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Haematology > HS5 & 6 > Flashcards

HS5 & 6 Flashcards

1
Q

What is arterial thrombosis?

A

Arterial thrombosis is any thrombosis occurs in artery

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2
Q

Where does arterial thrombosis occur?

A

In almost all cases of arterial thrombosis, it occurs at the site of atheroma

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3
Q

Describe the pathogenesis of arterial thrombosis

A

Atherosclerosis of the arterial wall, plaque rupture and endothelial injury expose blood to subendothelial collagen and tissue factor.

These the stimulate platelets to aggregate.

The formation of a platelet-rich “white thrombus” occurs, and can occlude the vessel.

Vessel occlusion can cause an infarction, e.g. myocardial infarction, tissue necrosis

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4
Q

In what ways can you treat arterial thrombosis with drugs?

A
  • Inhibit platelets
  • Inhibit fibrin formation
  • Augmentation of fibrinolysis
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5
Q

What antithrombotic drugs can be used to treat arterial thrombosis?

A
  • Aspirin
  • Heparin
  • ADP receptor antagonists (e.g. clopidogrel, prasugrel)
  • Platelet GPIIb/IIIa inhibitors (e.g. ReoPro, tirofiban)
  • Thrombolytics (e.g. Streptokinase, tPA)
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6
Q

What else can be done to treat arterial thrombosis, if drug treatment is ineffective?

A

Surgical Intervention:

  • Balloon angioplasty
  • Stenting
  • CABG
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7
Q

How does aspirin treat arterial thrombosis?

A

It inhibits platelet cyclooxygenase (COX-1)

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8
Q

Does aspirin have any side effects?

A
  • Dyspepsia
  • Heartburn
  • GI bleeding
  • Allergy
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9
Q

By what mechanism does dipyridamole treat arterial thrombosis?

A

Dipyridamole inhibits the phosphodiesterase enzymes that normally break down cAMP (increasing cellular cAMP levels and blocking the platelet aggregation response to ADP) and/or cGMP.

It inhibits the cellular reuptake of adenosine into platelets, red blood cells and endothelial cells leading to increased extracellular concentrations of adenosine.

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10
Q

Does dipyridamole have any side effects?

A

Transient Ischaemic Attack

Stroke

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11
Q

How is clopidogrel used to treat arterial thrombosis?

A

Clopidogrel is known as a second generation platelet inhibitor.

Clopidogrel acts by inhibiting the ADP receptor on platelet cell membranes.

It is a prodrug, which requires CYP2C19 for its activation.

The drug specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in activation of platelets and eventual cross-linking by the protein fibrin

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12
Q

Are there any side effects associated with clopidogrel?

A

Thrombotic stroke

MI

Peripheral Arterial Disease

Unstable Angina

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13
Q

How are GPIIb/IIIa inhibitors used to treat arterial thrombosis?

A

GPIIb/IIIa inhibitors block the fibrinogen from binding with the platelet receptors.

It blocks aggregation completely to all agonists, but does not block adhesion or procoagulant activity.

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14
Q

Give examples of GPIIb/IIa inhibitors

A

Abciximab

Eptifibatide

Tirofiban

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15
Q

Give examples of conventional platelet inhibitors

A

Aspirin

Dipyridamole

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16
Q

Give examples of second generation platelet inhibitors

A

Clopidogrel

GPIIb/IIIa inhibitors (Abciximab, Eptifibatide, Tirofiban)

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17
Q

Give examples of third generation platelet inhibitors

A

New P2Y 12 antagonists:

  • Prasugrel
  • Cangrelor
  • Ticagrelor

PAR-1 antagonists:

  • Vorapaxar
  • E-5555
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18
Q

Describe the features of P2Y 12 antagonists

A

Prasugrel:

  • More efficient when converted to active drug,
  • irreversible antagonist

Cangrelor:

  • No need for prodrug metabolism
  • Reversible antagonist
  • IV infusion only

Ticagrelor:

  • No need for prodrug metabolism
  • Reversible antagonist
  • Orally active
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19
Q

What is the mechanism of Vorapaxar

A

It is a thrombin receptor antagonist

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20
Q

How do thrombin receptors function?

A

Thrombin receptors are Protease-activated receptors (GPC-receptors)

Thrombin, a serine protease, binds to and cleaves the extracellular N-terminal domain of the receptor.

