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sem 2 CVS > Thrombosis > Flashcards

Thrombosis Flashcards

1
Q

what is coagulation?

A

an inflammatory process which prevents blood loss

the conversion of fibrinogen tethers into fibrin and then cross linking of the fibrin clot

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2
Q

what activates coagulation?

A

inflammation

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3
Q

what is primary haemostasis?

A

aggregation of platelets

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4
Q

what is secondary haemostasis?

A

conversion of fibrinogen into fibrin via a protease called thrombin
-thrombin itself is converted from prothrombin through a cascade of steps

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5
Q

what do anticoagulants do? give some examples

A

they prevent thrombosis

-heparin, warfarin and EDTA

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6
Q

what reverses thrombosis?

A

fibrinolysis

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7
Q

what causes arterial thrombosis and what is the consequence?

A
  • Mostly result from atheroma rupture or damage to the endothelium (e.g. MI, stroke)
  • Platelet-rich “white” thrombosis, mostly primary
  • May block downstream arteries
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8
Q

what causes venous thrombosis and what is the consequence?

A
  • Often results from stasis or a hyper-coagulant state (e.g. DVT)
  • Platelet-poor “red” thrombus, mostly secondary
  • Can go back to the RHS of the heart and block pulmonary circulation
  • Might pool in the legs, more static
  • May move to lungs
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9
Q

does arterial or venous thrombosis occur more often and which is more serious?

A
  • venous is more serious

- venous occurs more often

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10
Q

usually coagulation is inhibited - by what?

A

o Prostaglandins
o Antithrombin and Heparan
o Nitric Oxide

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11
Q

what is tPA (tissue plasminogen activator)?

A

converts plasminogen into plasmin, an enzyme which acts on clots to produce D dimers (a fibrin degradation product)

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12
Q

what is vWf (vonWilleband factor)?

A

activates platelets and makes them clump together

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13
Q

what do TF’s (tissue factors) do?

A

damage to endothelium or inflammation exposes the tissue factor which is one of the initiators of the clotting cascade

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14
Q

what happens when you get damage to the endothelium?

A
  • damage to the endothelium exposes sub-endothelial cells (present underneath the endothelium, blood supply doesn’t usually see them)
  • tissue factor released by the sub-endothelial cells will initiate clotting
  • von Willebrand factor is present in endothelial cells so that gets released, and there is also some present in circulating blood
  • platelets are activated when they bind to von Willebrand factor
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15
Q

what is a consequence of having von Willebrand present in circulating blood?

A

means if blood really slows down you can get a clot forming- ie. you can start a clot without tissue damage

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16
Q

how do prostaglandins and NO inhibit coagulation:

A

resist clotting by inhibiting platelets

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17
Q

how do anti-thrombin and Heparan inhibit coagulation:

A

prevent clots from forming

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18
Q

what is Virchow’s Triad?

A

Describes the three broad categories of factors that are thought to contribute to thrombosis:

1) stasis
2) endothelial damage
3) hyper-coagulant state

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19
Q

what is thrombosis?

A

clot formation
- can be local coagulation
OR
- clotting of the blood in a part of the circulatory system

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20
Q

why is it thought that stasis contributes to thrombosis?

A

because static blood lacks kinetic energy and tends to clot
e.g. when you’re not moving around, in hospital lying in bed for ages or a long haul flight - on these flights you’re meant to wear those stockings to stop your blood pooling in your legs

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21
Q

why is it thought that endothelial damage contributes to thrombosis?

A

damage to the lining of the blood vessels, vWf released

e.g. surgery or cannula

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22
Q

give example of when a hyper-coagulant state contributes to thrombosis?

A

e. g.
- in sepsis, your entire system becomes hyper coagulated causing death
- there could be a genetic predisposition
- when taking drugs like HRT and oestrogen
- pregnancy because oestrogen levels are very high so you have a high hyper-coagulable state

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23
Q

why might you have a hyper-coagulant state while pregnant?

A

because of high oestrogen levels

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24
Q

what are the roles of valves in veins?

A

they prevent backflow of blood

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25
Q

what does the contraction of nearby muscles do to veins and why might it cause stasis?

