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Medicine Sem 2 > Case 8 > Flashcards

Case 8 Flashcards

1
Q

when there is damage to a vessel, haemostasis is achieved via several mechanisms. what are they?

A
  1. vascular constriction
  2. formation of platelet plug
  3. formation of blood clot as a result of blood coagulation
  4. eventual growth of fibrous tissue into the blood clot to close the hole in the vessel permanently (fibrinolysis)
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2
Q

describe vascular constriction

A
  • most immediate protection against blood loss
  • upon damage to a vessel, the smooth muscle in the vascular wall contracts due to the activation of the sympathetic nervous system

The smooth muscle contraction results from:

  1. nervous reflexes - initiated by pain nerve impulses that originate from the traumatised vessel or nearby tissues
  2. local myogenic spams (vasospasm)
    - increases the vasoconstriction further as a result of local myogenic contraction of the blood vessels
    - this can last for minutes or even hours, during which time the processes of platelet plugging and blood coagulation can take place
    - initiated by direct damage to the vascular wall
  3. local autacoid factors e.g. endothelin and serotonin
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3
Q

for smaller vessels, what is primarily responsible for the vasoconstriction?

A
  • platelets

- by releasing a vasoconstrictor substance, thromboxane A2

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4
Q

how big are platelets?

A

1-4 micrometres in diameter

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5
Q

how many platelets are produced from 1 megakaryocyte?

A

4000

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6
Q

how are platelets eliminated?

A
  • eliminated from the circulation by the tissue macrophage system
  • more than a half of all platelets are removed by macrophages in the spleen
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7
Q

what’s in the cytoplasm of an activated platelet?

A
  1. Contractile proteins: Actin, myosin and thrombosthenin.
  2. Residuals of both the endoplasmic reticulum and the Golgi apparatus that synthesize various enzymes and especially store large quantities of calcium ions.
  3. Mitochondria that are capable of forming ATP and ADP.
  4. Enzyme systems that synthesize prostaglandins.
  5. Fibrin-stabilizing factor, involved in blood coagulation.
  6. A growth factor that causes vascular endothelial cells, vascular smooth muscle cells, and fibroblasts to multiply and grow, thus causing cellular growth that eventually helps repair damaged vascular walls.
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8
Q

what does the cell membrane of activated platelets contain?

A
  1. glycoproteins
    - these repulse adherence to normal endothelium
    - instead, they cause adherence to injured areas of the vessel wall, especially to injured endothelial cells and even more to exposed collagen from deep within the vessel wall
  2. phospholipids
    - these are present in large amounts
    - these activate multiple stages in the blood-clotting process
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9
Q

what are the stages of platelet plug formation?

A
  1. adhesion and activation
  2. secretion/release
  3. aggregation
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10
Q

describe the process of platelet plug formation

A

when platelets come in contact with a damaged vascular surface, especially with collagen fibres in the vascular wall, the platelets change their characteristics drastically:

  • they begin to swell
  • they assume irregular forms with numerous irradiating pseudopods protruding from their surfaces
  • there is also a structural change from small rounded discs to flat plates with markedly increased surface area
  • their contractile proteins contract forcefully and cause the release of granules that contain multiple active factors
  • they begin to adhere to collagen in tissues and to the protein called von Willebrand factor that leaks into the traumatised tissue from the plasma
  • glycoprotein Ib (GpIb), found on the cell membrane of the platelets adheres to the collagen by binding to vWF
  • glycoprotein IIb-IIIa adheres to the collagen by binding to vWF
  • the vWF acts as a bridge between platelet surface receptors and exposed collagen
  • glycoprotein Ia (GpIa), found on the cell membrane of the platelets, adheres to the collagen by direct binding to the collagen
  • activated platelets secrete large quantities of ADP
  • prostaglandin synthesis is activated, which results in the production of thromboxane A2
  • the ADP and the thromboxane A2 induce additional platelet aggregation through: activating other platelets, platelet GpIIb-IIIa receptor binding to fibrinogen, increasing vasoconstriction
  • activated platelets secrete serotonin which increases vasoconstriction
  • activated and damaged endothelial cells secrete endothelin, causing vasoconstriction
  • this cascade effect of activated platelets activating more platelets forms the platelet plug
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11
Q

what’s the platelet plug like at first? and how does it change?

A
  • usually loose at first, but it’s successful in blocking blood loss if the vascular opening is small
  • then, during the subsequent process of blood coagulation, fibrin threads form - these attach tightly to the platelets, thus constructing an unyielding plug
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12
Q

why does a blood clot form?

A

as a result of continuous platelet activation and aggregation with the invasion of fibroblasts

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13
Q

what happens after the clot is formed?

