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Venous thromboembolism comprises both deep vein thrombosis and pulmonary embolism and is a vital cause of morbidity and mortality in critically ill patients. VTE affects 1-3 people in 1000 per year. (1, 2)
PE arises from a DVT, which is the formation of a fibrin blood clot, in the pelvic or deep veins in the legs. Clots break off and pass through the venous system and the right side of the heart before lodging in the pulmonary circulation. (1) Damage is caused when the embolus becomes trapped in a small capillary causing ischemia or infarction of the surrounding tissue.
There are 2 subgroups of PE. There is non-massive PE and massive PE. In non-massive PE less than 50% of the pulmonary vascular bed is blocked, and in massive PE more than 50% of the pulmonary vascular bed is blocked.
The symptoms of PE include acute breathlessness, chest pain, cough, anxiety and increased pulse rate, whereas the symptoms for DVT, include pain and swelling in the leg. (3) There are many risk factors in acquiring DVT/PE including age over 40, obesity, cigarette smoking, hypertension, recent surgery, recent stroke or MI, obesity, prolonged bed rest and a history of a previous PE/DVT. The most talked about risk factor is prolonged travel which can be associated to DVT/PE. (4) It can be more prevalent in women due to the risk factors of pregnancy, oral contraceptives and hormone replacement therapy. (5)
Diagnosis of a PE and DVT can be made by diagnostic imaging and should be performed within 24 hours if possible. For DVT, a venography or ultrasound can be used, whereas for PE, a ventilation perfusion lung scan is used. Lung ventilation perfusion scan helps detect PE because the ventilation part of the test looks at the ability of air to reach all parts of the lungs, at the same time as the perfusion part assesses how well the blood circulates within the lungs. (6) Also a pulmonary angiography - also called CTPA can be performed in which pulmonary blood vessels are x-rayed to detect arteriovenous malformations. A pulmonary angiography is invasive and is potentially dangerous so therefore a ventilation-perfusion lung scan is preferred over it. (7) Although, the most commonly used test is the computed tomography (CT) scan of the chest as it is non-invasive and quick to perform. (4)
In a blood test, D-dimer can be measured, which is a small protein fragment present in blood after a blood clot is degraded by fibrinolysis. A negative d-dimer value is normal and rules out the possibility that an active blood clot is forming. A positive result points towards the likelihood of deep vein thrombosis and pulmonary embolism being present. An elevated result does not necessarily mean that a blood clot is present therefore requires for additional testing, as this test is not conclusive. (8) Oxygen levels can also be measured, and would be used to confirm the diagnosis.
Parenteral anticoagulants are used initially in order to achieve rapid anticoagulation. (9) Heparin should be started in patients that have an intermediate or high probability of DVT/PE until the diagnosis is excluded by diagnostic imaging. (6) Unfractionated heparin (UFH) should only be considered when giving a first dose bolus in PE, or when a rapid reversal of effects may be required. The dose at which it is given for an I.V bolus is 5000 units or 75 U/kg body weight, followed by maintenance I.V infusion dose of 18 U/kg/h. (10, 11).
If not, then low molecular weight heparin (LMWH) should be given as they are safer and easier to administer, as they are once daily subcutaneous injections, with equally the same efficacy as unfractionated heparin. The mechanism of action of heparin is that it inactivates thrombin and factor Xa via an anti-thrombin dependent mechanism, producing the major anticoagulant effect. Inactivating factor Xa causes inhibition of thrombin production. Inhibition of thrombin production or thrombin inactivation in turn inhibits formation of the cross-linked fibrin polymer which is what forms a firm clot. (15)
Only after DVT/PE is confirmed, oral anticoagulation treatment should be commenced, most commonly warfarin. For each individual patient, the dose of warfarin is adjusted according to the measurement of the International Normalised Ratio (INR). (10, 12) The usual dose is around 1-15mg/day. It should be started with heparin therapy in any case for 4-6 days, so that the INR is >2 for 2 consecutive days, after which heparin treatment is stopped, and oral anticoagulant treatment is continued. When INR is stable, it should be monitored at 4-8 week intervals, but more regularly when unstable or due to any changes in medicines and clinical state. (6) Warfarin is a vitamin k antagonist and produced its anticoagulant effect by inhibiting the vitamin k dependant synthesis of factors II, VII, IX and X and also the regulatory factors protein C, protein S and protein Z. Duration of treatment depends on risk factors and previous history of PE/DVT.
