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Cardio and Resp Week 3 > Hemostasis, Thrombosis and treatment > Flashcards

Hemostasis, Thrombosis and treatment Flashcards

1
Q

Define hemostasis

A

The process by which blood leakagae from a vesel is stopped.

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2
Q

State the 3 stages of hemostasis

A
  • Vasoconstriction
  • Platelet plug formation
  • Coagulation cascade
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3
Q

Define thrombosis

A

Formatoin of a blood clot in blood vessels or heart that occludes blood flow.

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4
Q

State ways in which blood coagulation and platelet activation is normally supresed

A
  • Undamaged endothelium is said to be non-thrombogenic, and only becomes thrombogenic upon damage
  • Layer of GLYCOCALYX on the surface of endothelial cells
  • Endothelial cells produce prostacyclin and nitric oxide
  • Presence of natural anticoagulants in the blood, such as Anti-thrombin 3 (also known as as Antithrombin Heparin cofactor)
  • Surface protein called thrombodulin binds to thrombin, preventing it converting fibriniogen to fibrin
  • Heparin, although it only really works with Antithrombin 3, imrpoves the effectiveness of antithrombin 3 by 100 fold
    • ​Effects are quite low physiologically, but heparin is typically used more in blood storge
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5
Q

Describe the process of vascular spasm in hemostasis. Why is it caused? How long does it typically last?

A
  • Immediately after blood vessel injury, smooth muscle in the blood vessel tunica media causes walls to contract
  • Spasm caused by:
    • Release of substances from damaged tissues
    • nervous reflexes
  • Last minutes to hours
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6
Q

On the platelet cell membrane is a coat of that repulses adherence to normal endothelium and causes adherence to injured areas of the vessel wall, particularly to exposed

A

Glycoproteins

Collagen

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7
Q

Describe the platelet plug formation stage of hemostasis

A
  • platelets are exposed to damaged vascular surface, causes individual platelets to swell and activate various pseudopods that allow
  • The platelet surface becomes sticky
  • They release substances that promote further vasconstriction and promote platelet aggregation
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8
Q

State the substances that platelets secrete when exposed to endothelial damage

A
  • Thromboxane A2
  • Serotonin (5-HT)
  • ADP (responsible for the stickiness.

All of these act as vasconstrictors and also activate other platelets.

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9
Q

What is the coagulation cascade?

A

Enzyme cascade in which a lood clot is formed

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10
Q

Over what time scale will a clot form?

A

Minor injury: 1-2 minutes

Severe - 15-20 seconds

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11
Q

Starting from when we have generated Prothrombin activator, state the steps that result in the generation of a clot

A
  • Prothombin activator in sufficient amounts of CALCIUM causes conversion of prothrombin to Thrombin
  • Thrombin causes the polymerizaton of fibrinogen into fibrin fibres within 10-15 seconds
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12
Q

Which organ produces pro-thrombin?

A

The liver

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13
Q

What organ is responsible for production of most coagulation factors?

A

Liver

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14
Q

Explain the differences in TRIGGERS for the extrinsic and intrisic pathways - bearing in mind both lead to the formation of protrhombin activator, which then causes prothrombin conversion to THROMBIN, and all of the subsequent clotting steps.

A
  • Extrinsic pathway is triggered by substances (TISSUE FACTOR) leaking from EXTRAVASCULAR TISSUES
  • Intrisic pathway is triggered by exposure of blood to collagen from traumatized blood vessel wall
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15
Q

The clot itself is formed of a meshwork of fibrin fibres running in all directions and entrapping red blood cell, platelets and plasma. Within a few minutes of forming, a clot begins to CONTRACT. The fluid from inside the clot is expelled from the clot, and is reffered to as SERUM. This is because unlike plasma it does not contain fibrinogen and other clotting factors. Therefore, can serum clot?

A

NO

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16
Q

Explain what hapens during clot retraction. What is the role of fibrin stabilizing factor?

A
  • After 20-60 minutes, clot contracts ad expells the serum fluid
  • Pulls the fibrin framework together in order to form a smaller mass
  • Pulls the edges of the broken blood vessel together
  • Platelets are cruical for the retraction process. platelets release fibrin stabilizing factor which causes more and more cross-linking between fibrin
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17
Q

The fibrinolytic system is the physiological repair system for removing blood clots, which involves generation of what enzyme(also namethe pro enzyme)? What does this enzyme act on?

