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Haematology and transfusion sciences > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

define Haemostasis

A

a dynamic process where blood coagulation is rapidly initiated at the site if injury to prevent blood loss and promote injury repair and healing

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2
Q

what are the 3 main haemostatic functions

A

maintentance of blood in a fluid state within the vascular system.

to arrest bleeding at the site of injury by formation of a haemostatic plug.

removal of the plug when healing is complete and a return to fluidity

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3
Q

what happens haemostatically in a normal physiology

A

a delicate balance between clotting and bleeding and therefore deficiency or exaggeration of any one may lead to either thrombosis or haemorrhage

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4
Q

what causes bleeding in the balance

A

when the balance is shifted to bleeding

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5
Q

what happens when the balance is shifted towards clotting

A

thrombosis

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6
Q

what are the three phases of haemostasis

A

primary - primary platelet plug formation

secondary - stable clot formation

tertiary- fibrinolysis (clot dissolution)

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7
Q

what are the components involved in haemostasis

A 
blood vessels - endothelium
platelets
plasma proteins
-coagulation factors
-their inhibitors
-fibrinolytic system
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8
Q

how intact endothelium naturally anti-thrombogenis

A

the endothelium isolates blood from clot-promoting substances which is beneath the endothelium

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9
Q

name some pro-coagulant molecules

A

von Willebrand Factor
Collagen
Tissue Factor
Plasminogen Activator Inhibitor 1 (PAI-1)

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10
Q

name some anti-coagulant molecules

A 
nitric oxide (NO)
prostacyclin (PGI2)
tissue factor pathway inhibitor (TFPI)
tissue plasminogen activator (t-PA)
heparan sulphated proteoglycans (HSPG)
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11
Q

whats the overview of platelets

A

anuclear, small (2-3um), cellular fragments highly refractile and disk-shaped

platelet membrane - phospholipid bilayer, receptor sites

granules
dense
alpha

microfilaments - pseudopodia

microtubules - contraction

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12
Q

what are three plasma proteins

A

coagulation factors
natural inhibitors
fibrinolytic system

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13
Q

what are coagulation factors

A

inactive enzymes or zymogens: predominately serine proteases

activated by cleavage: exposes the active site

substrate of active factor: zymogen of another

numbered by roman numerals and a indicates active

in order of discovery not order of activation

many of the coagulation factors require co-factors to function effectively

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14
Q

what is the classic model of coagulation (1905)

A

prothrombin catalysed by thrombokinase +calcium ions leads to thrombin

thrombin causes fibrinogen to become fibrin

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15
Q

what is the cascade/ waterfall model of coagulation (1964

A

there are two pathways
the intrinsic (contact) pathway
extrinsic (tissue factor) pathway

the third pathway came later and thats the common pathway

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16
Q

what happens in the intrinsic pathway

A

factor XII, HMWK and prekallikrein activate FXI

FXIa activates FIX

FIXa combines with FVIII and phospholipid: activates FX

ensues to final common pathway

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17
Q

what happens in the extrinsic pathway

A

tissue factor and FVIIa form a complex (TF:FVIIa): activates FX

TF:FVIIa also activates FIX (intrinsic) helps increase FXa

ensues to final common pathway

18
Q

what happens in the common pathway

A 
prothrombin activator produced on surface of activated platelets:
FXa
\+FVa
\+phospholipid
\+calcium ions

the activator cleaves prothrombin (FII) into thrombin (FIIa)

thrombin (FIIa) induces fibrin (FIa) polymers from Fibrinogen (FI)

thrombin also activates FXIII - cross links fibrin clot making it stronger

thrombin activates FVIII and FXI: upregulates cascade

19
Q

what are the anomalies for the cascade model

A

high molecular weight kininogen (HMWK), pre-kallikrein and FXII deficiences not associated with bleed, but prolonged APTT

some mammals dont have FXII - not required for normal haemostasis

FXI deficiency (haemophilia C) - variable haemostatic defects

FVIII deficiency (haemophilia A) and FIX deficiency (haemophilia B)- serious bleeding despite intact extrinsic pathway

tissue factor:FVIIIa activates both FIX adn FX

argues against the idea that these pathways are independent generators of FXa

20
Q

how is the endothelium involved in primary haemostasis

A

tissue injury leads to vascular spasm of the smooth muscle-localised to area of damage

release of endothelins: vasoconstriction

vasoconstriction slows/stops blood flow-tourniquet effect

small vessel damage my be plugged

larger vessels may require platelets and coagulation factors

Pro-coagulant molecules expressed/ revealed: eg collogen

tissue factor exposed: generates small smount of thrombin

von Willebrand factor multimers released

PRO-COAGULANT FACTORS> anti-coagulant factors

21
Q

what are the three main phases in platelet plug formation

A

Adhesion
activation
aggregation

22
Q

what happens in platelet adhesion

A

initial step: adhesion to extracellular matrix (collagen)

platelets roll, adhere and spread on collagen matrix-activated monolayer

mediated by interactions between:
vWF adn glycoprotein (GP) Ib/V/IX receptor (high shear blood flow)
collagen and GPVI (major): activation and de-granulation

