thromboembolic disease

Question 1

whats a thrombus

Answer 1

The term “thrombosis” refers to the formation of a blood clot within a blood vessel (venous or arterial) during life. It is a pathological process. A thrombus is a mass within the vascular lumen, which consists of fibrin and varying amounts of other blood constituents (platelets, red cells).

Question 2

what is virchow’s triad

Answer 2

Causes of Thrombosis

The 3 pre-requisites for thrombus formation and propagation are collectively known as Virchow’s triad, after Virchow who recognised them over 150 years ago. These are:

1. Abnormal blood flow (stasis): bed rest, long coach/plane journeys, immobilisation in plaster, venous obstruction by tumours etc.
2. Vessel wall abnormalities (damage to the vessel wall): atheroma, trauma, infective thrombophlebitis, vasculitis, invasion of vessel wall by malignancies etc.
3. Abnormalities in blood constituents (changes in the blood): polycythaemia, inherited hypercoagulable states such as Protein C and Protein S deficiency etc:

Question 3

what is a VTE

Answer 3

Venous thromboembolism is a term which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT and PE are two facets of a single disease. PE arises out of DVT in 90% of cases at post mortem. Lower limb DVT is present in 70- 80% of patients presenting with a proven PE.

Question 4

what is Thrombophilia

Answer 4

• This term describes an inherited or acquired tendency for venous thrombosis (ie. DVT with or without associated PE).

Question 5

Features that should make you suspect thrombophilia

Answer 5

• Venous thromboembolism before the age of 40-45 years
• Arterial thromboembolism before the age of 30 years
• Thrombosis in an unusual anatomical site eg. cerebral vein
• Recurrent venous thrombosis or thrombophlebitis
• Clear family history of venous thrombosis showing any of features 1-4
• Recurrent miscarriages (ie. 3 or more) – antiphospholipid syndrome

Question 6

Investigation of suspected thrombophilia

Answer 6

1. Detailed history – including personal and family history (first degree relatives). Ask about spontaneous thrombotic events. History of documented thromboembolism especially useful if available, but reasonable to accept a plausible history. Ask about additional risk factors, including use of combined pill and HRT.
2. Physical examination

3.Laboratory investigations
full blood count – look for thrombocytosis or polycythaemia
cholesterol and triglycerides for selected patients with apparent high risk of arterial thrombosis
battery of tests for inherited and acquired thrombophilia – Factor V Leiden, protein C, protein S, antithrombin, prothrombin G20210A mutation, lupus anticoagulant tests and anticardiolipin antibodies, hyperhomocysteinaemia

4.Other appropriate investigations – laboratory, imaging, other.

Question 7

Inherited thrombophilias associated with venous thromboembolism

Answer 7

Factor V Leiden

The most common of the heritable thrombophilias. Activated factor V coagulation factor molecules are normally deactivated by a naturally occurring anticoagulant molecule, protein C. People who have inherited an abnormal factor V molecule (factor V Leiden), which cannot be so easily degraded by protein C, have an increased tendency to venous thromboembolism.

Protein C and Protein S Deficiency

Both are vitamin K dependent natural anticoagulant proteins and therefore their activity is markedly reduced by warfarin therapy.

Antithrombin Deficiency

Antithrombin is a serine protease inhibitor - a natural anticoagulant - and is particularly active against factors IIa and Xa. Its action is markedly enhanced by heparins. Antithrombin deficiency is associated with a higher risk of thrombosis than deficiencies of Protein C and Protein S.

Prothrombin G20210A mutation

This defect is associated with increased prothrombin levels and an increased risk of thrombosis.

Question 8

Acquired thrombophilias associated with venous thromboembolism

Answer 8

Polycythaemia

1. Increased blood viscosity: The increased number of red cells results in sluggish flow with increased tendency to thrombosis.
2. Increased coagulability with excess fibrin formation

Thrombocytosis or hyperaggregable platelets
Very high platelet counts >1000 x109/L increase the risk of thromboembolism. Essential thrombocythaemia is a myeloproliferative disorder that results in excess platelet production, and is associated with both arterial and venous thromboembolism.

