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VENOUS THROMBOEMBOLISM
PREGNANT WITH A PAINFUL LEG

SCENARIO
Patricia Aledambo is 36 years old and in general good health, although she has been overweight since her teens. She says her husband likes her that way and she has no plans to diet. However, she has stopped smoking now that she is pregnant with her second child. Two weeks ago she returned from a visit to her parents in South Africa. Her blood pressure was slightly raised at a routine antenatal examination just after she returned, so she has been taking it easy and having plenty of bed rest since then. She visits her GP because of persisting pain in her left leg, which gets worse on standing or walking.

On examination her leg is found to be swollen, warm, and painful to palpation between the knee and ankle. There is pitting oedema in the swollen leg. The GP refers her urgently to the local A&E department. During examination in the A&E a Wells score was calculated at 3. A detailed history revealed that her mother had had a pulmonary embolus after Patricia had been born. She was given an injection and warned that she would need injections on a daily basis for the time being. She was then sent home after being booked in for her injection and further tests the next day.

LEARNING OBJECTIVES

1. Define terms - Wells score - Pitting oedema 2. Describe the venous drainage of the lower limb 3. Deep vein thrombosis: - Epidemiology - Pathophysiology - Clinical presentation

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- Treatment - Prognosis 4. Pulmonary Embolism: - Link to DVT - Signs and symptoms

TERMS
Wells score - this is the most widely used clinical probability assessment a patients risk of current DVT (see main text).

Pitting oedema -

1. INTRODUCTION

The annual global incidence of deep vein thrombosis (DVT) is roughly 1 per 1000. The risk of DVT for inpatients is considerably higher: 10-20% for general medicine patients and 40-80% in patients having hip or knee surgery (Cayley, 2007). The condition, most commonly caused by thrombus formation in a deep calf vein, has significant mortality due to associated risk of pulmonary embolism (PE) and morbidity due to post-thrombotic syndrome. This paper considers DVT in the context of a 36-year-old pregnant woman who seemingly presents with the condition.

2. VENOUS DRAINAGE OF THE LOWER LIMB

The venous drainage of the lower limb comprises both superficial and deep veins (Fig. 1). The great and small saphenous veins are the two major superficial veins, found in the subcutaneous tissue. The great saphenous vein runs from the dorsal venous arch of the foot, ascends along the medial aspect of the leg and drains into the femoral vein, distal to the inguinal ligament. The small saphenous vein

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arises from the lateral side of the foot, ascending between the heads of the gastrocnemius muscle and draining into the popliteal vein, in the popliteal fossa (Moore et al., 2011).

The deep veins in the lower limb typically occur as pairs that flank the major arteries. The veins and arteries are encased together in a vascular sheath; arterial pulsations compress the vein and help move blood along the deep veins. The posterior tibial artery ascends deep in the calf muscle, uniting with the posterior tibial and the fibular vein posterior to the knee, forming the popliteal vein (Marieb and Hoehn, 2010). This becomes the femoral vein in the thigh, which is joined by profunda femoris in the terminal region of the vein. The femoral vein becomes the external iliac vein after passing deep to the inguinal ligament, which on joining with the internal iliac, becomes the common iliac vein. The left and right common iliac veins then unite to form the inferior vena cava.

Figure 1. Venous drainage of the lower leg (Moore et al., 2011).

There also exists a number of perforating veins that allow the passage of blood from the superficial to the deep veins. Flow in the reverse direction, i.e. from deep to superficial, is prevented by valves as well as by compression of the perforating veins by contracting muscle.

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3. VENOUS THROMBOEMBOLISM

3.1 PATHOPHYSIOLOGY OF DEEP VEIN THROMBOSIS

The formation of thrombus was postulated by Virchow to be caused by three main, interrelated factors: slowed down or static blood flow (haemostasis); damage to the vessel wall; and blood hypercoagulability. This pathophysiologic notion is still valid today, some 150 years later. In agreement with Virchows triad, thrombi occur in regions of low flow (i.e. veins) and low shear stress, most commonly in the valve pockets of the deep calf veins of the leg (distal deep vein thrombosis) (Nicolaides et al., 1971). The thrombus may then extend proximally past the popliteal vein, to the femoral or pelvic veins. This is termed proximal deep vein thrombosis and associated with more complications.

