Tuesday, December 11, 2018

Xarelto & Menstruation (or What I Learned as a Premenopausal Woman Having Periods on Blood Thinners)

This is an uncharacteristically personal blog post, but my hope is that the next active, menstruating person who is put on blood thinners and searches the internet for "blood thinners and periods" finds the info I wish I had in the beginning.

I'm also a science teacher (not a medical doctor), and I do get a little over-enthusiastic describing the physiology involved in these topics.

If you are a current or former student, or just squeamish about medical stuff: be forewarned, I'll be discussing my periods and a lot of bleeding, so if that creeps you out, don't read it. :)

And, finally, if you don't feel like reading the whole post, just know that Heavy Menstrual Bleeding (HMB) affects ∼90% of women with an underlying bleeding disorder and ∼70% of women on anticoagulation (source). So, if you are still menstruating and are put on blood thinners (especially NOACs such as Xarelto which carry a high risk of HMB), do yourself a favor--keep a menstruation journal and check in with a gynecologist ASAP. From what I've experienced and read, your cardiologist is not going to ask you about your periods--so you will want to bring it up.

If you are interested in the scientific details, I recommend the journal article How I treat heavy menstrual bleeding associated with anticoagulants (Blood, 2017).

I also recommend this blog by another younger woman on blood thinners: Blood Thinners and Periods – What Your Doctor Failed to Tell You. She shares, "Out of the 7 doctors I’ve interacted with, only 1 mentioned menstruating on blood thinners being possibly different than without." My experience was similar, but with fewer doctors.

Here is an outline of this post:
  • PART 0: Varicose Veins and Blood Clots 
  • PART 1: Learning About Blood Thinners
  • PART 2: What I Wished I Knew From the Start
  • PART 3: Learning About Menstruation (on Blood Thinners)
      • How heavy is too heavy?
      • Where is this blood coming from?
      • Why (menstrual) clots?
      • What are my options?
  • PART 4: Solutions and Take-Aways (spoiler alert: it involves an IUD)
      • SOLUTION 1: Reclaiming my periods (mostly)
      • SOLUTION 2: Reclaiming my independence

PART 0: Varicose Veins and Blood Clots


I have a history of superficial venous thromboses (SVT). As their name suggests, these blood clots are superficial, located just below the skin’s surface and, unlike deep vein thromboses (DVT), are not life-threatening. Superficial vein thrombophlebitis (swelling associated with clots) is generally caused by an injury to the vein and appears in veins where blood flows slower than normal, such as varicose veins (this decreased blood flow is also called venous insufficiency). However, it is worth noting that most people with varicose veins do not develop thromboses (clots).
Even a slight injury can cause a varicose vein to become inflamed. Unlike deep vein thrombosis, which causes very little inflammation, superficial venous thrombosis involves a sudden (acute) inflammatory reaction that causes the blood cot (thrombus) to adhere firmly to the vein wall and lessens the likelihood that it will break loose. Unlike deep veins, superficial veins have no surrounding muscles to squeeze and dislodge a blood clot. For these reasons, superficial venous thrombosis rarely causes a blood clot to break loose (embolism). (source: Merck)
So, though they are painful and annoying, my superficial clots are not going to kill me. As stated above, they are not likely to contribute to a pulmonary embolism (PE), a life-threatening condition where a blood clot in the leg breaks loose and travels through the bloodstream to the lung. People show have a unprovoked DVT/PE can be put on blood thinners for life. I was only on blood thinners for three months.

Venous Ablation
I've had a lot of superficial clots, beginning in my late 20s. I had a venous ablation in my right leg 10+ years ago and wear 20-30 mmHg medical compression stockings on both legs most days--especially on airplanes, long car rides, or days where I do a lot of sitting (such as parent-teacher conferences). If you are interested, you can read more about radiofrequency ablation therapy for varicose veins here -- they basically use radio waves to heat up, destroy, and collapse your great saphenous vein (I recommend that link--it includes a very cool body map).

