THROMBOSIS

What is thrombosis?

A thrombosis is a clot inside a blood vessel which restricts or blocks blood flow. Maintaining the liquid state of the blood depends on complex interactions between blood cells, the cells lining the blood vessels and substances in the blood itself. These promote coagulation when required, but prevent it at other times. For example, injury, exposure to air and to collagen fibres at the site of damage initiates the clotting process. Collagen is a fibrous protein and a major component of cartilage, bone and connective tissue. Blood platelets become sticky and aggregate and a network of fibrin fibres forms which binds the clot together (Figure 1), stopping bleeding.

In some disease states, this balance fails and clots develop inside arteries. This may result in a heart attack or stroke (see Ischaemic Heart Disease and Stroke). If a clot forms in a vein (venous thromboembolism, VTE) deep in the tissues, the obstruction to blood flow can cause painful ischaemia and may have serious long-term consequences. There is also a risk that part of it may detach and travel to the heart, brain, or lungs, where it can cause a heart attack, stroke or pulmonary embolism. Clot formation in a major vein (deep vein thrombosis, DVT) after operations such as hip or knee surgery, or through prolonged immobility, such as during long-distance air travel, can put life at risk. A clot in a superficial vein causes inflammation, known as phlebitis, but carries less risk of detachment and, with rest, normally settles down quickly. Clot and plaque formation (see Atherosclerosis) are both made more likely by risk factors such as smoking, high cholesterol, high blood pressure and diabetes (see Hypertension and Diabetes).

Who does thrombosis affect?

It has been estimated that venous thromboembolism causes around 32,000 deaths each year in the UK. Pulmonary embolism following deep vein thrombosis is the immediate cause of death in 10 per cent of all patients who die in hospital. The total cost of managing venous thromboembolism in the UK was estimated in 2005 at approximately £640 million.

Present treatments and shortcomings

From a medical point of view, there are two separate, though overlapping, issues. The first is the prevention of blood clots. This may be a temporary requirement after an operation or accident, or it may be part of long-term management after a first heart attack or other problems with the circulation. The second is the removal or reduction of clots once they have formed. These situations present different challenges and require different medicines (Figure 2).

Thrombosis prevention involves the use of either anti-platelet agents, or anti-coagulants that inhibit components of the process that produces the fibrin tangles in clots. The best-known anti-platelet medicine is aspirin, which decreases platelet stickiness and markedly reduces the risk of a heart attack or stroke in those who have already had one, or who have unstable angina (see Ischaemic Heart Disease). Dipyridamole (Persantin, Boehringer Ingelheim) is also used for this purpose, alone or in combination with aspirin. A more recently introduced oral anti-platelet medicine is clopidogrel (Plavix, sanofi-aventis/BMS), which prevents clumping of blood cells.

Heparin and heparin derivatives such as dalteparin (Fragmin, Pfizer), enoxaparin (Clexane, sanofi-aventis), tinzaparin (Innohep, Leo) and bemiparin (Zibor, Amdipharm) are the main medicines used for short-term prevention of blood clotting in the hours immediately following a heart attack or stroke, and during operations such as angioplasty. Also used in acute heart problems are Integrilin (GlaxoSmithKline), Aggrastat (Merck Sharp & Dohme) and the monoclonal antibody abciximab (ReoPro, Lilly). They are normally given under specialist care by injection, in addition to aspirin and heparin. Also used for prevention of venous thromboembolism during surgery, as well as for treatment of deep vein thrombosis and pulmonary embolism, is fondaparinux (Arixtra, GlaxoSmithKline).

The treatment of clots that have already formed is mainly with so-called clot-busting medications such as Streptase from ZLB Behring, or alteplase (Actilyse, Boehringer Ingelheim), tenecteplase (Metalyse, Boehringer Ingelheim) and reteplase (Rapilysin, Roche). These medicines must all be given by injection under expert supervision and within three to six hours of suspected heart attack if they are to be of benefit. Fondaparinux or heparins such as enoxaparin and dalteparin are also indicated for the treatment of clots in pulmonary embolism and deep vein thrombosis. Bleeding and depressed platelet counts are side-effects associated with heparins and careful monitoring may be required to avoid overdosing.

What's in the development pipeline?

A considerable number of new compounds are in development for the prevention of venous thromboembolism Many of these are inhibitors of activated Factor X. At Phase 3, Bayer has oral rivaroxaban (BAY 59-7939) in trial for prevention of VTE after surgery. Another orally administered agent at Phase 3 is the capsule formulation of heparin being developed by Emisphere Technologies. Sanofi-aventis is also studying enoxaparin for use in VTE prevention in interventions such as angioplasty.

There are further agents for VTE prevention in Phase 2 trials. Astellas has YM-150 under study for post-surgery prevention and Lilly is developing LY517717 for the same purpose. Schering-Plough's SCH 530348 and sanofi-aventis's SR 123781 and AVE 5026 are also in Phase 2 study for VTE prevention.

At Phase 1, new compounds include Inspire Pharma's anti-platelet agent INS50589, EMD 503982 (Merck Pharmaceuticals) and AVE 3247 (sanofi-aventis) and TGN 167 and TGN 255, being developed by Trigen Holdings.

The other main category of new agents under development for VTE prevention are thrombin inhibitors. The furthest advanced is dabigatran (Rendix, Boehringer Ingelheim), which is in Phase 3 study. Other thrombin inhibitors at Phase 2 are AZD 0837 (AstraZeneca), MCC-977 (Mitsubishi Pharma) and PD-348292 (Pfizer).

New compounds are also under development for VTE treatment. These include both Factor Xa inhibitors and thrombolytic enzymes. Amongst the first group, sanofi-aventis is developing idraparinux for the long-term treatment of deep vein thrombosis (Phase 3). This long-acting compound only needs to be injected once a week, unlike most other medicines in this class. Meanwhile, Bristol- Myers Squibb has two direct Factor Xa inhibitors in Phase 2 trial: BMS-562247 (apixaban) and DPC-906 (razaxaban).

New thrombolytics are also under development. Menarini has amediplase in Phase 3 trial for thrombolysis in acute MI, and this may also have uses in other situations such as pulmonary embolism.

A number of other quite different approaches to thrombosis management are also being explored. For example, AstraZeneca's AZD 6140 is in Phase 3 trial in acute coronary syndrome, while Eisai is studying E-5555 in Phase 2 trial for the same condition and Daiichi-Sankyo has DZ-697b in Phase 1 trial. Thus, it is clear that there is still major research and development effort going into developing better thrombosis treatments.

Figure 2: Once the immediate post-stroke period is passed, physiotherapy is of vital importance for regaining function as far as possible.

FOR FURTHER INFORMATION CONTACT:

Lifeblood - The Thrombosis Charity
PO Box 1050, Spalding, Lincs PE12 6YF.
Phone: 01406 381017
Website: www.thrombosis-charity.org.uk

Anticoagulation Europe (UK)
PO Box 405, Bromley, Kent BR2 9WP.
Phone: 020 8289 6875
Website: www.anticoagulationeurope.org 127 Thrombosis