A

it retracts, closing the vessel further by pulling the damaged endothelial cells together

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14
Q

what is a blood clot composed of?

A
  • a meshwork of fibrin fibres running in all directions and entrapping blood cells
  • platelets
  • plasma
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15
Q

what are the two courses a blood clot can follow once it has been formed?

A
  1. it can be invaded by fibroblasts, which will subsequently form connective tissue all through the clot
  2. it can dissolve
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16
Q

describe the invasion of fibroblasts

A

normally, the course of the invasion by fibroblasts is followed
- this begins within a few hours after formation of the blood clots which is promoted at least partially by growth factor secreted by the platelets

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17
Q

describe the dissolution of a blood clot

A

when excess blood has leaked into the tissues and tissue clots have occurred where they are not needed, special substances within the clot itself usually become activated

  • these function as enzymes to dissolve the clot - prostacyclin
  • the breakdown product of fibrinolysis (dissolving of the clot by breaking down fibrin) is a protein called D-dimer
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18
Q

what is prostacyclin?

A

its synthesised by endothelial cells lining the walls of arteries and veins; it’s a potent vasodilator and a potent inhibitor of platelet aggregation

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19
Q

what does whether the blood will coagulate depend on?

A

the balance between the coagulant and anticoagulant factors:

  • in the blood, the anticoagulants predominate so that the blood does not coagulate while it’s circulating in the blood vessels
  • when a vessel is ruptured, procoagulants from the area of tissue damage become ‘activated’ and override the anticoagulants and then the clot develops
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20
Q

what is TF/FIII?

A

tissue factor

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21
Q

what is FII?

A

prothrombin

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22
Q

which coagulation factor is associated with haemophilia A and B?

A

FVIII and FIX

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23
Q

where are most coagulation/anticoagulation/co-factors produced?

A

in the liver

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24
Q

what are the substances that play a minor role in blood coagulation?

A
  • high molecular weight kininogen (HMWK)
  • prekallikrein

These substances form a complex on damaged collagen and are activated to:

  • kininogen
  • kallikrien
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25
Q

does deficiency of HMWK or prekallikrein result in bleeding disorders?

A

nope

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26
Q

blood coagulation takes place in three essential stages - what are these?

A
  1. prothrombin activator is formed from the extrinsic/intrinsic pathway
  2. prothrombin activator, in the presence of Ca2+ converts prothrombin to thrombin
  3. thrombin causes polymerisation of fibrinogen molecules into fibrin fibres
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27
Q

what also plays an important role in the conversion of prothrombin to thrombin?

A

platelets because much of the prothrombin first attaches to prothrombin receptors on the platelets already bound to the damaged tissue

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28
Q

what is prothrombin? where’s it formed?

A

prothrombin is an unstable plasma protein formed in the liver, that can split easily into thrombin
- prothrombin is formed continually by the liver and it’s continually being used throughout the body for blood clotting

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29
Q

which vitamin is required by the liver and why?

A

vitamin K is required by the liver for normal formation of prothrombin and a few other clotting factors

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30
Q

describe the extrinsic pathway for initiating the formation of prothrombin activator

A

it begins with a traumatised vascular wall or traumatised extravascular tissues that come in contact with the blood
this leads to the following steps:
1. traumatised tissue releases tissue factor (TF) - a complex of phospholipids and a lipoprotein
2. TF activates FVII into FVIIa (lipoprotein + factor VII = VIIa)
3. TF and FVIIa (TF:VIIa) together, under the influence Ca2+ ions, activate FX forming FXa
4. FXa combines with phospholipids (from TF) and FV, under the influence of Ca2+, forming prothrombin activator

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31
Q

what is an accelerator of prothrombin activation?

A
  • in the presence of calcium ions, prothrombin splits to form thrombin
  • at first, the Factor V in the prothrombin activator complex is inactive, but once clotting begins and thrombin begins to form, the proteolytic action if thrombin activates Factor V
  • this then becomes an additional strong accelerator of prothrombin activation
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32
Q

what does the final prothrombin activator complex consist of?

A
  • FXa and FV
  • FXa is the actual protease that causes splitting of prothrombin to form thrombin
  • FV greatly accelerates this protease activity (positive feedback as a result of thrombin)
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33
Q

what helps to increase the splitting of prothrombin to thrombin?