In August 2018, I felt a familiar pain and an ultrasound confirmed I had three new clots. This time, with my history of SVT, my vein doctor wanted me to go on blood thinners and follow through with the (previously optional) left leg ablation. So, that's how I ended up on Xarelto (generic name: rivaroxaban).


PART 1: Learning About Blood Thinners

 

I knew nothing about blood thinners except that "old people" took them. According to WebMD, "about 2 million to 3 million people take blood thinners every year."  According to doctors and pharmacists I talked to, the majority of these people are older adults--mostly men, and women who have gone through menopause. I imagine this is why heavy menstrual bleeding (HMB) seems to rarely be discussed at appointments or in the literature.

Blood thinners (or anticoagulants), despite their name, do not actually thin the blood; nor do they dissolve existing clots. They do interfere with blood clotting in general, they can help prevent new clots from forming, and they keep existing clots from becoming larger. This gives your body time to remove the clot on its own by activating a protein (plasmin) which breaks down the fibrin mesh (on the outside, we recognize fibrin in a scab). Anticoagulants are different than the so-called "clot-busting" drugs (thrombolytics) that are used in the case of heart attack, stroke, or massive pulmonary embolism--those drugs activate plasmin to actually break up the clot ASAP.

Here's a (rather complex) overview of how clotting works:
The coagulation cascade is triggered by tissue factor release from tissue trauma or vascular injury. Tissue factor in the presence of calcium forms a complex and cleaves clotting factors X and IX to their activated forms (factors Xa and IXa). The prothrombinase complex is then assembled and cleaves prothrombin (factor II) to factor IIa (thrombin). Thrombin is one of the most potent activators of primary (platelet-mediated) and secondary (clotting factor-mediated) hemostasis (stopping of blood loss, or clotting). (source)
Thrombin facilitates the conversion of a soluble plasma protein called fibrinogen into long, insoluble fibers or threads of the protein, fibrin. Fibrin threads form "an interlocking network of fibers and a framework for the clot. This net of fibers traps and helps hold platelets, blood cells, and other molecules tight to the site of injury, functioning as the initial clot." (source)
Xarelto is a direct factor Xa inhibitor.

I learned that blood thinners (anticoagulants in particular) generally include three types:

(1) vitamin K antagonists - these are perhaps the most well-known and work by reducing your body’s ability to make vitamin K. Without vitamin K, your liver has trouble making blood-clotting proteins. It is also necessary to have to have your liver monitored while taking these, and you have to be careful about what you eat--particularly around foods high in vitamin K.
  • Warfarin (Coumadin)

(2) Heparins - it is my understanding that this is administered through IV or injections at home. Heparins keep one of the clotting proteins, thrombin, from doing its job.
  • fondaparinux (Arixtra) , inhibits factor Xa
  • unfractionated heparin (UFH)
  • low-molecular weight heparins (LMWH) 

(3) non-VKA oral anticoagulants (NOACs) - These are newer, easier to take (pill form), and require no dietary restrictions or extra monitoring. (Us "younger" folks are most often put on NPACs now.) Plus, when you stop Xarelto, it is out of your system within 24 hours. NOACs keep your body from making fibrin, the protein the forms the clot’s mesh.
  • dabigatran (Pradaxa®)
  • rivaroxaban (Xarelto®)
  • apixaban (Eliquis®)
  • edoxaban (Lixiana [Europe/Asia], Savaysa [Nth Am]).

Some of these blood thinners, mostly older anticoagulants, have antidotes for when a person on anticoagulation has major bleeding, or when there is a need for urgent surgery (source). Most internet searches on Xarelto highlight that, for at least a long while, Xarelto did not have an antidote. This terrified me. (I was afraid to fall in a bike accident and bleed to death (irrational, but true). I didn't know what would happen if I was in a car accident.) Ends up Andexanet alfa was approved as antidote for Factor Xa inhibitors Xarelto and Eliquis in May 2018, under the trade name AndexXa. PHEW. 

