Blood Clots, Birth Control and Female Athletes: Are We Missing Important Risk Factors?

Over the last several years, stories of young women, many of them athletes (here, here), suffering from dangerous and sometimes deadly blood clots have filled the press and academic literature (here, here, here). Often mentioned in passing is the fact that these women were taking hormonal contraceptives at the time of the event. As a mom of a female athlete, a lifelong jock myself, and a researcher, I cannot help but wonder if we aren’t missing critical connections between some very common real life variables that predispose young women to serious health risks. Are athletic women more at risk for hormonal birth control-induced blood clots than other women? I think they might be.

We all know, or at least should know, that hormonal contraceptives increase the risk of blood clots for any woman who uses them. We often don’t pay attention to those warnings, especially when we are young, consider ourselves healthy, and when we are athletes. We ignore the warnings because taking birth control is, in many cases, a practical decision. Hormonal contraceptives, whether in the pill, patch, implant, vaginal ring, shot, or IUD, regulate if and when we bleed. That is, we bleed on a schedule, controlled entirely by synthetic hormones.

Scheduling is wonderful for female athletes. With no control over the scheduling of competitions, the ability to schedule one’s period is a great advantage. Let’s face it, competing while bleeding and cramping is never fun and near impossible for women with painful periods. Who wants to spend years training for that one event, only to have her period start? No one.

Optimal athletic performance requires that we control extraneous variables to the extent possible. Controlling one’s period takes care of a major variable in the life of the female athlete. And since it prevents pregnancy, hormonal birth control is a win-win.

Or is it?

Aside from the fact that hormonal contraceptives impact athletic performance (a topic of great debate and conflicting research), induce a variety of unwanted side effects, and that pill bleeds are not periods, hormonal contraceptives increase the risk of blood clots, quite significantly. Conservatively, birthcontrolsafety.org, estimates that out of the nearly 11 million women who use hormonal contraceptives (pill, patch, or ring), approximately 20,000 will develop blood clots and about 600 women will die, every year. There are no data on how many of these women were athletes or exercised intensely; however, it is likely that the numbers are pretty high given the high rate of hormonal contraceptive use in the general population.

Intense exercise, which is the foundation of athletic training, increases the risk of blood clots independently of gender or birth control usage. Indeed, some research suggests that the risk for deep vein thrombosis, blood clots in the legs, may be significantly higher for athletes than the general population. An interaction between hormonal contraception and exercise is likely to increase the odds of blood clots rather significantly. As women, the combination of those two variables alone should give us pause, but when we consider all of the other real world variables that also increase blood clotting and that just so happen to be prevalent in the life of the female athlete, the risk becomes quite concerning.

When Clots are Formed: Virchow’s Triad for the Athlete

When we look at the mechanisms involved in clotting and bleeding, we should remember that blood clotting itself is a necessary and protective mechanism against injury. Without the ability to clot, all sorts of complications can arise from everyday activities. Equally important are the body’s compensatory mechanisms that are designed to prevent too much clotting and to clear out clots once the immediate danger has ceased. The balance of power between the factors that promote clotting and those promote bleeding must be maintained within a fairly narrow window. Disruption to either side creates problems. Hormonal contraceptives shift that balance towards clotting and the normal components of athletic training and competition, shift the balance even further. When we add a few more variables, in any combination, synergies develop and the cumulative effects make female athletes using hormonal contraceptive at risk for serious, and sometimes deadly, blood clots.

Blood Clots and Athletes: The Basics

Blood clot formation is more likely when there are disruptions in blood flow. This can happen with:

1. Injury to the blood vessel wall (even microinjury induced by a medication or chemical exposure)
2. Depression of blood flow dynamics
3. Changes to blood constituents (clotting factors)

These factors constitute what is called Virchow’s Triad, after the German pathologist Rudolph Virchow who developed a framework in 1884.

