5.2. Hemostasis and the role of thrombocytes. Blood coagulation. Fibrinolysis. Physiological anticoagulant mechanisms. Flashcards

1
Q

I. Hemostasis
1. Definition of hemostasis

A

prevention of bleeding from a damaged vessel (prevention of hemorrhage)

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2
Q

I. Hemostasis
2. What are the stages of hemostasis?

A

PRIMARY HEMOSTASIS
1. Vasoconstriction
2. Increased tissue pressure
3. Formation of a platelet plug

SECONDARY HEMOSTASIS
Coagulation (formation of a blood clot)

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3
Q

I. Hemostasis
3A. What are the mechanism and role of vasoconstriction (primary hemostasis)?

A

1/ Mechanism:
- Upon injury of the blood vessel wall, there is an immediate response called vasoconstriction
- Vasoconstriction will decrease blood flow towards injured area, leading to decrease in blood loss

2/ Role: to give more time for more effective hemostatic processes to take place

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4
Q

I. Hemostasis
3B. What are the causes of vasoconstriction (primary hemostasis)?

A

1/ Neurogenic reflex
2/ Endothelin release
3/ Release of vasoconstrictor substances

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5
Q

I. Hemostasis
3B1. How does neurogenic reflex participate in vasoconstriction (primary hemostasis)?

A

produces vasoconstriction

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6
Q

I. Hemostasis
3B2. How does Endothelin release participate in vasoconstriction (primary hemostasis)?

A
  • Endothelin Binds to to ET-receptor on SMC (smooth muscle cell), leading to vasoconstriction
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7
Q

I. Hemostasis
3B3. What are the vasoconstrictor substances that are released by thrombocytes? Consequences?

A

Chemical released by thrombocytes

  • Thromboxane A2 (TXA2, synthesized by platelets)
    => Ca2+ signal
    => Vasoconstriction
  • Serotonin (synthesized by platelets)
  • Epinephrine (not synthesized, taken up by platelets) => ⍺1 adrenergic receptor acting on smooth muscle contraction
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8
Q

I. Hemostasis
3C. Mechanism and role of Increased tissue pressure?

A

Increased tissue pressure contributes to hemostasis because:
- It decreases radius, which causes significant decrease in blood flow; decrease r by a factor of 2 would diminish flow by a factor of 16 according to - Poiseuille law.
E.g, We do this naturally by pressing a finger against a small cut to stop the bleeding.

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9
Q

I. Hemostasis
3D. What is the role of Platelet plug formation (step 3 in primary hemostasis)?

A

platelets plug small ruptures in the endothelium

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10
Q

I. Hemostasis
3E. What are the stages of Platelet plug formation (step 3 in primary hemostasis)?

A

1/ Adhesion
2/ Activation
3/ Aggregation

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11
Q

I. Hemostasis
3F. What are platelets?

A

platelets are fragments of megakaryocytes

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12
Q

I. Hemostasis
3G. What are characteristics (structure) with corresponding functions of platelets

A

1/ Have a dense tubular system
-> Acts as a Ca2+ storage

2/ Have dense granules containing ADP, serotonin and polyphosphates to activate platelets

3/ Have alpha granules which contain clotting factors

4/ Have actin + myosin for later contraction to reduce the size of the clot

5/ Have adhesion glycoproteins found on their surface
ex: GPIa/IIa, GPVI

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13
Q

I. Hemostasis - Stages of platelet formation
3H1. Why is platelet adhesion necessary? When will platelet adhesion occur?

A

1/ Platelets do not adhere to endothelium directly because platelets have negative surface charge and so do the endothelium (proteoglycans – heparan sulfate).
2/ Platelet adhesion occurs in response to ↑ shear stress at platelet surface or endothelial cells, and in response to vessel injury or humoral signals.

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14
Q

I. Hemostasis - Stages of platelet formation
3H2. What are the steps af platelet adhesion?

A

1/ Platelets first adhere to the injured space via glycoprotein-collagen binding with glycoprotein GP VI and GP Ia – IIa
=> This is a Direct platelet interaction

2/ Endothelial cells also release the von Willebrand factor (vWF) which also binds to exposed collagen and then create an indirect interaction between GP Ib – IX – B

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15
Q

I. Hemostasis - Stages of platelet formation
3I1. How are platelets activated?

A

Binding of GP VI to collagen initiates tyrosine phosphorylation cascade -> Phospholipase C (PLC) activation -> IP3 -> Ca2+-release = platelet is activated
*Note: Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3

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16
Q

I. Hemostasis - Stages of platelet formation
3I2. What are the 5 consequences of increased concentration of intracellular Ca2+?