A

Plasmin (plasminogen)

FIbrin

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18
Q

Explain how the activation of plasminogen leads to the dissolution of clots

A
  • When a clot is formed a large amont of plasminogen is trapped
  • This plasminogen will not cause lysis of fibrin until it is properly activated
  • The injured endothelium will slowly reease Plasminogen activator - after a few days, this will convert plasminogen to plasmin, which in turn removes the clot
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19
Q

What is the name of the system that dssolves clots

A

Fibrinolytic system

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20
Q

Define thrombosis, thrombus and emboli

A
  • Thrombus is a just a word for clot
  • Thrombosis is a pathology when a thrombus occludes a blood vessel
  • Emboli is when a portion of a clot breaks off and is essentially just floating in the blood
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21
Q

Describe the difference between arterial and venous thrombosis (include diffrence between white and red thrombi) . Also state where each of these most commonly occurs.

A

Arterial Thrombosis

  • These clots are primary WHITE due to HIGH platelet content, and are typically at the sight of atherosclerotic plaque rupture
  • Typically occurs at Coronary artery, or cerebral artery - can lead to MI or Stroke

Venous Thrombosis

  • These clots are RED because of the high fibrin content and number of trapped erythrocytes
  • Often occurs in deep veins in legs- Possible that a fragment can bud off and form pulmonary embolus
  • Can happen to lack of activity (economy class syndrome)
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22
Q

Define Anticoagulatnts, antithromboitcs and thrombolytics

A

Anticoagulants - Inhibits the blood coagulation cascade

Anti-thrombotics - Inhibit the activation of platelets

Thrombolytics (fibrinolytics) - Dissolves blood clots

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23
Q

Anticoagulent agents are used for what two purposes

A
  • Prevention of venous thrombosis
  • Storage of blood outside body for analysis or transfusion
24
Q

Anti-platelet(anti-thrombotic) drugs are used to treat what?

A

Arterial thrombosis

25
Q

What is Von Willebrand disease?

A
  • Blood clotting disorder
  • Deficiency of Von Willebran factor which binds factor 8 and binds platelets to collagen
26
Q

What is Haemophillia A?

A

Deficieny in factor 8

27
Q

What is hemophillia B

A

Deficiency in factor 9

28
Q

What is Haemophillia C?

A

Deficiency in Factor 11

29
Q

Haemophillia A and B are X-linked. What does this mean?

A
  • Males carrying the mutation will have have the phenotype
  • Females only have the phenotype if they have two mutated X chromosomes
30
Q

The heparaprin-anthirthrombin III complex inhibits which clotting factors?

A

2a, 9a, 10a, 11a, 12a

31
Q

How is Heparin typically administered?

A

IV

32
Q

Does heparin cross the BBB?

What are some uses of heparin? (in vivo and in vitro)

A

NO

  • Treatment of DVT (stops the clots that are already there getting bigger)
  • Pre-eclampsia
  • In vitro anti-coagulant
33
Q

What are side effects of heparin?

A
  • Risk of hemorrhage
  • Possible allergic reactions
34
Q

What protein is a heparin antagonist and is used to reverse the side effects of heparin therapy?

A

Protamine

35
Q

Oral anticoagulants are typically Vitamin antagonists.

What drug is a structural analogue of this vitamin?

A

K

Warfarin

36
Q

Explain the mechanism of warfarin (mention how vitamin K works)

A
  • Vitamin K is involved in the carboxylation of glutamic residues in clotting factors 2, 7, 9 and 10
  • Warfarin blocks vitamin K recycling and therefore CARBOXYLATION of factors 2,7,9 and 10 therefore calcium is unable to bind on, and coagulation doesn’t take place.
37
Q

Why would you not prescribe both aspirin and warfarin at the same time?

A

Because there would be a much higher chance of hemorrhage.

38
Q

Give uses of warfarin

A
  • Venous thrombosis (to prevent further growth of clots)
  • prevent pulmonary embolism
  • Prophylaxis of thrombosis in patients with insertion of prosthetic heart valves
39
Q

What are the side effects of warfarin?

A
  • Risk of hemorrhage
  • Crosses the BBB and placenta - should not be used in pregnancy as it could cause hemorrhage in foetus
40
Q

How the effects of warfarin be reversed?