A

platelet phospholipids

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34
Q

describe the intrinsic pathway for the formation of prothrombin activator

A

begins with trauma to the blood or exposure of the blood to collagen from a traumatised blood vessel wall:

  1. trauma to the blood alters two important clotting factors in the blood: Factor XII and the platelets
    - when XII is disturbed it takes on a new configuration forming XIIa
    - the blood trauma also damages the platelets releasing platelet phospholipids that contain the lipoprotein called platelet factor 3
  2. the XIIa acts enzymatically activating Factor XI to form XIa
    - this reaction also requires high molecular weight kininogen and is accelerated by prekallikrein
  3. XIa then activates Factor IX into IXa under the influence of Ca2+
  4. IXa acting with VIIIa and with the platelet phospholipids and factor 3 activate Factor X into Xa, occurring under the influence of Ca2+
    - when either Factor VIII (haemophilia) or platelets (thrombocytopenia) are in short supply, this step is deficient
  5. Xa combines with V and phospholipids to form prothrombin activator, under the influence of Ca2+
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35
Q

where is fibrinogen formed? what’s it size like?

A

in the liver

- it has a large molecular size

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36
Q

why does polymerisation of fibrinogen molecules comes about?

A
  • normally, little fibrinogen leaks from blood vessels into interstitial fluids due to its size
  • when the permeability of capillaries becomes pathologically increased, fibrinogen does then leak into the tissue fluids in sufficient quantities to allow clotting of these fluids in much the same way that plasma and whole blood can clot
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37
Q

what is thrombin? what does it do?

A

a protein enzyme that removes four peptides from each molecule of fibrinogen, forming a molecule of fibrinogen monomer which under the influence of Ca2+ polymerises with other fibrin monomers forming fibrin fibres

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38
Q

how is fibrin held together initially and finally?

A
  • initially, the fibrin monomers are held together by weak non-covalent hydrogen bonds
  • platelets trapped within the clot then release fibrin-stabilising factor which is activated by thrombin and acts as an enzyme forming covalent bonds between the fibrin monomers, as well as cross-linkages between adjacent fibrin fibres
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39
Q

describe clot retraction

A

After the clot is formed, it begins to contract expressing most of the fluid within it:

  • the fluid expressed is called serum because all its fibrinogen and most of the other clotting factors have been removed; in this way serum differs from plasma
  • therefore, serum cannot clot

Platelets are necessary for clot retraction to occur:

  • failure of clot retraction indicates a low platelet count
  • platelets in blood clots attach to the fibrin fibres in such a way that they actually bond different fibres together
  • furthermore, platelets entrapped in the clot continue to release procoagulant substances such as fibrin-stabilising factor
  • platelets contribute directly to retraction by activating platelet thrombosthenin, actin and myosin molecules
  • this helps compress the fibrin meshwork into a smaller mass - the contraction is activated and accelerated by thrombin as well as Ca2+ ions in the platelet
  • as the clot retracts, the edges of the broken blood vessel are pulled together, thus contributing still further to haemostasis
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40
Q

describe and explain the positive feedback of clot formation

A
  • a clot initiates a positive feedback to promote more clotting

This is mainly caused by the proteolytic action of thrombin on numerous other blood-clotting factors:

  • thrombin has a direct proteolytic effect on prothrombin itself, tending to convert this into still more thrombin
  • thrombin acts on some of the blood-clotting factors responsible for the formation of prothrombin activator
  • these effects include acceleration of the actions of Factors VIII, IX, X, XI and XII and aggregation of platelets

Once a critical amount of thrombin is formed, a positive feedback develops that causes still more blood clotting and more and more thrombin to be formed; thus, the blood clot continues to grow until blood leakage ceases

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41
Q

when are calcium ions necessary? and for what?

A

except for the first two steps in the intrinsic pathway, calcium ions are required for promotion or acceleration of all the blood-clotting reactions

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42
Q

how can blood be prevented from clotting when it’s removed from the body?

A

by reducing the calcium ion concentration

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43
Q

describe the interaction between the extrinsic and intrinsic pathway

  • how are they both initiated
  • what is the speed of them
A

it’s clear from the schemas of the intrinsic and extrinsic systems that after blood vessels rupture, clotting occurs by both pathways simultaneously

  • tissue factor initiates the extrinsic pathway
  • contact of Factor XII and platelets with collagen in the vascular wall initiates the intrinsic pathway
  • the extrinsic pathway is explosive, once initiated; its speed of completion is limited only by the amount of tissue factor released from the traumatised tissues and by the quantities of Factors X, VII and V in the blood
  • the intrinsic pathway is much slower to proceed
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44
Q

what are the most important factors for preventing clotting in the normal vascular system?

A
  1. the smoothness of the endothelial cell surface
  2. a layer of glycocalyx on the endothelium which repels clotting factors and platelets
  3. a protein bound with the endothelial membrane, thrombomodulin - thrombomodulin binds and inactivates thrombin, it also activates Protein C
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45
Q

what happens when the endothelial wall is damaged?