3.2 PATHOPHYSIOLOGY OF PULMONARY EMBOLISM

An embolism is a fragment of a thrombus that has broken free and travelled in the circulation to be lodged in a distant vessel of smaller diameter. The most significant complication of DVT is the embolisation of the thrombus to the pulmonary vessels in the lung, resulting in a potentially fatal pulmonary embolism. If DVT is left untreated, around 50% of patients will go on to develop symptomatic pulmonary embolism, which carries a ~10% risk of death in the first hour of onset (Kearon, 2003). Deep vein thrombosis and pulmonary embolism can be collectively termed venous thromboembolism (VTE).

3.3 RISK FACTORS

The risk factors for venous thromboembolism are numerous (Table 1) and their interactions complex. As in this case, a patient may possess many risk factors, each one with cumulative effect. There is also a significant risk of VTE during hospitalisation, either due to an acute medical illness such as myocardial infarction, the prolonged bed rest, or from surgery. All hospitals patients at risk should be given prophylaxis and encouraged to be exercise their legs as much as possible (Kumar and Clark, 2005).

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Risk factors for acute DVT Age Immobilisation Surgery Trauma Malignancy Primary hypercoagulable states History of DVT Family history Use of oral contraceptives Oestrogen replacement Pregnancy and puerperium Presence of phospholipid and anticardiolipin antibodies Central venous catheters Inflammatory bowel disease Obesity Myocardial infarction or chronic heart failure Varicose veins

Hypercoagulability Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Stasis Yes Yes Yes Yes

Venous injury

Yes

Yes

Yes Yes Yes Yes Yes

Table 1. Risk factors for acute deep vein thrombosis. Risk factors for patient in bold, adapted from (Strijkers et al., 2011).

The previous history of pulmonary embolism in the patients mother is significant. It could suggest the patient has an inherited predisposition to thrombosis. Coagulation factor abnormalities such as factor V Leiden and a variant of prothrombin known as G21020A greatly increase the risk of thrombosis (Eichinger et al., 2002). Less commonly, a patient may possess a deficiency in a natural inhibitor of thrombosis such as antithrombin, protein C or protein S. Abnormally high levels of clotting factors or hyperhomocysteinaemia also confers increased risk (Kyrle and Eichinger, 2005).

3.4 CLINICAL FEATURES

The presentation of DVT is variable, and may be asymptomatic. The patient in this case presented with many of the classic presenting features: pain in the calf, redness and swelling; The blockage inherent to DVT leads to venous outflow obstruction. This increases the capillary and venous hydrostatic pressure forcing fluid into the interstitial space. This results in the oedema seen in this case.

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Pulmonary embolism is notoriously difficult to detect clinically; missing the variable and subtle presentation of PE is a significant contributor to its high mortality. Unexplained, sudden onset dyspnoea is the most common and may be the only symptom of PE. The patient may also present with haemoptysis and pleuritic chest, but only when infarction has occurred. On examination the patient may be tachypnoeic with a pleural rub and course crepitations on auscultation (Kumar and Clark, 2005).

3.5 DIAGNOSIS

The diagnosis of deep vein thrombosis and pulmonary embolism typically follows a diagnostic algorithm (Fig. 2). The various diagnostic modalities are used sequentially to avoid unnecessary tests, but also to ensure a diagnosis is not missed.

Figure 2. Typical algorithm used in the diagnosis of DVT. Abbreviations used: CUS - compression ultrasound. Adapted from (Goldhaber and Bounameaux, 2012).

