparin treatment over several days
32
Q

What other inhibitor works similarly to anti-thrombin? How is it different?

A

Heparin Co-Factor II
1. Plasma antiprotease that inhibits coagulation in a mechanism similar to AT.
2. Primarily an inhibitor of thrombin but with less affinity for thrombin and reacts more slowly the AT.
3. Much less affinity for heparin than AT therefore minimal role in heparin therapy.

33
Q

What increases Heparin Co-Factor II affects?

A

Dermatan Sulfate (mucopolysaccharide from vessel wall surface) greatly increased its inhibitory effect.

34
Q

What is the outcome of a deficiency of Heparin Co-Factor II?

A

Hereditary deficiencies reported : Does not always cause thrombosis.

35
Q

What coagulation inhibitor inhibits thrombin and kallekrein? What kind of molecule is it?

A

Alpha 2 Macroglobulin
Large glycoprotein works through inhibition of Thrombin and Kallekrein
Inhibits thrombin much slower rate than AT

36
Q

How does alpha 2 macroglobulin work?

A
  1. Physically traps target enzymes but allows the enzyme active sites to remain intact allowing small amount of target zymogen to be activated.
  2. Two known deficient families asymptomatic.
37
Q

What does alpha 1 antitrypsin inhibit?

A

Alpha 1 Antitrypsin : an alpha globulin that is a potent inhibitor of Factor XIa. It is a weak inhibitor of trypsin (a Factor XII activator) and may inactivate thrombin at a weak rate.
– Hereditary deficiencies have not been associated with thrombosis.

38
Q

What is the main inactivator of the contact system factor X11a and X1a? What does it also inhibit?

A

C1 Inactivator: is the main inactivator of the contact system factors XIIa, and XIa and also an inhibitor of Kallekrein.
–Accounts for 95% of Factor XIIa inhibition and 50% of Kallekrein’s inhibition.

39
Q

What does protein C complexed with Protein S inhibit?

A

Protein C complexed with Protein S is a potent inhibitor of Factors Va, VIIIa

40
Q

What is the mode of action of protein C and S?

A

Mode of Action:
1. At the site of injury, Thombin binds to endothelial cell receptor; thrombomodulin. 2. This allows Thrombin to cleave Protein C to form Activated Protein C.
3. Protein S binds to the complex allowing activated Protein C to proteolytically degrade Factors V and VIII.

41
Q

What is types of disorders result from protein C or S deficiencies?

A

Deficiency of either Protein C or S results in serious thrombotic disorders.

42
Q

What kind of molecule is Tissue Factor Pathway Inhibitor (TFPI) and where is it synthesized?

A

Single polypeptide chain protein synthesized by endothelial cells.

43
Q

What coagulation factor inhibits Xa and Tissue Factor and how?

A

Tissue Factor Pathway Inhibitor (TFPI) inhibits coagulation by forming a complex with Factor Xa to form TFPI:Xa that inhibits both factors Xa and the tissue factor complex (TF:VIIa).

Hematology 2 (23 decks)

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