A
  • its smoothness and its glycocalyx-thrombomodulin layers are lost, which activates both Factor XII and the platelets
  • moreover, platelet activation may be inhibited, e.g. prostacyclin
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46
Q

what are Protein C and Protein S? where are they made?

A
  • vitamin K dependent proteins

- made in the liver

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47
Q

what does activated Protein C do?

A
  • inactivates Factors Va and VIIa and to a much lesser extent, thrombin
  • enhances fibrinolysis by activating the tissue plasminogen activator (tPA) inhibitor
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48
Q

what enhances the action of Protein C?

A

the action of Protein S - it binds protein C to the platelet surface

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49
Q

what does activated Protein S do?

A

inactivates Factors Va and VIIa

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50
Q

what is the first inhibitor to act?

A

Tissue Factor Pathway Inhibitor (TFPI)

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51
Q

where is TFPI found?

A

found in plasma and platelets (within granules)

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52
Q

why is there accumulation of TFPI?

A

due to platelet activation

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53
Q

what does TFPI do?

A

inhibits Factors VIIa and Xa

54
Q

where is antithrombin synthesised? what does it do?

A
  • synthesised in the liver and endothelium
  • indirectly inhibits thrombin
  • also suppresses IXa, Xa, XIa and the VIIa part of the VIIa/tissue factor complex
55
Q

what’s the primary regulator of coagulation?

A

antithrombin

56
Q

what does antithrombin III do?

A

inhibits thrombin and other serine proteases by binding to the active serine site
- serine proteases catalyse the action of thrombin

57
Q

what does tissue plasminogen activator (tPA) do? and what is it?

A
  • inactivates thrombin and ADP
  • it’s a protease and cleaves plasminogen to form plasmin
  • plasmin, in turn, cleaves fibrin and other coagulants to degrade thrombi (fibrinolysis)
  • a large amount of plasminogen is trapped in the clot and the endothelium slowly releases tPA that eventually converts plasminogen to plasmin, which in turn removes the remaining unnecessary blood clot
58
Q

vitamin K is essential for the formation of which coagulation factors? why?

A
  • prothrombin (Factor II)
  • Factor VII
  • Factor IX
  • Factor X
  • Protein C
  • Protein S

Vitamin K is essential for the formation of these as it adds a carboxyl group to the glutamic acid residues

59
Q

what happens to the vitamin K? and how is it returned back to normal?

A

In adding the carboxyl group to glutamic acid residues on the immature clotting factors, vitamin K is oxidised and becomes inactive:
- vitamin K epoxide reductase complex 1 (VKOR c1) reduces vitamin K back to its active form

60
Q

what inhibits VKOR c1?

A

warfarin

61
Q

where and how is vitamin K synthesised?

A
  • continually synthesised in the intestinal tract by bacteria
  • therefore, vitamin K deficiency seldom occurs due to dietary reasons
62
Q

how does vitamin K deficiency normally occur?

A

in gastrointestinal disease it often occurs as a result of poor absorption of fats from the gastrointestinal tract
- the reason is that vitamin K is fat soluble and ordinarily absorbed into the blood along with the fats

63
Q

what is the treatment for vitamin K deficiency?

A

vitamin K supplements: phytomenadione

64
Q

what is thrombocytopenia?

A
  • is the presence of very low numbers of platelets in the circulating blood
  • this increases the risk of bleeding from small venues or capillaries
65
Q

what’s the skin of people with thrombocytopenia like?

A

it displays many small, purplish blotches, giving the disease the name thrombocytopenia purpura

66
Q

what is the treatment for thrombocytopenia?

A
  • giving fresh whole blood

- splenectomy: the spleen removes platelets

67
Q

what are the two most common inherited disorders of bleeding? what are they caused by?

A

haemophilia A and von Willebrand disease

  • these are caused by defects involving Factor VIII and vWF
  • these two proteins exist together in the plasma as part of a single large complex
  • Factor VIII has two active components, a large and a smaller component

Smaller component:
- important in the intrinsic pathway for clotting
- deficiency of this causes haemophilia A
Larger component:
- deficiency of this causes von Willebrand’s Disease

68
Q

explain the Factor VIII-vWF complex

  • where is vWF produced
  • what’s a benefit of the complex
A
  • vWF is produced by the endothelial cells and, to a lesser extent, by megakaryocytes
  • once Factor VIII reaches the circulation, it binds to vWF
  • vWF stabilises Factor VIII increasing its half-life
69
Q

what does vWF do? what secretes it? where is it found?

A
  • vWF promotes the adhesion of platelets to the subendothelial matrix
  • some vWF is secreted from endothelial cells directly into the subendothelial matrix, where it lies ready to promote platelet adhesion if the endothelial lining is disrupted
  • endothelial cells and platelets also release vWF into the circulation
  • upon vascular injury, this second pool of vWF binds collagen in the subendothelial matrix to further augment platelet adhesion
  • vWF promotes platelet aggregation by binding to activated GpIIb/IIIa
70
Q

what is the most common inherited bleeding disorder in humans?

