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Cardiopulmonary Renal > Primary And Secondary Fibrosis > Flashcards

Primary And Secondary Fibrosis Flashcards

1
Q

What is hemostasis?

A

A precisely orchestrated process involving platelets, clotting factors, and endothelium that occurs at the site of vascular injury and culminates in the formation of a blood clot, which serves to prevent or limit the extent of bleeding (Arrest of bleeding/ prevention of hemorrhage)

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2
Q

Summarize steps in hemostasis

A
  1. Vascular spasm/ vasoconstriction
  2. Platelet plug formation/ primary hemostasis
  3. Blood coagulation/ secondary hemostasis
  4. Clot stabilization and resorption
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3
Q

Describe vascular spasm

A

-trauma to vessel walls results in smooth muscle contraction

  • Contraction caused by
    • Local myogenic spasm
    • Factors released from injured vessel wall (endothelial, serotonin when endothelial lining is damaged)
    • Nervous reflexes

Vasoconstriction is transient and cannot cause long term cessation of bleeding

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4
Q

Summarize the events of platelet plug formation: primary hemostasis

A
  • Greatly limits loss of blood from site of injury by forming plugs
  • small cuts in blood vessels often sealed by platelet plugs
  • Lab tests: bleeding time and platelet aggregation tests

Stages of platelet plug formation

  • platelet adhesion to the damaged surface
  • platelet activation
  • platelet recruitment and platelet aggregation
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5
Q

What is platelet adhesion?

A

Endothelial injury facilitates platelet adherence and activation (prevented under normal circumstances by negative changes on both platelets and endothelial cells)

Mediated by platelet receptors: GP-la and Gp-lb

The receptors bind to subendothelial matrix e.g. collagen, vWF

Adhesion of platelets to exposed basement membrane at site of injury

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6
Q

What is the role of von Willebrand factor in platelet adhesion

A
  1. Platelet Gpla binds collagen- structural changes like development of pseudopods to promote platelet-platelet interactions
  2. Von Willebrand factors binds to platelet receptor, Glycoprotein lb (Gplb)bresulting in changes in platelet membrane
  3. Binding also exposes GPllb/IIIa for binding of fibrinogen
    - vWF acts as a bridge between platelet glycoprotein (GPib) and collagen fibers ; facilitates platelet adhesion to vessel and aggregation
    - vWF complexes with factor VIII; carries it, stabilizes it and prevents its degradation (role in secondary hemostasis)
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7
Q

vWF deficiency is associated with:

A
  • defect in formation of platelet plug (primary hemostasis)

- defect in coagulation (instability of factor VIII) -defect in secondary hemostasis

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8
Q

What events occur after initial platelet adhesion ?

A

Platelet activation: shape change- this leads to both increased thromboxane A2 and degranulation (dense granule has ADP), Activates platelets, promotes aggregation

In addition, ADP binds to receptor on neighboring platelets
-increases intracellular Ca2+ and decreases intracellular cAMP levels (facilitates platelet aggregation )

Platelet aggregation cannot take place without ADP stimulation

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9
Q

How does increased intracellular Ca2+ stimulate platelet cells to synthesize TXA2?

A

Phospholipid based signal transduction —> membrane phospholipids( Ca2+ activates Phospholipase A which cleaves phospholipids to release Arachadonic acid)

-cyclo-oxygenase (COX)(aspirin inhibits COX)which supplies 2O2 to arachidonic acid to form Prostaglandin G2 (PGG2)

PGG2 forms prostaglandin H2 (PGH2) reacts with Thromboxane synthase) to form Thromboxane A2 (TXA2)

TXA2 induces platelet aggregation by activating other platelets; enhances vasoconstriction

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10
Q

What is the significance of fibrinogen in platelet aggregation?

A

Platelet aggregation is mainly mediated by fibrinogen. Fibrinogen binds to GPIIb/IIIa on adjacent platelets.

GPIIb/IIIa defect: Glanzmann Thrombasthemia

Formation of platelet plug/ primary hemostasis

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11
Q

What are the steps in formation of platelet plug (primary hemostasis)?

A
  1. Subendothelial collagen exposure
  2. Platelet adhesion via GPIa and GPIb (via vWF) to subendothelial collagen
  3. Platelet activation, shape change and degranulation (ADP release)
  4. ADP binds to neighboring platelets to increase intracellular calcium and decrease intracellular cAMP; increased TXA2
  5. Platelets recruited to injury site
  6. Platelet aggregation via fibrinogen and linking adjacent platelets via GPIIb/IIIa
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12
Q

Describe lab tests for platelet plug formation (primary hemostasis)

A

Defects in platelet plug formation result in increased bleeding time and defective platelet aggregation with stimulants

Formation of the platelet plug requires von Willebrand factor, adequate number of platelets, intact Gplb and GpIIb/IIIa platelet receptors.

