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Deep Venous Thrombosis From Pathogenesis to Prevention

Preventing this disease is cheaper than treating its consequences and more importantly one cannot put a price on the loss of life involved

"While we await the results of the data currently being generated in our country, every physician should be familiar with and initiate protocols for the prevention and treatment of DVT" - Dr Raghu Varadarajan Hepatobiliary and Transplant Surgeon Dr Kamakshi Memorial Hospital Chennai

Thrombosis of the deep venous system is not an uncommon occurrence in hospitals around the world. Yet this condition remains under diagnosed and adequate preventive measures more often not undertaken leading to sequelae including increased in hospital morbidity and mortality.

Thrombosis of the vena cava was first recognised by Schenk in 1644 but it was only in the mid 19th century that Virchow observed the association between venous thrombosis and Pulmonary Embolism (PE). Although heparin was introduced in the mid 1930s it is only in the last 25 years or so, that the pathophysiology of Deep Venous Thrombosis (DVT) has become understood and progress made in the diagnosis and treatment of the condition, often known as a silent killer.

Incidence

According to Dr Fredrick Anderson of UMass Medical School Center for Outcomes Research, each year about 6,00,000 patients will experience venous thrombo-embolism. At least 50,000 and perhaps as many as 200,000 patients will die from pulmonary embolism. The incidence of DVT in India is unclear but awareness of this condition has made physicians believe that the incidence is more or less similar to other reports published worldwide and indeed sudden deaths during the post operative period may in fact be attributable to pulmonary embolism secondary to asymptomatic thrombosis. This has prompted a nationwide effort to collect data and a DVT registry has been set-up at DVTIndia.com. In addition, the Venous Association of India has been founded under the auspices of the Vascular Society of India and has emphasised the importance of this condition at recent meetings across the country.

Pathogenesis

A thrombus consists of a solid mass or plug formed within the vein from components of the blood stream. The process of thrombosis is different from clotting of blood, where the initiation of a cascade system within the blood leads to the generation of thrombin, fibrinogen and fibrin. Thrombosis on the other hand is characterised by a series of events involving blood platelets. Platelets adhere to sites of endothelial cell damage and in that process, release a number of potent factors that lead to further platelet aggregation and the local formation of fibrin leading to thrombosis. Factors likely to promote thrombosis fall into three major groups, also known as Virchow's triad. They are:

• Changes in the vessel wall.
• Changes in the pattern of blood flow and
• Changes in the constituents of blood.

Changes in the Vessel Wall

This picture demonstrates patient for Nephrotectomy with TED Anti-embolism stockings applied Pre-op and Kendall SCD prior to procedure in addition to pharmacological prophylaxis

Changes in the vessel wall may occur as a result of chemical trauma as in intravenous injection of a drug or due to mechanical trauma. The resulting endothelial cell damage predisposes to thrombosis. Post-operative venous thrombosis of the lower limbs may be a consequence of such mechanical trauma. During anaesthesia, there is a loss of normal muscle tone and the weight of the limb in combination with a hard operating table may be sufficient to cause trauma to the venous endothelium. Thus, surgery itself appears to be a very potent stimulus for venous thrombosis.

Changes to the Pattern of Blood Flow

This may occur due to the general condition of the patient such as congestive cardiac failure or due to local factors such as reduction in the speed of blood flow. Local slowing of blood particularly in the veins of the lower limb takes place during prolonged dependence of the limb and reduced muscle pumping activity as seen in patients immobilized in bed, especially after surgery. Dissection of the deep veins of the calf has shown that more than 50 per cent of surgical patients at autopsy had evidence of venous thrombi, the clinical diagnosis of which is difficult as most patients are asymptomatic.

Changes to the Constituents of the Blood

Changes to the constituents of the blood as in platelet aggregation, thrombophilia disorders (eg. Antithrombin 3, Protein S, C deficiency) and plasma lipid profile may contribute to thrombosis. There is a strong co-relation between cigarette smoking and its effect on platelet function as it may have an effect on adhesion of platelets to the underlying vessel wall.