A

Von Willebrand Disease

71
Q

what are the symptoms of vWD?

A
  • spontaneous bleeding from mucous membranes
  • excessive bleeding from wounds
  • prolonged bleeding time in the presence of a normal platelet count
72
Q

what are the three types of von Willebrand disease?

A
  1. Type 1:
    - Associated with reduced quantity of circulating vWF.
    - Mild to moderate quantitative vWF deficiency.
    - Accounts for 70% of all cases.
  2. Type 2:
    - Characterised by qualitative defects in vWF.
    - vWF is expressed in normal amounts, but mutations are present that lead to defective assembly.
    - This can also be caused by a deficiency in the large component of Factor VIII.
    - Associated with mild to moderate bleeding.
    - Accounts for 25% of all cases.
  3. Type 3:
    - Associated with extremely low levels of functional vWF and corresponding severe clinical manifestations.
73
Q

how does von Willebrand disease affect platelets?

A

patients with von Willebrand disease have defects in platelet function despite a normal platelet count

74
Q

what does a deficiency of vWF give rise to a secondary decrease in?

A

factor VIII levels because vWF stabilises factor VIII

75
Q

what is haemophilia A caused by?

A

by mutations in factor VIII which is an essential co-factor for factor IX in the coagulation cascade

76
Q

what is Factor VIII a co-factor for?

A

factor IX

77
Q

how is haemophilia A inherited?

A

as an X-linked recessive trait

78
Q

symptoms of haemophilia A?

A
  • in all symptomatic cases there is a tendency towards easy bruising and massive haemorrhage after trauma or operative procedures
  • ‘spontaneous’ haemorrhages frequently occur in regions of the body normally subject to trauma, particularly the joints, where they are known as haemarthroses
79
Q

what’s the partial thromboplastin time (PTT) and prothrombin time (PT) of patients with haemophilia A?

A
  • they typically have a prolonged PTT and a normal PT

- these tests point to an abnormality of the intrinsic coagulation pathway

80
Q

what is partial thromboplastin time? what is thromboplastin? what’s prothrombin?

A
  • a blood test that looks at how long it takes for blood to clot
  • blood test that’s done to investigate bleeding disorders and to monitor patients taking an anticlotting drug
  • thromboplastin is a plasma protein aiding blood coagulation through catalysing the conversion of prothrombin to thrombin
  • a protein present in blood plasma which is converted into active thrombin during coagulation
81
Q

what are the similarities and differences between PT and PTT?

A
  1. PT and PTT are used in the practice of medicine to trace bleeding problems
  2. PT stands for prothrombin time and is used to ascertain whether the dosage of Warfarin needs to be adjusted or not - Heparin is measured by PTT, which stands for partial thromboplastin time
  3. clotting factors II, V, VII and X are checked by PT, while clotting factors I, II, V, VII, IX, XI and XII are measured by PTT
  4. both are used in order to identify what type of haemophilia is afflicting a patient or for other bleeding problems
  5. PT measures extrinsic coagulation while PTT measures intrinsic coagulation
82
Q

what is required for diagnosis of haemophilia A?

A

Factor VIII-specific assays are required for diagnosis

83
Q

what’s the treatment for haemophilia A?

A

infusions of recombinant factor VIII

84
Q

what’s haemophilia B?

  • distinguishable from haemophilia A?
  • how inherited?
  • PTT and PT?
  • treatment?
A
  • severe factor IX deficiency produces a disorder clinically indistinguishable from factor VIII deficiency (haemophilia A)
  • this should not be surprising, given that factors VIII and IX function together to activate factor X in the intrinsic pathway
  • like haemophilia A, it’s inherited as an X-linked recessive trait and shows variable clinical severity
  • as with haemophilia A, the PTT is prolonged and the PT is normal
  • treatment is infusions of recombinant factor IX
85
Q

what’s thrombosis?

A

the formation of a solid or semi-solid mass from the constituents of the blood while moving within the vascular system during life

86
Q

what are the three primary abnormalities that lead to thrombus formation?

A

Virchow’s triad:

  1. endothelial injury
  2. stasis or turbulent blood flow
  3. hypercoagulability of the blood
87
Q

what can physical loss of endothelium lead to?

