DVT / PE

• Pathophysiology and epidemiology

  • Venous thrombi can form in the deep veins of the legs or pelvis (DVT). Most form in the calf, with around 10% progressing to the proximal leg and becoming (more) symptomatic.
  • 50% of untreated proximal thrombi progress to pulmonary embolism (PE), the commonest type of venous thromboembolism (VTE).
  • Less commonly, PEs are caused by fat, fluid, or infective emboli.
  • Annual incidence of DVT: 1/1000.

• Signs and symptoms

  Symptoms:

  • Leg pain, which may be along the vein.
  • Respiratory: acute SOB, pleuritic chest pain, haemoptysis, cough.
  • Systemic: dizziness, fever.

  Signs:

  • Cyanosis
  • Swollen, tender, red leg.
  • Cardiac: ↑HR, AF, ↑JVP.
  • Chest: ↑RR, pleural rub, pleural effusion.
  • Pulsus paradoxus.

• Risk factors

  DICE:

  • DVT or PE past medical history, or thrombophilia
  • Immobility, leading to venous stasis. May be due to recent surgery or travel. Surgery (and trauma) may also directly cause thrombi, especially when affecting the lower leg.
  • Cancer, which activates thrombin. Prostate and ovarian are particularly associated.
  • Estrogen, which increases fibrinogen, prothrombin, and clotting factor levels. Causes: pregnancy, postpartum, contraceptive pill, HRT, and obesity.

  Others:

  • Age
  • Other conditions: HF, IBD, nephrotic syndrome, polycythaemia rubra vera.

  Transient risk factors (e.g. post-op, OCP) are referred to as 'provoking' factors in context of VTE.

• Investigations

  Diagnosis

  Screening:

  • Screen with 2-level Wells DVT score (≥2 is +ve) or 2-level Wells PE score (≥4 is +ve).
  • D-dimer if Wells -ve, using an age-adjusted threshold if >50 years.
  • Consider starting with pulmonary embolism rule-out criteria (PERC) if suspicion low (<15%) and stop at that point if negative, otherwise proceed to Wells ± D-dimer as above if positive.

  Confirmation:

  • Imaging if either Wells or D-dimer is +ve.
  • Suspected DVT: proximal leg (above knee) compression US within 4 hours. If US not immediately available, start interim anticoagulation and get US within 24 hours. If US -ve, get D-dimer (if not done yet), and repeat US in 1 week if D-dimer +ve.
  • Suspected PE: CTPA or V/Q SPECT. If not immediately available, start interim anticoagulation. If scan -ve, proximal leg US if you suspect DVT.

  Other investigations

  • CXR in PE: may show wedge-shaped infarct (rare), but more for ruling out other conditions.
  • ECG in PE: most commonly, sinus tachycardia (50%). Less commonly (20-30% each), RV strain (T inversion in V1-3), S1Q3T3 (prominent S in lead I, and Q wave and inverted T in lead III), RBBB, and right axis deviation.
  • ABG in PE (optional): ↓O2, ↓CO2, ↑pH.
  • Baseline FBC, U&E, LFT, and coag if starting anticoagulation, but don't delay treatment while awaiting results.
  • Unprovoked VTE → consider thrombophilia screen only if planning on stopping treatment. Look for underlying cancer only if suggested by history, exam, and basic bloods.

• Management

  Overview

  Anticoagulation to prevent recurrent VTE is the mainstay of treatment.

  Start with ABCDE approach if acutely unwell:

  • If SpO2 <90% → O2.
  • If hemodynamically unstable (SBP <90, 'massive PE') → unfractionated heparin ± thrombolysis with alteplase.

  Intermediate/high risk patients may require admission for initial management, while stable low risk patients can be managed as outpatients.

  Anticoagulation

  Duration:

  • Start with 3 months, or 3-6 months in active cancer.
  • Stop after 3 months if provoking factor no longer present e.g. post-op, OCP use.
  • Continue long-term if unprovoked, recurrent, or provoking factor still present, unless high bleeding risk (HAS-BLED ≥4).

