Diseases Categorised Under Venous Thromboembolism Biology Essay


Pulmonary embolism is one of the diseases categorised under venous thromboembolism along with deep vein thrombosis (DVT). PE can occur in healthy people, medical patients or post-operative individuals.1 23 to 69 episodes of VTE can be found each year in 100,000 population and about 33% of the cases being acute PE.2 For the patients with acute PE, about 10% of them die within the first one to three months.2,3 41% of the VTE cases among post-surgical patients were PE.4 About 1% of the death of hospitalised patients was attributed to acute PE while approximately 10% of all hospital fatalities were PE-related.2,5 More than 90% of the deaths from PE was due to patients not being diagnosed and treated.6

The incidence of asymptomatic PE in the post-surgical phase is common especially in patients with DVT where symptoms are not present in addition to not been taking prophylactic medications for VTE.3 The risk factors for PE can be classified into patient-based and non-patient-based factors. Patient-based factors are previous episode of PE, age, metastatic cancer, and prolonged bedrest due to medical conditions. Examples of non-patient-based factors are trauma, prolonged travel, knee or hip fracture, laparoscopy, orthopaedic surgery and damage in spinal cord.7 PE is a common complication of DVT.3 DVT happens when thrombus, a clot is formed in the non-superficial veins as a result of hypercoagulability and it usually extends proximally. More than one thrombus can be formed and the primary location can be in the blood vessels found deep in the arms or pelvis. The thrombus can break off from the vessel wall and become embolus. The embolus can travel to the arteries in the lungs and thus causing PE. The presence of blood clots in the pulmonary arteries causes obstruction of the arteries. Activated platelets also release compounds such as thromboxane and serotonin which cause vasoconstriction. Consequently, the pulmonary vascular resistance is increased. This creates dead volumes in the alveolus and causes diversions of blood flow which leads to impairment of gas exchange. The increase in right ventricle afterload causes the oxygen consumption of the right ventricle to rise. The tension of the right ventricular wall increases and this may cause right ventricular ischaemia followed by cardiac failure.8,9

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The clinical diagnosis of PE is not straightforward as it can be confused with a variety conditions. The symptoms of PE are usually not specific. PE is suspected in the presence of cough, chest pain, tachycardia, dyspnoea, haemoptysis and/or sudden loss of consciousness. Massive PE is characterised by low arterial blood oxygen, haemodynamic instability, and/or cyanosis.8,9 The likelihood of PE is enhanced when there is known predisposing factors such as history of previous VTE.9 Diagnostic tests for PE include electrocardiogram (ECG), chest X-ray, computerised tomography (CT), computerised tomographic pulmonary angiogram (CTPA), arterial blood gas (ABG) analysis, and ventilation/perfusion (V/Q) scan.9,10,11 ECG commonly indicates tachycardia and T-wave inversion in suspected PE. Chest X-ray is particularly suitable for differential diagnosis of other similar conditions such as pneumonia and pulmonary oedema. Reduced partial pressure of oxygen in arterial blood (PaO2) from ABG analysis helps the diagnosis of PE but PaO2 can be normal in minor PE. Hence, ABG analysis, ECG, and chest X-ray have limited role in the diagnosis of PE.9,12 CTPA remains to be the best recommended method for the investigation of suspected PE. It is very sensitive for PE where the exclusion of PE can be made safely based on negative results. PE is confirmed when there is abnormal filling in the proximal and segmental vessel. V/Q scan serves as an alternative imaging procedure for PE especially in patients without underlying lung conditions and in women of child-bearing age.11

The pharmacological agents involved in the management of PE are unfractionated heparin (UFH), low molecular weight heparin (LMWH), warfarin, thrombolytic agents and fondaparinux.2,3

Heparin is a glycosaminoglycan that acts by binding to antithrombin. This leads to the modification of conformation of antithrombin that greatly potentiates its activity to inhibit the clotting enzymes such as thrombin, factor Xa and factor IXa. When these proteins are inactivated, the coagulation cascade is interrupted. The formation of fibrin clot and activation of platelets stimulated by thrombin are prevented as a result of inactivation of thrombin.13,14 LMWHs such as enoxaprin, dalteparin, and tinzaparin are fragments of heparin which are about one third of the molecular weight of heparin. They are produced from the enzymatic or chemical depolymerisation of heparin. They have a lower ability to inhibit thrombin because they are smaller in size and unable to bind to antithrombin and thrombin simultaneously. However, their ability to inhibit factor Xa is comparable to that of heparin.14

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Fondaparinux is a synthetic pentasaccharide that exerts anticoagulation effect through selective inhibition of factor Xa. Fondaparinux binds to antithrombin and causes a permanent modification in the structure of antithrombin. The modified antithrombin then inhibits factor Xa and thus the conversion from prothrombin to thrombin is also prevented.15