A
  • exposure of the subendothelial ECM
  • adhesion of platelets
  • release of tissue factor
  • local depletion of PGI2 (prostacyclin) and plasminogen activators
  • However, it should be emphasized that endothelium needs not be removed or physically disrupted to contribute to the development of thrombosis.
  • Any disturbance in the dynamic balance of the prothombotic and antithrombotic activities of endothelium can influence local clotting events
  • Thus, dysfunctional endothelial cells can produce more procoagulant factors or may synthesize less anticoagulant effectors.
  • Endothelial dysfunction can be induced by a wide variety of insults such as hypertension.
88
Q

what abnormalities of the vessel walls leads to alterations in blood flow?

A 
Arteries
- atheroma; inflammation
Heart
- myocardial infarction; rheumatic endocarditis; atrial fibrillation; turbulence
Veins
- trauma; inflammation
- chemicals: sclerosants: irritant substances injected to induce thrombophlebitis and hence to obliterate varicose veins, glucose: atheroma in diabetes mellitus
Arteries
- turbulence: aneurysms; plaques; spasm
Capillaries
- inflammation
89
Q

how does turbulence contribute to arterial and cardiac thrombosis?

A

by causing endothelial injury or dysfunction, as well as by forming counter currents and local pockets of stasis; stasis is a major contributor in the development of venous thrombi
- normal blood flow is laminar such that the platelets flow centrally in the vessel lumen, separated from endothelium by a slower moving layer of plasma

90
Q

so, what does stasis and turbulence do?

A
  1. promote endothelial activation, enhancing pro-coagulant activity in part through flow-induced changes in endothelial cell gene expression
  2. disrupt laminar flow and bring platelets into contact with the endothelium
  3. prevent washout and dilution of activated clotting factors by fresh flowing blood
91
Q

what is hypercoagulability?

A
  • this is defined as any alteration of the coagulation pathways that predisposes to thrombosis
  • it can be divided into primary (genetic) and secondary (acquired) disorders
92
Q

describe thrombi and what can this indicate?

A
  • thrombi often have grossly and microscopically apparent laminations called lines of Zahn
  • they represent pale platelet and fibrin deposits alternating with darker red cell-rich layers
  • such laminations signify that a thrombus has formed in flowing blood
  • their presence can therefore distinguish ante-mortem thrombosis from the bland non-laminated clots that occur post-mortem
93
Q

what are thrombi occurring in heart chambers or in the aortic lumen designated?

A

mural thrombi

94
Q

are arterial and venous thrombi occlusive?

A

Arterial thrombi are frequently occlusive
- typically consist of a friable meshwork of platelets, fibrin and degenerating leukocytes
Venous thrombosis is almost invariably occlusive
- typically contain more enmeshed red cells and relatively few platelets

95
Q

what is the fate of a thrombus?

A

If a patient survives the initial thrombosis, a combination of the following happens:

  • propagation - thrombi accumulate additional platelets and fibrin
  • embolisation - thrombi dislodge and travel to other sites in the vasculature
  • dissolution - the result of fibrinolysis, which can lead to the rapid shrinkage and total disappearance of recent thrombi
  • organisation and recanalization - older thrombi become organised by the ingrowth of endothelial cells, smooth muscle cells and fibroblasts - capillary channels eventually form that re-establish the continuity of the original lumen, albeit to a variable degree
96
Q

what are the most common sites of venous thrombosis?

A

leg and the pelvis

97
Q

why is deep vein thrombosis more serious?

A

these thrombi are more likely to embolise to the lungs

98
Q

what are the clinical features of DVT?

A
  • pain in the calf, often with swelling, redness and engorged superficial veins
  • there may be ankle oedema
99
Q

what are the tests for DVT?

A
  • ultrasound is the standard method of diagnosing a DVT

- D-dimer test is diagnostically useful

100
Q

what do pulmonary embolisms originate from?

A

in more than 95% of cases, PEs originate from leg deep vein thromboses

101
Q

what’s a paradoxical embolism?

A

refers to an embolus which is carried from the venous side of circulation to the arterial side, or vice versa

102
Q

what are the two main pathophysiologic consequences that emboli result in?

A
  1. respiratory compromise
    - producing an intrapulmonary dead space and resulting in impaired gas exchange
    - after some hours the non-perfused lung no longer produces surfactant
    - alveolar collapse occurs and exacerbates hypoxemia
  2. haemodynamic compromise
    - producing a reduction in the cross-sectional area of the pulmonary arterial bed which results in a elevation of pulmonary-arterial pressure and a reduction in cardiac output
103
Q

what is the clinical course of PE?

A
  • sudden onset of dyspnoea is most common and often the only symptom of PE
  • pleuritic chest pain and haemoptysis (coughing up blood) are present only when infarction has occurred
  • large pulmonary embolism can lead to instantaneous death
104
Q

how do you diagnose PE?

A
  • spiral computed tomographic angiographic
  • ventilation-perfusion scan
  • positive D-dimer test
105
Q

what’s treatment for PE?

