By Dr Ng Soo Chin

22 February 2009 - What is venous thromboembolism (VTE)? In the normal state, blood flows through our blood vessels smoothly, powered on by the contractions of our heart, which basically works as a tireless pump.

In abnormal circumstances, whereby there is formation of a blood clot (thrombus) in the venous system, usually in the lower limbs, deep vein thrombosis (DVT) is said to have occurred. There is a tendency for a thrombus to detach from the veins and move on as an embolus and lodge further upstream in the lungs, causing pulmonary embolism (PE).

Since DVT and PE are different spectrums of the same disease, VTE (venous thromboembolism) is commonly used to cover both the conditions.

Clearly, some things have gone terribly wrong when VTE occurs because there is an extremely fine balance between the formation of a blood clot and the clot breaking up. In normal circumstances, blood clots only form at the site of injury to stop/prevent bleeding and not in the normal vessels to impede normal circulation.

How does VTE happen?

VTE happens in the setting of a “perfect storm” when a combination of pro-coagulant factors (promoting blood clots) operate at the same time and manage to overwhelm the natural anticoagulant and fibrinolytic (clot breaking) system.

For instance, an obese elderly patient going for pelvic surgery to remove a malignant tumour has a very high likelihood of getting VTE post operatively due to venous stasis, immobilisation and prothrombotic state of cancer.

Sometimes VTE can occur in relatively young patients with no clear-cut provoking factors. Some of them have a family history of VTE and may also suffer from recurrent attacks of VTE or VTE occurring at unusual sites such as the liver, upper limbs, small intestine or brain. These patients suffer from a hereditary hypercoagulable state or thrombophilia.

Some of the known hereditary causes of thrombophilia include anti-thrombin III, protein S or protein C deficiency. Factor V Laiden is a common cause of hereditary thrombophilia amongst Caucasians.

Some of the thrombophilia causes are not inherited but acquired. For instance, the anti-cardiolipin syndrome (ACA) is a common cause of VTE in Asian patients while patients with cancer or myeloproliferative disorders have an increased risk of VTE.

What are the effects of VTE?

The immediate effect varies and ranges from hardly any symptoms to catastrophic sudden death. When a big embolus has lodged at the bifurcation (fork) of the pulmonary trunk, the blood supply can be shut down completely within seconds and these patients die within a matter of minutes even with active resuscitation.

A swollen and painful lower limb is the commonest complaint and if there are associated pulmonary embolisms with small clots, they may complain of chest pain, breathlessness or cough out blood in the sputum.

The long term effect can be debilitating – the affected limb can suffer from post thrombophlebitic syndrome. Because of damaged venous valves after the thrombosis, the blood flow back to the heart can be impaired and this will result in life long limb swelling, pigmentation and chronic ulceration of the affected limb.

Patients with repeated pulmonary embolism can develop pulmonary hypertension leading to breathlessness and heart failure.

What is the size of the problem?

VTE is a common medical problem in the West, with an incidence of around 100 per 100,000 hospital admissions. It is estimated that up to 1% of hospitalised patients in the West die of PE.

In the Far East, the incidence is lower, but growing. A Singaporean study shows the incidence of VTE has increased three times over a 10 year study period and the incidence increased to 15.8 per 100,000 hospital admissions. This trend is likely to manifest in Malaysia as our population ages, more surgeries are done, especially cancer and orthopaedic operations, and with better awareness of VTE and higher pick-up rates due to improved investigative facilities. The higher incidence of autoimmune diseases in the Far East also contributes to the VTE load.

How is VTE diagnosed?

The symptoms and signs of VTE can be mimicked by many other conditions. It is very important that a VTE diagnosis is confirmed with specific tests.

For DVT, a colour Doppler using ultrasound and the D-dimer test are useful diagnostic tests. The chance of picking up VTE with colour Doppler is good in proximal veins but calf vein thrombosis may be missed with colour Doppler. A venogram used to be the gold standard but it is losing popularity because it is a painful and time consuming procedure. The D-dimer is a good exclusion test, meaning patients with negative D-dimer tests are highly unlikely to have VTE.