Defect in any of the following results in increased bleeding time/ defective platelet aggregation

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13
Q

Describe blood coagulation (secondary hemostasis)

A

Conversion of blood from liquid state to a solid, gel like state”

Aim- convert soluble fibrinogen to insoluble fibrin (stabilize the platelet plug) conversion of fibrinogen to fibrin requires thrombin

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14
Q

Summarize how thrombin is formed?

A

Thrombin formation occurs via 2 pathways:

  1. Intrinsic pathways
  2. Extrinsic pathways
  • Cascade of enzymatic reactions that transform proenzymes to their active forms (irreversible proteolytic activation)
  • Most clotting factors present in circulation in an active form
  • Product formed at each step catalyzes the next step
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15
Q

Summarize extrinsic pathway for the activation of factor X

A

PT- prothrombin time
INR- international normalized ratio

Tissue injury —> release of tissue factor (factor III)(1e)

Factor VII activated by tissue factor to VIIa (2e)

Factor VIIa and tissue factor, Ca+ and platelet phospholipids, activate factor X—> 3e—> Xa(active factor X)

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16
Q

How does the intrinsic pathway occur organically?

A

Activation of factor XII(1i)—> activation of factor XI(2i) —> activation of factor IX(3i)—> thrombin activates factor VII—> VIIIa(4i)—> IXa, VIIIa, platelet phospholipids and Ca2+ , activate factor X to Xa(5i)

17
Q

How is the intrinsic pathway done in thee lab?

A

APTT - Activated partial thromboplastin time

Negatively charged surface/glass beads changes factor XII—> factor XIIa(1i)

Factor XIIa converts factor XI to factor XIa(2i)

Factor IX is converted to factor IX by factor XIa(3i)

Factor VIII reacts with thrombin (4i) to form factor VIIIa

Factor VIIIa reacts with factor IXa in the presence of Ca2+ and platelet phospholipids also reacts with factor X To form factors Xa(active active factor X)

18
Q

Describe the common pathway of clotting -formation of thrombin

A

Intrinsic and extrinsic pathways form factor Xa

Factor V (via thrombin and prothrombinase complex, Ca2+, Va, PL, Ca2+ ) to form factor Va

Factor Va + factor Xa and Ca2+ and platelet phospholipids

This converts factor II (Prothrombin) to form factor IIa(thrombin )

Prothrombinasecomplex converts prothrombin to thrombin

19
Q

Summarize the common pathway

A

1c: thrombin activates factor V—> Va
2c: Xa with Va, phospholipids and Ca2+ forms prothrombinase complex
3c: prothrombinase complex converts prothrombin to THROMBIN
4c: thrombin acts on fibrinogen to form fibrin
5c: thrombin activates factor XIII to XIIIa
6c: fibrin monomers are covalently cross linked by factor XIIIa to form cross-linked fibrin (Hard clot)

20
Q

What is the role of thrombin (factor IIa)?

A
  • Critical step in coagulation cascade
  • Thrombin activates Factor VIII and Factor V and further amplifies the coagulation cascade
  • Thrombin also converts fibrinogen (factor I) to fibrin (factor Ia)

Helps in formation of ‘stable thrombus’ by activating factor XIII

  • Thrombin also activates platelets
  • Thrombin also activates the anticoagulant system
21
Q

How does fibrinogen become its soluble form?

A

Fibrinogen (plasma protein) synthesized by liver

4c: thrombin cleaves fibrinogen to form the the fibrin monomer

Fibrin monomers aggregate and linked via hydrogen bonds, forming fibrin polymer (soft clot)

22
Q

What formation of hard clot mediated by?

A

Formation of ‘hard’ clot is mediated by factor XIII activated by thrombin

  • thrombin (factor IIa) activates factor XIII (5c)
  • Factor XIIIa catalyzes formation of covalent links between adjacent fibrin monomers to form ‘hard clot’ , or ‘stable fibrin’ linked by covalent bonds (6c)
23
Q

What are the extrinsic pathway factors?

A

Factor III-Tissue factor

Factor VII

24
Q

What are the intrinsic pathway factors?

A

Factor VIII

FACTOR IX

Factor XI

Factor XII

25
Q

What are the common pathway factors?

A

Factor I- fibrinogen

Factor II- prothrombin

Factor IV-calcium

Factor V

Factor X

Factor XIII

26
Q

What are the key factors of clotting cascade?

A
  • Conversion of fibrinogen to fibrin (4c) and stabilization of fibrin (6c) requires thrombin (IIa)
  • Thrombin formation requires factor Xa (Xa, Va, Ca2+, platelet phospholipids- prothrombinase complex -2c

Xa generated by

  • Extrinsic pathway (1e-3e) through VII and III (activated on injury)
  • Intrinsic pathway(1i-5i)-through XII, XI, IX, and VIII

Laboratory tests for the coagulation cascade:

  • Prothrombin time(INR): extrinsic pathway
  • Activated partial thromboplastin time (aPTT): intrinsic pathway

Cardiopulmonary Renal (35 decks)

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