Case studies: Would you get VTE treatment right in these patients?
70-year-old man with a smoking history of 50 packs a year.
35-year-old woman who is in the third trimester of her first pregnancy.
58-year-old male with a 10 year history of chronic kidney disease.
82-year-old woman who has recently moved to a rest home due to failing health.
40-year-old female who presents for advice on preventing clots during long-haul flights.
70-year-old man with cancer presents with a suspected DVT
Mr HP is a 70-year-old man with a smoking history of 50 packs per year. He has hypertension, which is being treated, and moderate obesity.
Last month, he presented with a persisting non-productive cough and intermittent chest pain. Chest X-ray showed a mass in the right upper lobe and further investigations confirmed an inoperable adenocarcinoma of the lung.
He has recently commenced out-patient chemotherapy and now returns to your surgery with leg pain. He reports that his right leg has become swollen and uncomfortable when standing for long periods, but reports no recent falls or injury.
He is afebrile, but you notice that the right calf is warmer than the left, with a 3 cm difference in circumference. There is mild tenderness behind the knee, but no varicose veins or skin changes. You suspect a deep vein thrombosis (DVT).
1. What tests will you order to confirm your diagnosis?
Compression ultrasound (CUS) of the right leg should be performed as soon as possible.
If an ultrasound cannot be obtained on the same day, the patient should be started on low molecular weight heparin (LMWH) to prevent extension or embolisation of a suspected thrombus.
Magnetic resonance venography is not yet validated as a diagnostic technique, and the use of both clinical risk scores (e.g. Wells’ score) and D-dimer testing are not appropriate in patients with cancer.
CUS shows occlusive thrombus in the right popliteal vein, extending 20 cm into the posterior tibial and peroneal veins.
2. What factors should be considered before commencing anticoagulation?
Mr HP has a proximal thrombosis, associated with active malignancy and ongoing chemotherapy.
His cancer is the most significant risk factor for a spontaneous thrombosis; other factors include age and obesity.
He will require therapeutic anticoagulation for at least three months. You review his blood tests, taken two days earlier: full blood count is within normal ranges, with platelets of 180 x 109/L, and creatinine is not increased.
He is not being treated with any antiplatelet medications or nonsteroidal anti-inflammatories, and has given up alcohol. His blood pressure is well controlled on metoprolol.
Significant factors to consider before starting anticoagulation are other medications, prior bleeding history (none in this patient), renal function and poorly controlled hypertension.
Formal scoring systems such as HAS-BLED have been developed for atrial fibrillation patients, but are not useful in venous thromboembolism (VTE).
3. What therapy will you choose and how will you monitor progress?
After discussion with his treating oncologist, you commence a LMWH as a twice-daily regimen. Available LMWH options include enoxaparin, nadroparin and dalteparin – for full dosing instructions, please refer to the Approved Product Information, available from the manufacturers.
Randomised trials have shown that warfarin is less effective than LMWH in treating cancer–associated thrombosis, and there is insufficient evidence to support the use of a non–vitamin K anticoagulant (DOAC) in these patients.1,2
He will need regular blood tests during his chemotherapy to ensure that platelet counts remain above 50 x 109/L and his renal function is maintained.
You ask that he return for review in two weeks when his leg is less swollen and he is walking freely. A follow-up ultrasound at 4–6 weeks after initiation of therapy may be helpful in assessing his response.
He will need to remain on LMWH for at least three months – anticoagulants should not be ceased while he is still receiving cancer treatment, such as chemotherapy.
Specialist advice from his oncologist and from a referral centre for thrombosis management may be needed to choose an appropriate option for secondary clot prevention.
References: 1. Lee A et al. N Engl J Med 2003;349:146–153. 2. Hull RD et al. Am J Med 2006;119(12):1062–72.
Pregnant woman in 3rd trimester, with a family history of clots, presents with a lower limb DVT
Ms JM is a 35-year-old woman who is in the third trimester of her first pregnancy (29 weeks). She has no significant past medical history and antenatal checks to date have been normal.
She presents with a 3-day history of discomfort behind the left knee. Her ankles have been swelling at the end of the day, but she now feels that the left leg is more swollen than the right.
