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MBCHB3: Blood, Immunity and Infection > Lecture 12: Physiology of coagulation > Flashcards

Lecture 12: Physiology of coagulation Flashcards

1
Q

What is coagulation a balance between?

A

Pro-coagulants + Platelets + clotting factors (Excess causes thrombosis)

vs

Anti-coagulants, inhibitors of thrombosis (excess causes bleeding)

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2
Q

What things come to mind in the case of the child with easy bruising?

A
  • Excessive bleeding
  • Lacking one or more of coagulation factors
  • Lacking or impaired platelets

Unlikely to be too many inhibitors i.e medicines

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3
Q

What is physiological heamostasis?

A

Physiological heamostasis:

  • Blood vessel wall disrupted
  • Form a thrombus to heal the defect
  • Platelet rich, generally limited in size.

Dysregulation = Thrombosis

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4
Q

What happens in thrombosis?

A
  • Formation of an abnormal thrombus
  • Vessel wall generally intact

Venous: Red cells and fibrin
Arterial: Platelet rich and occlusive

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5
Q

Describe step one of primary hemostasis:

A

Step one: platelet plug

  • Disrupted endothelium
  • Platelets tether via VWF/collagen
  • Activation of platelets recruit more through release of mediators (Dense granule:TXA2/ADP/Thrombin) and alpha granules.
  • Shape change to the spiny sphere
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6
Q

Describe the crossover between platelets and clotting pathway

A
  • Thrombin activates platelets (PAR 1 and 4)
  • Platelets supply fibrinogen and V from granules
  • Activated platelet membrane supports coagulation reactions
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7
Q

Describe secondary heamostasis

A
  • A sequence of enzymatic reactions is initiated that culminates in the formation of fibrin strands
  • A fibrin mesh (Also called a clot) is formed and entraps the plug
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8
Q

Describe the simple principles of coagulation:

A

Vessel injury and platelet plug formation

  • > Activating clotting factors (tissue factor)
  • > Thrombin 2a (key one) and this converts fibrinogen to fibrin (mesh)
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9
Q

What are the two pathways of the coagulation cascade? (important for lab understanding)

A

Intrinsic and extrinsic pathways

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10
Q

Describe the intrinsic coagulation pathway:

A

Insert picture

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11
Q

Describe the extrinsic pathway

A

Insert picture

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12
Q

What does the coagulation cascade depend on?

A

Enzymatic reactions

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13
Q

Describe the concept of enzyme catalytics:

A
  • Must be anchored in appropriate configuration = increased speed
  • Cofactors can assist binding to permit efficient rapid cleavage. Much faster than when there is no cofactor.
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14
Q

What are the physiological pathways of coagulation?

A
  • Coagulation occurs through tissue factor pathway first at the vessel wall and then on activated platelet surface
  • Contact pathway (Xii) not required for repair of damaged vessels (useful in lab, not in the body physiologically)
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15
Q

Describe blood coagulation, complex 1:

A

Complex one:

Tissue wall injury

  • Exposes sub-endothelial tissue and thus tissue factor. This activates clotting cascade in proximal blood
  • Tissue factor binds Factor 7a (a = activated)
  • Converts factor 9 to 9a
  • 7a+TF or 9a, convert 10->10a.
  • This trio activates prothrombin (factor 2) forming thrombin (2a) at site of vessel injury

Thrombin activates factors 7,8,11 ((activates the cofactors needed in the next complexes))

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16
Q

Describe blood coagulation, complex 2

A

Intrinsic pathway:
Complex 2 is the formation of 9a(protease),8a Complex, it converts 10->10a but requires Ca and platelet phospholipid.

Common pathway;

10a+5a
= Conversion of prothrombin to thrombin

17
Q

Describe blood coagulation, complex 3

A

Xa (protease) binds va (Co-factor) (from thrombin and endothelial), converting prothrombin to thrombin

Huge amount of thombin formed (compared to extrinsic 10ase (Tissue factor+Viia). (This is another feedback loop because it activates more 8 and 5 so the cascade continues)

This enhances formation of all other factors and is cyclical , ramps up and shuts down.

Following thrombin burst, this crosslinks (fibrinogen->fibrin)

18
Q

Describe the transient nature of tissue factor

A

Tissue factor present very briefly. All activated factors go to activated platelets

  • Present on sub endothelial issues i.e smooth muscle, fibroblasts and can be increased in cancer.

NOT expressed on endothelium or cellular components of blood.

19
Q

What are the inhibitors of the coagulation cascade?

A

Tissue pathway factor inhibitor (TFPI) (inhibits 7a/TF complex)

Antithrombin, inhibits 9a, 10a and thrombin formation

Protein C and protein S(cofactor) inhibit factor 7a and 5a.

20
Q

Thrombin has many roles, what does it do?

A
  • Converts fibrinogen to fibrin
  • Activates factors: 7, 5, 11 (feedback loop to 9a), 8:fibrin crosslinks
  • Activates protein C
  • Potent platelet activator
  • Other inflam roles
21
Q

What should we think about for the common pathway?

A

Xa
Va
Thrombin (2a)
Fibrinogen (1)

22
Q

How do factors 8 and 5 work?

A

slide 30…

23
Q

What are the co-factors for 8a and 5a?

A

8a:

  • Ca
  • 9a
  • Phospholipid

5a

  • Ca
  • 10a
  • Phospholipid
24
Q

What are the vitamin K dependent proteins?

A

Factors 2 (prothrombin), 7, 9, 10

Protein C and S

deficiency = heamolytic disease of newborn

25
Q

Vitamin K is regulated in the liver, what is its actions?

A
  • Carboxylates glutamate residues in the GLA domains of vit k dependent proteins
  • Absence of carboxylation results in failure to bind membranes and lack activity
  • Cyclical process within the liver
26
Q

What does Vit K deficiency result in?

A

Bleeding

Vit K from diet and bowel bacteria. In newborns with heamorrhagic disease of newborn, vit K supplements given at birth

27
Q

Is contact activation important?

A

Only in lab test: APTT

28
Q

What has the contact system being linked with?

A
  • Linked to killikren system in innate immunity
  • Thrombosis, which is platelet mediated
  • Thromboses i.le central lines
29
Q

Write some notes on anti-thrombin:

A

Antithrombin: Requires a natural heparin like compound to enhance process

  • Inhibits thrombin
  • Inhibits factor 10a
  • Less efficient inhibitor of 9a and 11a
30
Q

Write some notes on protein C:

A
  • Protein S is cofactor
  • Inactivates factor 5, 7
  • Activated by thrombin via thombomodulin
31
Q

Write some notes on fibrinolysis:

A

Bodies mechanism to keep coagulation from becoming excessive and breaking down clots.

  • Tissue plasminogen activator converts plasminogen to plasmin which breaks down fibrinogen to FDPs and fibrin into D-dimer (important lab test of clotting)
32
Q

When is coagulation occuring?

A

All the time in the microvasculature

33
Q

Is the bleeding abnormal?

A
  • Start with bleeding history
  • Family hx
  • Trauma/surgery?

MBCHB3: Blood, Immunity and Infection (41 decks)

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