Heamostasis Flashcards
What is heamostasis? What is it for?
Cellular and biochemical process than ensures both specific and regulated cessation of bleeding
Use-prevent blood loss
Constant balance between excessive bleeding (low heamostasis) and excessive thrombosis (stroke, MI etc)
What is (in simple terms) the bodies response to bleeding
1) Vessel contriction-limit blood flow
2) primary heamostasis (VWF + PLATELETS) are recruited to area-aggregrate and adhere and provide surface for 2ndary heamostasis
3) 2nd ary heamostasis stabilisation with fibrin
4) Vessel repair and dissolutio of clot
What is present in a typical vessel wall? Why does it matter to heamostasis?
Initial layer of endothelial (inheritently anti-coagulatant)
BUT-under-tunica intima, media and adventitia-natrually pro-coagulant)
What is the first response to injury?
Vessel constriction-mainly for small vessels-LOCAL contractile activity-response
Where do platelets come from? How would u describe them? What are the 4 main receptors that important? what granules do they have? Are their cell wall static
Platelets (small, anuclear, short lived (10days)-numerous (150-350x10^9)-originate from megakaryocyte in BM (themselves from HPSC)-move to site of injury and have “tendrils” that poke through vessels and provide platelets
GPVI-Collagen GPiB/V/IX-binds VWF aiib3-binds fibrinogen A2B1-interact collagen P2Y-ADP(and others to respond to many different situation)
platelets have a granules-(growth factor, fibrinogen, FV, VWF) dense granules (ADP, ATP, serotonin, CA)
Very active/dynamic Phopsholipid membrane-when activated-negative PL move to outisde-attract clotting factors
also dynamic cytoskeleton-change shape when active
What are the 5 main roles of platelets?
Heamostasis+thrombosis cancer Artherosclerosis Inflammation Infection
What is the second event after bleeding? What does the binding? What happens after activation?
Main aim: platelets get targetted to area of bleeding
Need VWF-in blood is scrunched up (cant interact with Platelets)-but as exposed collagen-VWF becomes linear and expose platelets binding site-bind+activate (spread)
BIND USING GBiB
(platelets can interact with collagen but only in low flow)
Activation-start thrombin cascade + release of many factors =increase platelet recruitment
A2bB3-platelets binds together+accumulate
cascade going on at the same time-fibrin is what will ultimately clot the bleed
What is Von Willibrands disease? And what other disease leads to a bleeding phenotype (based on primary heamostasis)? At what range of platelets is it considered low?
Mutation in VWF (not enough or not working)-cant even start initial heamostasis-bad
can also get patelet dysfunction/dysumber
Most people have “too many” platelets anyways
But under 40x10^9-can get spontaneous bleeding
What initiates the coagulation cascade?
Extrinsic pathway-Tissue factor from the vessels is shown and binds FVII (Will go o the activate FX, which WITH FV) activated ProThombin (to thrombin)
Also activated FIX (which WITH FVIII) also activates FX
Where are most of the clotting factors made? what types of proteins do you find in the cascade?
Liver-most plasma ones
Endothelia cells make VWF, TM, TFPI
Megakaryocytes-VWF, FV
Lots of zymogens-FVII, IX, X, XII, XIII, II (activate -add an a)-all serine proteinases
Cofactors-TF, FVa, TVIIIa
Inhbitors - TFPI, PC, PS, Antithrombin
WHat is Tissue factor?
Cellular receptor and coafactor for FVII (membrane protein)-on surface of extravascular cells
Initiation of cascade
Found more in certain important tissues
(Gla domain on FVII is what binds-FiX, FX and PC, PS, Prothrombin also have it (and similar EGF1,2 and Serine Prot domains)
What is a gla domain in heamostasis?
Several glutamic acid groups that get changed by Vitamin K carboxylase that adds ____ group that increases affinity to calcium
This is what makes them fold in a way to bind TF
Warfarin is an anti-coagulant becomes its a Vit K antagonist
What are the second and third and fourth steps of secondary heamostasis?
Activated FVII activates FX and FIX
FXa activates Thrombin-but very slow
Thrombin activates FV and FVIII
FVa cofactor to FXa greatly increase activity
FVIIIa cofactor to FIX and greatly increases activity
no need for TF at this point-cascades off very fast
What are commons disease associated with secondary heamostasis?
Heamophilia A (FVIII) and B (FIX)
How is coagulation regulated/Stopped?
3 main players - PC+PS, Antithombin and TFPI
To prevent over coagulation