Antiphospholipid Antibodies
First identified as lupus anticoagulants in patients with systemic lupus erythematosus. Despite prolonging in vitro clotting times they are associated with thrombosis. Diagnosis rests on demonstration of the lupus anticoagulant activity and/or the presence of IgG or IgM anticardiolipin antibodies. Also associated with arterial thrombosis and recurrent miscarriages.

Homocystinaemia
Homocysteine is an amino acid that is formed during the conversion of methionine to cysteine. Inherited enzyme deficiencies in its metabolic pathways can result in increased blood concentrations of homocysteine, as can acquired problems such as vitamin B12 deficiency. Homocystinaemia is associated with venous thromboembolism and is an independent risk factor for coronary artery disease and peripheral vascular disease.

Question 9

Clinical syndromes of venous thromboembolism

Answer 9

• Deep vein thrombosis in lower and upper limbs
• Pulmonary embolism
• Thrombosis in unusual anatomical sites eg. intracranial venous sinuses,
portal vein, hepatic vein (Budd-Chiari)
• Veno-occlusive disease – after BMT etc
• Superficial thrombophlebitis – does not normally require anticoagulation

Question 10

Clinical symptoms/signs of DVT

Answer 10

THESE ARE NOT RELIABLE
• Pain, swelling and redness of affected limb
• Calf muscle induration and tenderness
• Local increase in temperature
• Unilateral oedema
• Accentuation of venous pattern

Question 11

Differential diagnosis of lower limb DVT

Answer 11

1. Infective cellulitis – localised pain, swelling and often marked tenderness. Leg often looks red and shiny and is hot to touch; may have very sharply defined borders (as in erysipelas). Significant fever often present, particularly if bacteraemic; breaks in skin, especially between toes or co-existent fungal infection can be useful clues. May co-exist with DVT.
2. Ruptured Baker’s cyst – usually occurs in context of osteoarthritis or rheumatoid arthritis. Examine back of knee.
3. Calf haematoma – usually history of trauma, but there may be none. Look for bruising.
4. Also other orthopaedic problems such as muscle strain/tear or compartment syndrome.
5. Lymphatic problems e.g. lymphoedema, lymphangitis and leg oedema in a paralysed limb

Question 12

Diagnosis of DVT

Answer 12

There are 3 aspects to diagnosis of DVT

1. Clinical assessment
2. Imaging
3. D-Dimer test

Question 13

1. Clinical assessment of probability for lower limb DVT

Answer 13

Although clinical diagnosis of DVT is imprecise, various probability models have been devised which help to predict the likelihood of DVT in any particular patient. These models should always be used in conjunction with objective diagnostic tests. One such validated model is the Wells’ score, which combines risk factors for venous thromboembolism and clinical examination findings:
Two-level DVT Wells Score

Question 14

imaging for possible DVT

Answer 14

(a). Duplex ultrasound (with compression)
This is the investigation of choice for DVT. It is non-invasive, painless and readily available. It is highly sensitive for the detection of occlusive proximal thrombi, but less so for calf thrombi.

(b). Contrast venography
Historical gold standard but has been superseded by duplex ultrasound. Most useful in non-post-phlebitic legs, but it is invasive, expensive and can be painful.

(c). Other imaging techniques
CT venography – compression ultrasonography is less accurate for veins above the common femoral vein. CT venography can be used to diagnose inferior vena cava and iliac vein thrombosis, as well as thrombosis of the common, deep and superficial femoral veins.
Magnetic resonance venography (especially contrast-enhanced) may be useful, but time, cost and resource issues apply.

Impedance plethysmography – good sensitivity for detection of proximal DVT, but has poor specificity.

Question 15

D-Dimer test in suspected DVT

Answer 15

Measurement of D-dimers (one of the breakdown products of cross-linked fibrin) has a high sensitivity but low specificity for acute VTE. This is because D-dimers are raised in a number of conditions other than VTE e.g. pregnancy, malignancy, post- operatively, soft tissue injury. Therefore, it should not be used as a routine screening test for VTE. However, a negative D-dimer particularly when combined with a clinical probability assessment can be invaluable in excluding VTE in patients in whom such a diagnosis is suspected. Thus, the greatest utility of D-Dimer testing is for its negative predictive value in patients with a low clinical pre-test probability for acute VTE.