A clinical probability assessment is an essential first step in the diagnosis of venous thromboembolism (Table 2). This stratifies patients according to risk, identifying those with high or intermediate probability of DVT or PE who may require pharmacological intervention before diagnostic tests. This initial assessment improves diagnostic accuracy and may be more important clinically than the diagnostic tests which follow (Wells, 2006).

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Wells score for DVT* Clinical feature Cancer Paralysis or recent cast Bed rest > 3 days or surgery within 4 weeks Pain on palpation of deep veins Swelling of the entire leg Pitting oedema Dilated superficial veins Alternative diagnosis at least as probable as DVT Wells score for PE** Previous PE or DVT Heart rate > 100 beats per minute Clinical signs of DVT Recent surgery or immobilisation Alternative diagnosis less likely than PE Haemoptysis Cancer Score +1 +1 +1 +1 +1 +1 +1 -2

+1.5 +1.5 +1.5 +3 +3 +1 +1

Table 2. Scoring systems to assess probability of DVT and PE. * Patient with a score of 0 are termed low risk, 12 are intermediate risk and 3 or greater are high risk. ** Patients with a score of 0 1 are low risk, 26 are intermediate risk, and 7 are high risk. Adapted from (Wells et al., 1997) and (Goldhaber and Bounameaux, 2012).

Fibrin D-dimer is a degradation product of cross-linked fibrin and will be present in the blood following fibrinolysis of a blood clot. The detection of D-dimer is a sensitive, but non-specific test for venous thromboembolism. D-dimer levels are also elevated in pregnancy, infection and malignancy (Hirsh and Lee, 2002). However, D-dimer is useful at ruling out DVT - in cases with a low clinical probability, a negative D-dimer means deep vein thrombosis can be safely ruled out (Wells et al., 1997).

In patients with a high clinical probability or a positive D-dimer (or both), the confirmation of deep vein thrombosis is usually by compression ultrasonography. Typically the femoral and popliteal veins are compressed and imaged with ultrasound; non-compressibility in the vein indicates thrombosis (Lensing et al., 1989). This method shows high specificity (96%) and sensitivity (95%) in detecting proximal, symptomatic DVT, but is less effective in detecting calf vein thrombosis (Hirsh and Lee, 2002).

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In cases where ultrasound is inconclusive, not feasible or disagrees with a high clinical probability, a venogram may be performed. This remains the gold standard in diagnosing DVT, but it is expensive and invasive, and should only be performed in these special cases.

3.6 TREATMENT
3.6.1 Anticoagulation The purpose of anticoagulation for DVT is to prevent extension of the thrombosis, recurrence of DVT and reduce the chance of pulmonary embolism. Low-molecular-weight heparin (LMWH) is the anticoagulant of choice in the majority of patients with confirmed acute DVT (Hirsh and Lee, 2002). LMWH has a number of advantages compared to unfractionated heparin (UFH): LMWH administration does not require constant monitoring; it can be administered by subcutaneous injection; it has more predictable pharmacodynamic properties (Hirsh et al., 2001). Furthermore, LMWH has been shown to be more effective and safer than UFH in the initial treatment of VTE (Erkens and Prins, 2010). It is used routinely as prophylaxis in patients at risk. However, LMWH may be contraindicated in cases of renal insufficiency.

The injection the pregnant patient received in this case would most likely have been low molecular weight heparin (LMWH). Both LMWH and UFH appear to be safe to use during pregnancy, and do not cross the placenta. However, more studies are needed to determine the effectiveness and safety of anticoagulation for DVT in pregnancy (Yaakob et al., 2010). The further tests the patient received would probably not only be the D-dimer and compression ultrasonography diagnostic tests, but also a blood test. This could help ascertain baseline coagulation levels, as well as indicate liver or renal dysfunction that may contraindicate certain treatments.

