Venous Thromboembolism – Lecture Notes

Aetiology: Venous Thromboembolism

  • Acute provoking risk factors: hospitalisation, surgery, trauma or fracture of lower limbs or pelvis, immobilisation incl plaster cast, long haul travel, recent oestrogen therapy in last 2 weeks, IV device such as cannula.
  • Chronic predisposing factors: Inherited: Protein C, S, antithrombin III deficiency, Factor V Leiden, Prothrombin gene 20210A mutation.
  • Chronic predisposing factors: Acquired: Age, obesity, cancer, leg paralysis, oestrogen, pregnancy or puerperium, major medical illness (incl cardioresp disease, IBD, nephrotic syndrome, myeloproliferative disorder), previous VTE.
  • Chronic predisposing factors: Inherited or acquired: high plasma homocysteine, high coagulation factor VIII, IX, XI, antiphospholipid (anticardiolipin) antibody.

Diagnosis: Deep Vein Thrombosis (DVT)

Wells Clinical Model to predict pretest probability. Each feature scores + 1, except final one that scores – 2:

  • Active cancer with treatment, including palliative, in last 6 months; paralysis, paresis or recent plaster immobilisation of legs; bedridden for > 3 days or major surgery within last 12 weeks; localised tenderness along distribution deep venous system; entire leg swollen; calf swelling > 3 cm compared to normal measured 10 cm below tibial tuberosity; pitting oedema greater in symptomatic leg; non-varicose, collateral superficial veins; previous documented DVT; alternative diagnosis at least as likely DVT (NB carries negative 2 score).
  • Score ≥ 3 = high (53% prevalence); score 1-2 = moderate (17% prevalence) and score ≤ 0 = low (5% prevalence) pretest probability.

Diagnostic approach in patients with suspected DVT is then based on above pretest probability score, use of compression ultrasound and D-dimer:

  • Pretest probability low: perform D-dimer and if negative, rules out. If D-dimer positive, perform compression ultrasound (USS) proximal leg veins. If USS negative – rules out. If USS positive, treat.
  • Pretest probability moderate or high: perform USS. If normal, perform D-dimer and if negative, rules out. If D-dimer positive, repeat USS in one week, and if still normal – rules out.
  • Pretest probability moderate or high: perform USS and if abnormal, treat (and if abnormal at one week – see above).

Wells P, Owen C et al. Does this patient have deep vein thrombosis? JAMA 2006; 295:199-207. [Reference]

Treatment (of DVT)

  • Low molecular weight heparin (LMWH) SC for 5-7 days. Preferred to IV unfractionated (UFH). Use enoxaparin 1mg/kg BD. LMWH is easier to administer, no blood testing, smoother therapy with less treatment failures (or overtreatment), less risk of bleeding, less heparin-induced thrombocytopenia (HIT). Initiate warfarin and continue for 3-6 months.
  • Or can give enoxaparin 1.5mg sc once daily, but BD is preferred if high risk such as iliac vein thrombosis, obese or have cancer.
  • UFH iv is alternative for 5-7 days aiming for APTT 1.5 – 2.5 (avoid subtherapeutic values), plus warfarin initiated as above.
  • Fondaparinux new synthetic pentasaccharide that binds antithrombin and enhances activity towards Factor Xa, but not to thrombin. As effective as LMWH in DVT and UFH in treating PE.
  • Calf-vein DVT alone may be treated with outpatient LMWH for 1 week then a repeat USS. If no propagation (80%), stop treatment but continue with support stockings and repeat USS at 10-14 days. If propagated at either time, continue heparin another 4-5 days whilst commencing warfarin for 3-6 months.
  • Alternatively, calf-vein DVT may go untreated, with repeat USS to exclude propagation above knee (20%) at 1 week, and also at 10-14 days. If negative, no further action but recommend stockings and aspirin for ‘at risk’ times such as prolonged travel.

Blann A, Lip G. Venous thromboembolism. BMJ 2006;332:215-9. [Reference]

Ho WK, Hankey G. Venous thromboembolism: diagnosis and management of deep venous thrombosis. MJA 2005;182:476-81. [Reference]

Pulmonary Embolism

Clinical features:

  • Important PE symptoms are dyspnoea (73%), chest pain (66% – not always pleuritic), cough (37%), apprehension, sweating, haemoptysis and syncope.
  • Important signs are tachypnoea > 20/min (70%), crepitations (51%), tachycardia (30%), low grade fever.
  • Important laboratory findings are atelectasis or parenchymal abnormality on CXR, PaO2 under 80 mmHg in absence of lung disease.
  • ECG: sinus tachycardia common; AF, RAD, RBBB. Note S1Q3T3 is neither sensitive nor specific.
  • Absence of dyspnoea plus tachypnoea > 20 / min has a negative predictive value (NPV) for a PE of 90%; absence of these and pleuritic pain has NPV of 97%; with absence of CXR changes or low PaO2 as well in the remainder virtually excludes PE.