Ms JM also reports feeling more short of breath when climbing stairs or hurrying, but denies chest pain.
On examination, you note that her left leg is tender over the popliteal fossa and upper calf, with a slight asymmetry in calf size. Cardiac and respiratory examinations are normal, with no tachycardia or signs of pulmonary hypertension.
1. What tests could rule out a DVT?
Compression ultrasound of the leg is the standard investigation for deep vein thrombosis (DVT) and can be performed reliably in pregnancy, although imaging of the iliac veins may not be possible later in pregnancy.
The scan shows an occlusive thrombus in the left superficial femoral (a deep vein) and popliteal veins.
2. Given her reports of dyspnoea, should further investigation for pulmonary emboli be ordered?
Imaging for pulmonary embolism (PE) in pregnancy has higher risks of radiation exposure to mother and foetus, especially if a computed tomography pulmonary angiography is performed without shielding. An isotope perfusion scan (without the ventilation mode) can be an alternative option.
In this patient’s case, her physical examination does not suggest a large PE (no tachycardia or respiratory distress, normal cardiac and respiratory examinations), and the management of her DVT will be effective if she does have small emboli.
When you discuss the results of the ultrasound, Ms JM notes that several family members have had venous thromboses and needed anticoagulation. She says there is “something in the family that predisposes to clotting”.
3. Is a thrombophilia screen indicated based on her family history, and will the results change management?
The most commonly inherited thrombophilic variants in Europeans (heterozygous Factor V Leiden and Prothrombin 20210 variants) will not change her management if found.
Levels of Protein C and S may be altered in pregnancy, making diagnosis of a deficiency difficult. Antithrombin 3 deficiency may be treated with antithrombin concentrates in addition to anticoagulation, but only around the time of delivery. Testing of this patient is unlikely to change her treatment or the duration of anticoagulation.
4. Which anticoagulant will you prescribe and for how long?
Risk factors to consider before anticoagulation is the pregnancy itself, with combined anatomical and hormonal changes.
Bleeding risks are very low in this age group. In pregnancy, both warfarin and direct oral anticoagulants (DOACs) are contraindicated and LMWH are the standard agents used, though their use must be weighed against the benefit vs risk of treatment. LMWHs are listed as Category C.
Ms JM is started on a twice-daily dose of LMWH (100 IU/kg) which is well tolerated. After six weeks, she is switched to a daily dose of LMWH, to be continued for three months (and at least six weeks postpartum).
She has several discussions with her obstetric team about her delivery plan. They note that it may not be possible to have epidural anaesthesia while on LMWH, and decide to induce her at 35 weeks, 24 hours after her last dose of LMWH.
She has an uneventful vaginal delivery and prophylactic LMWH is recommenced 12-hours postpartum, increasing to her treatment dose two days later.
Discussion with the obstetric team about how to manage LMWH around time of delivery is advised. She will require anticoagulation for at least six weeks postpartum (for the hormonal changes to settle).
58-year-old man with CKD, recently discharged from hospital, presents with upper limb DVT
Mr JD is a 58-year-old male with a 10-year history of chronic kidney disease due to membranous glomerulonephritis.
He has not required dialysis to date, but serum creatinine is significantly elevated at 300 mmol/L (calculated creatinine clearance of 25 mL/min).
Mr JD is reviewed regularly by his nephrologist and has just been discharged from hospital after a 6-day admission for community-acquired pneumonia.
Due to poor venous access, a central line was placed to administer intravenous antibiotics and removed just before his discharge.
He presents to your surgery two days later complaining of a swollen and painful right arm on the side where his central line was sited. He is afebrile, with an increase in diameter of the upper arm and some axillary tenderness. He has mild ankle oedema and some crackles in the lung bases, but no signs of consolidation.
You are concerned that he may have developed an upper limb deep vein thrombosis (DVT) secondary to his central line. He is taking oral antibiotics in addition to his regular medications.
You order an urgent upper limb ultrasound which shows an occlusive thrombus in the right subclavian vein extending proximally to the internal jugular which has non-occlusive thrombus present.
1. Is further imaging required to evaluate his thoracic outlet and a referral to vascular surgery?
Given his recent hospitalisation with infection and central line placement, the upper limb DVT is likely to be secondary to these factors rather than to an anatomical problem.