Finally, you cannot take Ibuprofen, Naxopren (Aleve), or any other nonsteroidal anti-inflammatory drugs (NSAIDs) while taking blood thinners, as these medicines also thin your blood.

When you go on blood thinners, doctors seem to suggest getting (1) an electric razor and (2) a soft toothbrush, to minimize bleeding. I certainly wish my doctor had also added (3) an appointment with your gynecologist. One recent article clearly states, "Premenopausal women should be advised of the potential effect of anticoagulant therapy on menstrual bleeding at the time of treatment initiation." But that didn't happen in my case and I certainly did not expect what happened next.


PART 2: What I Wished I Knew From the Start


I never talked to my doctor in person initially about blood thinners. He prescribed them over the phone and scheduled a follow-up appointment in 3 weeks. Those three weeks were full of a lot of (scary) bleeding and anxiety. We'll get to the heavy periods later, but it ends up the symptoms of anemia - tiredness, dizziness, light-headedness, fatigue, shortness of breath, irregular or fluttering heartbeat - seem pretty similar to the symptoms of anxiety. So, it was hard for me to tell if I was losing too much blood, or just freaking out about it.

At the 3-week visit, the doctor stressed to me that Xarelto (or any blood thinners) do not make you any more likely to start bleeding. Rather, once I started bleeding, it would be harder to stop. (Apparently, older men often complain of blood in their urine when starting blood thinners, but that is most often due to a pre-existing, yet undiagnosed, condition.) I don't randomly start bleeding, I seldom fall off my bike--why would this be any different on Xarelto? (The light-headedness from blood loss/anxiety was one reason I did stay off the bike for a while.)

The doctor also confirmed that Xarelto did have an antidote (PHEW) and that he has only had to use it once in his career thus far. Xarelto is out of your system quickly (within 24 hours) making it different than the older blood thinners. (In fact, the doctor had me take my last Xarelto the day of my venous ablation, a minor surgery. Weird.)

Finally, and most relief-worthy, the doctor shared that Xarelto had a lower risk of cerebral (brain) bleeds than older blood thinners (like warfarin), though a slightly higher risk for gastrointestinal bleeding; BUT nothing I did from the neck down would be life-threatening. He said, "If you fall off your bike and skin up your legs, it's going to bleed for a while and look really scary, but it is not ultimately going to be a problem." He stressed that only if I hit my head, or fell super-awkwardly on a joint, should I take myself to the ER.

I'm not going to lie to you, when I got my first good cut on Xarelto (skinned my heel), I was a wreck, not knowing what to expect (spoiler: it bled a lot). However, what I learned next about periods made my superficial concerns laughable....

Finally, I also wish I knew what was "normal" and what was "too much" for a menstrual period. I don't typically talk to other women about how much they bleed. In hindsight, I've always had relatively heavy periods lasting 5-8 days. But when I found myself unable to change a tampon without blood running down my hands and dripping on to the floor on day 4 of my first Xarelto period, I figured I had a problem. The days following confirmed that this. was. not. normal.

I've since learned that "A normal menstrual cycle is defined in terms of frequency of 24 to 38 days (the regularity of which can vary between ± 2 and 20 days) with a duration of flow between 4.5 and 8 days and a volume of monthly blood loss between 5 and 80 mL per cycle."

Heavy menstrual bleeding (HMB) happens when you have:

  • Bleeding that lasts more than 7 days.
  • Bleeding that soaks through one or more tampons or pads every hour for several hours in a row.
  • Needing to wear more than one pad at a time to control menstrual flow.
  • Needing to change pads or tampons during the night.
  • Menstrual flow with blood clots that are as big as a quarter or larger.

Yep, I had all of that.


PART 3: Learning About Menstruation (on Blood Thinners)


Those first weeks, when I was worried about superficial cuts or unlikely head trauma, I severely underestimated how this all worked with menstruation (most people on blood thinners, as mentioned, are men or post-menopausal women). I realized later, despite being a science teacher, that I did not even really understand how periods worked. It was wild, kinda scary, and I learned a lot.