The natural history of a thrombus may range from organisation, where it is replaced by a solid plug of collagenous tissue, recanalisation where blood flow is re-established through the thrombus or embolisation where it is detached from the underlying wall and travels in the venous circulation. If it persists in a plaque like fashion on the surface of the vessel wall without impeding the blood flow, it is known as a mural thrombus. The post-phlebitic syndrome is the long-term result of DVT in some patients. Whether the DVT is symptomatic or asymptomatic, this syndrome, which is characterised by varicose veins, edema, skin pigmentation, induration and ulceration, is often the result of venous damage sustained during an episode of thrombosis.

Risk Assessment for DVT

Since assessment of risk for DVT can be complicated, several diagnostic scoring systems such as the Wells Diagnostic Algorithm have been developed. All these methods rely on recommended guidelines along with history and examination for risk assessment and physicians classify patients as having a low, moderate or high probability of developing DVT.

Low-risk patients: General medical patients and surgical patients younger than 40 years who undergo minor operations (general anesthesia lasting fewer than 30 minutes) are at a low risk for DVT.

Moderate-risk patients: Surgical patients older than 40 years who undergo major operations requiring anesthesia lasting longer than 30 minutes, but who have no additional DVT risk factors, are at moderate risk of developing postoperative DVT. In addition, malignancy, some types of chemotherapy, myocardial infarction and congestive cardiac failure increase the risk for venous thromboembolism.

High-risk patients: Following major abdominal surgery, the incidence of DVT may be up to 30 percent. Urological and gynecological surgery, particularly in older women, is also associated with significant risk (7 to 45 percent DVT), and caesarean section also carries a high risk.

Cardiac surgery is considered to be of moderate risk although the patient may have additional risk factors such as malignancy which makes this a higher risk category. Neurosurgical patients are also a high-risk group as the risks of DVT range from 9 to 50 per cent.

Orthopaedic surgery such as hip or knee replacement and hip fracture repair are examples of the highest risk surgery. Data from the National Institute of Health consensus show the overall incidence of DVT after elective hip surgery to be from 45 to 70 per cent, of clinical PE to be about 20 per cent and of fatal PE to be from one to four per cent. Because of this, most orthopaedic surgeons insist that their patients receive the most effective peri-operative prophylaxis available.

Many patients undergoing hip or knee surgery are old, and this alone increases the risks of thrombosis. Other risk factors of these procedures are major dissection and trauma at operation, trauma to the femoral vein and immobility of the patient both before and after the operation. Other types of very high-risk surgery are operations to remove malignant tumors in the thoracic region. Patients undergoing thoracic surgery because of malignancy are already in poor general condition, the surgery may be long and involve extensive dissection and pressure on large veins, all of which puts the patient at risk of venous thromboembolism.

Diagnosis

The clinical diagnosis of DVT can be difficult. Many present with pulmonary embolism without the thrombosis being clinically apparent and in those with classic clinical signs, only about 50 per cent have DVT. Cellulitis adds to the problem. The classical description of pain upon dorsiflexion of the foot (Homan's sign) and spontaneous maintenance of the relaxed foot in abnormal plantar flexion is not helpful in diagnosis as it is very nonspecific. Clinical features are from obstruction to venous drainage such as limb pain and tenderness and unilateral swelling of calf or thigh. However involvement of the iliac bifurcation, pelvic veins, or the vena cava produces bilateral leg oedema. Patients often present with distension of superficial veins, increase in skin temperature and skin discolouration and DVT must always be considered in the differential diagnosis of patients with low-grade fever in the post-op period.

Investigations

The choice of tests available for screening and diagnosis of DVT may depend upon local protocols, each with its own advantages and drawbacks. They are measurement of D-Dimer, fibrinogen-uptake test, Impedance Plethysmo-Graphy (IPG), Doppler ultrasonography, Duplex ultrasound scanning and venography. Except for D-Dimers and Duplex scanning, other tests are now primarily of interest as historic or research methods. If DVT has occurred for no apparent reason especially in a young patient, a full thrombophilia profile should be performed.

The recommended policy is to initially arrange for a D-Dimer. This test has a high sensitivity but poor specificity as high concentrations occur in other disorders. Nevertheless, a negative test can exclude the need for further investigation.