After initial treatment with LMWH or UFH, long-term prevention of recurrent venous thromboembolism is typically achieved with the use of vitamin K antagonists such as warfarin. These must be monitored by the prothrombin time, expressed in terms in the international normalised ratio (INR). It is thought an INR between 2.0 and 3.0 provides the optimal balance of thrombus prevention and risk of bleeding (Kyrle and Eichinger, 2005). However, it is important to note that in this case warfarin would not be administered due to the chance of warfarin embryopathy and other teratogenic effects.

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The duration of anticoagulation treatment should be dictated by considering the balance of the risk of recurrent thrombosis and the risk of bleeding. The risk of bleeding from the initial LMWH or UFH is 2-5%; the risk of serious bleeding from warfarin is around 3% per year (Levine et al., 2001). In patients with a low chance of recurrent, such as a thrombosis caused by surgery, anticoagulation should be given for 3 months. For those in which the risk of recurrence significantly outweighs the risk of bleeding, anticoagulation may be given indefinitely (Kyrle and Eichinger, 2005).

Recently, the oral factor Xa inhibitor rivaroxaban has been approved in treating, as well as preventing, VTE (NICE, 2012). It has been shown to be at least as effective as standard clinical practice (LMWH injections followed by a vitamin K antagonist), without the need for regular monitoring with blood tests (INR) (EINSTEIN Investigators, 2010). Rivaroxaban therefore shows great potential as a simple, single-drug anticoagulation therapy in the treatment of venous thromboembolism.

3.6.2 Thrombolysis The role of thrombolysis in the treatment of DVT remains unclear. It carries a higher risk of bleeding (~3-fold) compared to UFH, with a 2% rate of intracranial haemorrhage (Levine et al., 1995). However, thrombolysis has greater potential for complete clot lysis compared to anticoagulants, and may reduce some of the morbidity associated with DVT. Therefore, as long as strict eligility critieria are used, thrombolysis may have a future role in DVT treatment (Watson and Armon, 2004).

3.6.3 Vena caval filter The implantation of a vascular filter in the inferior vena cava (IVC) may be indicated in cases of DVT where there is a serious risk of bleeding from anticoagulants (e.g. thrombocytopenia), where anitcoagulants have proven ineffective or where there is serious active bleeding. The treatment intends to prevent the embolisation of free thrombi, however, the long-term benefit from this intervention seems modest (Hirsh and Lee, 2002).

3.7 PROGNOSIS

Post thrombotic syndrome of the leg occurs in 43-47% of patients within two years of developing symptomatic DVT (Kahn et al., 2008). This is a debilitating, chronic condition caused by venous hypertension associated with DVT. It is characterised by pain, itching and swelling in the leg which is

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exacerbated by standing. The use of below-knee compression stocking reduces the risk of developing post thrombotic syndrome by approximately 50% (Prandoni et al., 2004).

Venous ulceration occurs in 3-5% of those who develop post thrombotic syndrome (Strijkers et al., 2011). These leg ulcers are painful, difficult to treat and significantly impair the patients quality of life. The morbidity associated with DVT is therefore significant; treatments such as thrombolysis that reduce the incidence of post thrombotic syndrome are currently being investigated (Watson and Armon, 2004, Strijkers et al., 2011).

4. CONCLUSION

Proper use of prophylactic treatment, continued implementation of proven clinical strategies and the development of new drugs and therapies will hopefully reduce the significant mortality and morbidity associated with this condition.

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5. REFERENCES

CAYLEY, W. E. 2007. Preventing deep vein thrombosis in hospital inpatients. BMJ, 335, 147-151. EICHINGER, S., WELTERMANN, A., MANNHALTER, C., MINAR, E., BIALONCZYK, C., HIRSCHL, M., SCHONAUER, V., LECHNER, K. & KYRLE, P. A. 2002. The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism. Arch Intern Med, 162, 2357-60. ERKENS, P. M. & PRINS, M. H. 2010. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev, CD001100. NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE, N. I. F. H. A. C. 2012. Rivaroxaban for the treatment of deep vein thrombosis and prevention of deep vein thrombosis and pulmonary embolism [Online]. Available: http://www.nice.org.uk/nicemedia/live/13332/59383/59383.pdf [Accessed 22/11/12 2012]. GOLDHABER, S. Z. & BOUNAMEAUX, H. 2012. Pulmonary embolism and deep vein thrombosis. The Lancet, 379, 1835-1846.