This patient was treated with unfractionated heparin (UFH). UFH and warfarin had always been the standard anticoagulation treatment for both PE and DVT, with the exception of massive PE. However, recently, evidence provided through numerous studies showed that LMWH is also effective in the treatment of PE/DVT. (13, 14)
There are many differences between LMWH and UFH, the prime way being through their pharmacokinetics. (11) Firstly, LMWH has an average molecular weight of 5kDa whereas for UFH it is 15kDa. The bioavailability of LMWH is 92-100% compared to 30-50% for UFH. The half-life for intravenous administration of LMWH and UFH is 2 hours and 1 hour respectively, whereas for subcutaneous administration of LMWH and UFH it is 4 hours and 2 hours. From this we can notice why UFH might be chosen over LMWH as the half-life is shorter and therefore the effects of it can be reversed more easily if the patient encounters a problem. Yet, the longer half-life of LMWH, with a higher bioavailability gives the advantage and ease of once daily subcutaneous dosing. (11)
LMWH does not have a dose-dependant clearance, whereas UFH does. Furthermore, the occurrence of both heparin-induced thrombocytopenia and osteoporosis is low with LMWH and high with UFH. (15) Also, routine activated partial thromboplastin time (APTT) monitoring is required for UFH and not LMWH which is monitored to look out for the treatment effects such as bleeding. (7, 15) The target range for APTT ratio is usually 1.5-2.5. Therefore the APTT ratio has to be monitored in this patient to reach the target range.
Dolovich L.R et al carried out a meta-analysis comparing UFH with LMWH on the basis of efficacy and safety, which concluded that LMWH is as effectual as UFH in prevention of venous thromboembolism that are recurrent, but say it is unlikely that LMWH is superior in treating venous thromboembolism. (16) However, there are numerous advantages in using LMWH over UFH including a more consistent relationship between dose and response, ease of administration, better side-effect profile and fixed dosage. (7, 15, 16) In another trial it was found that there are also major bleeding complications when UFH is administered, but LMWH is safe with regard to this complication. (17, 18) In addition to this it was found that low-molecular weight heparins reduce the mortality rates over 3 to 6 months, although the reason for this was unknown. Similarly, it was observed that cancer patients being treated with LMWH benefited by three months over UFH, in terms of mortality. The conclusion that was drawn from this trial was that due to LMWH being able to be used in outpatients compared to unfractionated being used in hospitalised patients, it can therefore be seen as cost-effective in the long-term due to treatment being at home than in hospital, even though currently LMWH is higher priced.
Furthermore, to support the superior efficacy of LMWH over UFH, it was established from another article that this is because of UFH acting on both factor Xa and thrombin in about the same way, while LMWH having a stronger action on factor Xa. As mentioned before, some studies show that LMWH is as effective in treating PE as UFH, whereas other studies show that LMWH is more effective in treating PE.(18)
In contrast to the previous conclusions drawn from studies and meta-analyses, another meta-analysis concluded that in relation to effectiveness, incidence of major and minor bleeding and thrombocytopenia, there was no statistically significant difference between LMWH and UFH. Yet, it still was consistent with previous meta-analyses in showing that there is a significant difference in total mortality with use of LMWH, again with no explanation. (16,2)
Most literature is based on DVT and PE alone, without the presence of another condition, but some also show evidence of LMWH being effective in people that are obese, or have renal failure. (15) This is vitally important as the patient has renal failure and is in the category of those that are overweight. Therefore the patient may benefit more from using LMWH as compared to UFH.