Contrast venography has long been the gold standard of diagnosis for DVT. However, it is highly invasive and has substantial morbidity and mortality unlike the other diagnostic tests for DVT. This has been replaced more recently by Magnetic Resonance Venography (MRV) and has been shown to be a very sensitive and specific test for deep and superficial venous disease in the lower legs and in the pelvis. A great value of this test is that unsuspected non-vascular causes for leg pain and oedema are often seen on the scan.

Since the late 1980s, Duplex ultrasound scanning has become the principal diagnostic screening test for DVT in most hospitals throughout the western world. However, its reliability is dependent upon the skill of the user and it may miss a non-occlusive thrombus in up to 40 per cent of cases involving the iliac or pelvic veins.

If a patient presents 'on call' with a suspected DVT, treatment must be started immediately and investigations initiated as soon as possible the next day, considering the potentially fatal complications of this condition. Patients who do show clinical signs of PE such as dyspnea, chest pain or haemoptysis require urgent investigation and rapid treatment if the diagnosis of PE is confirmed. As with DVT, clinical examination alone and simple investigations such as chest X ray and ECG are unreliable methods of diagnosis. Previously conventional pulmonary angiography was used but it is invasive and time consuming. Ventilation perfusion (V/Q) scan is another method to diagnose the probability of PE. However, the findings may be non-diagnostic. CT angiography is the preferred method of choice nowadays in confirming the diagnosis, bearing in mind that small (sub-segmental) emboli may be missed and patients with impaired renal function may not be suitable for this technique.

Prevention of Venous Thrombo-embolism

Prophylaxis for DVT to those who are at risk should be a routine practice in all hospitals, provided there is no contraindication to its use. It is neither complicated nor expensive. Data suggests that the use of modern methods of DVT prophylaxis will reduce the incidence of DVT during the post-operative period by two-thirds and may prevent death from pulmonary embolism in one patient out of every 200 major operations. A study on 60,000 patients in more than 32 countries, called 'Endorse' revealed that though the risk of DVT is very high, only 17 per cent patients in India received any prophylaxis to prevent it.

Prophylaxis

There are two types of prophylaxis - mechanical methods and pharmacological agents.

Going back to Virchow's triad, all prophylaxis is directed either at suppressing the activation of blood coagulation or at increasing venous blood flow in the leg veins. However, some general measures for prevention start even before surgery, if it is a planned procedure. They include ambulating the patient and ensuring good hydration. After surgery, early mobilisation of patients and physiotherapy should be instituted as soon as possible, as they stimulate calf muscles and put pressure on the calf and leg veins. This discourages stasis and venous pooling of blood in the lower extremities.

Mechanical methods are virtually free of side effects.

Graded Compression Stockings: These have been shown to be effective in reducing post-operative venous thrombosis in general surgical patients. The stockings are in-expensive, should be considered in all at-risk surgical patients and should be fitted individually to ensure that pressure is correctly graded (highest at the ankle and decreasing in a proximal direction).

Intermittent pneumatic leg compression enhances blood flow in the deep veins of the legs. This method is virtually free of side effects and is particularly useful in patients at high risk of bleeding, such as those undergoing neurosurgery, major knee surgery and prostatic surgery. Studies have shown that mechanical compression reduces the chance of DVT in surgical patients from 24per cent to as less as 9per cent and is as effective as low-dose heparin in patients undergoing abdominal surgery.

Pharmacological Agents: Includes low dose unfractionated heparin, low-molecular-weight heparins (LMWHs), warfarin and dextran. The latter two are not commonly used in practice especially with warfarin as it requires dose adjustment according to prothrombin time. Low-dose heparin does not require laboratory monitoring of Partial Thromboplastin Time (PTT) and is simple to administer. It is one of the agents of choice for moderate to high-risk general surgical and medical patients, and in the international multi-centre trial, the frequency of both fatal and nonfatal complications was reduced by 50 to 70 per cent.

When used as prophylaxis, heparin can be administered by sub-cutaneous injection at a dose of 5,000U every 8 or 12 hours post-operatively. Ideally the first dose should be given 2 hours preoperatively but when the risk of bleeding is higher the practice is to usually wait until immediately after surgery. Heparin is then continued for about seven days or until such time as the patient becomes fully ambulant.