Question 16

1. For confirmed uncomplicated proximal lower limb DVT: what is the treatment

Answer 16

(a) Anticoagulation:
o start treatment immediately with heparin. In stable patients, outpatient ambulatory treatment with a low molecular weight heparin within the framework of an integrated care pathway is the initial treatment of choice.
o Warfarincanbestartedatthesametimeasheparin.
o Continue low molecular weight heparin for at least 5 days whilst the
patient is being loaded with warfarin. The heparin is discontinued once the INR has stabilised in the therapeutic range (2.0-3.0) for two consecutive days; warfarin should be continued.
o Duration of warfarin treatment will depend on assessment of VTE recurrence risk.
o The subsequent monitoring and prescribing of warfarin would normally be done in an anticoagulation clinic.

Question 17

Duration of initial anticoagulation in acute uncomplicated proximal DVT

Answer 17

The risk of recurrent VTE (DVT or PE) is an important consideration in deciding on the optimal duration of anticoagulation. This must be weighed against the risk of bleeding from anticoagulation. Assessment of the recurrence risk will be determined among other things by the circumstances in which the DVT occurred (ie. provoked versus unprovoked) and whether D-Dimer is normal or elevated after completion of initial warfarin therapy etc. Careful analysis of factors which predict risk of recurrence and risk of bleeding in the individual patient is particularly important when making decisions on long-term anticoagulation

It is not possible to be prescriptive about every individual VTE event. However, in general:

DVT provoked by surgery and non-surgical transient factors (eg. oral contraceptive pill, pregnancy, plaster cast) – warfarin for at least 3 months; in practice 6 months. Long-term anticoagulation is not recommended.

DVT provoked by cancer - patients with cancer-provoked DVT are at high risk of recurrence. For such patients, low molecular weight heparin is more effective than warfarin. These patients should initially be treated for 6 months with low molecular weight heparin rather than warfarin.

First unprovoked DVT – warfarin for at least 6 months; long-term anticoagulation (i.e. lifelong) should be considered

Recurrent unprovoked DVT – warfarin for at least 6 months; long-term anticoagulation (i.e. lifelong) should be considered

Question 18

other than anticoagulation what is the treatment For confirmed uncomplicated proximal lower limb DVT

Answer 18

1 Graduated compression stockings combined with early mobilisation: help pain and swelling to resolve more quickly; there is no increased risk of pulmonary embolism from early mobilisation. The use of these stockings also reduces the incidence of the post-thrombotic syndrome. The patient should be advised to wear the stockings on the affected limb for at least 2 years and should be replaced two or three times a year according to the manufacturer’s instructions. Graduated compression stockings are contraindicated in patients with peripheral vascular disease.

2. In the event of high clinical suspicion of DVT where diagnostic investigations cannot be immediately performed, start heparin treatment (with low molecular weight heparin) until the diagnostic investigations can be done. Anticoagulant treatment is stopped if these are negative.
3. For symptomatic calf DVT diagnosed by contrast venography, treatment is Warfarin for six weeks to three months depending on whether the precipitating cause can be removed.
4. Outpatient treatment is unsuitable for certain groups of patients, such as those with
   • Known allergy to heparin or history of heparin-induced thrombocytopenia
   • Severe medical co-morbidities
   • Severe acute venous obstruction (phlegmasia cerulea dolens)
   • Significant renal impairment (creatinine clearance <30 ml/min)
   • Poor adherence to treatment
   • Communication difficulties
   • Active bleeding or a significant bleeding risk
   • Poor social circumstances
   • Poor mobility

Question 19

Complications of DVT

Answer 19

1. Pulmonary embolism (discussed below).
2. Post-thrombotic syndrome – a chronic complication of DVT that is characterised by leg swelling, pain and occasionally, venous ulceration. It is due to venous valvular incompetence resulting from damage to venous valves during or following acute DVT, persistent venous outflow obstruction resulting from incomplete recanalisation of the vein, or both.
3. Severe acute venous obstruction (phlegmasia cerulea dolens) – this is a rare cause of acute ischaemia of the lower limb. In this condition, massive thrombosis of all the major limb veins occurs leading to gross swelling and obstruction of the arterial supply.
4. Paradoxical embolism – A rare situation in which infarction is seen within the systemic circulation as a consequence of pulmonary embolism in an individual with an atrial septal defect.