A
  • low molecular weight heparin
106
Q

what is prothrombin time?

A

the time taken for blood clotting to occur in a sample of blood to which calcium and thromboplastic/tissue factor have been added

107
Q

what’s normal PT time?

A

12-16 seconds (INR = 1)

108
Q

what does PT specifically measure?

A

VII, X, V, prothrombin and fibrinogen (‘extrinsic’ pathway)

109
Q

what does a prolonged PT indicate?

A

a deficiency in any of these mentioned coagulation factors

110
Q

what is international normalised ration (INR)? how does it work? what is the normal INR range? what does high and low INR mean?

A

the ratio of a patient’s PT to standardised ‘normal’ PT

  • for each batch of tissue factor, the manufacturer assigns as international sensitivity index (ISI), which indicates the activity of the tissue factor with a standardised sample
  • the IS usually varies between 1.0 and 2.0
  • normal INR range: 0.9 - 1.3
  • high INR indicates high risk of bleeding
  • low INR indicates high chance of clotting
111
Q

what is D-dimer?

A

a protein product of the breakdown of fibrin in blood clots

112
Q

what is the D-dimer test? what does a negative result mean? what’s its main use?

A
  • this test measures the levels of the D-dimer protein
  • a negative result rules out thrombosis
  • its main use is to exclude thromboembolitic disease where the probability is low
  • the test is used in protocols for the diagnosis of pulmonary embolism
113
Q

what is ventilation-perfusion scan used for? how does it work? what’s suggestive of a recent pulmonary embolism?

A

Used in the detection of pulmonary thromboemboli

  • ventilation is assess by inhalation of Xenon-133 gas
  • perfusion is assessed by the injection of macroaggregates of 99mTc-albumin
  • a ‘filling defect’ in the perfusion scan accompanied by preserved ventilation (V/Q mismatch) is highly suggestive of a recent pulmonary embolism
114
Q

what does heparin do? explain.

A

heparin inhibits coagulation by activating antithrombin III

  • antithrombin III inhibits thrombin and factor X and other serine proteases by binding to the active serine site - serine proteases catalyse the action of thrombin
  • binding of heparin to antithrombin III changes its conformation and accelerates its rate of reaction by increasing its affinity for serine proteases
  • thrombin, compared to factor X, is more sensitive to the inhibitory effect of the heparin-antithrombin III complex
  • to inhibit thrombin, it’s necessary for heparin to bind to the enzyme as well as to antithrombin III
  • heparin + antithrombin III + serine proteases = inhibition of thrombin
  • to inhibit factor X, it’s necessary for heparin to bind to antithrombin III
  • heparin + antithrombin III = inhibition of factor X
  • the LMWHs increase the action of antithrombin III on factor Xa but not its action on thrombin
115
Q

where is heparin found abundantly? and why?

A

In the body, heparin is only found abundantly in the tissue surrounding the capillaries of the lungs & liver
- the capillaries of the lungs and liver receive many embolic clots formed in slowly flowing venous blood; sufficient formation of heparin prevents further growth of the clots.

116
Q

what is warfarin? what does it do?

A
  • vitamin K antagonist
  • inhibits vitamin K epoxide reductase component 1 (VKORC1), thus inhibiting the reduction of vitamin K epoxide to its active hydroquinone form
  • this interferes with the post-translational y-carboxylation of glutamic acid resides in clotting factors II, VII, IX and X
117
Q

what type of inhibition is warfarin?

A

competitive - reflecting the structural similarity between warfarin and vitamin K

118
Q

are there drug interactions with warfarin?

A

Some NSAIDs (e.g. ibuprofen in Nurofen Plus) result in a temporary increase in the concentration of free warfarin in plasma by displacing warfarin from its binding sites on the plasma albumin

This increases prothrombin time (increases INR) and results in increased bleeding

119
Q

what are the 3 philosophies of health promotion?

A
  1. Social engineering:
    - this assumes that ill health is caused by social phenomena such as poverty, poor living conditions, lack of education, inappropriate cultural norms and inadequate health care.
     Objectives should be to improve living standards, change norms and improve health-care services.
  2. Individual prevention:
    - this believes that health is strongly influenced by the behaviour and conditions of individuals and can, therefore, be improved by changing the individual’s health behaviours by education, advertising, specific physical interventions such as seat belts.
  3. Individual empowerment:
    - this involves giving people responsibility for their health and to change their social conditions.
     Empowerment can be effective, but people can choose to not make health their priority.
120
Q

what can cause alterations in blood flow?

A
  • Prolonged immobilisation
  • Obesity
  • Pregnancy
  • Cancer
121
Q

what can cause hypercoagulable states?

