Gene Variants Boost Blood Clot Risk

There is a difference between arterial and venous blood clots. Blood clots in the arteries form when plaque in calcified vessels bursts and the body perceives it as an injury. This activates the platelets, which clump together and form a clot. In the worst case, it can lead to a stroke or heart attack. A venous thrombus, on the other hand, usually forms in the leg when the blood stagnates for too long. This can activate the body's coagulation system, allowing the clotting system to be activated and the blood to clot, blocking blood flow. If the clot breaks loose and travels with the blood to the lungs, it can lead to pulmonary embolism, a life-threatening condition.

Venous thrombosis is in fact one of the most common causes of death in the world. It is a common disease that has always been somewhat overshadowed by arterial blood clot.

"Venous thrombosis is in fact one of the most common causes of death in the world. It is a common disease that has always been somewhat overshadowed by arterial blood clots," says Bengt Zöller, a specialist in general medicine at Skåne University Hospital and professor of general medicine at Lund University.

In Sweden, more than 10,000 people suffer from venous thromboembolism each year and that number appears to be increasing. Several factors are contributing to this increase. One of the strongest risk factors is age, and as the number of older people in Sweden grows, the number of clots is also increasing. Ten per cent of 80-year-olds experience a blood clot at some point. The risk also increases if you are overweight or tall.

"The muscles control the blood flow in the veins and the legs become like columns of fluid where the force of gravity is strong. Too much sedentary and inactive behaviour, then, is harmful. Only the valves of the veins prevent backflow and if these are damaged, the risk of blood clots can increase. Therefore, tall people are more prone to blood clots, as their larger veins provide less blood flow, combined with the fact that blood must travel a greater distance back to the heart."

Because the heart pumps blood out into the arteries, there is much higher blood pressure in the arteries than in the veins, which can contribute to atherosclerosis. High blood pressure, high levels of blood lipids and smoking are all risk factors for atherosclerosis of the arteries. But because the veins are a low-pressure system, the vessels do not become atherosclerotic. Therefore, neither high blood pressure nor blood lipids are associated with venous clots and smoking is considered only a weak to moderate risk factor. Being overweight, on the other hand, is a very significant culprit. Obesity has a negative impact on venous circulation, especially when combined with the fact that overweight people are often less active. Some clotting factors are also affected by obesity.

"In terms of diet, there are fewer studies, but ultra-processed foods have been associated with a slightly increased risk of blood clots, and plant-based, healthy foods with a reduced risk. In our studies, we have also seen that commercial fishermen have a lower risk, which may be due to a higher omega-3 content in their diet."

There are also specific situations in which the risk of venous blood clots is particularly high. The risk of blood clots increases when blood flow is reduced, such as when travelling by air for long periods of time or when lying in bed for several days. Surgery or inflammation that damages the vessel wall can also lead to an increased tendency to clot. Particularly during pregnancy, blood clotting factors increase and levels of some protective proteins may decrease.

"In these risk situations, prophylaxis in the form of blood thinners may be particularly important if other risk factors are also present."

Other risk factors are the genetic variants that affect different parts of the blood's clotting ability. In Sweden, we have a high prevalence of APC (activated protein C) resistance due to an inherited mutation in the gene for coagulation factor V, called Factor V Leiden. About 10 per cent of Swedes have this mutation, which is considered the most common coagulation mutation among Indo-Europeans.

"Evolutionarily, bleeding less has been an advantage, but in our modern, sedentary society, APC resistance is becoming a risk factor."

Bengt Zöller and his fellow researchers have now identified the strongest genetic risk factor since Factor V Leiden was discovered. They used data from the population-based Malmö Kost Cancer study, involving 30,000 Malmö residents. By selecting 27 genes previously associated with clotting disorders, they found three variants that, when taken together, were as significant a risk factor for venous blood clots as Factor V Leiden: ABO, F8, and VWF each increased the risk of venous blood clots by 10 to 30 percent.

"And the more of these variants a person has - the higher the risk. An individual with five of these gene variants has a 180 per cent higher risk of venous thrombosis. Unlike Factor V Leiden, which is only found in Indo-Europeans, these three different mutations are found in between five and fifty per cent of various populations around the globe."

As these genetic variants are present in all populations, the next step is to investigate how the number of risk genes affects the duration of treatment with anticoagulants after a blood clot.

"I think tailoring treatment based on risk assessment will become increasingly important," concludes Bengt Zöller.