Lecture 12: Physiology of coagulation Flashcards
What is coagulation a balance between?
Pro-coagulants + Platelets + clotting factors (Excess causes thrombosis)
vs
Anti-coagulants, inhibitors of thrombosis (excess causes bleeding)
What things come to mind in the case of the child with easy bruising?
- Excessive bleeding
- Lacking one or more of coagulation factors
- Lacking or impaired platelets
Unlikely to be too many inhibitors i.e medicines
What is physiological heamostasis?
Physiological heamostasis:
- Blood vessel wall disrupted
- Form a thrombus to heal the defect
- Platelet rich, generally limited in size.
Dysregulation = Thrombosis
What happens in thrombosis?
- Formation of an abnormal thrombus
- Vessel wall generally intact
Venous: Red cells and fibrin
Arterial: Platelet rich and occlusive
Describe step one of primary hemostasis:
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
Describe the crossover between platelets and clotting pathway
- Thrombin activates platelets (PAR 1 and 4)
- Platelets supply fibrinogen and V from granules
- Activated platelet membrane supports coagulation reactions
Describe secondary heamostasis
- 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
Describe the simple principles of coagulation:
Vessel injury and platelet plug formation
- > Activating clotting factors (tissue factor)
- > Thrombin 2a (key one) and this converts fibrinogen to fibrin (mesh)
What are the two pathways of the coagulation cascade? (important for lab understanding)
Intrinsic and extrinsic pathways
Describe the intrinsic coagulation pathway:
Insert picture
Describe the extrinsic pathway
Insert picture
What does the coagulation cascade depend on?
Enzymatic reactions
Describe the concept of enzyme catalytics:
- 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.
What are the physiological pathways of coagulation?
- 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)
Describe blood coagulation, complex 1:
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))
Describe blood coagulation, complex 2
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
Describe blood coagulation, complex 3
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)
Describe the transient nature of tissue factor
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.
What are the inhibitors of the coagulation cascade?
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.
Thrombin has many roles, what does it do?
- 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
What should we think about for the common pathway?
Xa
Va
Thrombin (2a)
Fibrinogen (1)
How do factors 8 and 5 work?
slide 30…
What are the co-factors for 8a and 5a?
8a:
- Ca
- 9a
- Phospholipid
5a
- Ca
- 10a
- Phospholipid
What are the vitamin K dependent proteins?
Factors 2 (prothrombin), 7, 9, 10
Protein C and S
deficiency = heamolytic disease of newborn
Vitamin K is regulated in the liver, what is its actions?
- 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
What does Vit K deficiency result in?
Bleeding
Vit K from diet and bowel bacteria. In newborns with heamorrhagic disease of newborn, vit K supplements given at birth
Is contact activation important?
Only in lab test: APTT
What has the contact system being linked with?
- Linked to killikren system in innate immunity
- Thrombosis, which is platelet mediated
- Thromboses i.le central lines
Write some notes on anti-thrombin:
Antithrombin: Requires a natural heparin like compound to enhance process
- Inhibits thrombin
- Inhibits factor 10a
- Less efficient inhibitor of 9a and 11a
Write some notes on protein C:
- Protein S is cofactor
- Inactivates factor 5, 7
- Activated by thrombin via thombomodulin
Write some notes on fibrinolysis:
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)
When is coagulation occuring?
All the time in the microvasculature
Is the bleeding abnormal?
- Start with bleeding history
- Family hx
- Trauma/surgery?