Warfarin is an inhibitor of vitamin K that disrupts the cycle where vitamin K inter-converts with its epoxide form. Vitamin K is important in coagulation because it is a cofactor needed for transformation of glutamates into γ-carboxyglutamates on the N-terminus of the coagulation factors. When the vitamin K cycle was interrupted, the liver will produce coagulation factors which are partially carboxylated or completely decarboxylated with decreased biological activity.14

Thrombolytic agents used in the management of PE include streptokinase, urokinase and alteplase. They work by converting plasminogen into plasmin. Plasmin then causes the degradation of fibrin and dissolution of blood clot. Thrombolytics cleave and inhibit fibrinogen as well as coagulation factors II, V and VIII. The conversion of fibrinogen into fibrin is interrupted by the rise in blood levels of fibrin and fibrinogen degradation products.16

Evidence-based treatment

Anticoagulants are the mainstay of management of PE. The superiority of anticoagulants over placebo was shown in a study in 1960 by Barritt and Jordan. The study demonstrated that the rate of death from recurrent PE in the placebo group was 25% while all patients in the anticoagulant group survived.17 The goals of initial anticoagulant therapy are the prevention of fatality and recurrent episodes with a reasonable risk of haemorrhage.3

Risk stratification is one of the components of management of PE. Patients can be categorised into high risk, moderate risk and low risk PE. Cardiogenic shock or sustained hypotension (systolic blood pressure<90mmHg for >15 minutes) are characteristics of high risk PE. Patients with moderate risk PE are haemodynamically stable with evidence of myocardial damage and/or right ventricular dysfunction. Patients with low risk PE have neither myocardial injury nor right ventricular failure.3,18 In this case scenario, Mrs X had low risk PE because she appeared to have normal blood pressure and pulse rates. She also did not show evidence of cardiac damage and dysfunction.

Patients with suspected PE should receive anticoagulation when they are waiting for the confirmation of diagnosis. Anti-clotting agents such as intravenous UFH, subcutaneous LMWH, and subcutaneous fondaparinux can produce rapid anticoagulation.3 The initial loading dose of intravenous UFH is recommended to be 5000units and then 18units/kg/hour as maintenance infusion rate. The UFH intravenous infusion rate is adjusted accordingly to achieve target APTT which is 1.5-2.5 based on weight-based nomograms. As for LMWH such as enoxaparin, it is administered subcutaneously with a dosage of 1mg/kg twice daily or 1.5mg/kg once daily. Tinzaparin can also be given via subcutaneous injection at a dose of 175units/kg once daily. The recommended dosage regimen for fondaparinux also depends on the patient’s weight. Subcutaneous injection of 5mg fondaparinux once daily is given to adults who weigh less than 50kg, 7.5mg for adults who weigh 50kg to 100kg and 10mg for adults with body weight more than 100kg.2,19 Only one anticoagulant should be used at one time.

Duration of anticogulation with either UFH, fondaparinux, or LMWH should be minimum 5 days. It was shown in 2 randomised clinical trials that 5-7 days of treatment with UFH was equally effective as 10-14 days of treatment with UFH in patients with DVT with the provision that there was also sufficient long-term anticoagulant treatment. Vitamin K antagonist, such as warfarin should be started ideally at the same time when parenteral anticoagulation was initiated or the nearest possible time. For warfarin, the recommended starting dose ranges between 5mg to 7.5mg once daily to attain a target international normalised ratio (INR) of 2.5. Two studies that involved hospitalised patients demonstrated that a start dose of 5mg was linked to reduced risk of excessive anticoagulation in comparison to 10mg. Parenteral anticoagulation should be terminated when the patient’s INR had been within the recommended therapeutic range of 2.0-3.0 for two consecutive days.2,3

A systematic review of four studies that involved 1229 patients with PE showed that there were no significant differences in terms of risk of recurrent VTE between the group treated with fixed dose of LMWH and adjusted dose of UFH. The odds ratio was 0.88 and the 95% confidence interval was 0.48-1.63. An odds ratio of less than 1 indicated that fixed dose LMWH was better than adjusted dose of UFH but this superiority was not significant because the confidence interval included the value 1.0.20

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One randomised controlled trial that involved 3000 participants have demonstrated that fondaparinux was as effective as UFH in various aspects of treatment of PE. The recurrence of VTE for the group treated with fondaparinux was 3.8% while it was 5.0% for the group treated with UFH (absolute difference=-1.2%, 95% confidence interval 3.0 to 0.5). The mortality rates at 3 months for both fondaparinux and UFH groups were 5.2% and 4.4% respectively (absolute difference=0.8%; 95% confidence interval, 1.0 to 2.6). The rate of major bleeding during intital treatment using fondaparinux was 1.3% and 1.1% for UFH (absolute difference=0.2%, 95% confidence interval -7 to 1.1). The differences between these values were not statistically significant.21

