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Physiology 1 > Thrombosis/Haemostasis > Flashcards

Thrombosis/Haemostasis Flashcards

1
Q

What is Haemostasis?

A

Defined as the process of arresting (stopping) bleeding and keeping blood within a damaged blood vessel.

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2
Q

What are the 2 types of haemostasis?

A

Primary haemostasis – Aggregation of platelets to form platelet plug which serves as the basis of a blood clot.

Secondary haemostasis – Formation of cross – linked fibrin forms fibrinogen. Fibrin stabilises the platelet plug formed in primary haemostasis.

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3
Q

What is an anticoagulant and how does it work?

A

Anticoagulants, e.g. heparin and warfarin, prevent or reduce coagulation, clotting, of the blood.
Most anticoagulants work by inhibiting one of the proteases involved in the clotting cascade.

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4
Q

What is fibrinolysis?

A

Fibrinolysis is a process that leads to the break down of blood clots

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5
Q

What is the main enzyme involved in fibrinolysis and How does it work?

A

Plasmin, a protease, cleaves the clot at multiple places producing fragments, D dimers. These D dimers are then are the degraded by other proteases.

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6
Q

What can cause a thrombus to form in an artery?

A

Arterial thrombi may be caused by atheroma rupture or damage to the endothelium (eg. MI, stroke).

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7
Q

What can cause a thrombus to form in a vein?

A

Conditions where there is venous stasis or a hyper-coagulant state (e.g. Deep vein thrombosis).

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8
Q

Describe the differences between the composition of a venous thrombus and an arterial thrombus?

A

Arterial thrombi are composed of lots of activated platelets with some fibrin while venous thrombi are composed of a lot more fibrin with few platelets as well as red blood cells.

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9
Q

What are the 2 types of embolism that can form from a dislodged venous thrombus?

A

Pulmonary embolism

Paradoxical embolism

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10
Q

How can a paradoxical embolism form?

A

Formed if thrombus moves from venous to arterial circulation. Can occur if a foramen ovale is still present or if there’s an atria/ventricular defect.

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11
Q

What is tissue factor and where can it be found?

A

Tissue factor is a transmembrane receptor for coagulation factor VII. it is found within the subendothelial cells.

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12
Q

What role does tissue factor have within coagulation?

A

Binding of coagulation factor VII within the blood to tissue factor initiates the extrinsic pathway of the coagulation cascade.

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13
Q

Apart from tissue factor what else can also be found within the subendothelial cells?

A

von Willebrand factor

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14
Q

What is von Willebrand factor?

A

It is a glycoprotein which binds to other proteins involved in the coagulation cascade.

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15
Q

What are some of the proteins that von Willebrand factor binds to and what are the effects of this binding?

A

Binds to factor VIII thus stabilising it.

Also binds to certain glycoprotein receptors present on platelets which allows them to aggregate and adhere to the exposed collagen of the damaged vessel.

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16
Q

What is heparan and what does it do?

A

Heparan is a substance that is structurally similar to the anticoagulant herparin. It binds to the protein Antithrombin causing a conformational change in shape leading to its activation.

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17
Q

What is antithrombin and how does it inhibit coagulation?

A

Antithrombin is a glycoprotein that binds to and causes the inactivation of several coagulation factors within the coagulation cascade including thrombin.

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18
Q

Apart from antithrombin, what other substances inhibit coagulation? How do they do this?

A

Nitric oxide and Prostacyclin both inhibit platelet activation

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19
Q

What is tissue plasminogen activator?

A

Tissue plasminogen activator is a serine protease found on endothelial cells

20
Q

How does tissue plasminogen activator initiate fibrinolysis?

A

It catalyses the reaction that causes plasminogen to be converted into plasmin
Plasmin then cleaves the fibrin clot at various points to form D dimers

21
Q

What are the 3 main factors that contribute to thrombosis as described by Virchow’s triad?

A

Stasis - static blood lacks kinetic energy and tends to clot
Hyper-coagulant state
Endothelial damage

22
Q

How does blood flow through venous valves contribute to thrombosis?

A

Flow of blood through the valves of the veins isn’t that smooth and blood tends to eddy, move in a circular motion, which increases the risk of the blood becoming static and therefore increases the risk of thrombosis

23
Q

What is deep vein thrombosis?

A

Formation of a blood clot (thrombus) within a deep vein in the body, usually in the leg.

24
Q

How does deep vein thrombosis lead to the formation of an oedema?

A

Thrombus blocks venous return meaning the leg swells with fluid - oedema.
This is because the Increased hydrostatic pressure caused by the thrombus means more filtration - fluid moves from vein to the interstitial fluid causing imbalance.

25
Q

What are the 2 types of deep vein thrombosis that can occur?

A

Distal deep vein thrombosis

Proximal deep vein thrombosis

26
Q

Why is distal DVT less dangerous than proximal DVT?

A

Distal veins are smaller than proximal ones so thrombus formed in distal DVT are quite small. This means it will rarely cause a pulmonary embolism or post-thrombotic syndrome as thrombus isn’t large enough to block the veins.
Thrombus formed from proximal DVT are bigger and so can block the veins and cause these problems.

27
Q

What is post-thrombotic syndrome? What are some of the symptoms?

A

post-thrombotic syndrome is a chronic complication of DVT.