Off the bat, by using Virchow’s triad, we can identify several potential risks for clotting that are likely more prevalent for athletes, male and female. For example, periods of intense exertion increase blood pressure, heart rate and the shear stress on the vascular walls (inducing damage and inflammation), which increases clotting propensity for athletes; while conversely, the athlete’s slower resting heart rate and lower blood pressure when not in competition, makes clearing those clots efficiently much more difficult. Similarly, periods of dehydration increase blood viscosity, slowing blood flow, as does inflammation and muscular hypertrophy via venous or arterial compression. Injuries and surgeries damage the vascular and arterial plumbing and slow blood flow. Extended travel compresses leg vasculature (and sometimes arm vasculature depending one’s sleeping position) and slows blood flow. Heck, even repeated movements can compress veins or arteries in different regions of the body and slow blood flow. What is athletic training if not repetition, hours upon hours of repetition?

Now consider these variables occurring against the backdrop of hormonal birth control, which changes the very balance of power between clotting and bleeding, effectively overriding many of the systems in place to ensure that clots don’t persist and causes problems. Throw in a few other decidedly female variables that also increase clotting, like monthly NSAID use to stave off menstrual pain, a propensity towards headaches and migraines, a latent genetic disorder or two, maybe even a less than optimal diet, and we have a recipe for disaster.

A Deeper Dive: Common Clotting Triggers for Athletes

Injury to the blood vessel wall

Injury to the blood vessel wall can develop by a number of mechanisms. The most obvious are those that result from direct injuries that occur over the course of training or competition. Surgery falls into this category. The rate of blood clots that evolve into pulmonary emboli after shoulder surgery ranges from 0.17% – 5.1% depending upon the type of surgery. Deep vein thrombosis after knee surgery, however, complicates some 2-13% of cases and upwards of 60% with some procedures. We cannot forget, also, that women are apt to have surgeries related to reproductive health issues, e.g. those related to endometriosis or ovarian cysts.

Less obvious are the micro-injuries or insults to vascular endothelial cells. Micro-injuries are surprisingly easy to induce over the course of athletic training and even in everyday living. They are not commonly recognized as risk factors for blood clots and there are few data that address these types of injuries; perhaps because their effects are likely part of a more complicated set of variables that combine to initiate and/or prolong the clotting, and are not immediately identifiable. I would argue that we ought to consider these risk factors especially in female athletes who use hormonal contraceptives because they are likely quite common. Here are just a few.

Contrast Dyes used for Imaging

Before any injury is surgically managed, imaging studies are common. The contrast dyes used for these studies induces micro-injuries to vasculature where the dye is circulated and are known to induce clots.

Vaccines and Medications

A number of medications and vaccines induce varying degrees of vasculitis or vascular microinjury. The most recent evidence of this is the HPV vaccine. For female athletes, something as simple as this or other vaccines, could initiate a clotting cascade that becomes difficult to end when hormonal contraceptives are involved. Similarly, the most commonly prescribed class of antibiotics, the fluoroquinolones (Cipro, Levaquin, Avelox and others), induce vascular microinjury among other side effects (tendon rupture, rhabdomyolosis, and neuropathy to name but a few).

Nutrient Deficiencies

Nutrient deficiency can induce vascular injuries via mitochondrial cascades. This one is a little bit more complicated and often a longer term process but one that adds to the overall propensity to clot. Briefly, mitochondria are responsible for and/or involved with a long list of functions ranging from bioenergetics (ATP production), to inflammation, steroid synthesis and cellular apoptosis, even platelet aggregation (an important variable in clot formation and dissipation). Mitochondria need several core nutrients to power enzymatic reactions. Most folks, even athletes, are deficient in several of these nutrients, especially if on hormonal contraceptives. Hormonal contraceptives deplete vitamins B1 [thiamine], B2 [riboflavin], B6, B9, B12 (worse if one is a vegetarian/vegan), C, E, magnesium (many athletes are magnesium deficient regardless of contraceptive usage), zinc, and CoEnzyme Q10. Simultaneously hormonal birth control may elevate vitamin K concentrations (which increases clotting), and also, increase copper and iron (too much iron favors hypercoagulation). Nutrient deficiencies and abnormalities cause mitochondrial dysfunction (and a whole host of other problems). Mitochondrial dysfunction leads to cell dysfunction, leading to molecular changes in the vasculature (and elsewhere), injuries, and a propensity for clotting ensues. Mitochondrial damage would also lead to changes in blood flow dynamics and blood constituents. So mitochondrial damage, though more subtle, can affect the entire triad of variables.