A
  • transfuse patient with coagulation factor concentrates
  • Oral vitamin K can given but reversal is slow since carboxylation of coagulation factors takes a while
41
Q

Warfarin has a small theraputic window, with there being a balance between giving too little (therefore not preventing clotting), and giving too much and increasing the risk of hemorrhaging.

Explain what is meant by International Normalisation Ratio for Warfarin prescribing

A

The high incidence of haemorrhage requires careful monitoring of patient’s clotting time (PT ratio) assessed using the International Normalisation Ratio (INR)

The INR is derived from the ratio of a patient’s prothrombin time to a normal (control) sample (which is not on any medications).

  • Higher INR increases the risk of haemorrhage
  • Lower INR increases the risk of thrombosis.

Monitoring in inconvenient and expensive. There are

usually warfarin clinics that patients have to attend.

42
Q

GIve examples of newly introduced oral anticoagulants and state how they work

A
  • Dabigatran exilate (directly inhibits thrombin)
  • Rivaroxaban (Factor 10a inhibitor)

Both of these act very quickly

43
Q

How long does it take for the effects of warfarin to manifest?

A

1-3 days

44
Q

What is the classic go-to antiplatelet drug?

A

Aspirin

45
Q

Explain how aspirin acts as an anti-platelet therapy. What is a typical dose of aspirin for anti-platelet therapy

A
  • Usually start with a high dose of 300mg to inhibit thromboxane synthesis followed by regular daily doses of 75mg
  • Aspirin acetyates a serine residue on the active site of COX1
  • Unlike nucleated cells, platelets cannot synthesize protein due to a lack of nucleus,
46
Q

Explain how dipridamole is used as an anti-thrombotic

A
  • Inhibits platelet aggregation by inhibition of cyclic nucleotide phosphodiesterase
  • Results in an INCREASE in the build of cAMP and cGMP, thereby enhancing the effects of prostacyclin and nitric oxide
47
Q

Explain how Adenosine receptor antagonists can be used as anti-thrombotics

A
  • Under normal circumstances, ADP can induce platelet aggregation by binding to the GPCR P2Y12
  • Adenosine receptor antagonists bind irreversigbly to the P2Y receptor via a disulphide bond
48
Q

Explain how abciximab can be used as an anti-thrombotic therapy

A
  • Gycloprotein 2b/3a under normal circumstances is expressed on the surface of platelets
  • These receptors undergo conformational change upon activation by endothelial damage, which allows them to bind fibrinogen
  • This allows bridges to be formed between platelets and allows platelet adhesion
  • Abciximab binds to the glycoprotein receptors, therefore impairing platelet adhesion
49
Q

Explain how Epoprostenol can be used as an anti-thrombotic therapy

A
  • Is an IP receptor (prostacyclin receptor) antagonist
  • Given IV
  • Prostacyclin typically causes vasodilation as well as inhibiting platelet aggregation
50
Q

Thrombolytics (Fibrinolytics) are therapies used to dissolve clots.Explain how Streptokinase can be used as a thrombolytic

A
  • Streptokinase is a protein extracted from cultures of streptococci bacteria
  • Streptokinase activates plasminogen
51
Q

How is the host immune system problematic with streptokinase?

A
  • Host will produce antibodies against it, meaning the dose should not be repeated after it has been used
  • Also cannot be used after a streptococcal infection
52
Q

What are side effects of streptokinase

A
  • Risk of hemorrhage
  • Allergy
53
Q

What are Alteplase and duteplase?

A
  • Human recombinant plasminogen activator
  • Binds to fibrin that is already in a clot - whilst in the clot, it activates plasminogen to form plasmin - allowing degradation of the clot
  • Does not give rise to antibodies like Streptokinase
54
Q

Explain the difference between hemorrhagic stroke and ischaemic stroke

A
  • Hemorrhagic stroke is when there is a bleed from an artery in the brain
  • Ischaemic stroke is when there is occlusion of portion of the brain
55
Q

What are the main two uses of fibrinolytics?

A

Venous thrombosis

Ischaemic stroke

56
Q

What type of stroke should fibriniolytics NEVER be used?

A

Hemorrhagic stroke

57
Q

If there is an incidence of hemorrhage in use of fibrinolytics, which can be used to stop the bleed?

A

Tranexamic acid (inhibits fibrinolysis)

Cardio and Resp Week 3 (6 decks)

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