The prevention and cure of deep vein thrombosis

Deep vein thromboses in the legs can be the result of injury or surgery, and if they break off and move to the lungs to form pulmonary embolisms, the results can be fatal. A number of drugs are available and in development for the treatment and prevention of the condition

Deep vein thrombosis has hit the headlines recently, with a number of widely-reported cases of otherwise healthy passengers collapsing shortly after long-haul flights. The pulmonary embolisms responsible are caused by blood clots elsewhere in the body, often the leg, breaking off, and working their way through the circulation until they reach the lungs. The resulting pulmonary embolisms are life-threatening and, in the case of aeroplane passengers, this invariably happens without warning.

However, far from being a condition limited to a few long-distance travellers, deep vein thrombosis (DVT) is much more widespread. It is a very real potential complication in surgical procedures, notably knee and hip replacement operations. It can be caused by an injury to the vein, after surgery or radiation therapy. Poor circulation can be a factor, particularly when allied to lack of activity or prolonged bed-rest. Pregnancy also gives an increased risk, as the blood has an increased tendency to clot to prevent excessive bleeding in childbirth.

Symptoms include redness and tenderness in the affected area of the body, pain and swelling in the vicinity, fever, increased heart rate, sore or painful joints, and a sudden, unexplained cough.

blocked blood flow

The condition involves the formation of a blood clot, or thrombus, within a deep vein, frequently in the calf or thigh, which may partially or even completely block the flow of blood in the vein. The coagulation cascade is triggered off by the birnding of serine protease Factor VIIa, in the blood, to tissue factor, a receptor found on the surface of blood vessels after inflammation or damage. This catalyses the formation of the serine protease Factor Xa, which leads to the final protease involved in the cascade, thrombin.

This protease is responsible for the production of the protein fibrin from fibrinogen, which creates the structure that holds the clot together. It also causes platelet aggregation.

An important treatment for the prevention of clots is exercise, but a number of drug treatments are also available and in development that thin the blood and prevent clots.

Heparin is a sulphated polysaccharide that occurs naturally within the body. Treatment with standard heparin is given initially with a loading dose, followed by continuous infusion. Low molecular weight heparins (LMWH) are far more straightforward to administer than standard heparins, as they can be given twice daily by standard subcutaneous injection. As long as the dose is adjusted for weight, there should be no need for monitoring. Large-scale trials have shown little difference in results between standard heparin and LMWHs, and once-daily dosing should be possible to treat DVT in the leg.

The most common indication for heparin therapy is in the prevention of clots following surgery, and the treatment of DVT. In the US, it is estimated that over 3 million surgical procedures are performed each year where the patient is at risk of clotting, and over 250,000 cases of DVT are reported.

The current preventative therapy recommended in the US is 10–14 days of heparin treatment post-surgery, and recent literature suggests that 4–5 weeks is the optimum. The recommended treatment for DVT is 1–2 weeks of injectable heparin, followed by 90–180 days of the orally-available anticoagulant warfarin.

Pharmacia's LMWH dalteparin sodium (Fragmin) has recently been given US FDA approval in a once-daily formulation for the prevention of post-operative clots. Trial results showed that initiating treatment post-operatively was as effective in preventing as starting before the operation, with the advantage of less bleeding occurring during the operation itself. The usual duration of treatment is 5–10 days, and it is licensed for use for up to 14 days.

orally-available formulation

An orally-available formulation of heparin would make administration of the drug much easier. US-based company Emisphere is working on just such a formulation, in which the heparin is administered in conjunction with a delivery agent that promotes its absorption in the gut. A Phase II study on DVT prophylaxis in patients undergoing total hip replacement was completed in late 1998, and the liquid oral formulations were shown to have comparable activity and safety to injectable heparin. A Phase III trial was begun in December 1999.

A solid dosage form of heparin began Phase I trials in March 2000, and a version of LMWH is also in development.

Coumarins are the most widespread anticoagulants in common use, and the most frequently prescribed of these is warfarin sodium, marketed in the US by DuPont as Coumadin, and in the UK as Marevan by Goldshield. It is a synthetic compound which acts as a vitamin K inhibitor, which thus indirectly inhibits the formation of plasma clotting factors VII, IX and X, plus prothrombin, also known as factor II. However, there are substantial difficulties with prescribing as it is extremely dose-sensitive.

treatment in combination

Warfarin is much more difficult to administer than heparins, despite being orally available. Treatment is usually started in combination with either heparin or LMWH, but the dosage for warfarin is so variable from person to person that it is largely a case of trial and error in conjunction with dose–response algorithms.

AstraZeneca is working on an oral direct thrombin inhibitor. Its lead compound, coded H376/95, is currently undergoing Phase III trials. The company has listed the product profile of the 'ideal' oral anticoagulant as follows:

Of these, it says warfarin only meets the first criterion, but its H376/95 matches up with all nine points, and its goal is not only to replace warfarin in its approved indications, but also to expand the use of anticoagulation.

oral anticoagulation therapy

AZ claims the compound is the first significant advance in oral anticoagulation therapy in 50 years, and is initially being targeted at the long-term treatment of DVT, plus the prevention of strokes in patients with atrial fibrillation.

It is also investigating its use in the prevention of venous thromboembolism after orthopaedic surgery. The recently-competed Methro III trial confirmed both its efficacy and safety, but the statistical endpoint of superior efficacy was not met. This has delayed the filing for the initial indication of prophylaxis of DVT in total knee and hip replacement surgery until at least the second half of 2002 while the company carries out further Phase III studies. AZ is also working on two further antithrombotic agents: a factor Xa inhibitor and novel P2T agonists, both of which have yielded positive preclinical data.

Several plant-derived prophylactic therapies are available, notably low doses of aspirin. The drug has the advantage of having a rapid onset, but potential side-effects include allergic reactions, and gastric ulceration in the longer term.

Another plant-derived product that may have value in the prevention of DVT is Ginkgo biloba. The plant has been used in traditional Chinese medicine for the treatment of poor blood circulation, varicose veins and thrombosis, and is claimed to strengthen blood vessels and improve blood flow.

Lab studies have shown ginkgo extracts improve blood flow and inhibit platelet activation, and few side-effects have been reported.

biotechnology targets

Thrombosis is also proving a popular target for biotechnology companies. For example, Corvas has discovered a family of proteins in the hookworm, a parasite that has evolved efficient anticoagulation mechanisms for feeding on blood. These NAP proteins act as small protein inhibitors of Factor Xa and Factor VIIa/tissue factor.

A recombinant version of NAPc2, which is a Factor VIIa/tissue factor inhibitor, has completed two Phase I trials, and the method for administration is similar to that for LMWH. Late 1998 saw the company begin an international multicentre open-label dose-ranging Phase II study of rNAPc2 for the prevention of DVT in knee replacement.

3-Dimensional Pharmaceuticals, based in Exton, PA, US, is working on an orally-active direct thrombin inhibitor programme, which has recently become the subject of an agreement with Centocor. The programme's lead anticoagulant, 3DP-4815 is currently in Phase I development. It stops clotting by inhibiting the enzyme thrombin, hence stopping the conversion of fibrinogen to fibrin and the creation of clots.

The compound is a result of 3DP's DirectedDiversity combinatorial chemistry technique, and the company says it has a number of follow-up compounds also in development.