A
  1. Exocytosis of granules
    → ADP, 5-HT, epinephrine, Ca2+, procoagulant factors, fibrinogen…
    → Positive feedback
  2. Phospholipase A2 (PL2) activation
    → TXA2-production → positive feedback → platelet activation increased
  3. Cytoskeletal rearrangement
    → platelets undergo shape change, increased surface
  4. Exposure of GPIIb-IIIa integrin complex
    → fibrinogen binding, platelet aggregation
  5. Phospholipid externalization
    → coagulation cascade
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17
Q

I. Hemostasis - Stages of platelet formation
3I3. The 5 consequences of increased contraction of intracellular Ca2+
-> What are the consequences of Exocytosis of granules?

A

→ ADP, 5-HT receptors (serotonin receptors), epinephrine, Ca2+, procoagulant factors, fibrinogen…
→ Positive feedback

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18
Q

I. Hemostasis - Stages of platelet formation
3I4. The 5 consequences of increased contraction of intracellular Ca2+
-> What are the consequences of PLA2 activation?

A

→ TXA2-production → positive feedback → platelet activation increased

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19
Q

I. Hemostasis - Stages of platelet formation
3I5. The 5 consequences of increased contraction of intracellular Ca2+
-> What are the consequences of 3. Cytoskeletal rearrangement?

A

→ platelets undergo shape change, increased surface

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20
Q

I. Hemostasis - Stages of platelet formation
3I6. The 5 consequences of increased contraction of intracellular Ca2+
-> What are the consequences of 4. Exposure of GPIIb-IIIa integrin complex?

A

→ fibrinogen binding, platelet aggregation

21
Q

I. Hemostasis - Stages of platelet formation
3I7. The 5 consequences of increased contraction of intracellular Ca2+
-> What are the consequences of 5. Phospholipid externalization?

A

→ coagulation cascade

22
Q

I. Hemostasis - Stages platelet formation – 2. Platelet activation
3j. How is platelet activation inhibited?

A

By synthesis of PGI2 and NO in endothelial cells, it will inhibit the increase of intracellular Ca2+ concentration which subsequently inhibit platelet activation and aggregation
- PGI2 -> PGI2 – R (GS) -> Cause increase in cAMP
- NO -> GC -> Increase in cGMP

*Note:
- Prostaglandin I2 (PGI)

23
Q

I. Hemostasis - Stages of hemostasisPrimary hemostasis – 3. Platelet plug formation
3K. What are the Steps of platelet aggregation?

A

1/ Thrombus initially develops through the stabilization of discoid platelet aggregate

2/ Shedding of microparticles from the platelet plasma membrane (caused by a high shear stress) also contributes to aggregation

3/ ADP + TXA2 released from platelets attract more platelets to the affected area

4/ Exposed GP IIb-IIIa binds to RGD sequence and RGD proteins
- RGD sequence is a tripeptide Arg-Gly-Asp motif in a subunit of fibrinogen
- RGD proteins are vWF, fibrinogen, fibronectin and vitronectin
=> Platelets cross-bind to each other

24
Q

I. Hemostasis - Stages of hemostasisPrimary hemostasis – 4. Blood coagulation a
3L. What are Characteristics of blood coagulation?

A

1/ Occurs primarily because of the conversion of fibrinogen to fibrin (via thrombin)

2/ Thrombin itself must first be activated and have the necessary cofactors to perform this function
- Thrombin activation occurs via intrinsic and extrinsic pathway
- Intrinsic (contact activation) and extrinsic (tissue factor) converge at the activation of factor X

25
Q

I. Hemostasis - Stages of hemostasisPrimary hemostasis – 4. Blood coagulation a
3M. How does Intrinsic pathway work?

A

1/ Intrinsic pathway: activated by factors that are found within blood.
2/ Factors XII gets activated = XIIa -> XIIa converts factor XI to factor XIa -> XIa activates factor IX to factor IXa
-> IXa forms the “intrinsic tenase complex” with VIIIa, phosphotidylserine (PS) and Ca2+ = (Ixa – VIIIa – PS – Ca2+)
-> Intrinsic tenase converts factor X to factor Xa
-> Factor Xa is generated on the platelet surface

