Chapter 131: Thrombosis and thromboembolism

A thrombus is defined as a clot formed in the circulation from the constituents of the blood, whereas emboli are fragments of thrombus that break off and block vessels downstream. Almost half of adult deaths in Western countries are due to thrombosis of coronary or cerebral arteries, or to pulmonary embolism.¹ A thrombus is the result of a cascade of events involving platelets, RBCs, coagulation factors and the vessel wall.

Conditions predisposing to thrombosis:

• thrombophilia

• thrombocytosis (platelets)

• polycythaemia rubra vera

Thrombophilia²

Thrombophilia refers to a disorder of haemostasis in the form of a primary coagulopathy leading to a tendency to thrombosis. This should be considered in patients with major unprecipitated venous thromboembolism with or without a strong family history of venous thrombosis. Several causes can be tested, both inherited and acquired:

• inherited:

  • – factor V Leiden gene mutation (activated protein C resistance)

  • – prothrombin gene mutation

  • – protein C deficiency

  • – protein S deficiency

  • – antithrombin deficiency

• acquired:

  • – antiphospholipid antibodies (anticardiolipin or anti-ß₂ GPI)

  • – elevated homocysteine level

  • – lupus anticoagulant

The above factors can all be measured in the laboratory with specific genetic tests, coagulation or antibody-based tests. Other acquired causes (regarded as risk factors) include malignancy, oral contraceptives, HRT, immobilisation, obesity, smoking, pregnancy and major surgery. Most DVTs do not require investigation for an underlying cause, but consideration should be given to screening patients who have had an unprovoked DVT. Refer to a haematologist if thrombophilia is proven or suspected. Of particular interest is factor V Leiden, which occurs in about 4% of Caucasians; the relative risk of venous thrombosis is increased three to seven times in heterozygotes and 80 times in homozygotes.²

Indications for investigation

• Recurrent or unusual thrombosis

• Arterial thrombosis <30 years

• Skin necrosis, especially on warfarin

• Recurrent fetal loss

• Familial thromboembolism

Venous thromboembolism

A feature of venous thrombosis is that it develops in normal vessels, with key factors being stasis and increased coagulability, including thrombophilia. The classic example is deep venous thrombosis of the leg veins. Another poorly recognised thrombosis is axillosubclavian venous thrombosis, which is associated with pulmonary embolism in 30% of cases.³

Other sites of deep vein thrombosis are the pelvic/ovarian veins, which should be suspected in a person at risk with pelvic pain and swollen upper thighs, mesenteric venous thrombosis and cerebral sinus thrombosis, which are usually due to thrombophilia.

Deep venous thrombosis

Past history is very important.

Risk factors

• Family history

• Thrombophilia

• History of previous thromboembolism

• Drugs (e.g. OCP, tamoxifen, HRT)

• Malignancy (watch idiopathic DVT)

• Increasing age; age >40

• Varicose veins

• Significant illness, esp. heart failure and cancer

• Other chronic illness

• Recent surgery

• Major/orthopaedic surgery

• Immobility

• Long flights

• Pregnancy/puerperium

• Obesity

• Dehydration

There is an up to 20% association with pulmonary emboli, of which 30% may be fatal. DVT may be asymptomatic, but usually causes tenderness in the calf. DVT may present with painless unilateral leg swelling. Because of the potentially serious consequences from untreated thromboembolism, it is essential to objectively confirm or exclude clinically suspected disease.

Examination

May be low-grade fever.

Examine both legs. Look for:

• swelling of calf and thighs

• asymmetry

• erythema

• superficial veins

Feel for:

• warmth

• tenderness (gently squeeze calves)

• pitting oedema

Don’t test Homan’s sign (pain on sharp dorsiflexion of foot) as it may dislodge a thrombus.

Refer to Wells criteria (e.g. <www.nice.org.uk/guidance/cg144/chapter/guidance#terms-used-in-this-guidance> or <www.mdcalc.com/wells-criteria-for-dvt/>).

Investigations

• Duplex ultrasound: accurate for above-knee thrombosis; improving for distal calf

• Should be repeated in 1 week if initial test normal

• Contrast venography: reserved if ultrasound doubtful

Note:

• MRI appears to be very accurate for DVT, but is not yet available generally.

