L15 Physiological Coagulation do 1st Flashcards
What are the pro-coagulant factors - causing blood to clot vs the anti-coagulant
factors that act in a balance- seesaw
Pro: clotting factors, platelets
Anti: Inhibitors of coagulation:
- natural found in the body
- medications
- fibrinolytic proteins
What is the difference between physiological haemostasis and Thrombosis (Venous vs Arterial)
Including thrombus make up
PH: Physiological haemostasis: To keep the body going all the time, when a blood vessel wall disrupted a thrombus formed to heal the defect.
- platelet rich generally size limited.
T: Formation of an abnormal thrombus where the vessel wall is generally intact
- Venous: protein rich clot: RBC and fibrin
- Arterial: platelet rich, occlusive, white.
Describe what happens in 1’ haemostasis again
See pg 106
- Disrupted endothelium
- leads to platelet tethering to VWf or collagen (adhesion)
- Aggregation:
- Activation of platelets recruits more through release of activators/aggregators eg. thromboxane
- Platelet shape change to spiney sphere due to release of activators serotonin, ADP
- Fibrinogen binds platelet together.
What is 2ndary haemostasis and what is its goal, when is it activated
- Coagulation cascade is activated at the same time of platelet activation.
- Goal: Form thrombin which converts fibrinogen to fibrin.
Fibrin forms a mesh that stabilises platelet plug
Describe the steps in blood coagulation -physiological coagulation cascade
Including which require Ca2+ and phospholipid
- Endothelial disruption exposes: Tissue factor (potent trigger)
- F7 binds to TF, undergoes shape change activation
3.F7a/TF initiation complex on subendothelial matrix can activate
–F10 to F10a,
–F9 to F9a
Then is shut off by TF pathway inhibitor
- F10a can slowly convert a small amount of prothrombin to thrombin. (requires Ca2+ and phospholipid)
- Thrombin then amplifies the coagulation pathway by
activating F5, 8 and 11 - which makes more 9.
At activated platelet surface.
6. F8a (cofactor) complexes with 9a (protease), Ca2+ and Plipid to make tenase complex which rapidly makes 10a.
- F10a complexes with 5a, Ca2+ and Plipid and rapidly converts prothrombin into thrombin
- The lots of Thrombrin cleaves fibrinogen to fibrin.
- It also activates F11 to converts f9 to 9a
- more f8a, f5a
- activates protein C via thrombomodulin
What are the two ways that 2ndary haemostasis is kept localised to the site of injury
- TF pathway inhibitor present in platelets and plasma accumulates at site of coagulation due to platelet activation. It binds FXa and TF7a complex and stops further Xa activation preventing widespread activation of coagulation away from site of injury.
- The formation of complexes on the activated platelet surface requires
- Ca2+ from outside and
- Phospholipid from the platelet to bind on platelet.
Helping to keep it localised to site of platelet plug.
Where is TF expressed usually/not usually. can you have TF deficiency
Can’t have deficiency as early embryos bleed out
It is expressed on subendothelial tissues= SM, fibroblasts.
Not expressed on endothelium or cellular blood components. Abnormal expression can be seen in cancers.
Apart from TFPI what are the other physiological inhibitors of coagulation.
Deficiencies in these are very severe clotting not v compatible w life.
- Protein C (protease) and Protein S (cofactor) work to inhibit F8a and 5a.
- Anti-thrombin, inhibits mainly Thrombin - which reduces amplification and F10a.
+ less efficiently and F9a and 11a
This requires heparin as a co-factor
What are the Vit K dependent proteins in the coagulation pathway and why are they dependent on Vit K
Prothrombin (2), 7, 9 and 10
+ Protein C and Protein S
These proteins have a glutamates in their GLA domain which has to be carboxylated by Vitamin K to allow them to bind to membranes and have activity.
What the sources of Vit K and result of deficiency
Vit K is absorbed from diet in leafy greens and is produced by bowel bacteria. It has recycling process within liver.
- Deficiency in adults can follow after antibiotic treatment in hospital,
- poor fat soluble vitamin absorption (lack of bile)
Can lead to haemorrhagic disease of the newborn bc bb are naturally deficient so given Vit K injection at birth
Describe the steps involved in the contact/intrinsic coagulation pathway
- Contact with negatively charged surface (glass, central line) causes spontaneous activation of F12.
- F12a activates
- -F11 to 11a which can activate F9 to 9a - This can go on to convert 10 to 10a down the common pathway for coagulation thus start the formation of thrombin
Compare the severity of F12 deficiency to F11 deficiency.
What pathway are they related to. Which pathway is the usual physiologically.
F12 is Not associated with bleeding whereas F11 only has mild symptoms.
This is because they are part of contact activation of clotting which is rare physiologically.
Contact activation is only relevant for APTT testing. Extrinsic is the usual
What is the function of Fibrinolysis and how does it happen -> activating factors
What are the two inhibitors of fibrinolysis
To prevent excessive clotting by breaking down fibrin so that normal vessel structure is re-established.
- Plasminogen converted to digestive enzyme Plasmin (activated by Tissue Plasminogen Activator (TPA) and uPA )
- This cleaves fibrin making D dimers.
Fibrinolysis inhibited by
- Antiplasmin which binds to plasmin
- Thrombin Activated Fibrinolysis Inhibitor (TAFI) which prevents plasminogen binding to a clot by removing lysine residues
What causes crosslinking of fibrin strands to form a cross-linking fibrin polymer
Factor 13a in the presence of Ca2+ can cross link the D domains of fibrin