A tethered ligand corresponding to the new N-terminus, SFLLRN, is then unmasked, binding to the second extracellular loop of the receptor and activating it

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21
Q

Give examples of future platelet inhibitors

A

Collagen receptor inhibitors:

  • GPVI favoured target
  • Block main activation pathway
  • Snake venoms and synthetic CRPs available as ligands

VWF inhibitors:

  • Saratin (calin)
  • Anti-VWF mAb
  • Aurintricarboxylic acid (ATA)
  • Show good efficacy in animal models of endarterectomy
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22
Q

How does aspirin work to reduce platelet aggregation?

A

Aspirin works by permanently inhibiting COX-1.

In a cell, the nucleus will stimulate the production of new COX-1. As platelets are anucleate, they cannot produce new COX-1 to replace the COX-1 that has been inhibited, and so new platelets must be produced.

If a therapeutic dose of aspirin is given once a day, this consistently inhibits the COX-1 in the blood stream, and so reduces platelet aggregation.

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23
Q

Give examples of clot busters

A

tPA

uPA

SK

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24
Q

How do clot busters work?

A

tPA, uPA, and SK convert plasminogen to plasmin

tPA and scuPA activate fibrin bound plasminogen.

It is available as a recombinant molecule as it is expensive.

SK and uPA activate free plasminogen, and SK may provoke an immune reaction

25
Q

Where is venous thrombosis found?

A

In the venous circulation where there is less flow.

26
Q

How does venous thrombosis arise?

A

It is thought to arise as a consequence of Virchow’s triad:

  • Stasis
  • Vessel wall damage
  • Hypercoagulable state
27
Q

Describe the features of venous thrombosis

A
  • Occurs at site of stasis
  • Initial event is coagulation and fibrin formation
  • Forms a fibrin-rich “red thrombus”
  • Vessel occlusion causes discomfort and pain
  • Risk of pulmonary embolism (Inflammation of the vessel wall may or may not be present)
28
Q

What factors contribute to stasis in the venous circulation?

A
  • Viscosity (raised Hct, raised fibrinogen)
  • Immobility (bed rest, sedentary posture)
  • Ischaemia may contribute to endothelial damage
  • Accumulation of activated coagulation factors
  • Reduced exposure to endothelial-bound TM
29
Q

What types of factors can contribute to hypercoagulable states?

A

Acquired

Inherited

Mixed/Unknown

30
Q

What acquired factors can contribute to hypercoagulable states? (11)

A
  • Age
  • Previous thrombosis
  • Immobilisation
  • Major surgery
  • Orthopaedic surgery
  • Malignancy
  • High oestrogen oral contraceptives
  • Pregnancy and postpartum period
  • Antiphospholipid syndrome
  • Polycythaemia vera
  • Air travel
31
Q

What inherited factors can contribute to hypercoagulable states?

A
  • AT deficiency
  • Protein C deficiency
  • Protein S deficiency
  • Factor V Leiden
  • Prothrombin 20210A
  • Dysfibrinogenaemia
32
Q

What mixed/unknown factors can contribute to hypercoagulable states?

A
  • Hyperhomocysteinaemia
  • High FVIII levels
  • APC resistance
33
Q

What is heritable thrombophilia?

A

There is no definition of what inherited thrombophilia is, but it is an inherited trait that confers a tendency for venous thrombosis.

Many genes are implicated, but only five have been shown to increase risk > two-fold.

Studies have shown that screening has little predictive value. Even if you find someone with an inherited thrombophilia, it doesn’t show that they will get thrombosis.

Risk factors tend to interact synergistically.

34
Q

Heritable thrombophilia comes in two types: type 1 and 2. What are the differences between type 1 and type 2?

A

Type 1 is a quantitative deficiency of the enzyme (detected by immunoassays)

Type 2 is a qualitative (functional) deficiency in which enzyme activity falls below that predicted by protein concentration:

  • F2G2021A mutation increases plasma prothrombin concentration by ~ 30%
  • F5G1691A mutation renders FVa resistant to inactivation
35
Q

What is the most common heritable cause of activated venous thrombosis?

A

Activated Protein C resistance (FV Leiden)

(Accounts for 20-40% of thromboembolic events)

36
Q

How many cases of aPC resistance are caused by a point mutation in the gene FV?

A

Around 90%

37
Q

What is the most common form of activated protein C resistance?

A

FV Leiden

38
Q

How does a point mutation in the FV gene affect the protein?

A

This Arg506-> Gln mutation renders FVa unresponsive to aPC while retaining its procoagulant activity

39
Q

How does a point mutation in the FV gene affect the risk of thrombosis?

A
  • Homozygotes (< 1%) 50-100 fold risk of thrombosis
  • Heterozygotes (3-7%) 5-10 fold risk of thrombosis
40
Q

How do environmental factors affect the risk of thrombosis?

