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Haematology > haemostasis > Flashcards

haemostasis Flashcards

1
Q

what is thrombocytopenia *

A

low platelet count

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2
Q

ways that a thrombus can manifest *

A

thrombophilia

venous/arterial thrombosis

cancer - many people die because of cardiovasc event

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3
Q

what is haemostasis

A

the cellular and biochemical proess that enables the specific and regulated cessation of bleeding in response to vascular insult

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4
Q

what is haemostasis for

A

to prevent blood loss from intact and injured vessels, enables tissue repair

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5
Q

describe the delicate balance of haemostasis

A

increased fibrinolytic factors and anticoag proteins, and decreased coag factors and platelets = bleeding

decreased fibrinolytic factors and anticoag proteins, and increased coag factors and platelets = thrombosis

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6
Q

what can the result of thrombosis be *

A

DVT

pul emb

death

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7
Q

conditions that cause bleeding *

A

vWD

haemophilia

thrombocytopenia

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8
Q

summarise the haemostatic cascade *

A

vessel constriction - local vascualr sm contraction - limit blood flow

formation of unstable plug - platelet adhesion, platelet aggregation - act as physical barrier, provide surface for coagulation - this is primary

stabalisation of the plug with fibrin - blood coag stops blood loss

vessel repair and dissolution of clot - cell migration/proliferation nad fibrinolysis - restored vessel integrity - clears away the clot

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9
Q

describe teh normal vessel wall of the artery *

A

endothelium is anticoag - smooth surface for blood flow - EPCR and TM are anticoagulant on surface of endo

subendo - procoagulant - matrix proteins are associated with recruitment of platelets and tissue factor (TF) is initiator of the cascade

in the lumen are latent clotting factors and VWF

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10
Q

where is the platelet plug important *

A

small vessels

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11
Q

describe platelets *

A

small - 2-4um

anuclear - but are cells

life span 10 days

150-350x10(power 9)

from megakaryocytes which are multiploidy (16n) and multilobular nuclei - they migrate to teh vessel wall in the marrow - send proplatelet protusions - platelets leave into circulation

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12
Q

what is the importance of the platelet cytoskeleton *

A

for morphology, shape change, pseudopods, contraction and clot retraction

in platelet activation shape changes from discoid to starish shaped cell

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13
Q

what are the multiple roles of platelets

A

haemostatsis

cancet

atherosclerosis

inflammation

infection - interact with leukocytes to promote clearance of infection

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14
Q

summarise primary haemostasis *

A

vwf travels in globular formation in blood - platelet binding sites are concealed from GpIb on platelets

vascular damage exposes subendo collagen - cwf recognises this - vwf binds to collagen = structural transition of vwf, the shear force of blood flow converts it to linear conformation - exposing sites for platelet binding - platelets bind - this recruits platelets to site of damage

at low shear platelets can bind directly to collagen via GPVI and a2B1

platelets become activated because of simulation from collagen and thrombin - further recruit platelets

activated platelets produce other platelet agonists - ADP and thromboxane - stimulate the new platelets that are recruited

integrin aIIbB3 holds platelets together, also bind to fibrinogen = platelet plug

platelet change membrane composition - so -ve phospholipid surface - this attracts clotting factors

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15
Q

descrihe the change in platelet shape during primary haemostasis *

A

flowing disc shaped

rolling ball shaped

hemisphere shaped - firm but reversible adhesion

spreading platelet - seal site of injury, irreversible adhesion

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16
Q

how does VWD affect primary haemostasis *

A

mutation in protein mean initial binding to collagen doesnt occur - so have problem with initial platelet recruitment

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17
Q

how can platelet disorders cause bleeding *

A

if deficient or dont function right

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18
Q

describe the various severity of thrombocytopenia *

A

<100x10(9) - mild – no spont bleeding, but bleeding with trauma

<40 - spontaneous bleeding is common eg because of autoimmune thrombocytopenia

<10 severe spontaneous bleeding eg because of treatment for leukaemia

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19
Q

signs of immune thrombocytopenia *

A

purpura

multiple bruises

eccymoses

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20
Q

what is the main reason for the secondary clotting cascade *

A

thrombin produced by clotting cascade converts soluble fibrinogen to insoluble fibrin

thrombin is a serine protease and is the central enzyme in the clotting cascade

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21
Q

what happens when clot gets bigger than are of damage *

A

platelets embolise and break off - cleaved or removed

need both fibrin and platelets for the stable clot

22
Q

what are the components in coagulation *

A

liver main site of synthesis plasma haemostatic proteins

endothelial cells have and make proteins - vwf and anticoagulant molecules (tm and TFPI)

magakaryocytes contain vwf factor V (clotting factors)

clotting factors circulate as inactive precursers - serine protease zymogens or cofactors - activated by proteolysis

the cofactors in te cascade are tf FVa, FVIIIa

23
Q

describe serine protease domain containing proteins *

A

once activated te serien protease domain catalyses proteolysis of target substrate

they contain catalytic triad - His/asp/ser

they cleave substartes after specific arginine and lysine residues

24
Q

what are the serine protease containing enzymes *

A

fVII
FX

prothhrombinFIX

FXI

Protein c

25
Q

describe secondary haemostasis *

A

exposure of tf on the extravascular tissue to clotting factors

FVII/FVIIa binds to cell surface via Gla domain (Gla domain gives it the ability to react with phospholipid surface), all domains of FVIIa bind to TF - TF makes it more active

