Future Therapeutics Flashcards
(7 cards)
The coagulation cascade
target common pathway to achieve maximum effect
warfarin = bad
- lots of drug-drug interactions
- diet interactions
- too slow off-rate
rivaroxaban
- direct-acting, orally active
- low dose and dual anti-platelet
- good but high bleeding risk
dual pathway therapy?
- aspirin and rivaroxaban or and P2Y12 inhibitor
- so some anti-platelet and some anti-coagulant activity
Haemostasis
- haemophilia is caused by a lack of factors
- lack of FVIII or FIX = haemophilia A or B
- A and B are bleeding disorders
- FXI and FXII loss do not result in bleeding disorders so could be targeted?
- FXI and FXII involved in thrombosis but not haemostasis
- FXIa inhibition options = small molecule, peptide mimetic, RNA aptamer, yellowfish sole anti-coagulant protein, Abs, antisense olignucleotides etc.
FXII and thrombosis
- platelet plug obscures tissue factor so prevents further coagulation (self-limiting)
- other platelets on top are not covered in fibrin and so are torn off by high shear
- they embolise further along the vessel
- so would need to activate coagulation at the top of the thrombus so fibrin canform and occlude vessel
- how if FXII activated?
How ix FXII activated at top of the platelet mass?
- non-physiological negative charged surfaces e.g. glass
- DNA, polyphosphatases, collagen and RNA
platelet polyphosphatases
- inorganic linear chain
- in some bacteria and in platelet dense granules
- secreted during platelet activation
- PolyP activates FXII
- increased length of PoluP = increased activation of FXII
Overview of FXII and polyphosphatases
- FXII involved in thrombosis
- platelet polyPs can increase coagulation
- but are pore activators of FXII
- another FXII activator involved
- FXII different in thrombosis and haemostasis
Leukocytes
- monocytes express TF in response to stimuli
- buds off into microvesicles
- may promote thrombosis
- neutrophils produce ROS and proteases
- neutrophils also form neutrophil extracellular traps (NETs)
- without proteases, thrombosis decreases but bleeding increases (shown in KO mice)
neutrophil elastases
- inhibit TFP1 via cleavage
- which inhibits FVII activated by trauma
- = further coagulation
Netutrophil extracellular traps
- NETs release proteases, histones, DNA
- bind fibrinogen and vWF
- creates substrate for more platelets to bind
- histones bind negative membranes to form toxic pores and kill cells
- coronary thrombi have histones but deep vein thrombi don’t, suggesting they have more NETs
- NETs have role in tissue damage
- when NET formation is prevented, occlusion takes longer (need to develop a more stable and potent molecule to do this)