A

squashes veins, acting as a pump to return blood to the heart

blood tends to eddy (eddy = circular movement) around the valves and doesn’t move as much, increasing the risk of stasis

26
Q

Deep Vein Thrombosis

A
  • If venous return is blocked, the affected organ becomes congested with fluid
  • There is increased pressure so there is more filtration
27
Q

what is the risk with deep vein thrombosis?

A

risk that the thrombosis might become dislodged and make its way back to the heart

28
Q

what are the different fates of a thrombus?

A
  1. Resolution i.e. thrombolysis, where the clots breaks down
  2. Embolism i.e. moves to another location and lodges somewhere else, blocking a vessel
  3. Organised i.e. clot becomes covered by the endothelium, and the vessel will become slightly narrower and less stretchy
  4. Recanalised and Organised i.e. reanalysed is where holes can be made in the thrombus
    and the blood forces its way through. These holes can become organised as new endothelial cells can grow on their insides
29
Q

how can an embolic stroke happen

A

clot can enter the brain and lodge in a vessel and cause an embolic stroke

30
Q

where does proximal DVT occur and what are the symptoms?

A
  • occurs in deeper vessels

- pain, swelling, maybe even ulcers

31
Q

where does distal DVT occur?

A
  • distal is when it occurs down in the lower leg
32
Q

why is distal DVT rarely that serious?

A

because the vessels in the lower leg are quite small

33
Q

which one has a higher risk of pulmonary embolism and post-thrombotic syndrome: proximal or distal DVT?

A

proximal has a higher risk of pulmonary embolism and post-thrombotic syndrome

distal rarely causes pulmonary embolism or post-thrombotic syndrome

34
Q

what is post-thrombotic syndrome?

A
  • when the thrombus doesn’t break off and lodge somewhere else
  • inflammation along with venous damage to the venous valves from the thrombus itself
  • valvular incompetence combined with persistent superficial obstruction inducing a rupture of small superficial veins, subcutaneous haemorrhage and an increase of tissue permeability
35
Q

what are the symptoms of post-thrombotic syndrome?

A
  • pain
  • swelling
  • discoloration
  • ulceration
36
Q

if the thrombus breaks off, where can it go to?

A

the RHS of the heart

37
Q

when does a saddle embolism occur?

A

large venous thrombus travels to the heart and as its leaving the RV it gets lodged and sits at the bifurcation of the pulmonary artery, blocking both pulmonary arteries

causes rapid death

38
Q

small venous thrombus and large venous thrombus - which one is asymptomatic and which one causes rapid death?

A

small - asymptomatic

large - rapid death

39
Q

what happens in platelet adherence?

A
  • Von Willebrand factor on subendothelial cells activates platelets (change shape a little bit). Platelets bind to these sub endothelial cells (specifically the collagen)
  • Circulating VWF may bind to exposed subendothelial cells
  • Activated endothelial cells can also express VWF
40
Q

what happens in platelet activation?

A
  • The activated platelets start to release factors that escalate things
  • They release Thromboxane A2 (TxA2) & Adenosine diphosphate (ADP) which induce receptors for fibrinogen
  • These bind to receptors on adjacent platelets and increase the expression of the glycoprotein complex GPIIb/IIIa. These factors behave in a paracrine (causes a change in adjacent cell) and autocrine fashion (causes a change in itself)
  • Platelets can also be activated by thrombin, collagen and many other mediators
41
Q

what happens in platelet aggregation?

A
  • Fibrinogen acts as a loose tether holding the platelets together (this is not blood coagulation, first sign of clotting but it is not actually clotting them yet)
  • Fibrinogen is the soluble precursor to fibrin and is in the circulating in the blood
42
Q

3 stages of platelets

A

adherence, activation, aggregation

43
Q

when there is a clump of platelets, what do they form?

A

a negatively charged phospholipid surface which is required for coagulation
(the conversion of fibrinogen tethers into fibrin and then cross linking of the fibrin clot)

44
Q

what are the coagulation pathways?