How heavy is too heavy?

On the aforementioned Day 4 of my first Xarelto period, I was scared. I made the mistake of Googling "Xarelto and periods." Don't do that--it's terrifying. I kept my Googling to more scientific search terms and learned a lot from this article Heavy menstrual bleeding: work-up and management.

The CDC page states, "Menorrhagia [now called HMB] is menstrual bleeding that lasts more than 7 days. It can also be bleeding that is very heavy. How do you know if you have heavy bleeding? If you need to change your tampon or pad after less than 2 hours or you pass clots the size of a quarter or larger, that is heavy bleeding. If you have this type of bleeding, you should see a doctor."

Let's talk about clots for a minute. Normal menstrual clots are smaller than a quarter and only occur occasionally, usually toward the beginning of your menstrual cycle. Abnormal clots are larger than a quarter and occur frequently. (source) By day 5, I was passing some gnarly clots (I'll spare you the details). By then, I was also keeping a menstruation journal and documenting EVERYTHING (times, size and number of pads/tampons, percent filled upon removal, frequency and estimated diameter of clots. I calculated approximate volume blood loss using the measurements below--I was WAY over 80 ml for that first (and second) cycle.

Regular absorbency tampons: 6 to 9 grams
Super absorbency tampons: 9 to 12 grams
Super plus absorbency tampons: 12 to 15 grams
Ultra absorbency tampons: 15 to 18 grams

By the second week, I had made an appointment with a gynecologist. My vein doctor (a cardiologist) had been rather dismissive about the bleeding, asking (not unkindly) if I could just "tough it out." My primary doctor backed off all together, saying that it was not her area of expertise and that I should find a gynecologist who takes my insurance. I just wanted to bleeding to stop.

That first period was 10 days long, with three of those days (thankfully two on the weekend) involving setting a timer for every 1.5 hours (including throughout the night) to swap Super+ tampons before they'd leak onto the backup pad. Most of the time, I made it in time. Work (teaching middle school) was a challenge--it was hard to raise my voice without feeling light-headed, I occasionally I had to leave the room to lay down when I felt like I was going to faint, and I had to very strategically plan my bathroom access. And remember, you can't take Ibuprofen or Aleve ... Tylenol is better than nothing, but it just wasn't the same.

Where is this blood coming from? (or the shedding of uterine lining):

I did not know where all the blood was coming from. I asked my gynecologist that first visit, bewilderedly, "Is it coming from my veins?!" Her answer was "sort of." It was actually coming from my arteries.

Most of us learned that menstruation typically occurs in a 28-day cycle. Something like: "During the follicular phase (days 1 to 14) estrogen levels rise, the uterine lining (endometrium) thickens. During the luteal phase (days 14 to 21), the corpus luteum (CL) produces estrogen and progesterone. If fertilization does not occur, at the end of this 28 day cycle, the lining sheds." You've probably even seen a diagram like the one below:


Boy, did I not understand what was happening during that whole "shedding of the lining" part. Ends up, there are a lot of blood vessels involved, and those blood vessels need to clot in order to stop the cycle's bleeding.

I learned that the endometrium consists of two layers, the top being called the "functionalis layer." These layers are supplied by arteries.


image source (obgynkey.com)

As the menstrual cycle progresses, these arteries grow at a faster rate than the endometrial layer, resulting in coiling of the arteries. Near the end of the menstrual cycle (day 27), the coiled arteries get so coil-y that they constrict, and cut off blood flow (vasoconstriction) to that layer of the endometrium (endometrial hypoxia) and that layer dies. We experience the subsequent breakdown and and expelling of tissue as our period. Menstrual bleeding is generally arterial rather than venous bleeding. This source gets into waaaay more detail about all this, if you are interested in reading more.

