Thrombosis occurs when a clot inside a blood vessel restricts or blocks blood flow. It can lead to heart attacks or strokes. Major research by pharmaceutical companies has developed medicines to dissolve clots or to stop them forming. These have saved many lives.
Thrombosis occurs when a clot inside a blood vessel restricts or blocks the blood flow. Maintaining the liquid state of the blood depends on complex interactions between blood cells, the endothelial cells lining the blood vessels and substances in the blood itself. While they promote coagulation when required, they 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. When a blood vessel breaks, blood platelets become sticky and gather at the wound. A network of fibrin fibres forms which binds the clot together, and thus stops the bleeding.
In some disease states, this balance fails and clots develop inside arteries. This may result in a heart attack or stroke. If a clot forms in a vein deep within tissue, there is a risk that part of it may detach itself and travel to the heart, lungs or brain, where it can cause an obstruction (a thromboembolism), with serious consequences. Clot formation after major operations where collagen is involved, such as hip replacement or knee surgery (known as deep vein thrombosis, DVT), or through prolonged immobility, such as bed-rest while in intensive care or during long-distance air travel, can put life at risk.
A clot in a superficial vein might give rise to inflammation, known as phlebitis, but carries less risk of detachment and, with rest, normally settles down quickly. The likeliness of clot and plaque formation increases with risk factors such as smoking, high cholesterol, high blood pressure and diabetes.
About ten million people worldwide die every year from strokes and heart attacks making them one of the biggest killers on earth.
Research suggests that one in 12 white EU citizens carries a gene mutation that makes inherited thrombosis more likely - a significant target for prophylaxis if effective medicines can be developed. In patients undergoing surgical knee replacement without medical prophylaxis, DVT events have been found in up to 85 per cent of all cases.
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 circulatory problem. The second is the removal or reduction of clots once they have formed. These situations present different challenges and require different medicines (for details see Table).
Thrombosis prevention involves the use of either anti-platelet agents, or anti-coagulants that inhibit components of the cascade 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. Other compounds with a different molecular structure but similar action are also used for this purpose, possibly in combination with aspirin.
A more recently introduced oral anti-platelet medicine blocks the ADP-receptor on platelets and keeps them from clumping together. The molecule has shown a protective effect beyond that provided by aspirin and other medicines such as ACE inhibitors and cholesterol-lowering statins and, like these, is indicated for long-term protection.
Also effective in the long-term prevention of recurrent venous thromboembolism are derivatives of coumarin that work as vitamin K antagonists and prevent the production of clotting factors in the liver. A low dose regimen of such medicines has been shown to give a major reduction in the risk of DVT recurrence. Variants in the gene encoding vitamin K epoxide reductase complex 1 affect the response of individuals to coumarin compounds and may explain differences in dose requirements among patients.
Heparin and low-molecular weight (LMW) heparin derivatives are the main agents used for short-term prevention of blood clotting in the hours immediately following a myocardial infarction or stroke and during operations such as angioplasty. Inhibitors of the glycoprotein 2b/3a receptor that is involved in platelet aggregation are also used for this purpose, and these include a cyclic heptapeptide, a tyrosine derivative and a monoclonal antibody. These medicines are normally given under specialist care by intravenous injection, in addition to aspirin and heparin or LMW heparin derivatives.
The new category of thrombin inhibitors is used for the prevention and treatment of DVT and for post-infarction prevention. The therapeutic principle for this approach has been available since 2008. The advantage of this new class of medicines is their fixed oral dose.
For the prevention of DVT in adult patients undergoing hip or knee replacement surgery, a newly developed inhibitor of activated blood clotting factor X (F Xa) has been authorised since 2008. Inhibition of F Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and the development of thrombi.
The treatment of clots that have already formed is mainly carried out with so-called ‘clot-busting’ medications such as the enzyme streptokinase, or the more specific recombinant forms of the naturally-occurring tissue plasminogen activator (TPA). These medicines transform the naturally-occurring molecule plasminogen in the blood into plasmin, an enzyme which splits fibrin tangles and dissolves existing clots.
If they are to be of benefit, plasminogen activators must all be given intravenously under expert supervision and within three to six hours of suspected infarction. LMW heparins are also indicated for the treatment of clots in pulmonary embolism and deep vein thrombosis. They are given by subcutaneous injection and careful monitoring is required to avoid overdosing.
The new medicines in development are mainly anti-coagulants. One group is directed at inhibiting F Xa and another at inhibiting thrombin. An orally administered agent at Phase 3 is a capsule formulation of heparin. For the long-term treatment of DVT, long acting compounds are being developed that only need to be injected once a week.
Other approaches are an antagonist of ADP-binding to platelets. At the early clinical stage, researchers are investigating a compound that inhibits plasminogen activator inhibitor (PAI-1), and another group is to start clinical trials in acute myocardial infarction with a dual thrombolytic and anti-thrombotic agent.
For the thrombolytic treatment of acute myocardial infarction, a pegylated recombinant staphylokinase variant is in Phase 2 clinical trials. This may also be of use in other situations such as pulmonary embolism. Another new approach under review examines microplasmin, a LMW form of natural plasminogen. This compound is being studied for the treatment of ischaemic stroke, peripheral arterial occlusive disease and bleeding into the vitreous of the eye.
Whenever a thrombosis occurs, doctors still have to walk the tightrope of anticoagulant dosing until an antithrombotic therapy has been found that specifically targets life-threatening thrombi. Progress is being made, although it tends to be on a step by step basis.
Biotechnology enables the design of new medicines that are very precisely targeted at specific steps in the formation or breaking down of blood clots. Hopefully, this will result in significantly improved clinical outcomes for the various life-threatening manifestations of thrombosis.