  Drug choice:

  • Direct oral anticoagulants (DOACs) are 1st line for most, including moderate CKD and active cancer. Apixaban and rivaroxaban are preferred as they can be started immediately, while edoxaban and dabigatran must follow 5 days LMWH.
  • LMWH (see heparins) is an alternative choice in CKD and active cancer, or used as a short-term bridge to long-term edoxaban, dabigatran, or warfarin.
  • Warfarin is an alternative that can be used in any patient population, but is only 1st line in antiphospholipid syndrome and Stage 4 CKD (or LMWH). Must initially be combined with LMWH until INR >2.

  Other considerations

  Catheter-directed thrombolysis for DVT:

  • Consider for significant symptomatic iliofemoral DVT if symptoms <2 weeks, good functional status, and low bleeding risk.
  • Reduces risk of post-thrombotic syndrome.
  • Mechanical thrombectomy without thrombolysis is an alternative if thrombolysis contraindicated.

  Mechanical interventions:

  • Compression stockings may relieve leg symptoms in DVT but do not reduce post-thrombotic syndrome.
  • IVC filters: consider if anticoagulation contraindicated or PE occurs despite anticoagulation.

  Distal DVTs:

  • NICE do not discuss/recommend treating distal DVTs (below knee, infrapopliteal 'calf clots') – about 1/4 DVTs – as there is limited evidence of benefit and a low risk of progression to serious pathology. They only recommend proximal leg US in suspected DVT, not whole leg US, and treatment of proximal DVTs.
  • However, some guidelines and researchers say that these should be treated. Consider serial US if asymptomatic – to look for proximal propagation – or anticoagulation for 6-12 weeks if symptomatic and/or high risk.

• Complications

  Recurrent VTE:

  • 1/3 in 10 years after unprovoked VTE.
  • Low risk if post-surgical VTE.
  • Recurrent DVT can be hard to diagnose as residual US abnormalities remain for 6-12 months.

  DVT complications:

  • Cellulitis/thrombophlebitis: can resemble, cause, or follow DVT.
  • Post-thrombotic syndrome.

• VTE prevention in hospital and after surgery

  All inpatients should be assessed for VTE risk (e.g. using Department of Health VTE risk assessement tool), and most will have prophylaxis prescribed if VTE risk outweighs bleeding risk.

  Pharmacological VTE prophylaxis

  In-hospital:

  • Offered to medical and surgical patients.
  • LWMH 1st line, fondaparinux 2nd line. UF heparin is another option in CKD.
  • It should be avoided in those with risk factors for major bleeding: active bleeding, anticoagulant use, bleeding disorder, acute stroke (unless very high risk e.g. thrombophilia, prior VTE), lumbar puncture or spinal anaesthesia planned, BP >230/120, platelets <75.
  • Start at admission – unless surgery within 12-24 hours – and continue until discharge.
  • Give up to 12 hours pre-op (LMWH half-life is 4 hours), re-start 6 hours post-op, except spinal and cranial surgery where gap must be 24 hours pre- and post-op.

  Treatment may continue at home in surgical patients discharged before completing recommended durations:

  • LMWH continued for 7 days after most major surgery, or even 28 days after adominal cancer surgery.
  • LMWH or DOAC continued for 2-4 weeks after most major lower limb orthopedic surgery, and up to 6 weeks if prolonged immobilization and has other risk factors.

  Mechanical VTE prophylaxis

  • Offered to surgical patients in addition to pharmacological prophylaxis.
  • Options: compression stockings, intermittent pneumatic compression (IPC) devices, foot impulse devices.
  • In medical patients, it is used when pharmacological prophylaxis is contraindicated, except stroke where IPC is 1st line given the high bleeding risk from anticoagulation.
  • Contraindications: PVD or peripheral bypass grafts, peripheral neuropathy, severe peripheral oedema, skin problems on legs.

  Other medications

  • Advise surgical patients to stop taking any estrogen-containing contraceptive or HRT 4 weeks before surgery.
  • Consider stopping antiplatelets 1 week before surgery.
  • Minimize other risk factors, most importantly immobility and dehydration.
  • If there is a high risk of bleeding, most patients on warfarin (e.g. AF) should stop 5 days before surgery and be switched to LMWH, with an INR target of <1.5. Very high risk patients (e.g. metallic heart valve) should get IV heparin, which has a 2 hour half life so can be continued until 4 hours before surgery.
  • Stop DOACs 24h before surgery.

• Heparins

  Mechanism

  Rapid anticoagulation by activating antithrombin III, which inactivates thrombin and factor 10.