Regarding duration of therapy both LMWH and UFH are given for at least 5 days as this is established to be most effective. (2) In addition, from another study we saw the disadvantages of UFH which include an unpredictable anticoagulant effect, altering noticeably in patients according to their age, sex, body weight, smoking status and renal failure. This once again emphasises that because this patient has renal failure, it would be better to switch to LMWH. (14)
Therefore, in light of all this information, it can be concluded that LMWH has replaced UFH, and as a result the first choice in treating this patient would be to use LMWH as there are many more advantages proven by studies and meta-analyses, as discussed previously, and more importantly in terms of this patient having renal failure, it is definitely more suitable for the patient to be treated with LMWH.
To avoid recurrence of both fatal and non-fatal episodes of VTE, long-term anticoagulant therapy is commenced. (9) The most commonly prescribed oral anticoagulant, warfarin, was prescribed in this patient, which requires regular monitoring of INR.
Oral anticoagulants are shown to be effectual for prevention of both primary and secondary VTE and this has been observed by many clinical trials. (19)
Concerning duration of therapy, it is vital that the patient is treated for the relevant duration of action according to their risk factors, severity and reappearance of DVT/PE because it has been proven that recurrence of DVT can occur due to shorter duration of anticoagulation therapy as shown by a population-based study (20) and randomized clinical trials. (21, 22) The recommended duration of warfarin therapy following a first occurrence of DVT and PE is three months as a minimum. (6) Previously, this patient suffered from a DVT 40 years ago, but was not treated with long-term oral anticoagulation therapy due to warfarin being contra-indicated in pregnancy. Therefore, because of a previous DVT and now being diagnosed with DVT and PE, she will be on prolonged therapy of warfarin. This is to ensure patient does not suffer from recurrent episodes, and due to her having permanent risk factors.
It is critical to take into account the side-effects, the main one being haemorrhage. A recent Meta analysis concluded that the effect of haemorrhage is exceptionally important in patients suffering from VTE, and therefore this should be considered when commencing long-term oral anticoagulation treatment. (21) This leads to the key issue regarding patient counselling showing it is fundamental when commencing on warfarin as each detail matters. Relevant counselling points include to take warfarin at the same time each day, not to miss a dose, and if a dose is missed, then not to take double the dose the next time. Another vital factor is to educate patient on importance of having INR monitored regularly and moreover to watch out for any common side-effects such as bruising and bleeding. There are also interactions such as with cranberry juice and with OTC aspirin, therefore patient should avoid these.
This patient was also given amoxicillin 500mg. This was not due to the PE or DVT, but because the patient had signs of an infection with a high white cell count (WCC) and C - reactive protein (CRP) value. Amoxicillin is a broad-spectrum antibiotic and is used to treat a wide range of infections.
In my opinion, this was justified, even though cause for infection was not known because the antibiotic was given as a prophylaxis. Patient is already ill with a DVT and PE, and it was to prevent any further illness. Therefore, I feel that this outweighs the disadvantage of developing antibiotic resistance.
However, from a recent study it was observed that coumarin anticoagulants, which include warfarin, are associated with an increased risk of bleeding when given in conjunction with antibiotics, especially amoxicillin. Amoxicillin causes an enhancement of the effect of warfarin and as a result the risk of bleeding increases. (24)
In conclusion, I strongly recommend, in accordance with the evidence that the UFH prescribed in this patient should be changed to LMWH. There are several limitations that arise when giving UFH in comparison with many advantages when giving LMWH, which is conveyed through the studies and trials shown. Further to this, LMWH is starting to be seen as first-line of treatment whereas previously this was not the case. Especially in this patient who has mild renal impairment, extra caution needs to be taken with what medicines are given, and LMWH is preferred over UFH.
In the case of oral anticoagulants, I feel it is necessary for the patient to be treated with them, as prevention of DVT and PE is vital, and this is also seen by various studies. The duration for this patient in particular, of taking warfarin for life is relevant due to her DVT history and due to the risk factors she has.
Antibiotic therapy in this patient was started, which I did feel is relevant in her case due to her elevated levels of WCC and CRP, showing signs of an infection, yet due to the evidence based around increased risk of bleeding with coumarins, patient needs to be closely monitored for the side-effects.