23
Q

what happens with platelet activation

A 
multiple pathways of activation:
collagen
adenosine diphosphate (ADP)
thromboxane A2 (TXA2)
adrenaline
serotonin

thrombin most potent activator: extremely low levels required

multiple effects:
platelet shpe change (stellate)
pro-inflammatory molecule expression: p-selectin
procoagulant activity
degranulation: ADP/TXA2 secretion
converts GP IIb/IIIa into active form: aggregation

Leads to recruitment and activation of platelets to growing stable plug

24
Q

what happens in platelet aggregation

A

GPIIb/IIIa central to platelet aggregation

promotes:
adhesion
aggregation
spreading of monolayer
thrombus formation/ stability-fibrinogen bound to GPIIb/IIIa bridges
25
Q

what are the three main phases of the cell based model

A

initiation
amplification
propagation

26
Q

what is the initiation phase of the cell based model

A

(tissue injury)

TF expressing cell rapidly binds FVIIa 1:1 complex

additional FVII activated: upregulated cascade

small smounts of FIX and FX activated

FXa directly but slowly activates FV

FXa binds to its cofactor FVa and its substrate FII:
prothrombinase complex

generation of small amounts of thrombin

27
Q

what is the amplification phase of the cell based model

A

the small amount of thrombin produced is pivotal to amplification

activates platelets: via FV adn FXI on platelet surface

cleaves and activates FVIII from vWF: platelet effects

amplification facilitates the availability of important co-factors: FVa and FVIIIa

increased activated platelets results in abundant phospholipid surface for coagulation to take place

28
Q

what is the propogation phase of the cell based model

A

platelet granule release: platelet recruitment

FIXa (initiation) binds to FVIIIa (amplification)

additional FIXa generated by FXIa (amplification)

FIXa binds to its cofactor FVIIIa and its sunstrate FX:
intrinsic tenase complex

FXa rapidly binds FVa (amplification) and FII:
thrombin burst

29
Q

What is the thrombin pivitol to?

A

procoagulant ‘V’ anitcoagulant
cleaves fibrinogen into fibrin
activates FV,FVIII and FXI: upregulates cascade
activates FXIII - crosslinks fibrinogen for further clot stabilisation
activates platelets via PAR-1 and PAR-4 receptor
inhibits fibrinolysis via thrombin activatable fibrinolysis inhibitor (TAFI
promotes anticoagulation: activation of protein C via thrombomodulimn

30
Q

name several naturally occuring inhibitors

A

antithrombin (AT) - previously known as ATIII
protein C (PC)
protein S (PS)
tissue factor pathway inhibitor (TFPI)

31
Q

how does antithrombin work

A

SERPIN-SERine Protease INhibitor

Primary targets are thrombin and FXa

Most potent inhibitor of thrombin

FIXa, FXIa and FXIIa also inhibited

Inhibitory activity thousand fold increased by heparins.

32
Q

how does protein C work

A

vitamin k-dependent serine protease

cleaves and inhibits FVa and FVIIIa

activated by a complex formed by thrombin and thrombomodulin- negative feedback

activated Protein C (APC) is inhibited by protein C inhibitor (PAI-3) - a serpin

binds to PAI-1 and inhibits its activity: enhancing fibrinolysis

33
Q

how does protein S work

A

Vitamin K –dependent glycoprotein

Cofactor for protein C

Protein S exists in 2 forms – bound and free

About 65% complexed to C4b-binding Protein (C4bBP), and is inactive

Only the free form has activity

APC independent anticoagulant: direct binding FVa, FXa and FVIII.

34
Q

how does TFPI work

A

TFPI secreted by the endothelium

TFPI directly inhibits FXa
then the FXa:TFPI complex
interacts and inhibits the FVIIa:TF complex

inhibitation of the extrinsic coagulation pathway

35
Q

what role does fibrinolysis play in the coagulation cascade

A

after the formation of the clot
the injured vessel is sealed/ bleeding stops
repair of the injury follows

at the end of the process the sealing clots need to be dissolved
removed occlusion from vessels
prevents tissue hypoxia

this is achieved by fibrinolysis

36
Q

what role does plaminogen play in fibrinolysis

A

its the precursor of plasmin
activated by t-PA: endothelial cell secreted serine protease
both plasminogen / t-pa bind to lysine residues on fibrin
t-pa:t1/2 (2-3 minutes) due to its potent inhibitor PAI-1
activated by u-PA: extravascular remodelling and repair
affinity for t-PA increases significantly in presence of fibrin clot

37
Q

what role does plasmin play in fibrinolysis

A

active serine protease
major enzyme of fibrinolysis
proteolytiv enzyme- enzymatic degradation of fibrin at over 50 cleavage sites
plasmin inhibitors prevent overactive plasmin
confones lysis to local area

38
Q

summerise initiation

A

vascualr endothelium injury and circulating blood cells are perturbed: interaction of plasma derived FVIIa and tissue factor

39
Q

summerise amplification

A

thrombin activates platelets, cofactors FVa and FVIIIa on the platelet surface and the FXI on the platelet surface

40
Q

summerise propogation

A

results in the production of a significant level of thrombin activity, generation of a stable plug a the site of injury and cessation of blood loss

41
Q

summerise termination

A

clotting process is limited to avoid thrombotic occlusion in surrounding normal areas of vasculature

Haematology and transfusion sciences (10 decks)

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