TF-fvIIa proteolytically activates FX and fIX by removing peptide from serine protease causing structural shift - switch to protease form

fxa - switch prothrombin to thrombin - inefficient

thrombin activates fv and fIX

FVIIIa feeds back and acts as cofactor for FIX = more fXa is made - this is more efficient than initiation step

the fxa joins with its cofactor fva - converts proithrombin to thrombin more efficiently

26
Q

describe TF *

A

initiator of coag

located at extravascualr site s

more in lungs,brain, heart, testes, uterus and placenta - more haemostatic protection

27
Q

describe factor 7 *

A

serine protease zymogen

secreted by liver

Gla domain

2 EGF like domains

serine protease domain

circulates at 10nM

1% plasma FVII circulates in active form

28
Q

describe the serine protease structure

A

FVII FIX FX PC all have it

homologous modular structure - 4 domains

gla domain

EGF domain - for protein-protein interactions

all circulate in plasma in zymogen form

activated by proteolysis

29
Q

describe gla domains *

A

defines vitamin k dependant proteins - need vit k for gla domains

contain 9-11 gamma-carboxyglutamic acid residues

give residue affinity for ca

cause change in conformation - so can bind to phospholids

30
Q

mechanism of action of warfarin *

A

vitamin K antagonist - interrupt post translational modification of proteases

clotting factors dont have gla domain

cant bidn to platelets

31
Q

what is lacking in haemophilia *

A

a - factor 8

b - factor 9

32
Q

what time of inheritance is haemophilia *

A

x linked

33
Q

what does TFPI do *

A

regulates the initation step - tf and f8a

34
Q

what does apc and protein s do *

A

regulate the production of 5a and 8a so downregulates thrombin production - but does nit affect the thrombin that is already there

35
Q

what does antithrombin do *

A

inhibit thrombin and 10a

36
Q

describe action of tissue factor pathway inhibitor *

A

tissue factor forms transmembrane complex with 7a - factor 10 binds and is activated

10a bindd to second kunitz domain of tfpi - this complex bind to tf-7a complex - now bound in inactive form

small amounts of tfpi - dampen procoagulant for small injuries

37
Q

describe the protein c pathway *

A

protein c is activated by thrombin-tm complex

active protein c inhibits thrombin generation by proteolytically inactivating procoag factors 5 and 8 a

38
Q

what is factor 5 leiden *

A

arg506 is switched for glutamine of factor 5a- which is the cleaveage site for protein c

factor 5a cant be inactivated as easily = increased risk opf thrrombosis

39
Q

how is coagulation localised

A

thrombin (factor 2a) binds to thrombomodulin on endothelial cell

tm turns thrombin into anticoag molecule that activates protein c by cleaving protein c which is bound to epcr and releasing activation peptide

this process activate protein c into apc a serine protease

apc and its cofactor protein s - shut down coagulation

40
Q

what is the role of antithrombin *

A

mops up serine proteases mainly factor 10 and thrombin that have been washed away from the origenal site of teh clot

it is a serine protease inhibitor - serpin

41
Q

what is the mechanism of heparin *

A

binds antithrombin - enhance its efficiency = increased inhibition of thrombin

42
Q

what are deficiencies in protein s and c and antithrombin risk factors for *

A

thrombosis

43
Q

describe fibrinolysis *

A

plasminogen is made in liver

tissue plasminogen activator binds to fibrin and is activated, then converts plasminogen to plasmin

plasmin chops up fibrin clot

fibrin degradation products are cleared in liver - elevated in DIC

44
Q

clinical use of tpa *

A

thombolysis - clot busting drugs

for mi and more commonly ischemic strokes

45
Q

list anticoagulant drugs, main thing they prevent *

A

heparin, warfarin, direct oral anticoagulants - inhibit 10a and thrombin

prevent venous thrombosis

46
Q

list anti-platelet drugs and what they are used to protecct against *

A

aspirin, P2Y12 blockers (reduce responsiveness of platelets)

protect against arterial thrombosis

47
Q

what haemostatic tests can be done *

A

PT and APtT - these are global read outs of haemostatic potential

do platelet function tests if people are bleeding for unknown reason

d-dimer - routine - d-dimer is a fibrin degredation product, after coagulation the level of d-dimer is increased - measure to see how much clotting has occured in the recent past - if high = at risk of thrombosis

48
Q

when is warfarin used *

A

when had DVT or pul emb

or to prevent clots eg when have artificial heart valve, a fib, thrombophilia, after operation

long term treatment

49
Q

when is heparin used *

A

to prevent and treat blood clots from medical conditions or procedures

used before surgery

immediate response

dic

thromboembolism

prophylaxis of pul emb

unstable angina

50
Q

mechanism of antiplatelet drugs *

A

they interfere with platelet aggregation - therefore inhibit thrombus formation

51
Q

indications for use of anti-platelets *

A

The primary prevention of atherothrombotic events in people who are at high risk.

The secondary prevention of atherothrombotic events in people with:

Acute coronary syndrome (ACS).

Angina.

Peripheral arterial disease.

Atrial fibrillation (AF) — in some people, although anticoagulants are more usually prescribed.

The secondary prevention of cardiovascular events in people after:

Myocardial infarction (MI).

Stent implantation.

Stroke or transient ischaemic attack.

The prevention of atherothrombotic events in people undergoing percutaneous coronary intervention (PCI).

Haematology (11 decks)

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