Question 20

what happens in an Upper limb DVT

Answer 20

Defined as thrombosis of the subclavian, axillary or brachial veins.
Symptoms include swelling of the upper limb, pain or discolouration of the limb, the presence of collateral veins affecting the upper arm, neck or chest wall. Complications include acute PE and post-thrombotic syndrome.

Question 21

investigation and treatment of upper limb DVT

Answer 21

Ultrasound imaging is the investigation of choice in the diagnosis of upper limb DVTs
Anticoagulant treatment of upper limb DVT is as described for lower limb DVT.

Question 22

Patterns of acute PE clinical presentation

Answer 22

60% present with pulmonary infarction syndrome (i.e. pleuritic chest pain ± dyspnoea ± haemoptysis). The patient may not be hypoxic and may have normal ECG.

25% present with isolated breathlessness

15% present with sudden circulatory collapse and acute right heart failure –
may occur in a previously well patient or in a patient with poor cardiorespiratory reserve

97% patients with PE will have 1 or more of breathlessness, tachypnoea and pleuritic chest pain

Question 23

Severity of PE – clinical risk groups

Answer 23

1. High risk PE (massive PE) - defined as PE so severe as to cause circulatory collapse and is due to acute right heart failure (i.e. systolic BP 90mmHg) but with evidence of right ventricular strain (elevated of troponin T due to myocardial injury, evidence of right heart strain on CTPA or ECHO)
2. Low risk PE - the patient is haemodynamically stable with no signs of right ventricular strain. The majority of patients fall into this category. They may be suitable for outpatient ambulatory care within a robust clinical governance framework.

Question 24

possible investigations in PE

Answer 24

1. Assessment of clinical probability of PE – Wells Score
2. CT Pulmonary Angiography (CTPA)
3. Ventilation/Perfusion lung scan (V/Q scan)
4. Duplex Ultrasound (with compression) – Most patients with PE also have a DVT as the two conditions are part of the same pathological process. This test is useful to increase the likelihood of reaching a diagnosis in patients with probable PE (Wells’ score > 4 or have a positive D-dimer test) whose CTPA is negative. In such patients, compression ultrasound may reduce the need for performing pulmonary angiography.
5. Echocardiography – will reliably diagnose massive PE - acute right heart strain or failure.
6. Pulmonary Angiography – most accurate but invasive.

Other useful investigations
1. CXR – often normal. Commonest findings in PE are linear or wedge-shaped opacities, small pleural effusions and (in massive PE) areas of oligaemia (increased translucency). Important in the exclusion of other diagnoses i.e. pneumonia, pneumothorax, heart failure and features of chronic airflow obstruction e.g. hyperinflation

2. ECG - changes usually only occur with larger emboli but are then common. Commonest finding is sinus tachycardia, but there may be evidence of right ventricular strain (RBBB, S1 Q3 T3 pattern, P-pulmonale, antero-septal T wave inversion or ST depression).
3. Arterial Blood Gases on air if O2 sats 4 (PE likely score). A negative D-Dimer reliably excludes PE in patients with low clinical probability. False positive results occur in critically ill patients with severe infection, trauma or inflammatory disorders, disseminated intravascular coagulation, vaso-occlusive sickle-cell crisis, vasculitis, superficial phlebitis and cancer
4. Troponin T – may be elevated in acute PE. Useful for risk stratification.

Question 25

treatment of PE

Answer 25

Treatment
1. Admit patient to hospital. Early discharge and outpatient treatment possible in carefully selected patients with low risk PE provided a robust integrated care pathway is in place (as per outpatient DVT management).