Another randomised controlled trial where 900 patients were randomly allocated to 3 different groups which were the group treated with UFH, enoxaparin 1.5mg/kg once daily or enoxaparin 1.0mg/kg twice daily. There were no significant differences between the rates of recurrent VTE for the 3 treatment groups. The 3 treatment groups also exhibited comparable safety profiles. The rates of bleeding complications among the 3 treatment groups were not significantly different. The frequency of thrombocytopenia was not significantly different among the 3 treatment groups. Therefore, the conclusion from the study was that subcutaneous enoxaparin was as safe and effective as UFH.22

The similarity of LMWH and UFH was reinforced by another randomised controlled trial with a sample size of 612. In this study, tinzaparin was compared with UFH. After 8 days of initiation of the therapy, 2.9% of the patients in UFH group and 3.0% of the patients in tinzaparin group died, experienced recurrent VTE or major haemorrhagic complication. The absolute difference of 0.1% was not significant (95% confidence interval, -2.7 to 2.6). The mortality rates for the UFH group and tinzaparin group were 4.5% and 3.9% respectively with an absolute difference of 0.6% that is non-significant (95% confidence interval, -2.6 to 3.8).23

1951 patients from major studies who presented with low risk, moderate risk or non-symptomatic PE were analysed in a meta-analysis. The treatment period lasted from 5 to 14 days and the results from meta-analysis showed that both LMWHs and UFH are equal in terms of safety and efficacy. The rates of recurrent VTE for both LMWH and UFH therapy were not significantly different as the odds ratio is 0.63 (95% confidence interval, 0.33 to 1.18). In terms of major haemorrhage, LMWH was not significantly superior to UFH as the odds ratio is 0.67 (95% confidence interval, 0.36 to 1.27). Both LMWH and UFH also produced similar death rates with an odds ratio of 1.20 (95% confidence interval, 0.59 to 2.45).3

A maximum of 92% of the patients with PE will get positive outcomes from thrombolytic therapy. This is in accordance to the positive changes found clinically and favourable echocardiography in the initial 36 hours of starting thrombolysis. Although lysis of thrombus can remain therapeutically beneficial in patients who have been symptomatic for 1 to 2 weeks, the greastest improvement is usually seen when thrombolysis is started within 2 days of onset of symptoms. For patients who survived after the first week of treatment initiation, there were no significant differences in the improvement in severity of vascular occlusion and right ventricular dysfunction between the group of patients treated with thrombolytics and the group treated with UFH. Thrombolysis can also increase the risk of haemorrhage significantly. Results from thrombolysis trials anticipated that the cumulative rate of major haemorrhage can be up to 13% and the rate of intracranial bleeding can be up to 2%.2 Six randomised controlled trials were studied in a meta-analysis and the results indicated that thrombolysis was not significantly better than heparin in low risk and moderate risk PE. However, the clinical superiority of thrombolysis over heparin can be observed in patients who presented with major PE and haemodynamic instability.24 Hence, thrombolytic drugs should be reserved for the groups of individuals that have high risk PE.


Based on the clinical evidence, the initial management of PE is using parenteral anticoagulants with the choice of UFH, LMWH or fondaparinux for a minimum of 5 days. All three anticoagulants are suitable to be used because they appear to have comparable efficacy and safety profiles. UFH, LMWH and fondaparinux were no significant superiority over each other in terms of recurrence of VTE. There was also no significant difference among the 3 drugs in terms of rates of major haemorrhagic complications. However, since UFH is administered intravenously, a more rapid anticoagulation effect can be attained as compared to LMWH and fondaparinux which are administered subcutaneously. Warfarin should also be initiated.

Mrs X was diagnosed with PE and she can be classified as a low risk PE patient. She was initially treated with intravenous infusion of UFH for 3 days and subsequently subcutaneous injection of enoxaparin. The utilisation of UFH as an initial anticoagulant was supported by clinical evidences as it was shown to be effective in the management of PE. However, Mrs X was not given a loading dose prior to the maintenance infusion and this was not in line with the recommendations (Agnelli and Becattini, 2010). Furthermore, warfarin was also not started while Mrs X was on intravenous UFH. The initiation of enoxaparin was also inappropriate. She was not given thrombolytics as she had low risk PE and she appeared to be haemodynamically stable. Hence, there were two aspects of Mrs X’s therapeutic management which were not appropriate while the remaining aspects were in line with the clinical evidences.