A
  • you can have the extrinsic or intrinsic pathway, which both lead into the common pathway
  • there is amplification of the signal at each step
  • there are multiple steps at which you can inhibit the process
  • small amounts of activated factors can have a big effect
45
Q

where are these factors that are involved in the coagulation pathways?

A

circulating around in the blood

46
Q

difference between the extrinsic and intrinsic pathways?

A

intrinsic is when you have a damage surface (eg. put blood onto a charged surface such as glass), extrinsic is with trauma

trauma means factor 7 will be activated

47
Q

what is the common pathway?

A
  • bulk of the coagulation pathway

- the common pathway reactions are easily overpowered by inhibitors

48
Q

explain the process of the common pathway:

A
  1. Factor IXa cleaves Factor X to form Factor Xa (also known as FXa)
  2. FXa cleaves prothrombin forming thrombin (FIIa), a protease which cleaves fibrinogen (a large molecule present in the plasma) into insoluble fibrin
  3. Thrombin cleaves factors V and VIII to form FVa & FVIIIa
  4. FVa and FVIIIa along with Ca2+ form 2 separate complexes: Tenase complex and Prothrombinase complex
  5. These complexes assemble on the charged phospholipid surfaces of activated platelets
  6. FVa & FVIIIa amplify the existing reactions making them hard to overpower
  7. Once enough thrombin has been generated, FXIII is activated, which crosslinks the fibrin fibres into a solid clot
49
Q

how does fibrinogen promote blood clotting?

A

by activating and forming bridges between blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor

50
Q

what is the business end of the clot?

A

To go from Fibrinogen to Fibrin to Cross-Linked Fibrin.

51
Q

how do the tenase and prothrombinase complex form?

tenase complex causes prothrombinase complex

A

Tenase complex: FVIIIa + FIXa = FXa

Prothombinase complex: FXa + FVa= Thrombin

52
Q

what does the prothrombinase complex consist of and where does it assemble?

A

factor Xa and its cofactor Va

  • assembles on the negatively charged phospholipid membrane of activated platelets in the presence of calcium ions, specifically the GLA domain (10-12 glutamic acids in the N-terminus of the molecule)
  • Factor X is bound to the –vely charged phospholipid via the GLA domain. Activating FX converts prothrombin to thrombin, which can make the fibrinogen (the tether).
53
Q

what is this process of converting prothrombin to thrombin dependent on and why?

A

Vitamin K dependent process

-need it to make the GLA domain

54
Q

how does warfarin affect the conversion of prothrombin to thrombin?

A

warfarin inhibits production of carboxygutamic residues in the GLA domain
-conversion is prevented

55
Q

how does the extrinsic pathway occur?

A

The extrinsic pathway is triggered by TF which activates FVII and Ca2+

Tissue factor (present on the sub endothelial cells which the blood does not normally see) is a receptor for FVIIa which is also bound to a negatively charged surface of platelet phospholipids along with calcium
a.	Once activated, FVIIa activates FXa and the common pathway is initiated
56
Q

where is TF present?

A

present on most subendothelial cells

57
Q

what happens when TF is exposed?

A

TF is exposed if the endothelium is damaged: ready for FVIIa to bind to and initiate coagulation

58
Q

do defects in the factors/mutations in the enzymes of the intrinsic pathway or defects in the factors of the extrinsic pathway have larger physiological effects?

A

extrinsic pathway defects/mutations have far larger physiological effects

59
Q

laboratory tests

A
  • Intrinsic pathway forms the basis of laboratory tests of coagulation
  • lab test distinguish between activating the intrinsic or extrinsic pathways in order to assess where a defect may be
60
Q

does intrinsic or extrinsic happen more in vivo?

A

extrinsic

61
Q

what can tPa be used to treat?

A

strokes and myocardial infarctions

62
Q

how is heparan involved in AT and inhibition of clotting?

A
  • Heparan binds to the enzyme inhibitor antithrombin III (AT, expressed by the endothelial cells), causing a conformational change that results in AT activation
  • Activated AT inactivates thrombin, factor Xa, factor VII and other proteases in the coagulation cascade

sem 2 CVS (17 decks)

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