Low-Molecular-Weight Heparins (LMWHs): They do not prolong PTT as much as unfractionated heparin and tend to produce less bleeding. They also have a longer half-life than standard heparin. Studies in both general and orthopaedic surgery have suggested that LMWHs are more effective than standard low-dose heparin and unless contraindicated, are safe when used for prophylaxis in surgical patients. A number of different LMWHs have been approved and are available in the Indian market today.

Combined Prophylactic Modalities

There is data comparing combinations of prophylactic agents or methods used alone. The Cochrane Database of Systematic Reviews, 2009 shows that combining the two methods was more effective than a single preventative measure. Compared to compression alone, compression plus anticoagulant clearly decreased the incidence of both symptomatic pulmonary embolism (from 2.7 per cent to 1.1 per cent) and DVT (from 4 per cent to 1.6 per cent). Compared with anticoagulants alone, combined compression and medication clearly reduced the incidence of DVT (from 4.21 per cent to 0.65 per cent). The effect on pulmonary embolism was not evident in the review. Therefore, patients benefit from the use of stockings or compression in addition to a pharmacological agent. There is still some debate as to exactly when and for how long prophylaxis for DVT should be given. Even established agents, such as low-dose and adjusted-dose heparin, are used earlier and longer by some surgeons. In spite of this, there is no doubt that an accepted method of combination prophylaxis is essential in moderate and high risk group of patients in order to prevent venous thromboembolism.

Treatment of DVT

Effective treatment of DVT is aimed at preventing clot propagation and recurrence of thrombosis. Prevention of massive or recurrent episodes of PE is also of prime importance. Any evidence of thrombophilia or other risk factors should be addressed.

As alluded to earlier, even if there is a suspicion of DVT, an infusion of unfractionated heparin is started, unless contraindicated. Once the diagnosis is established, this is followed by oral administration of warfarin. Based on validated protocols, warfarin can be started at a dosage of 5 or 10 mg per day and its dosage adjusted until an adequate International Normalised Ratio (INR), usually 2.5 to 3.0 is reached. Heparin infusion is continued until this point. Alternatively, dose adjusted LMWH can be sub-cutaneously administered. LMWH is the agent of choice for treating deep venous thrombosis in pregnant women and patients with cancer.

The treatment of distal DVT is again controversial. Without anticoagulant therapy, patients with symptomatic distal DVT have about a 20 per cent chance of propagation into the proximal veins, which could cause life-threatening pulmonary embolism. Furthermore, anticoagulant therapy helps to alleviate leg pain and swelling that can be severe, even in patients with less extensive distal DVT. Treatment for PE is similar to DVT except that thrombolysis is sometimes used for a massive embolus. In recurrent PE, vena cava filters are inserted especially if patients embolise in spite of warfarin therapy.

The intensity and duration of warfarin therapy depends on the individual patient, but treatment of at least three months usually is required for post-op uncomplicated DVT. Warfarin is recommended for at least six months following PE. Some patients with thrombophilias require lifetime anticoagulation.

In Conclusion

Although we lack substantial evidence, there is no reason to believe that DVT is less of a problem in India and many physicians may be under the impression that this life-threatening illness is not a problem in their hospital or among their patients. While it is true that an individual doctor may see relatively few patients with this disease, DVT is most likely an important problem overall, especially in the surgical population. The reality is that most of these problems can be avoided by simple, cost-effective measures. Preventing this disease is cheaper than treating its consequences and more importantly one cannot put a price on the loss of life involved.

The approach to DVT prevention should be similar to preventing postoperative wound infections. As with antibiotic administration, it is essential to know who is at risk, when to apply the preventive measure, and applying the appropriate measure. While we await the results of the data currently being generated in our country every physician should be familiar with and initiate protocols for the prevention and treatment of this condition. Attempts must also be made to educate the general public so that patients, family doctors and specialists can work together in preventing potentially fatal yet preventable complications of venous thrombo-embolism.

raghu.varad@gmail.com