• The plasma D-dimer can help to ‘rule out’ thrombosis. Where the clinical probability of venous thrombosis is low, a normal D-dimer effectively excludes the diagnosis. However, where clinical probability is high, appropriate imaging with Doppler ultrasound or a lung scan should be performed. A raised D-dimer is non-specific and does not help with diagnosis.

Treatment^3,4

Provide education and counselling. Admit to hospital (usually 5–7 days)—can treat as an outpatient. Drugs used in the treatment of thromboembolism are summarised in general format in TABLE 131.1.

• Collect blood for APTT, international normalised ratio (INR) and platelet count

• Check renal function

• LMW heparin e.g. enoxaparin or dalteparin

  or

  unfractionated heparin (UFH) 330 U/kg, SC loading dose then 250 U/kg bd SC (or monitor with APTT)

  or

  UFH 5000 U bolus IV then infusion in N saline (12 500 U over 12 hours)

  • – monitor with APTT after 4–8 hours then for 5–7 days

  or

  fondaparinux SC, according to weight e.g. 50–100 kg: 7.5 mg SC daily

• Oral anticoagulant (warfarin) for 3 months (or 6 months if unprovoked)

  commence on day 1 or 2, usually 5 mg nocte for 2 nights and then according to INR monitoring (max. 30 mg in 3 days)

• Do not give aspirin

• Mobilisation within the limits of pain, tenderness and swelling

• Class II graded compression stocking to affected leg in proximal DVT associated with significant swelling. The stocking may be above or below the knee depending on the extent of the swelling.

Long term: complete resolution 50–80% at 6 months and almost 100% by 12 months.

Prevention

Surgery

• Early ambulation

• LMW heparin or new anticoagulants for orthopaedic (for 14–35 days) or other high-risk surgery (for 1 week or until fully mobile) See TABLE 131.1

• Graded pressure elastic stockings

• Physiotherapy

• Pneumatic compression (especially in high-risk patients where heparin is contraindicated)

• Electrical calf muscle stimulation during surgery

Prolonged travel/immobilisation

• Keep hydrated—ample water.

• Avoid or restrict alcohol and coffee.

• Exercises—3–4 minutes per hour (e.g. walking, calf contraction—e.g. foot pumps, see FIG. 131.1, ankle circles, knee lifts).

• Injections—LMWH just prior to flying and on arrival for those at high risk. Use a prophylactic dose (e.g. enoxaparin 40 mg or dalteparin 5000 U—both SC injections twice daily).

Pulmonary embolism⁶

Refer to CHAPTER 40 for more detail on the clinical features and management of pulmonary embolism. CT pulmonary angiography is very specific and appears to be as sensitive as V/Q scanning for embolism, and is currently the preferred first-line investigation. The basis of treatment is LMW heparin and warfarin, as for DVT.

Arterial thromboembolism

The common serious manifestations of this are myocardial infarction, stroke, occlusion of the arterial system of the lower limbs and ‘eye’ embolism (e.g. central retinal artery thrombosis). Emboli originate from the left side of the heart, the carotid arteries or the iliac arteries. Atrial fibrillation is an important predisposing factor.

Preventing systemic embolism in atrial fibrillation⁶

Atrial fibrillation (AF) accounts for about 15% of ischaemic strokes caused by systemic embolism of cardiac thrombi. This risk gradually increases with age. Use of warfarin or DOAC reduces the annual incidence of stroke during AF from 4.5% to 1.4%—a risk reduction of almost 70%. The decision to use it or an antiplatelet agent is a difficult one and should be made in consultation with a cardiologist. Although aspirin reduces stroke rate by about 20% in patients with AF when compared with no treatment, it has half the effectiveness of warfarin/DOACs and is less able to prevent severe strokes. As a general rule, all patients with AF should start on warfarin or an appropriate DOAC unless <65 years old or have a major contraindication to its use. It is not indicated in patients with lone AF who are less than 60 years of age with no risk factors. If using warfarin, start with a low dose (e.g. 2–4 mg) and maintain an INR of 2–3 with regular checks. Anticoagulant therapy is also required to prevent embolism after cardioversion.

The direct oral anticoagulants (DOACs)⁵

The term DOAC is replacing NOAC as, over time, these medications become less ‘novel’. These alternatives to warfarin are currently indicated for thromboprophylaxis in non-valvular atrial fibrillation and post-hip and knee replacement surgery. Rivaroxaban is also approved for treatment and secondary prevention of DVT and PE. They need less monitoring than warfarin, but so far only dabigatran has an effective antidote (idarucizumab). Intracranial bleeding is less likely with DOACs compared with warfarin. Caution for use is required in renal impairment and they are contraindicated in patients with renal failure. This requires measurement of creatinine clearance (not eGFR, which does not allow for weight).