Blood Flow Dynamics – The Plumbing

Compression

Like the pipes in our houses, anything that blocks or compresses or otherwise slows the fluid through the pipes can induce a clog or, in this case, a clot. The most obvious of these factors is compression, as occurs on long plane/train/bus trips to and from competitions. According to AirHealth.org:

About 85% of air travel thrombosis victims are athletic, usually endurance-type athletes like marathoners. People with slower resting blood flow are at greater risk of stasis, stagnant blood subject to clotting. Also, they are more likely to have bruises and sore muscles that can trigger clotting. No other risk factor comes close to this. Age over 60 is supposed to be a risk factor, but these victims are younger, 82% of them under 60 [47% of air travel thrombosis cases are between the ages of 20-44].

According to some reports, the increased risk for clotting continues for up to 24 hours post competition, making the long trip home after an event particularly risky.

These are staggering numbers which are likely under-reported and under-studied. Imagine the risk for compression induced clotting to the female athlete who uses hormonal contraceptives. If she’s had an injury that required imaging with a contrast dye, or experienced any of the aforementioned other vascular insults, the risk increases.

May-Thurner Syndrome. Twenty percent of the population is believed to have a narrower than normal left iliac vein leading to blood clots in the pelvic region and left leg. Most do not know this until they end up in the hospital with a blood clot. For these women, the risk for deep vein thrombosis, particularly in the left leg is even higher, especially on birth control (most especially, I believe, though this is pure speculation, when using a cervical ring like the NuvaRing). Again, add long sit times, an injury perhaps, and we can begin to see how the risk for blood clots in the female athlete using hormonal contraception can be much higher than for her teammates who do not use hormonal contraceptives.

Paget-Schroetter Syndrome, an anatomical narrowing of the subclavian vein (just under the clavicle or collarbone) and repetitive use trauma either alone or together can initiate clotting from this region. Sports with high upper-body repetition such as swimming, gymnastics, rowing, tennis, baseball/softball, and others, are at most risk.

It is believed that the repetitive trauma that these sports require imposes strain on the subclavian vein leading to microtrauma of the endothelium and activation of the coagulation cascade. This alone is a risk factor for developing a blood clot, but when we add a few more variables, an intense competition, dehydration, a long flight home with upper body immobility and perhaps compression (sleeping on one’s arm), and enter these variables into an system primed for coagulation by hormonal birth control, the risk for dangerous blood clots increases significantly.

Viscosity

Sludgy matter doesn’t move through pipes too well. All manner of variables can affect the viscosity of blood. The most common in athletes is dehydration.

Dehydration

Dehydration is common in athletes, especially after a long competition. Dehydration increases the viscosity of the blood, slows the movement through the pipes. Put a dehydrated female athlete, who uses hormonal birth control on a long bus trip home, and clot risk increases. Add some past vascular damage, even minute and unrecognized, plus an injury or two, and the risk increases even more.

Blood Constituents – Changes at the Molecular Level

We can change the intrinsic clotting factors by a number of mechanisms: genetic, epigenetic and via medications (like birth control, NSAIDs and others) or environmental chemicals. There are over 20 proteins involved in maintaining the balance between clotting and bleeding and each of them can be altered towards a pro-clotting state by a myriad of variables (for a full list see here).

Genetics

Beginning with the genetic variables, 3-10 % of the population have heritable genetic mutations that increase their risk of developing blood clots quite significantly, absent other variables. Upwards of 50% of patients who have develop a clot carry one or more of these mutations. Unless there is a known family history of clotting disorders, most women who carry these mutations are unaware of their genetic risks. When these women utilize hormonal contraceptives, their risk of blood clots increases significantly by as much as 35x according to some data. I think all women should be tested for these genetic variables before being given hormonal birth control. Unfortunately, none are, until they end up in the hospital fighting for their lives. Now consider a female athlete who carries one of the mutations and is on hormonal birth control, travels, uses NSAIDs, has had an injury or two, and the likelihood of her developing deadly blood clots is very much increased.