Pulmonary embolism is reliably picked up by CT chest scans and pulmonary angiograms are now rarely done. It is important to be on the look out for VTE. As my old professor used to say, “what the mind does not know, the eyes do not see!”

What is the treatment for VTE?

VTE can be treated effectively with anticoagulation therapy, initially with heparin followed by an oral drug called warfarin. The unfractionated heparin needs to be given intravenously and needs close monitoring with repeated blood tests called PTT (Partial Thromboplastin Test).

Low molecular weight heparin (LMWH) has largely replaced unfractionated heparin because it has predictable biological availability and efficacy and needs no laboratory monitoring and has fewer side-effects (such as heparin-induced thrombocytopenia or osteoporosis).

Warfarin (a rodenticide) is a drug that needs careful monitoring and it is well known that the required drug dosage may vary greatly between different individuals. The dose should attain an INR (International Normalised Ratio) of two to three to achieve the aim of preventing clot extension without running the risk of bleeding.

Warfarin interacts with many medications and it is important to consult your doctor before adding on new medications.

There are thrombolytic agents available such as streptokinase and tissue plasminogen inhibitor, which are reserved for use in cases of pulmonary embolism causing unstable vital signs. They can break up the thrombus or blood clot quickly but carry a risk of bleeding complications.

How long is the treatment?

The duration of anticoagulation treatment depends on a few factors, namely whether the VTE is provoked or precipitated by a risk event such as surgery or immobilisation, any underlying hypercoagulable state and the extent and site of VTE and whether this is a recurrent attack.

The first attack of a provoked VTE needs three to six months of anticoagulation. Unprovoked VTE or recurrent VTE would need long-term anticoagulation of up to a year or more.

The duration of anticoagulation needs to be reviewed regularly and the term life-long anticoagulation should be replaced by long-term anticoagulation. This is especially for older patients who have other concurrent medical problems.

Certain life events, such as the occurrence of a bleeding peptic ulcer or hemorrhagic stroke, may cut short or change the mode of anticoagulation.

Can VTE be prevented?

The answer to this question is a resounding yes. Thromboprophylaxis or prevention of VTE is a much better option than treatment per se. The compelling reason is up to 80% of PEs occur without signs and two out of three deaths occur within 30 minutes, making treatment options rather limited. It is estimated that up to half of all PE and two out of three DVT cases can be prevented with thromboprophylaxis of high risk groups such as those undergoing cancer surgery, the elderly, the obese and patients whose prolonged immobilisation is expected.

The take-up rate of thromboprophylaxisis has not been that encouraging because of the following reasons. Some doctors feel VTE is uncommon amongst Asians while some are concerned about the increased risk of bleeding associated with use of thromboprophylaxis. It is regrettable that despite the body of evidence to show that thromboprophylaxis works and saves life, it is not being practised widely.

How is cancer-related VTE treated?

Sometimes VTE can be the first manifestation of underlying cancer. It can also arise while the cancer is being treated. It is important to treat the VTE promptly and studies have shown that LMWH is superior for long-term treatment of cancer-associated VTE as compared to initial treatment by heparin followed by warfarin therapy in terms of fewer VTE recurrences and bleeding complications.

LMWH should be continued as long as there is active cancer or while receiving chemotherapy. Interestingly, in control studies, the LMWH-treated patients survive their cancer longer compared to the warfarin-treated group. LMWH may have some actions against tumour growth or spread that warrants furtherstudy.

How to deal with VTE in pregnancy?

This will pose quite a headache, both in diagnosis and treatment. VTE symptoms are even less clear-cut in pregnancy than in the non-pregnant state.

Pregnancy is well recognised as a risk factor for VTE because the blood haemostatic system is primed towards stopping bleeding in delivery. Hence the clotting factors are higher while the natural anticoagulant system is toned down as pregnancy advances. The postpartum period (one month after delivery) is the most dangerous period as most VTEs are reported during this period.