26
Q

I. Hemostasis - Stages of hemostasisPrimary hemostasis – 4. Blood coagulation a
3N. How does Extrinsic pathway work?

A

1/ Extrinsic pathway: activated by tissue factor found outside of the blood (VSM)

2/ With injury to a blood vessel, the factor VIIa is exposed to tissue factor -> form a complex together with Ca2+ called the ‘’extrinsic tenase complex’’ (TF-VIIa-Ca2+)

3/ Extrinsic tenase complex activates factor X -> factor Xa (common pathway) and factor IX -> factor IXa (intrinsic pathway)
-> Factor Xa is generated by extrinsic tenase complex on the surface of fibroblasts

27
Q

I. Hemostasis - Stages of hemostasisPrimary hemostasis – 4. Blood coagulation a
3L. How does Final common pathway work?

A

1/ Factor Xa (gotten from both intrinsic + extrinsic pathway) forms a complex with factor Va, that is called ‘’prothrombinase complex’’

2/ Prothrombinase complex is used to activate prothrombin (II) into thrombin (IIa)
-> Thrombin cleaves fibrinogen to fibrin (fibrin mesh network)

28
Q

I. Hemostasis - Stages of hemostasisPrimary hemostasis – 4. Blood coagulation
3O. What are the 4 4 pro-coagulative effects by thrombin (IIa)?

A

1/ Activate platelets directly via PAR-2
2/ Catalyze the proteolysis of fibrinogen (I) into fibrin (Ia).
3/ Activate factor XIII (stabilizing factor) for cross links
4/ Activate factor V, VIII (positive feedback)

29
Q

I. Hemostasis - Stages of hemostasisPrimary hemostasis – 4. Blood coagulation a
3P. Compare Extrinsic vs Intrinsic pathway

A

1/ Extrinsic
- Starts early
- Explosive (within seconds)

2/ Intrinsic
- Starts later
- Slower (within minutes)
- Accelerates fibrin formation
- Stabilizes the blood clot

30
Q

I. Hemostasis - Stages of hemostasis - Secondary hemostasis – 4. Blood coagulation
3Q1. What is the structure of Gla proteins?

A

A complex consist of
- Procoagulants: prothrombin, factor VII, IX, X
- Anticoagulants: protein C & S

31
Q

I. Hemostasis - Stages of hemostasis - Secondary hemostasis – 4. Blood coagulation
3Q2. What does the synthesis of Gla proteins require?

A

1/ Requires vitamin K
2/ Occur in liver

32
Q

I. Hemostasis - Stages of hemostasis - Secondary hemostasis – 4. Blood coagulation
3R. How does Vitamin K-dependent carboxylation occur?

A

1/ γ-glutamyl carboxylase uses a vitamin K cofactor to convert glutamic acid into γ-carboxyglutamic acid, Gla (by adding carboxylic acid).

2/ In the process of serving as a cofactor (donate ē), vitamin K is converted to vitamin K epoxide. Vitamin K epoxide gets converted back into vitamin K quinone by epoxide reductase = reusable!

33
Q

I. Hemostasis - Stages of hemostasis - Secondary hemostasis – 4. Blood coagulation
3S. Importance of vitamin K in blood coagulation?

A

1/ Gla structure allows Ca++ to bind, which induces factor II, VII, IX, X to activate.

2/ Warfarin inhibits epoxide reductase, blocking vitamin K from getting recycled = coagulation cascade would not work properly.

34
Q

I. Hemostasis - Stages of hemostasis - Secondary hemostasis – 4. Blood coagulation
3T. What are the Steps of fibrin formation?