Corris P. A practical approach to the diagnosis of venothromboembolism. Clinical Medicine 2001; 1:274-280 [Reference]

Pretest Probability (PTP)

  • Use Wells’ Clinical Decision Rule to predict pretest probability (points in brackets):
  • Clinical signs and symptoms of DVT (3 points); alternative diagnosis less likely (3 points); heart rate above 100/min or immobilisation (or surgery) in last 4 weeks or previous DVT or PE (all 1.5 points); haemoptysis or malignancy (both 1 point).
  • Score > 6 = high (67% prevalence); score 2-6 = moderate (20.5% prevalence) and score < 2 = low (3.6% prevalence) pretest probability.

Diagnostic investigations

  • Stratified by pretest probability (PTP) and presence or absence of cardiorespiratory disease.
  • Low PTP. Perform D.dimer. If negative, rules out PE. If positive proceed to further testing – see below
  • Moderate or high PTP. Proceed to CTPA or isotope lung V/Q scan (consider V/Q especially if CXR normal):
    • Normal – excludes diagnosis (NPV > 96%).
    • High probability – treat (PPV 86-96%), unless contraindications to heparin.
    • Non-diagnostic – proceed to USS to define source of embolism in legs. Treat any positive. If negative, repeat USS. If positive, treat. If remain negative, no PE.

Kelly J, Hunt B. Role of D-dimers in diagnosis of venous thromboembolism. Lancet 2002; 359:456 458. [Reference]

Recent ‘dichotomous decision rule‘ has been validated, using just two Wells’ PTP categories, D.dimer and multislice CTPA only (‘Christopher Study’):

  • Wells’ Clinical Decision Rule (CDR) to predict pretest probability score ≤ 4 = ‘unlikely’, and score > 4 = ‘likely’.
  • CDR score unlikely (≤ 4), perform D.dimer and if negative, rules out = no PE. If D.dimer positive, perform CTPA. If CTPA negative rules out, if positive, treat.
  • CDR score likely (> 4), CTPA. If negative, rules out. If positive, treat.

Writing Group for the Christopher Study Investigators. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D.dimer testing, and computed tomography. JAMA 2006;295:172-79. [Reference] (Editorial Hull RD. JAMA 2006;295:213-15). [Reference]

Righini M, Le Gal G, Aujesky D et al. Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial. Lancet 2008;371:1343-52. [Reference] (Editorial Kyrle P, Eichinger S. Lancet 2008;371:1312-15). [Reference] NB: validated Christopher Study findings.

Collapsed or hypotense (shocked) patient with high PTP:

  • Urgent echo (ideally TOE) and give thrombolysis if positive. If nondiagnostic, proceed to CTPA, and give thrombolysis if positive.
  • Consider thrombolysis, in addition, for evidence of right heart failure or pulmonary hypertension, even in absence of shock. Also for massive ileofemoral thrombosis.

Konstantinides S et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. NEJM 2002;347:1143-50. [Reference] (Editorial: Goldhaber SZ. NEJM 2002;347:1131-2).

Treatment of Pulmonary Embolus (PE)

  • Unfractionated heparin IV followed by warfarin (as for DVT).
  • LMW heparin should replace unfractionated, as is as effective and safe and is considerably simpler.
  • Some patients (as have a 30-day mortality risk ≤ 1.5%) may safely be managed as outpatients, providing have none of the high-risk features of age ≥ 70; any one of cancer/ heart failure/ chronic lung disease/ CRF/ cerebrovascular disease; pulse ≥ 110; SBP < 100 mmHg; altered mental status; SaO2 < 90%.

Quinlan D, McQuillan A, Eikelboom J. Low-molecular-weight heparin compared to intravenous unfractionated heparin for treatment of pulmonary embolism. A meta-analysis. Ann Intern Med 2004; 140:175-83. [Reference]

Aujesky D et al. A prediction rule to identify low-risk patients with pulmonary embolism. Arch. Intern. Med. 2006;166:169-75. (Editorial: Moores L. Arch. Intern. Med. 2006;166:147-8). [Reference]

Lee C, Hankey G et al. Venous thromboembolism: diagnosis and management of pulmonary embolism. MJA 2005;182:569-74. [Reference]

ACEP: Clinical policy: critical issues in the evaluation and management of adult patients presenting with suspected PE. Ann Emerg Med 2003; 41:257-70 [Reference].

British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax 2003; 58: 470-484. [Reference]

Janata K. Managing pulmonary embolism. BMJ 2003; 326:1341-2. [Reference]

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