With his other medical problems, thrombolysis or placement of a venous stent will have higher risks and should not be first-line treatment. The line has already been removed, so you decide to commence anticoagulation after discussion with his renal specialist.
2. Which anticoagulants can be used in patients with significant renal impairment?
Unfractionated heparin infusions can be used with monitoring, but your patient is keen to avoid another period in hospital and more intravenous cannulae.
DOACs such as rivaroxaban and apixaban should not be used in patients with significant renal impairment (creatinine clearance below 30 mL/min).
Warfarin is the standard anticoagulant option in renal impairment, but he will require heparin cover while warfarin therapy is being initiated.
LMWH doses must be reduced in renal impairment and specialist advice can be helpful.
In Mr JD’s case, the renal specialist suggests commencing a once-daily dose of 0.8 mg/kg enoxaparin (see the Approved Product Information for full dosing instructions in renal impairment, available from the manufacturer) until his INR is over 2.0. Other LMWHs for consideration are dalteparin and nadroparin.
A loading dose of warfarin should not be given here, as his bleeding risk will be higher due to renal impairment. Therefore you commence warfarin at 5 mg nocte.
To ensure that the enoxaparin is not accumulating, you arrange for a peak anti-Xa blood sample (four hours after the morning dose) after the first three doses.
This test is within the target range for LMWH (0.5 to 1.2 anti-Xa IU/mL), so you continue with the daily dose. After six days of warfarin, his INR is 2.2 and enoxaparin is ceased.
3. How long should the patient remain on warfarin?
Mr JD’s upper limb DVT is provoked, so three months of anticoagulation should be sufficient. Careful INR control, avoiding other medications with antiplatelet effects and blood pressure control will be important to reduce his risk of bleeding.
You repeat the upper limb ultrasound at six weeks and the thrombus has reduced with residual non-occlusive clot only in the subclavian vein. His arm symptoms resolve within the first four weeks.
4. Does this patient need VTE prophylaxis for future hospitalisations?
Yes, he should receive dose-adjusted prophylaxis for any future hospitalisations or invasive procedures given his recent history.
Acute infection such as pneumonia is now recognised as a causative factor for VTE, likely driven by leukocyte responses to pathogens which activate platelets and trigger the coagulation cascade.
82-year-old nursing-home resident with CHF, risk of falls, presents with a DVT
Miss BG is an 82-year-old woman who has recently moved to a rest home due to failing health.
She has congestive heart failure and reduced mobility due to osteoarthritis of hips and knees. She has had several falls while living alone and is showing signs of early dementia.
During a visit to her rest home, her nurse asks you to look at her left leg, which has been causing her discomfort. There is no recent history of injury to the leg, but Miss BG has been reluctant to walk over the past two days due to pain.
You examine her leg, which has prominent varicose veins and hyperpigmentation of the lower calf suggestive of chronic venous insufficiency.
She has a firm, tender swelling near the popliteal fossa along a varicosity of the short saphenous vein.
There is also tenderness in the upper calf, but no redness or asymmetry. Her knee and ankle joints are mobile and not painful.
1. Can a D-dimer assay be used here to exclude thrombosis?
Interpretation of D-dimer levels in the elderly is problematic, as a higher cut off must be applied.
If you are proceeding to ultrasound imaging, there is no additional value in measuring D-dimers. The combination of a low pretest clinical probability (Wells’ score) and negative D-dimer is only a validated approach in ambulatory outpatients with suspected DVT.
This elderly woman now requiring nursing care does not fit the profile. Her risk factors for an acute DVT include age, immobility, varicose veins and heart failure.
You obtain a compression ultrasound which shows a thrombosed segment of the short saphenous vein (superficial thrombophlebitis) and also a 6 cm thrombus of the gastrocnemius muscular vein.
2. Can these “superficial” thromboses be managed without anticoagulation?
It is possible to manage small calf-vein thrombi or superficial thrombophlebitis by observation alone, but it is essential to check for clot extension by serial ultrasounds, for example at weekly intervals.
About 20% of these distal thrombi will extend, and there is a small risk of embolisation to the lung.1
In a symptomatic case of calf-vein thrombosis, many Australian specialists instead recommend a short period of anticoagulation. This avoids the risk of clot extension and may lead to a faster resolution of symptoms.