A
  • Oestrogen containing OCP (oral contraceptive pill)
  • Genetic thrombophilia (Factor V Leiden deficiency, Protein C and Protein S deficiency, antithrombin deficiency etc.)
  • Acquired thrombophilia (antiphospholipid syndrome, nephrotic syndrome, paroxysmal nocturnal haemoglobinuria)
122
Q

how is thrombus formation prevented?

A
  • endothelial cells in intact blood vessels - nitric oxide (vasodilator), endothelin (vasoconstrictor)
  • inhibit platelet activation: e.g. prostacyclin (prostacyclin is a vasodilator as well as having a role in suppressing platelet function)
  • tissue plasminogen activator (tPA) inactivates: thrombin, ADP
123
Q

Summary of the events of coagulation

A
  1. Initiation
    - tissue factor/FVII
    - extrinsic tenase (TF-VIIa-Xa)
    - trace of thrombin
    - TFPI (tissue factor pathway inhibitor)
    - No co-factors
  2. Amplification
    - Co-factors activated: FVa, FVIIIa
    - Large scale thrombin
  3. Propagation
    - Intrinsic tenase: IXa, VIIIa
    - Burst of thrombin (so we can produce fibrin from fibrinogen)
    - Prothrombinase complex: FXa, FVa
124
Q

describe the activation of platelets

A
  • Platelet must be activated – resting platelet (shape change) -> activated platelet
  • Platelet starts to swell due to things that occur inside the platelet
  • Also, starts to express adhesion molecules on its surface (e.g. P-selectin, GpIIb/IIIa) and pseudopodia and lamellipodia formation
  • Expression of phosphatidylserine and phospholipids
  • Degranulation: ADP, calcium thromboxane -> activation of other platelets
  • Small glycoproteins are expressed on surface when it becomes activated and these can then attach the platelet to other platelets
125
Q

what causes activation of platelets? what is the most potent platelet activator?

A
  • Other platelets -> agonists e.g. ADP
  • Coagulation cascade -> thrombin (most potent platelet activator) – will mass activate lots of platelets
  • Exposed subendothelium -> collagen
126
Q

describe platelet adhesion and granule release

A
  • Contact of platelets with collagen via glycoproteins and/or vWF (von Willebrand factor – allows linking of the platelet with the lining) in plasma (one important link is GPIb binding with vWF) (GPIa has a direct link with the collagen molecule – some have direct links, some need a linking molecule) (GPIIb and GPIIIa will link together and then link with vWF)
  • Activates prostaglandin synthesis
  • Stimulates ADP release from dense bodies
  • Platelets swell – promotes adhesion – comes into contact with other platelets more easily
  • Positive feedback – more ADP and TXA2
127
Q

what do ADP and TXA2 do?

A

induce platelet aggregation and formation of the platelet plug

128
Q

describe the initiation stage of coagulation

A
  • TF binds to FVII forming TF-VIIa complex
  • Binds to FX to form:
  • Extrinsic tenase converts FX to Xa
  • Small amounts of FIXa also produced
  • Trace thrombin produced (due to small amount of FX) – small amount produced (converts fibrinogen to fibrin)
  • Co-factors not available
  • TFPI: Tissue Factor Pathway Inhibitor inhibits further generation of FXa and FIXa
129
Q

describe the amplification stage of coagulation

A
  • Small amount of thrombin in initiation enters amplification
  • Activates co-factors FV and VIII and platelets
  • FVa is cofactor for FX
  • FVIIIa is cofactor for FIX
  • Large scale thrombin generation sufficient for fibrin clots
  • Coagulation moves from damaged endothelium to surface of activated platelet
130
Q

describe propagation 1 of coagulation

A
  • Intrinsic tenase complex:
    -utilise FIXa
    -using FVIIIa as its co-factor
  • FIXa binds to surface of platelets and associates with its co-factor, FVIIIa
  • Complex activates FX to FXa (intrinsic tenase complex)
  • 90% more FXa (x50 more efficient) than via Extrinsic tenase
    Extrinsic tenase complex: - important in getting it started
  • FVII and FX
    Intrinsic tenase complex: - much more efficient – important in making sure process continues to produce fibrin clot
  • FVIII, FIX and FX
131
Q

describe propagation 2 of coagulation

A

Prothrombinase complex:

  • FXa (integral – extrinsic and intrinsic)
  • Using FVa as co-factor – so can be more efficient
  • Prothrombin (factors combine with prothrombin)
  • Takes place on the platelet surface
  • Product: thrombin
  • Converts fibrinogen to fibrin
  • Factor XIII stabilises the fibrin cldesot (clot can only be broken down fibrinolysis)

Medicine Sem 2 (10 decks)

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