Warfarin

Warfarin is an oral agent used in the treatment and prevention of venous thromboembolism, unlike the antiplatelet drugs which have little or no benefit and are recommended in arterial disease. Before prescribing warfarin, the risk of bleeding should be evaluated and discussed with each patient. Indications for warfarin treatment are outlined in TABLE 131.2.

Actions⁴

• Antagonises vitamin K.

• Depresses factors VII, IX and X (half-life of 30–40 hours) and prothrombin.

• Achieves full anticoagulation effect after 5–7 days.

• Prothrombin time (INR ratio) of 2–3 times normal control indicates therapeutic effect.

• The INR is a good indicator of effectiveness and risk of bleeding.

• Duration of effect is 4–5 days after cessation.

• It can cause thrombocytopenia.

• Antidote is vitamin K ± plasma or prothrombin complex concentrate.

Initiation of warfarin treatment^7,8

An estimate of the patient’s final steady dose is made. The patient is commenced on this dose and the INR monitored daily and the dose altered accordingly.

• Measure INR first to establish baseline.

• Generally warfarin is commenced on same day or day after heparin is commenced.

• Heparin can be ceased when INR >2 for 2 consecutive days.

• Typical loading dose is 5–10 mg (o) daily (usually 5 mg) for 2 days (avoid dose >30 mg over 3 days without INR).

• Adjust the dosage according to an INR table (eTG Complete: Therapeutic Guidelines Ltd <www.tg.org.au>) from the third day. Some pathology laboratories offer patients this personalised adjustment service.

• Establish the INR in the therapeutic range, usually 2–3 (average 2.5).

• Maintenance dose is usually reached by day 5.

• The INR reflects the warfarin dose given 48 hours earlier.

• Warfarin is best taken in the evening and INR measured in the morning.

Note:

• Warfarin should be discontinued at 3 months following a first episode of a non-extensive venous thromboembolic event that occurred in the setting of a major, transient risk factor.⁹

• Watch for potential drug interactions.

Recommended target INR values are given in the box.

Overdosage of warfarin

Signs of warfarin overdosage include:

• unexpected bleeding after minor trauma

• epistaxis

• spontaneous bruising

• unusually heavy menstrual bleeding

• gastrointestinal bleeding

Management of overdosage¹⁰

1. Urgent measurement of INR is required.

2. If the only evidence of overdosage is a small increase of the INR above the therapeutic range, cessation of warfarin for 1 to 2 days followed by a continuation at a lower dose is appropriate.

3. If the INR is markedly elevated (>5.0) consider giving oral vitamin K e.g. 10 mg tablet.

4. If bleeding is minor, transient action as in point 2 is still appropriate.

5. If bleeding is persistent, or severe, or involves closed body cavities (such as pericardium, intracranial, fascial compartment), urgent admission to hospital is essential. The anticoagulation may need to be reversed by administering oral or parenteral vitamin K. Infusion of fresh frozen plasma and/or prothrombin complex concentrate (best option) may also be necessary.

Drug interactions

There are so many potential interactions between warfarin and other drugs that the following general principles should be applied:

1. Maintain the simplest possible drug regimens. Avoid polypharmacy.

2. Aspirin is contraindicated while the patient is on warfarin because of the combined antiplatelet and anticoagulation effects. The risk of gastrointestinal bleeding is also increased. Other NSAIDs should also be avoided (see TABLE 131.3).

3. If the patient’s drug regimen must be altered during warfarin therapy, then the INR should be followed closely until stable.

Advice to the patient

• Keep to a consistent diet.

• Do not take aspirin or liquid paraffin.

• Always mention that you take warfarin to any doctor, dentist or chemist you are consulting.

• Remember to take tablets strictly as directed and have your blood tests.

• Report signs of bleeding, such as black motions, blood in urine, easy bruising, unusual nose bleeds, heavy periods, ‘purple toes’.

Note: Give the patient the information sheet about risks.

Bleeding while on heparin

• Recheck APTT

• Cease or reduce heparin

• Admit patient—alert laboratory and haematologist

Antidotes:

• protamine sulphate will reverse (use with caution)

• fresh frozen plasma

• clotting factors (as guided by consultant)