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Yr 2 - Clinical Pathology > Thrombosis and Risk Factors > Flashcards

Thrombosis and Risk Factors Flashcards

1
Q

What is Virchow’s triad?

A

Fundamental factors that contribute to thrombosis:

  • Blood flow: stasis (predominantly venous)
  • Damage in vascular endothelium: hypercoagulability (arterial)
  • Changes in blood** **constituents: hypercoagulability (venous)
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2
Q

What is usually the primary pathological abnormality in arterial thrombosis?

A

Atherosclerosis

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3
Q

How can atherosclerosis of the vessel wall lead to arterial thrombosis?

A
  1. Rupture of atheromatous plaques
  2. Endothelial injury – expresses tissue factor
  3. Platelet aggregation and platelet thrombi lead to fine vessel occlusion
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4
Q

what are the risk factors for arterial thrombosis?

A
  • Smoking
  • Hypertension
  • Hypercholesterolaemia
  • Diabetes
  • Family history
  • Obesity
  • Physical inactivity
  • Age
  • Male
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5
Q

What are the 2 major contributors to the pathophysiology in venous thrombosis?

A
  • Venous stasis
  • Hypercoagulable states
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6
Q

Composition of venous thrombi?

A

Predominantly composed of fibrin (with a lesser role for platelet accumulation and aggregation than arterial thrombi)

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7
Q

Composition of arterial thrombi?

A

Mostly composed of fibrin and platelets

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8
Q

What is the most common clinical manifestation of venous thrombosis?

A

DVT

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9
Q

Why is a DVT frequently unrecognised?

A

As 80% are clinically silent – prevention is key

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10
Q

50% of patients with a proximal DVT have an asymptomatic PE. How has this occurred?

A

Thrombus travelled from the femoral/pelvic vein to a pulmonary artery;

  • DVT is found in 80% of patients with PE
  • Sudden death is the presentation in 20% of PE
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11
Q

What is post-thrombotic syndrome?

A

Can happen to people who have had DVT of the leg. The condition can cause chronic pain, swelling, and other symptoms in your leg due to damage to veins during DVT formation (causing sluggish flow).

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12
Q

What % of people will have recurrent VTE?

A

30%

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13
Q

What defines a ‘hospital acquired VTE’?

A

VTE within 90 days of discharge

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14
Q

What proportion of all VTE does hospital acquired VTE account for?

A

2/3

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15
Q

What is the;

a) prophylaxis
b) treatment

for reducing the incidence of hospital acquired VTE?

A
  • Prophylaxis: consistent risk assessment with tool (for both bleeding and thrombosis), appropriate prophylaxis (LWMH)
    • I.e. a patient may not be suitable for a blood thinner
  • Treatment: prompt diagnosis, unified care
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16
Q

Care pathway for hospital acquired VTE?

A
  1. Patient admitted to hospital
  2. Assess VTE risk and bleeding risk
  3. Balance risks of VTE and bleeding: offer VTE prophylaxis if appropriate, but n**ot** if the risks of bleeding outweighs the risk of VTE
  4. Reassess risks of VTE and bleeding within 24 hours of admission
  5. Reassess whenever clinical situation changes e.g. bleeding complication, unanticipated immobility
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17
Q

Risk factors for VTE?

A
  • Active cancer/cancer treatment
  • Age over 60 years
  • Critical care admission
  • Dehydration
  • Thrombophilia
  • Medical comorbidity: heart disease, metabolic, endocrine, respiratory pathologies, acute infectious diseases, inflammatory conditions
  • Surgery
  • Major trauma
  • Personal history of VTE
  • HRT or oestrogen-containing contraceptive therapy
  • Varicose veins with phlebitis
  • Obesity (BMI over 30kg/m2)
  • Pregnancy and postnatal period
  • Immobility
  • First degree relative with VTE
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18
Q

What are the 3 most important anti-coagulant factors in the blood?

A
  1. Protein C
  2. Protein S
  3. Anti-thrombin III
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19
Q

What can a deficiency in anti-coagulant factors lead to an increased risk of?

A

Venous thrombosis/PE; will often get at a young age (N.B. this is a rarer cause of VTE than the risk factors)

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20
Q

Function of the fibrinolytic system?

A

The fibrinolytic system functions to;

a) remove the clot after the vasculature is repaired
b) to degrade clots that form in the bloodstream.

The final step in this pathway is the plasmin-mediated cleavage of fibrin, creating fibrin degradation products.