Diagnostic procedures with significant radiation exposure, venograms for example, are best avoided. Spiral CT scans of the chest can be done with abdominal shielding. The D-dimer test loses its value as an exclusion test in pregnant women.

The key to early diagnosis is recognising the high-risk groups and being ever vigilant for VTE.

The treatment for VTE is somewhat simplified using LMWH but warfarin is not used for fear of adverse foetal effects.

What is the risk of VTE in air travel?

There are concerns of the risk of air travel, especially long-distance flights causing VTE. Recent studies have confirmed a two-fold increase in the risk of developing VTE in air travel as well as other forms of travel and the mechanism is thought to be immobilisation.

In individuals who use oral contraceptives, are carriers of the Factor V Leiden mutation, or who are particularly tall, short, or obese, this risk is considerably higher and may need thromboprophylaxis.

Simple measures like doing stretching exercises, drinking enough water (and not alcohol which tends to cause diuresis, where the body passes more urine, resulting in dehydration) would also help.

Can anticoagulation therapy be given as outpatient treatment?

The compelling reason to consider outpatient therapy is the considerable savings in cost. Only uncomplicated patients are suitable candidates for outpatient therapy. Any patients who are likely to have bleeding complications, liver or kidney impairments, a lack of social support or compliance issues are better treated as in-patients.

The risk of embolisation decreases markedly after two days of initiating anticoagulation and it may be prudent to observe patients with extensive proximal vein thrombosis in the ward.

What are the roles of surgical intervention such as putting in IVC filters?

There are limited situations for use of IVC filters, which are basically for patients who cannot be anticoagulated due to a bleeding tendency. They do not prevent DVT in the lower limbs, insertions carry a small risk and the procedure is costly.

Other interventional procedures such as catheter-directed thrombolysis using TPI are done only in selected cases after carefully weighing the potential risks versus benefits. The risks would include local and systemic bleeding while the benefits would be better recovery of limb function due to faster clearing of clots and reopening of vessels.

What are the likely advances in the near future?

Clearly warfarin is a cumbersome drug to use and despite the superior pharmacokinetics and safety profile of LMWH, there is still room for improvement.

An oral fixed-dose drug with no monitoring requirement would be a boon and there are a few contenders in advanced Phase III trials. The joy of easier anticoagulation is likely to be tempered by the expected high cost of the new drugs, making pharmcoeconomics a relevant issue before such new agents see widespread use.

Since prevention is the key to saving lives, VTE prophylaxis with various agents will likely be better defined in dosage and duration of therapy.

This article is contributed by The Star Health & Ageing Panel, which comprises a group of panellists who are not just opinion leaders in their respective fields of medical expertise, but have wide experience in medical health education for the public.

The members of the panel include: Datuk Prof Dr Tan Hui Meng, consultant urologist; Dr Yap Piang Kian, consultant endocrinologist; Datuk Dr Azhari Rosman, consultant cardiologist; A/Prof Dr Philip Poi, consultant geriatrician; Dr Hew Fen Lee, consultant endocrinologist; Prof Dr Low Wah Yun, psychologist; Datuk Dr Nor Ashikin Mokhtar, consultant obstetrician and gynaecologist; Dr Lee Moon Keen, consultant neurologist; Dr Ting Hoon Chin, consultant dermatologist; Prof Khoo Ee Ming, primary care physician; Dr Ng Soo Chin, consultant haematologist. For more information, e-mail starhealth@thestar.com.my. The Star Health & Ageing Advisory Panel provides this information for educational and communication purposes only and it should not be construed as personal medical advice. Information published in this article is not intended to replace, supplant or augment a consultation with a health professional regarding the reader’s own medical care. The Star Health & Ageing Advisory Panel disclaims any and all liability for injury or other damages that could result from use of the information obtained from this article.

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