2. Low risk PE – treatment same as for acute DVT.
3. Intermediate risk PE (sub-massive PE) - Administer bolus dose of IV Unfractionated Heparin 5000-10000 U (80 Unit/kg), followed by daily s/c LMWH. Follow with warfarin as per acute DVT. These patients should be monitored very closely on a cardiac-monitored bed and thrombolysis considered in the event of haemodynamic decompensation.
4. Massive PE – thrombolysis is first line treatment. If cardiac arrest imminent, may thrombolyse patient on clinical grounds alone. Follow thrombolytic therapy up with unfractionated heparin infusion and then warfarin. Note that thrombolytic treatment for PE does not dissolve the thrombus as completely as it does with acute coronary thrombosis and that bleeding is a risk.

Question 26

Duration of initial anticoagulation in acute PE

Answer 26

Duration of initial anticoagulation in acute PE
As for acute proximal DVT:

- Provoked PE – at least 3 months; in practice 6 months
- PE provoked by cancer – low molecular weight heparin rather than warfarin for 6 months
- First unprovoked PE – warfarin for at least 6 months; long-term anticoagulation should be considered
- Recurrent unprovoked PE – long-term anticoagulation

Question 27

action of heparin

Answer 27

Inactive by mouth so given only by injection. Many actions on the coagulation system but mainly accelerates antithrombin inhibition of factor Xa and factor IIa (thrombin). Acts immediately and does not cross the placenta.
Monitoring: APTT for unfractionated heparin, anti-Xa assay for low molecular weight heparin.

Question 28

what is LMW heparin, its benefits and when is unfractionated better?

Answer 28

Low molecular weight heparin: Ordinary (unfractionated) heparin consists of a mixture of molecules of different sizes. Purified low molecular weight fractions are manufactured from unfractionated heparin by chemical or enzymatic methods; they have the advantage of longer half-life so allow once daily s.c. dosing and may have less tendency to cause haemorrhage with equivalent anti-thrombotic effect.

They are more expensive, but have the following advantages:
1. Dosing is simple.
2. Monitoring is not usually required.
3. Low molecular weight heparin can be used for out-patient treatment of DVT
according to body weight.
4. Heparin induced thrombocytopenia (HIT), which may paradoxically be associated with thrombosis, is very rare.
Note, however, that use of low molecular weight heparin in renal failure is associated with a high bleeding risk, due to accumulation of the drug.

Unfractionated heparin is more suitable:
1. If the risk of bleeding is high (eg. renal impairment).
2. In situations where rapid reversal of anticoagulation is required.
3. In massive PE following thrombolysis.
4. In some cases of proximal lower limb DVT where LMWH appears not to be working.

Note that the low molecular weight heparins are less easily reversed with protamine sulphate compared to unfractionated heparin.

Question 29

how does warfarin work

Answer 29

Causes defective vitamin K dependent clotting factors to be manufactured. Active by mouth and long half-life but maximum effect attained only after three-five days, so heparin should be continued until then. Patients on warfarin should be issued with their own record book of warfarin dose/INR results and anticoagulant clinic appointments. This also contains advice on bleeding, alcohol and drug consumption and identifying warfarin tablet sizes.

Many drugs interfere with warfarin, making it more or less effective. Check before prescribing!

Warfarin crosses the placenta and is teratogenic. It is monitored using PT (INR).

The intensity (INR range) and duration of warfarin treatment depends on the indication. For example, for first DVT or PE, the target INR is 2.5 (range: 2.0-3.0) whereas in patients with recurrent venous thromboembolism whilst therapeutically anticoagulated, the intensity of the anticoagulation should be increased to a target INR of 3.5 (range: 3.0-4.0). Duration of warfarin for DVT or PE is as discussed earlier.