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HIRSH, J. & LEE, A. Y. 2002. How we diagnose and treat deep vein thrombosis. Blood, 99, 3102-10. HIRSH, J., WARKENTIN, T. E., SHAUGHNESSY, S. G., ANAND, S. S., HALPERIN, J. L., RASCHKE, R., GRANGER, C., OHMAN, E. M. & DALEN, J. E. 2001. Heparin and low-molecularweight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest, 119, 64S-94S. The EINSTEIN Investigators. 2010. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. New England Journal of Medicine, 363, 2499-2510. KAHN, S. R., SHRIER, I., JULIAN, J. A., DUCRUET, T., ARSENAULT, L., MIRON, M. J., ROUSSIN, A., DESMARAIS, S., JOYAL, F., KASSIS, J., SOLYMOSS, S., DESJARDINS, L., LAMPING, D. L., JOHRI, M. & GINSBERG, J. S. 2008. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med, 149, 698-707. KEARON, C. 2003. Natural history of venous thromboembolism. Circulation, 107, I22-I30. KUMAR, P. & CLARK, M. 2005. Clinical Medicine, Saunders Ltd. KYRLE, P. A. & EICHINGER, S. 2005. Deep vein thrombosis. The Lancet, 365, 1163-1174. LENSING, A. W., PRANDONI, P., BRANDJES, D., HUISMAN, P. M., VIGO, M., TOMASELLA, G., KREKT, J., WOUTER TEN CATE, J., HUISMAN, M. V. & BULLER, H. R. 1989. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med, 320, 342-5. LEVINE, M. N., RASKOB, G., LANDEFELD, S. & KEARON, C. 2001. Hemorrhagic complications of anticoagulant treatment. Chest, 119, 108S-121S. MARIEB, E. N. & HOEHN, K. 2010. Human Anatomy and Physiology, Benjamin Cummings. MOORE, K. L., AGUR, A. M. R. & DALLEY, A. F. 2011. Essential Clinical Anatomy, Lippincott Williams & Wilkins. NICOLAIDES, A. N., KAKKAR, V. V., FIELD, E. S. & RENNEY, J. T. 1971. The origin of deep vein thrombosis: a venographic study. Br J Radiol, 44, 653-63. PRANDONI, P., LENSING, A. W., PRINS, M. H., FRULLA, M., MARCHIORI, A., BERNARDI, E., TORMENE, D., MOSENA, L., PAGNAN, A. & GIROLAMI, A. 2004. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med, 141, 249-56. STRIJKERS, R. H. W., CATE-HOEK, A. J. T., BUKKEMS, S. F. F. W. & WITTENS, C. H. A. 2011. Management of deep vein thrombosis and prevention of post-thrombotic syndrome. BMJ, 343. WATSON, L. I. & ARMON, M. P. 2004. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev, CD002783. WELLS, P. S., ANDERSON, D. R., BORMANIS, J., GUY, F., MITCHELL, M., GRAY, L., CLEMENT, C., ROBINSON, K. S. & LEWANDOWSKI, B. 1997. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet, 350, 1795-8.

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WELLS PS, O. C. D. S. F. D. T. H. 2006. Does this patient have deep vein thrombosis? JAMA: The Journal of the American Medical Association, 295, 199-207. YAAKOB, C. A. C., ABU DZARR, A., ISMAIL, A. A., LAH, N. & HO, J. J. 2010. Anticoagulant therapy for deep vein thrombosis (DVT) in pregnancy. Cochrane Database of Systematic Reviews.

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