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21
Q

What can a deficiency in the fibrinolytic system lead to?

A

More prone to clots (but no clear clinical evidence of link to venous thrombosis)

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22
Q

General advice given to patients in hospital to reduce VTE?

A
  • Do not allow dehydration unless clinically indicated
  • Encourage mobilisation
  • Aspirin and antiplatelets are not adequate prophylaxis for VTE
  • Compression stockings
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23
Q

What are compression stockings?

A

Elastic stocking exact pressure on the leg at different compressions, aiding venous blood movement up the leg.

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24
Q

What drugs are given for pharmacological prophylaxis of thrombosis?

A

Blood thinners (given in lower doses than we would for treating a thrombotic event:

  • Low dose LMWH (low molecular weight heparin). More predicatable anti-coagulant effect than the old-fashioned heparin.
    • Once a day subcutaneous injection
    • Most common
  • Fondaparinux (synthetic pentasaccharide)
    • Substitute for LMWH;
      • Allergies
      • Heparin is derived from mucosal tissues of slaughtered animals such as pig’s lungs –> patients may be unwilling/allergic/religious
    • Given parenteral

N.B. the above medications cannot be given orally.

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25
Q

What is Fondaparinux a substitute for?

A

LMWH

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26
Q

Newer anticoagulants can be given orally. What are these?

A
  • Direct inhibitors of Factor 10a: rivaroxaban (apixaban) - oral
  • Directly thrombin inhibitors: dabigatran – oral
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27
Q

What is rivaroxaban? Mechanism?

A
  • Oral anticoagulant
  • Direct inhibitor of factor 10a
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28
Q

What is dabigatran? Mechanism?

A
  • Oral anticoagulant
  • Direct inhibitor of thrombin
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29
Q

Describe the difference in mechanism of old fashioned fractionated heparin and LMWH?

A
  • Heparin;
    • binds to natural anticoagulant factor called antithrombin
    • heparin enhances the action of antithrombin by binding to it
      • antithrombin inhibits thrombin and factor Xa (works against factor II as well - prothrombin)
  • Modern heparin (LMWH);
    • have much greater effect when they bind to antithrombin on factor Xa than they do on factor IIa
      • i.e. function more as inhibitors of factor Xa anti-coagulants than anti-thrombin anti-coagulants)
  • Old fashioned unfractionated heparin;
    • has equal effect in inhibiting both thrombin and factor Xa
    • will not be effective in inhibiting the effects of thrombin that is bound to clot that already exists
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30
Q

What does LMWH bind to? Effects of this?

A

Have much greater effect when they bind to antithrombin on factor Xa than they do on factor IIa i.e. function more as inhibitors of factor Xa anti-coagulants than anti-thrombin anti-coagulants)

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31
Q

What does unfractionated heparin bind to? Effects of this? What is this less effective against?

A

has equal effect in inhibiting both thrombin and factor Xa

will not be effective in inhibiting the effects of thrombin that is bound to clot that already exists

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32
Q

Mechanism of Fondaparinux?

A
  • smaller molecule than LMWH
    • will only inhibit factor Xa when bound to antithrombin –> no effect on thrombin at all
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33
Q

Mechanism of Rivaroxaban and Apixaban?

A
  • These are oral agents; more convenient and easier to extend treatment after discharge
  • Work directly on factor Xa without needing to bind to antithrombin
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34
Q

Mechanism of Dabigatran?

A
  • Taken orally
  • Direct inhibitor of thrombin resulting in;
    • decreased formation of fibrin
    • reduced thrombin-stimulated platelet aggregation; prevents the formation of thrombi.
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35
Q

Why are oral anti-coagulants useful?

A

more convenient and easier to extend treatment after discharge

36
Q

What 2 tests are done in order to rapidly exclude the possibility of DVT/PE? (symptoms can be vague)

A
  1. Wells score
  2. D-dimer test

Use these in an agreed algorithm

37
Q

What is Wells score?

A

The Wells score is a number that reflects your risk of developing deep vein thrombosis (DVT); Validated numerical clinical probability score

38
Q

What is a d-dimer test?

A
  • Fibrin is broken down by plasmin into monomers, releasing D dimers.
  • D-dimers are thus indicative of a clot being broken down
  • (Fibrin is a polymer with D and E subunits. Factor 13 covalently links fibrin to link E with 2D subunits)
39
Q

What happens if a patient has a high Wells score OR a raised d-dimer?

A

Will have imaging to see if there is a DVT

40
Q

What happens if a patient has a low Wells score AND a low d-dimer?