Symptoms include: Pain, swelling (oedema), skin discolouration

28
Q

How does DVT lead to the occurrence of the symptoms of post-thrombotic syndrome?

A

Inflammation and damage to the venous valves from the thrombus itself leads to valvular incompetence, when valves don’t close properly.
This combined with the persistent venous obstruction from the thrombus increases the pressure in the veins.
This increase in pressure in the veins causes rupture of superficial veins, subcutaneous haemorrhage as well as increase in tissue permeability

29
Q

What can occur to a small venous thrombus once formed?

A

May go through embolisation and lodge in the heart or go through it and lodge somewhere else within the body, e.g. lungs
In the lungs it may cause slight VQ mismatch or a small infarct zone
May also be broken down via fibrinolysis

30
Q

What can occur to a large venous thrombus once formed?

A

May go through embolisation and end up in the heart where it can cause saddle embolism. This is when a thrombus blocks both pulmonary arteries leading to death.
More likely to cause a pulmonary embolism as a saddle embolism is very rare.

31
Q

How do platelets adhere to the damaged surface of a blood vessel during coagulation?

A

Tissue damage exposes endothelial cells causing the release of the Von Willebrand factor from the subendothelial cells.
Once released the A1 domain of the Von Willebrand factor will bind to the GP Ib-IX-V complex found on platelets causing the platelets to adhere to the exposed collagen at the area of tissue damage.

32
Q

Once the platelets adhere to collagen what occurs?

A

Granules within the platelet release thromboxane A2 (TxA2) and Adenosine diphosphate (ADP).
These bind to their respective receptors on the platelets which causes the intracellular calcium levels within the platelets to increase.

33
Q

In what manner do thromboxane A2 and Adenosine diphosphate bind to their receptors on the platelets?

A

Bind to the platelets in a autocrine and paracrine way – They bind themselves and other platelets.

34
Q

What does the intracellular increase in calcium result in?

A

This increase in calcium causes the platelet to change shape but also triggers the calcium-dependent association of GPIIb and GPIIIa to form the glycoprotein receptor complex GPIIb/IIIa.
GPIIb/IIIa complex is then able to bind fibrinogen.

35
Q

What binds to the GPIIb/IIIa complex once it is formed and what occurs as a result of this binding?

A

Fibrinogen binds to GPIIb/IIIa complex on adjacent platelets and as a result causes adjacent platelets to aggregate together.

36
Q

What do the platelets form once they aggregate together?

A

Form a negatively charged phospholipid surface which is required for coagulation

37
Q

What are the 3 pathways involved in the coagulation casacade?

A

Intrinsic pathway
Extrinsic pathway
Common pathway

38
Q

Describe the steps involved in common pathway

A
  1. Factor IXa activates Factor X by proteolysis to create Factor Xa.
  2. Factor Xa cleaves prothrombin to form thrombin (IIa).
  3. Thrombin cleaves fibrinogen to form fibrin
  4. Thrombin also activates other factors involved in the coagulation cascade such as V and VIII and factor XIII.
  5. Once XIII is then activated, which crosslinks the fibrin fibres into a solid clot.
39
Q

What is required for the activation of Factor X and for the conversion of prothrombin into thrombin?

A

Both of these steps require the assembly of procoagulant enzymatic complexes

40
Q

What are the 2 procoagulant enzymatic complexes required?

A

Tenase complex - activates factor X

Prothrombinase complex - converts prothrombin to thrombin

41
Q

What is the basic structure of these procoagulant enzymatic complexes? Apply this basic structure to the tenase and prothrombinase complexes.

A

Composed of an enzyme, a cofactor, and the substrate associated on a cell surface

Tenase complex - factor IXa (enzyme), factor VIIIa (cofactor) and factor X (substrate)

Prothrombinase complex - factor Va (enzyme), factor Xa (cofactor) and prothrombin, factor II, (Substrate)

42
Q

Why do both of these complexes bind to the platelet membrane?

A

They are both activated by negatively charged surfaces such as the platelet membrane?

43
Q

How do these complexes bind to the platelet membrane?

A

Bind to the negatively charged membrane phospholipids via the GLA domain

44
Q

What is the GLA domain?

A

Protein domain that contains 10-12 glutamic acids in the N-terminus of the molecule which get converted to gamma-carboxyglutamic acid (Gla) residues via vitamin K-dependent carboxylation.

45
Q

Why are calcium ions also needed for these complexes to become active?

A

Calcium ions help the Gla residues promote the binding of the substrate to the platelet membrane.

46
Q

Describe the steps of the extrinsic pathway

A
  1. Trauma to vessel exposes subendothelial cells and tissue factor
  2. Factor VII binds to Tissue factor which is bound to a negatively charged surface of platelet phospholipids along with calcium.
  3. This binding causes Factor VII to become activated and form Factor VIIa (activated factor VII).
  4. Factor VIIa then goes on to become part of the tenase complex and activate factor X causing the common pathway to be initiated.
47
Q

Describe the steps of the intrinsic pathway

A
  1. Factor XII becomes activated once it becomes exposed to collagen of damaged vessel
  2. Factor XIIa acts as a catalyst to activate factor XI to Factor XIa
  3. Factor XIa then goes on to activate factor IX to factor IXa
  4. Factor IXa then goes on to form the tenase complex along with factor VIIa
  5. Tenase complex goes on to activate factor X leading to the common pathway being initiated.

Physiology 1 (31 decks)

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