Question 30

Treatment of Warfarin Overdosage

Answer 30

Treatment of Warfarin Overdosage

The risk of bleeding increases significantly with INR values > 5.0. GI tract and intracranial cavity are common sites. The commonest cause is alcohol and other drug interactions.
In treating warfarin overdosage consider:

1. whether the patient is bleeding or not
2. value of INR – the higher the INR, the higher the bleeding risk
3. the cause of the overdosage
4. INR 6-8, but no bleeding, or minor bleeding. Stop warfarin for 24-48 hours. Recheck INR and re-introduce drug at lower dosage and retest in 2-7 days.
5. INR > 8, no bleeding or minor bleeding. Stop warfarin for 48 hours and retest on third day before restarting warfarin at lower dose. Consider Vitamin K 2.5mg orally (Menadiol) or 1-2mg by slow iv injection (Phytomenadione). IV injection of Vitamin K achieves reversal of overanticoagulation more rapidly than oral; even so, IV vitamin K takes at least 6 hours to achieve this therapeutic effect.

NB: Large doses of Vitamin K can interfere with subsequent control for several weeks, and can take 12-24 hours to have a full corrective effect.

3. Life-threatening, sight-threatening or limb-threatening bleeding. Stop warfarin. Administer Prothrombin Complex Concentrate (Beriplex). Also give vitamin K 2-5mg i.v. (or more if warfarin is not to be reintroduced) to maintain reversal. Prothrombin Complex Concentrate is a plasma-derived product which contains the vitamin K dependent clotting factors – factors II, VII, IX, X, protein C and protein S. It is effective for urgent reversal of severe warfarin- associated bleeding. Fresh frozen plasma (FFP) is not recommended for this purpose because it does not completely reverse warfarin when given in the recommended doses (15ml/kg body weight), it takes at least half an hour to thaw for use, and a large volume is required relative to Beriplex. However,
   note that Beriplex is prothrombotic.

Question 31

what are New oral anticoagulants (NOACs) and adv / disadv?

Answer 31

In recent years, alternatives to vitamin K antagonists such as warfarin have been introduced into clinical use. These novel anticoagulant drugs fall into two main groups:

1. Direct thrombin inhibitors (DTI) which block both fibrin bound and circulating thrombin
2. Activated Factor X (Factor Xa) inhibitors

The advantages of both classes over warfarin are that:
1. They have wider therapeutic indices and therefore have an acceptable safety
profile
2. They have a faster onset of action
3. Their pharmacokinetic and pharmacodynamics effects are more predictable.
Thus there is less inter-patient variability and so monitoring is not required

The disadvantages of NOACs include:

1. Lack of reversibility – no specific antidote
2. Bleeding risk, especially GI bleeding risk

Question 32

what are Direct thrombin inhibitors (DTI):

Answer 32

An example of a DTI is Dabigatran. It is an orally administered drug which is licensed for:

1. primary prevention of VTE in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery
2. prevention of stroke and systemic embolism in adult patients with non- valvular atrial fibrillation
3. treatment of DVT and PE and prevention of recurrent DVT and PE in adults

Question 33

what are Factor Xa inhibitors:

Answer 33

This group can be subdivided into:
1. Oral anticoagulants which directly inhibit Factor Xa (eg. rivaroxaban,
apixaban)
2. Parenterally administered anticoagulants which indirectly inhibit Factor Xa
(eg. fondaparinux)

Rivaroxaban is licensed for the following indications (note differences in dosing schedules):

1. prevention of VTE in adult patients undergoing elective hip or knee replacement surgery
2. prevention of stroke and systemic embolism in adult patients with non- valvular atrial fibrillation and one or more risk factors
3. treatment of DVT and prevention of recurrent DVT and PE in adults.

Question 34

what is Fondaparinux

Answer 34

Fondaparinux is not a NOAC. It is given as a subcutaneous injection and is licensed for the following indications:

1. Prevention of VTE in adults undergoing major orthopaedic surgery of the lower limbs
2. Prevention of VTE in adults undergoing abdominal surgery who are judged to be at high risk of thromboembolic complications, such as patients undergoing abdominal cancer surgery
3. Prevention of VTE in adult medical patients who are judged to be at high risk for VTE
4. Treatment of adults with acute symptomatic spontaneous superficial vein thrombosis of the lower limbs without concomitant DVT.