A

Can exclude them having a DVT

41
Q

What is a negative predictive value?

A

Negative predictive value is the probability that subjects with a negative screening test truly don’t have the disease

42
Q

What is a positive predictive value?

A

Positive predictive value is the probability that subjects with a positive screening test truly have the disease.

43
Q

Describe the negative and positive predictive value for a d-dimer test?

A
  • Good negative
  • Poor positive; likely to be raised for many reasons, but is helpful upon admission

used as RULING OUT test not as a POSITIVE PREDICTOR of DVT

44
Q

What imaging tests would be done if a patient predominantly presents with pain and swelling of leg?

A

Ultrasound of veins in leg

45
Q

What imaging tests would be done if a patient predominantly presents with chest symptoms?

A

CT pulmonary angiogram to look at pulmonary arteries

46
Q

What is a VQ scan?

A

A ventilation-perfusion scan (or VQ scan) is used to diagnose or exclude a pulmonary embolism (PE);

  • Checks for the perfusion of the lungs (how much blood flow there is)
  • Checks for ventilation (how much air flow there is)
  • If there is impaired perfusion, it is indicative of a PE

But these are harder to interpret.

47
Q

What is a VTE?

A

Venous thromboembolism (VTE) is a condition in which a blood clot forms most often in the deep veins of the leg, groin or arm (known as deep vein thrombosis, DVT) and travels in the circulation, lodging in the lungs (known as pulmonary embolism, PE).

48
Q

If a VTE is discovered after imaging, what is the treatment?

A
  • Patient put on higher dose of anti-coagulation than would be used for prophylaxis
  • Direct thrombin inhibitors: Dabigatran
  • Direct anti-Xa activity:
    • rivaroxaban
    • apixaban
    • endoxaban
49
Q

Advantages of DOACs (rivaroxaban, apixaban and Dabigatran) over warfarin?

A
  • Wafarin;
    • Dose of warfarin varies 40 fold; patients need to be constantly monitored
    • Need a ‘run in period/initiation’ with an injectable agent –> warfarin takes about 5 days to start working
  • DOACs;
    • More predictable dose response; no need for routine monitoring
    • The dose is uniform for most patients
    • Rapid onset of action; don’t need a ‘run in period/initiation’ with an injectable agent –> initiation may be done directly with rivaroxaban and apixaban with no need for LMWH
50
Q

What is a DOAC? What are the 4 main ones?

A

Direct oral anticoagulant;

  • dabigatran
  • rivaroxaban
  • apixaban
  • edoxaban
51
Q

Why are DOACs direct?

A

because they block a single blood clotting factor to treat or prevent blood clots

52
Q

When would an anticoagulant dose reduction be recommended?

A

In specific populations, eg very elderly, renal impairment for VTE prevention and for AF

53
Q

Describe the initiation vs continued dose for rivaroxaban and apixaban?

A

For VTE, recommended dose at initiation is greater for rivaroxaban and apixaban

54
Q

LMWH is still used. When would it be used?

A

If you had high suspicion that patient had blood clot but had not yet had imaging results back –> single injection of LMWH (tinzaparin or enoxaparin)

55
Q

How are doses fixed for LMWH?

A

According to body weight

56
Q

How is LMWH administered?

A

Usually once daily by s/c injection

57
Q

What are the 2 main LMWH?

A
  • tinzaparin
  • enoxaparin
58
Q

How long should heparin and warfarin therapies overlap for? Why?

A

Heparin and warfarin therapies should overlap for approximately four to five days. The presence of a therapeutic INR does not confer protection from clot formation and expansion during the first few days of warfarin therapy because of the delay in the therapeutic inhibition of prothrombin.

59
Q

Pathway of treatment using warfarin and heparin (N.B. this is being used less and less)

A
60
Q

When are all DOACs contraindicated? What is used instead?

A

All DOACs are contraindicated in patients with severe hepatic disease in which warfarin is the only recommended anticoagulant in this patient population.

61
Q

For a first episode of proximal vein DVT or PE, how long is treatment given for?

A

Treat for 3-6 months. (For warfarin: target INR = 2.5)

62
Q

For recurrent episodes of VTE, how long is treatment given for?

A

Treat with long term anticoagulation

63
Q

What determines the length of treatment of VTE?

A
  • Severity
  • What was the risk factor that caused it? Can it be eliminated?
64
Q

Length of anticoagulation in a proximal DVT or PE that has occurred in absence of reversible risk factor?