With both genetic and acquired components, antiphospholipid syndrome (APS or APLS), also increases blood clot propensity. In fact, it is the most common cause of excessive clotting, and affects women more than men. APS is autoimmune condition that causes hypercoagulability of blood through unknown mechanisms. APS can occur on its own, or in conjunction with lupus and other rheumatic disease processes like Sjogren’s. Neither of these diseases is uncommon in female athletes, though hard data are difficult to come by. Anecdotally, Venus Williams has struggled with Sjogren’s and case reports abound of female athletes with Lupus (here, here).

Epigenetics

Epigenetics is a fancy term for events that happen above the genetic level. It is an emerging science where investigators look at variables that don’t directly alter the DNA, but rather, aberrantly turn on or off a particular gene. Environmental factors play a large role in epigenetics, medications, vaccines, other chemicals, diet and nutrition. So, just as a woman can carry heritable genetic mutations, she can also carry heritable epigenetic changes that turn on the genes controlling the clotting proteins or turn off those that prevent clotting. We can inherit these epigenetic changes from parents and even grandparents, but also, induce them via every day exposures and activities. I suspect that there are epigenetic components of one’s risk for blood clots.

Medication Induced Clotting

Here’s the big one that we don’t pay nearly enough attention to – medications and vaccines can induce clotting via multiple mechanisms, including changing the balance of power between clotting and bleeding. Briefly, and most importantly to female athletes are hormonal birth control and NSAIDs (ibuprofen and the like). The chemistry is a bit complex, but let us take a stab at it, because when these variables are combined with the normal activity of a female athlete, I believe her risk for blood clots shifts from the ‘if’ category to the ‘when’ category. For more information on the clotting cascade, here is a simple Khan Academy video.

Hormonal birth control increases all of our coagulation factors, but most especially, clotting factors VII and X, where plasma concentrations have been measured at 170% of normal. Fibrinogen (responsible for initiating the fibers that form the clot) is increased by 20%. Hormonal contraceptives also stimulate platelet aggregation (the initial plug that covers the injury), while simultaneously decreasing an anti-clotting factor called antithrombin III. Sit with that for a moment. This is the biochemical foundation that the female athlete is working with. Without doing anything else, her body is primed to clot.

Pro-clotting factors are increased to almost 3X their normal levels, while anti-clotting factors are diminished.

With this biochemistry, a body can only forestall excess clotting for so long. In fact, early reports suggest that clotting risk increases with time used. That is, clotting factors increase over the months and years one uses these medications. This may be why some of the most deadly clots, the pulmonary emboli and cerebral venous thrombi develop in women who have used contraceptives for years.

I have to add one more poorly understood hit to the coagulation system. NSAIDs alter platelet aggregation in some pretty complex ways and the mechanisms by which NSAIDs induce bleeding or clotting are just beginning to be understood. It is well known that NSAIDs like aspirin and ibuprofen can induce excessive bleeding. Gastric bleeds are one of the most common side effects of ibuprofen use. NSAIDs also carry with them increased risk of venous thromboembolism. Excessive bleeding but also excessive clotting–how is that possible? Certainly, it depends upon the formulation and which pathways the drug targets (Cox 2 inhibitors), but the emerging theory is that platelet aggregation may increase over time and become difficult to dissipate, because these medications block the enzyme responsible for keeping injured vessels free of clots while the damage is being repaired.

Another mechanism by which NSAIDs influence coagulation is via heart rhythm irregularities, like atrial fibrillation (at least for older populations, no data are available for younger athletes). With atrial fibrillation, we have a good chance of blood pooling which can result in clot formation. Finally, there is some evidence that NSAIDs increase vasoconstriction, which would impact blood flow. NSAID use is very common in the life of the female athlete and non-athlete alike with regular use both monthly, to stave off menstrual pain, and over the course of training to manage pain and injuries. It is possible that NSAID use may not only impact the post-injury healing process, but also, increase an athlete’s chances of developing a blood clot.

Now What?

Birth control is a personal choice. If pregnancy prevention is the only reason for using these hormonal contraceptives, there are non-hormonal options, including the old stand-bye, the condom, and newer devices for tracking. If scheduling is the primary consideration, I would consider whether or not the opportunity to schedule overrides the risks associated with using these products. Blood clots are a very real danger for athletic women without the additional risks that come with hormonal birth control. Are those risks worth taking?

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This article was published originally February 23, 2016.