A

1/ The formation of fibrin takes place when thrombin converts fibrinogen dimers to fibrin monomers

2/ To stabilize the fibrin mesh network, factor XIIIa (transglutaminase) (activated by thrombin) converts the fibrin monomers to a network of fibrin polymers
=> The fibrin network is then insoluble and much more difficult to break
=> When plenty of thrombin is available, a dense fibrin network is formed and traps blood cells and plasma, preventing further bleeding

35
Q

II. Anticoagulation mechanisms
1. What are the factors involved in anticoagulation?

A

1/ Paracrine factors
2/ Anticoagulant factors – inhibition of the clotting cascade
- Tissue factor pathway inhibitor
- Antithrombin
- Thrombomodulin
- Protein C and S
3/ Clearance of activated clotting factors

36
Q

II. Anticoagulation mechanisms
1A. How are paracrine factors involved in anticoagulation?

A

Endothelial cells generate prostacyclin, which promotes vasodilation and inhibits platelet activation. They also generate NO (stimulated by thrombin), which inhibits platelet adhesion and aggregation through cGMP.

37
Q

II. Anticoagulation mechanisms
1B. How are Tissue factor pathway inhibitor (TFPI) and Antithrombin involved in anticoagulation?

A

1/ Tissue factor pathway inhibitor (TFPI)
=> Glycosylphosphatidylinositol (GPI) – anchored to endothelial cell membrane inhibits VIIa

2/ Antithrombin III binds and inhibits thrombin & Xa
=> Heparins (mast cells, basophils) & Heparin-sulfate (endothelial surface) promotes this, inhibiting coagulation

38
Q

II. Anticoagulation mechanisms
1C. How is Thrombomodulin involved in anticoagulation?

A

Thrombomodulin is the Glycosaminoglycan on endothelial cells
-> Binds and removes thrombin from circulation
-> Binds to protein C

39
Q

II. Anticoagulation mechanisms
1D. How is protein C involved in anticoagulation?

A

Protein C binds to thrombin-thrombomodulin complex
-> Activated by thrombin
-> Protein C inactivates Va & VIIa

40
Q

II. Anticoagulation mechanisms
1E. How is protein S involved in anticoagulation?

A

Protein S is a cofactor of protein C

41
Q

III. Procoagulant effects of thrombin
1. What are the 4 Procoagulant effects of thrombin?

A

1/ Activation of platelets (through PAR-1)
2/ Activation of downstream components in the clotting cascade
3/ Positive feedback at several upstream levels of the cascade
4/ Inhibition of early fibrinolysis

42
Q

III. Procoagulant effects of thrombin
1A. What are consequences of Activation of downstream components in the clotting cascade?

A

catalyze the proteolysis of fibrinogen
-> activates XIII factor

43
Q

III. Procoagulant effects of thrombin
1B. What are consequences of Positive feedback at several upstream levels of the cascade?

A
  • catalyze the proteolysis of prothrombin
    -> catalyze the activation of XI factor
    -> catalyze the formation of the cofactors Va and VIIIa
44
Q

III. Procoagulant effects of thrombin
1C. What are consequences of Inhibition of early fibrinolysis?

A

high local concentration → activation of fibrinolysis-inhibitor

45
Q

IV. What are Anticoagulant effect(s) of thrombin?

A

Activation of Protein C (through thrombomodulin)

46
Q

V. Fibrinolysis
1. What are definition and role of Fibrinolysis?

A

1/ Definition: Breakdown of blood clot

2/ Role
- Prevents accumulatio of non-aquedate blood clot
- Removes already unnecessary blood clot

47
Q

V. Fibrinolysis
2. What is the mechanism of Fibrinolysis?

A

1/ When a clot is formed, a large amount of plasminogen is trapped in the clot along with other plasma protein
2/ The injured tissues and vascular endothelium slowly release t-PA and u-PA , which coverts plasminogen to plasmin a Ser protease)
3/ Plasmin causes degradation of fibrin

48
Q

V. Fibrinolysis
3. How is fibrinolysis inhibited?

A

1/ Process: synthesis of plasminogen activator inhibitor such as ⍺2-antiplasmin and ⍺2-macroglobulin
- Function: restriction of fibrinolysis

2/ TAFI (thrombin-activatable fibrinolysis inhibitor)
- Function: inhibit the conversion of plasminogen into plasmin

49
Q

VI. What are some anticoagulants medications?

A

1/ vitamin K antagonists (e.g, warfarin) which inhibit FIX, FX, FII, FVII
2/ Direct thrombin inhibitors (e.g, dabigatran) which inhibit FIIa
3/ Anticoagulant outside the body
- Heparin
- Ca2+ chelators