  Management

  • Get baseline FBC (platelets) and clotting studies.
  • Unfractionated heparin (UFH) requires IV infusion, while low-molecular weight heparin (LMWH) (e.g. dalteparin, enoxaparin) can be given SC.
  • Monitor LMWH with anti-factor 10a assay, and UFH with aPTT. Only used if there are questions about pharmacokinetics or adherence.

  Side effects

  • Bleeding. Protamine IV is the antidote.
  • ↑K+ due to aldosterone inhibition.
  • Osteoporosis, especially with UFH.
  • Injection site reactions.

  Heparin induced thrombocytopenia (HIT)

  • HIT is effectively synonymous with type 2 HIT (discussed here), a potentially life-threatening immune-mediated process occurring 5-10 days into treatment. Type 1 HIT is a mild, transient drop in platelets in first 2 days of treatment, and doesn't require heparin discontinuation.
  • A pro-thrombotic state with high risk of venous or arterial thrombosis.
  • Can also present with acute systemic reactions post-dose (fever, SOB, ↑HR) and injection site lesions.
  • Higher risk with IV UFH than SC LMWH.
  • If suspected, screen with 4Ts score to help distinguish HIT from incidental ↓PLT (commoner), and confirm with HIT antigen assay.
  • Management: stop heparin (including flushes) and switch to another anticoagulant e.g. argatroban, bivalirudin.

  Contraindications and cautions

  • Bleeding: active bleeding, active peptic ulcer, recent cerebral haemorrhage, haemophilia.
  • Thrombocytopenia or previous HIT.
  • Uncontrolled severe HTN
  • Infective endocarditis.
  • Recent eye or neurosurgery.
  • Hepatic or renal disease: reduce dose. Consider UFH or reduced-dose LMWH if eGFR <30.

• Post-thrombotic syndrome

  • Varicose vein-like symptoms: itch, swelling, dull pain.
  • Venous ulcers.
  • Can occur up to 12 months post-DVT.
  • Prevention: some evidence for catheter-directed thrombolysis, limited evidence for compression stockings.

• Thrombophilia

  Pathophysiology

  • An increased tendency to thrombus formation.
  • Most types of thrombophilia cause venous – not arterial – thrombosis. However, anti phospholipid syndrome (APS), Behcet's, and homocystinuria cause both arterial and venous thrombosis.
  • In thrombophilia, PT and aPTT are often normal – not reduced as one might expect – as clots are forming at a normal speed, but are just not breaking down as quickly.

  Factor V Leiden (FVL)

  • Point mutation of factor 5 at activated protein C (APC) cleavage site, leading to slower inactivation of factor 5 and hence longer activation of factor 10.
  • Commonest thrombophilia among Europeans: 5% are carriers.
  • Increased VTE risk: there is variable penetrance, but on average a lifetime absolute VTE risk of 10% (i.e. 5x general population) in heterozygotes but nearly 100% in homozygotes. Higher risk if also taking contraceptive pill or HRT.
  • Higher risk of pregnancy loss.
  • Given variable penetrance and low absolute risk of VTE, long-term anticoagulation and screening of asymptomatic relatives is not routinely recommended.

  Other heritable thrombophilias

  • Antithrombin III (AT) deficiency: rare but high risk. Leads to failure of AT to inactivate thrombin and factor 10.
  • Protein C and protein S deficiencies: normally, protein S activates protein C, with activated protein C (APC) inactivating factors 5 and 8. Deficiency in either leads to increased factor 5 and 8. May present with skin necrosis while on warfarin.
  • Prothrombin (factor 2) mutation: leads to increased levels, which inhibits fibrinolysis.

  Secondary thrombophilias

  • Chronic diseases: nephrotic syndrome, APS, Behcet's, cancer.
  • Temporary states: DIC, pregnancy.
  • Myeloproliferative disease: thrombocytosis, polycythaemia rubra vera.

  Thrombophilia screen

  Often not clinically useful, but consider for individuals with a VTE if:

  • <40 years old.
  • Recurrent unexplained VTE.
  • Family history of VTE.
  • Unusual site e.g. mesenteric or portal vein.

  Investigations:

  • APC resistance test. FVL PCR if APC is positive.
  • Blood smear.
  • Fibrinogen level.
  • Lupus Ab.
  • Antithrombin III, protein C, and protein S assays.