A

Consider long term (unless good reason not to)

65
Q

What should be considered when faced with recurrent VTE on therapeutic anticoagulation?

A
  • Consider cancer or APLS
  • DOACs consider;
    • adherence?
    • absorption?
    • body weight?
  • Warfarin; Increase target INR to 3.5
66
Q

Define thrombophilia

A

Thrombophilias are familial or acquired disorders of the haemostatic mechanism which are likely to predispose to thrombosis.

Inherited abnormalities must co-segregate with clinical thrombosis in the pedigree.

67
Q

Alternative definition of thrombophilia?

A

Patients who develop VTE:

  • Spontaneously
  • Of disproportionate severity
  • Recurrently
  • At an early age
68
Q

What are 6 examples of heritable thrombophilias?

A
  • Antithrombin deficiciency
  • Protein C deficiency
  • Protein S deficiency
  • Activated Protein C resistance/FV Leiden
  • Dysfibrinogenaemia
  • Prothrombin 20210A
69
Q

What 3 deficiencies can lead to thrombophilia?

A
  • Antithrombin deficiency
  • Protein C S deficiency
  • Protein S deficiency
70
Q

What is factor V Leiden?

A
  • In Factor V Leiden, the factor will not be degraded (it is resistant to cleavage), and so there will be a hypercoagulable state
  • Factor V Leiden is ‘APC resistant’, and associated in the majority of cases with a single point mutation in the factor V gene: G to A (1,691)
  • Not found in Far East and Africa

N.B. this is common and most people will never develop clots

71
Q

What is dysfibrinogenemia?

A

Dysfibrinogenemia is a coagulation disorder characterised by having an abnormal form of fibrinogen. Fibrinogen is a protein produced by the liver which helps control bleeding by helping blood clots to form.

72
Q

What is fibrinogen produced by?

A

The liver

73
Q

What is the Prothrombin 20210 Mutation?

A
  • Point mutation in 3’ untranslated region of the prothrombin gene
  • Associated with increased prothrombin levels
  • Confers 3x risk index for VTE
74
Q

What is the most common acquired thrombophilia?

A

Antiphospholipid syndrome APS

75
Q

What is antiphospholipid syndrome (APS)?

A
  • Autoimmune disorder; people develop autoantibodies against negatively charged phospholipids.
  • These phospholipids are important in the complexes that form during the coagulation cascade e.g. when prothrombin is cleaved to form thrombin, this is happening in a complex of clotting factors on the surface of phospholipids
  • These autoantibodies disrupt this mechanism and tip the balance towards a pro-coagulant state
76
Q

Clinical features of thrombophilias?

A
  • Deep vein thrombosis
  • Pulmonary embolism
  • Superficial thrombophlebitis
  • Thrombosis of cerebral, axillary, portal, mesenteric veins
  • Arterial thrombosis (APS, only)
  • Coumarin induced skin necrosis (PC deficiency)
  • Obstetric complications : fetal wastage (APS)
77
Q

What is superficial thrombophlebitis?

A

Superficial thrombophlebitis is inflammation of a vein just under the skin, usually in the leg. A small blood clot also commonly forms in the vein, but is usually not serious. The condition usually settles and goes within 2-6 weeks.

78
Q

Is arterial thrombosis a feature of heritable thrombophilias?

A

No; but it is a feature of the autoimmune thrombophilia of APS

79
Q

What is coumarin induced skin necrosis?

A

a condition in which skin and subcutaneous tissue necrosis occurs due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants (such as warfarin)

80
Q

Function of protein C and S?

A
  • Natural anticoagulants
  • Activated protein C and protein S complex will degrade Factors 5 and 8 (cofactors), impairing clotting
  • Deficiency in either protein will lead to a thrombophilic state
  • N.B. protein S is a cofactor for protein C
81
Q

Clotting cascade:

A
82
Q

What is factor V naturally degraded by?

A

Factor V will naturally be degraded by activated protein C, reducing thrombosis

83
Q

What is the most common familial thrombophilia?

A

Factor V Leiden

84
Q

Which thrombophilia is in association with recurrent foetal loss (>2)?

A

Antiphospholipid Syndrome

85
Q

Risk of VTE in thrombophilias

A

N.B. deficiency in anticoagulants is more of a risk than factor V Leiden

86
Q

When do patients with factor V Leiden tend to present?

A

When faced with a risk factor e.g. trauma, surgery

Yr 2 - Clinical Pathology (80 decks)

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