A

Risk is compounded by environmental factors (pill, smoking, trauma)

41
Q

What is antiphospholipid syndrome (APS)?

A

Antiphospholipid syndrome (or often also Hughes syndrome) is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies.

42
Q

What are the common features of APS?

A

Limb DVT

Pulmonary embolism

Thrombotic stroke

Also, pregnancy complications are common (recurrent miscarriage, pre-eclampsia)

43
Q

How is APS diagnosed?

A

You can get arterial, venous or microvascular thrombosis at any site.

You test for APS with high titre IgG or IgM against cardiolipin or ß2 GPI or positive lupus anticogulant test

You can also diagnose it if a woman has an unexplained miscarriage past 10 weeks gestation, or more than 2 consectutive miscarriages under 10 weeks gestation

44
Q

What is an embolism?

A

Occlusion of a vessel by material transported in the bloodstream

45
Q

How severe are pulmonary emboli?

A

85% are minor, symptomless, involving small vessels

10% are major, involving moderate vessels, causing breathlessness

5% are massive, involving large vessels, causing CV collapse and death

46
Q

How is DVT diagnosed?

A
  1. Patient history / physical examination
  2. X-ray venography
  3. Doppler Ultrasonography
  4. Impedance Plethysmography
  5. Plasma FDP levels
47
Q

How does AT-heparin effect various clotting factors?

A

It inactivates FIIa, FXa, FIXa

Heparan sulphate also performs this function in vivo

Low Molecular Weight Heparin (LMWH) primarily inactvates FXa

48
Q

How is thrombin and FXa inactivated?

A

(a) To inactivate thrombin, heparin binds AT via a pentasaccharide sequence and thrombin via a 13 unit sequence.
(b) To inactivate FXa, heparin binds AT via the pentasaccharide, but need not bind FXa LMWH (mean 15 units)

LMWH therefore inhibits primarily FXa

49
Q

Give examples of FXa inhibitors

A

Rivaroxiban, apixaban, endoxaban are all orally active direct FXa inhibitors

Fondaparinux is an indirect FXa inhibitor which is AT dependant

50
Q

Give examples of FIIa inhibitors

A

Hirudin

Bivalirudin

Lepirudin

51
Q

What are the features of heparin?

A

Administered by IV infusion or by SC bolus twice a day

Should be monitered with APTT

It has fast onset of action, less than an hour, and there is a risk of bleeding and HIT (Heparin-induced thrombocytopenia)

52
Q

What are the features of Low Molecular Weight Heparin (LMWH)?

A

Administered by IV infusion, or SC bolus once a day

No monitoring necessary

Fast onset of action (less than one hour)

Risk of bleeding

No risk of HIT

Increased cost compared to heparin

53
Q

What are the features of Warfarin?

A

Orally active

Monitor with PT

Slow onset of action (2-3 days)

Risk of bleeding

Contraindicated in pregancy

54
Q

What is Disseminated Intravascular Coagulation (DIC)?

A

Disseminated intravascular coagulation (DIC) is a serious disorder in which the proteins that control blood clotting become over active.

55
Q

What pathway does DIC follow?

A
  1. Senseless activation of coagulation within the systemic circulation
  2. Deposition of fibrin within microvasculature
  3. Formation of thrombin and platelet activation
  4. Widespread tissue ischaemia
  5. Multiple organ failure
  6. Death
56
Q

What are the major causes of DIC?

A
  • Sepsis
  • Malignancy
  • Surgery
  • Liver disease
  • Trauma
  • Pregnancy
  • Heat stroke
  • Snake venoms
57
Q

How does sepsis cause DIC?

A

A monocyte comes along to fight the bacterial infection, and finds a gram negative bacterium with endotoxin on its surface.

The monocyte then tries to engulf it and the endotoxin activates TNF-a in the monocyte.

You then get an increase in tissue factor and this triggers coagulation.

58
Q

How does sepsis cause bleeding?

A

Bleeding in sepsis is due to inhibition of thrombin by FDPs.

The fibrinogen is broken down into fibrin by the thrombin, and this then reacts with the plasmin to create FDPs.

This FDP then competes with the fibrinogen for the thrombin causing inhibition.

59
Q

What are strategies can be used to treat DIC?

A
  1. Try to remove the underlying cause
  2. Give blood products (platelets, plasma) to control bleeding
  3. Give PCCs (prothrombin complex concentrates) to avoid fluid overload (not aPCCs)
  4. Low-dose heparin or aPC may be useful to control excessive thrombin generation (not yet proved)

Haematology (12 decks)

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