Clotting versus bleeding – it’s all in the genes

If a person with a predisposition to clotting sits in a cramped seat of the economy section of a plane for a long-haul flight, then arrives at their destination with a very swollen leg, it is highly likely they have developed a deep vein thrombosis. This condition has been coined “the economy syndrome”. A number of people who have succumbed to this condition have tried to sue the airline when, in reality, they should be suing their relatives for giving them one of the relatively common genes that predisposes to clotting. 

These genes occur in around 1% of the population. Any precipitating factor such as prolonged immobilisation, as seen with lengthy travel, recovery from an operation or purely one of the new plagues of the 21st-century i.e. prolonged sitting from sedentary jobs (now known as e-thrombosis) or taking medications that may thicken the blood, such as the oral contraceptive pill or hormone replacement therapy, may precipitate an episode of thrombosis.

If you have a strong family history of clotting, such as recurrent DVTs, pulmonary embolus (clots travelling into the lungs) or even premature heart disease in people without major risk factors such as high cholesterol and hypertension, it is certainly worth having extensive blood testing looking for one of these common clotting abnormalities. The most common types are Factor 5 Leiden and anti-cardiolipin antibodies. Regardless of the specific diagnosis, we now have extremely effective treatments to prevent further clotting and the potentially lethal complications.

For situations where stronger blood thinning is necessary, the old workhorse, warfarin has been around for many decades. It is a highly effective blood thinning agent but it is very difficult to take, requiring regular blood tests and both the doctor and the affected person being very careful in terms of the prescription and ingestion of a variety of medications, food and alcohol.

Over the last decade, there have been a handful of highly effective medications known as direct oral anticoagulant drugs which are more effective than warfarin, appear to be much safer and don’t require regular blood tests nor do they require the same rigidity with diet, alcohol and the prescription of a variety of drugs. But, the stronger the blood thinner, the stronger the risk of bleeding.

Interestingly, at the other end of the spectrum, there are a small amount of people in society who have genetic bleeding disorders such as those with haemophilia or the less well-known condition, Von Willebrand’s disease. Again, if you have a strong family history or personal history of easy bleeding or bruising, it is worth being investigated for these bleeding disorders.

Researchers from Switzerland have investigated the clotting system targeting one of the components known as factor 12. It has been known for a number of years that humans who naturally lack factor 12 are at less risk of clotting but do not bleed more than those with normal factor 12 levels. This has also been confirmed in a number of laboratory animals. The Swiss researchers have found that an inhibitor of factor 12 appears to work very effectively at blocking the clotting process without increased bleeding. Mice, rabbits and pigs have been studied demonstrating this drug has been shown to be effective with no signs of toxicity.

Using an artificial lung model for people with severe lung disease who are very prone to clotting, this new inhibitor was found to be five times more effective than a standard blood thinner known as heparin.

The one problem with the inhibitor is that it was eliminated very quickly and required a constant infusion for effectiveness. Researchers are working on a long acting oral version which is certainly not available even for experimental animals at this stage. But, this does give great hope for the future to find an effective factor 12 inhibitor which will stop clotting without increasing bleeding risk.

Over the years there have been some suggestions that once we reach age 50, we should take a daily aspirin as a preventative against heart attack and stroke. There are even some suggestions that there is a reduction in a variety of common cancers. Should we be taking a daily aspirin? Three major studies released in 2018 suggested people should not take aspirin purely as a prevention against cardiovascular disease. The cardiovascular preventative aspects were outweighed by the increased bleeding risk and other problems such as reflux oesophagitis. There have been some suggestions that low dose aspirin may also reduce the risk of developing a variety of cancers, especially colorectal cancer. A recent report in the Journal of the National Cancer Institute looked at further data from the ASPREE trial following just over 9100 people living in Australia and the United States who were free of cardiovascular disease, dementia or any other significant disability at the start of the study. Most people in the study where over the age of 70 with a handful of people over the age of 65. They were given 100 mg of aspirin daily or a placebo. The follow-up was for just under five years and there were slightly increased death rates, mainly due to cancer in the aspirin group. 981 participants taking aspirin compared with 952 who were taking placebo developed a cancer. This was not statistically significant. But, there was around a 20% higher risk of metastatic cancer or a diagnosis of more advanced cancers in the people taking the aspirin compared with those given a placebo.

It is important to understand that the risk from aspirin in this specific situation is still quite low and it is more likely that the cancers were already present but undiagnosed in the people in this study and potentially the aspirin may have accelerated the spread of these existing cancers.

Other studies of younger populations than seen in this group did not show any increased cancer risk. It also suggested that to gain any benefit from the reduction in colo-rectal cancer in younger people, a person had to take aspirin for at least 10 years. Thus, it does appear that the deleterious effects of aspirin are age related and we should not be suggesting that anyone over age 65 takes aspirin as a preventative. It is, however, very important to realise that aspirin has been proven to be effective in those people with existing cardiovascular disease such as a prior history of heart attack, stent or coronary artery bypass grafting or in those people who have significant elevations in coronary artery calcium which predisposes them to significant risk for further vascular events.

For the vast majority of the population, we have a delicate balance between clotting and bleeding but for those outliers who are at either an increased risk of clotting or, at the opposite end of the spectrum, increased risk for bleeding, is important that they have a careful assessment with their doctor and their long-term risks are managed appropriately.