3. In this elderly lady with a history of falls, can a lower dose of anticoagulant be used?
Calf-vein DVTs and superficial thromboses have not been included in the large-scale clinical trials of VTE treatment, but several smaller studies suggest that low or intermediate doses of LMWH or fondaparinux are effective treatment for these smaller clots.2–4
A typical approach based on these small studies would be to give a daily SC dose of LMWH (e.g. enoxaparin 1 mg/kg daily provided renal function is normal) for 4–6 weeks. Available LMWH treatments include enoxaparin, dalteparin and nadroparin.
DOACs are also being used to treat calf-vein DVT, but dose reductions are not permitted.
Given that Miss BG is in residential care, in this case you elect to start a short course of 60 mg enoxaparin daily. Her leg discomfort has resolved when you review her a week later and you cease the LMWH at four weeks.
References: 1. Scarvelis D and Wells PS. CMAJ 2006;175(9):1087–92. 2. Scott G et al. Br J Haematol 2015;168(5):639–45. 3. Decousus H et al. N Eng J Med 2010;363(13):1222–32. 4. Decousus H et al. Arch Int Med 2003;163:1657–63.
40-year-old female with risk factors for DVT, frequent traveller on oral contraceptive pill, requests advice on clot prevention
Ms PS is a 40-year-old female who presents for advice on preventing clots during long-haul flights. She works for a travel agency and makes at least five overseas trips every year.
She is on the combined oral contraceptive and has had two pregnancies, but one year ago had a small calf-vein thrombosis diagnosed while recovering from knee arthroscopy. She is overweight with a BMI of 30, and on no other medications.
1. Is medical prophylaxis recommended?
There are no randomised trials to guide prophylaxis for travel, but your patient has several risk factors (prior provoked DVT, oral contraceptive pill and obesity), which may be additive in the setting of a long flight (over six hours duration). She needs to be aware of the small risk of bleeding from any prophylactic therapy.
2. Which antithrombotic agent would you recommend?
Aspirin is less effective than anticoagulants for the prevention of VTE, so if there is a decision to proceed with prophylaxis for her next flight, a low-dose anticoagulant should be considered.
Low–dose anticoagulation options for travel include a daily prophylaxis–dose injection of LMWH (dalteparin, enoxaparin or nadroparin) or the equivalent prophylactic dose of a DOAC (e.g. apixaban, rivaroxaban or dabigatran. See the Approved Product Information for full dosing instructions available from the manufacturer). Note that prophylactic doses of DOACs are not PBS subsidised for primary VTE prevention.
A schedule recommended by many specialists (but not based on clinical–trial evidence) is to take the first dose of prophylaxis on the day of travel (all have a rapid onset of action), with two further days of cover upon arrival.
Based on the low relative risk of travel, therapeutic doses of anticoagulants are not warranted. LMWH should never be added in patients already on therapeutic warfarin or DOACs.
3. Is laboratory thrombophilia testing advised before her next trip?
No, as her clinical history would not warrant indefinite anticoagulation even if a thrombophilic variant was detected. Nor would it change the intensity or duration of prophylaxis. You advise against any further testing.
4. What other strategies can reduce risk of travel-associated VTE?
Wearing compression stockings can reduce the degree of leg swelling associated with long-haul flights, but their effect on clotting risk is uncertain.
Keeping well hydrated and doing leg exercises are other common-sense measures, and excessive alcohol intake and the use of sedatives should be avoided.
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Professor Christopher Ward is head and director of research, department of haemotology and transfusion medicine, Royal North Shore Hospital, Sydney, and Professor of Medicine, Sydney Medical School, University of Sydney.
Professor Ward has received honoraria for advisory boards and lectures from Alexion, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Glaxo Smith-Kline, Instrumentation Laboratories, Janssen, Pfizer, Sanofi-Aventis and Specialised Therapeutics, conference support from Novartis and Roche and research support from Bayer, CSL and Pharmion.
This content was independently developed by Australian Doctor Group and sponsored by Sanofi Australia. The opinions expressed in this article are the author’s own and do not necessarily represent the views of Sanofi Australia.