I also had a scare when I remembered an embryology video I show in my science class... as the yolk broke from the follicle, a blood vessel burst (this is why you sometimes get those red dots on your egg yolks). I emailed my gynecologist and asked, "is there bleeding during ovulation?"  She said, "The risk of bleeding into the corpus luteum is slightly elevated, but your body should still be able to naturally stop that bleeding. Most people on blood thinners do not have issues with bleeding into corpus lutea. However, if it happens, symptoms include: Abdominal bloating, abdominal pain, lightheadedness, palpitations."  Once again, symptoms of the new IUD? Or anxiety over the blood thinners? Ugh.

So, here I was worried about a superficial cut on my heel, when my uterus was basically free-bleeding and there was nothing I could do about it. In fact, rivaroxaban (Xarelto) has a high instance of uterine bleeding occurrence (the bleeding rate was estimated at 29.8 percent) (source)


Why (menstrual) clots?

I was curious about the clots. I didn't understand... if I was on blood thinners, wouldn't I have fewer menstrual clots, not more? Turns out that "as the uterine lining sheds, it pools in the bottom of the uterus, waiting for the cervix to contract and expel its contents. To aid in the breakdown of this thickened blood and tissue, the body releases anticoagulants to thin the material and allow it to pass more freely. However, when the blood flow outpaces the body’s ability to produce anticoagulants, menstrual clots are released." (source)

If the bleeding is heavy, clots have time to form in the "pool," but the anticoagulants do not have time to act — so the blood clots.

What are my options?

Recently, HMB-related therapies (especially in anticoagulated patients) include hormonal therapy, tranexamic acid, anticoagulant management, and surgical interventions.  (You can read more details here.)

Basically, a thinner uterus lining will mean less bleeding.

Source: Management of Heavy Menstrual Bleeding on Anticoagulation

Surgical interventions

When in doubt, take it out. "Hysterectomy is the definitive treatment of HMB." (source) Apparently, if you were on blood thinners for life, the go-to option has been a hysterectomy (removal of the uterus) or endometrial ablation (removal of the thin layer of tissue that lines the uterus), both of which prevent your from ever having children in the future.

Tranexamic acid (US Brand name: Lysteda)
Tranexamic acid (an antifibrinolytic agent) works by blocking the breakdown of blood clots, which prevents bleeding. Apparently, it is taken three times a day for the first few days of the period. (People with the bleeding disorder von Willebrand’s disease are familiar with this treatment.  Side note: this disease is also under-diagnosed in men, since they do not menstruate or give birth.)

Anticoagulant management
Sometimes, doctors will recommend reducing the dose or skipping a couple doses during the start of your period. (Don't do this without consulting your doctor, as it may increase the risk for dangerous clots.) Or consider decreasing the DOAC blood thinner dose all together after the initial three months of full-dose anticoagulation

Hormonal therapy
It has been common practice to avoid prescribing hormone therapy and anticoagulants at the same time, but it is not well-studied. Many studies are now saying hormone treatments (like the birth control pill) are fine when taking a therapeutic dose of blood thinners (prevents clots anyway?).


There are a number of options but "the levonorgestrel intrauterine system (LNG-IUS, Mirena) is the most effective medical intervention for HMB and is recommended ... as the first-line option for HMB in women who also require contraception." This device diminished menstrual bleeding in more than 80% of women, but with intermenstrual bleeding in almost half of the women.

The Mirena (brand name) works by continuous release of 20 μg levonorgestrel every 24 hours, and reduces endometrial (the lining of the uterus) growth. The most common side effect associated with LNG-IUS and reason for discontinuation of treatment is menstrual irregularity, usually prolonged bleeding/spotting in the first 3 months. This may persist for a longer period in women with HMB. (Cohen, 2016) Levonorgestrel may also prevent ovulation (release of an egg from the ovaries) in some women." (source)

It's worth noting that some IUDs, such as the non-hormonal coper IUD, can actually make your periods longer and heavier. So, Mirena is the way to go. (Here's a nice IUD pros and cons list.)


PART 4: Solutions and Take-Aways (spoiler alert: it involves an IUD)



SOLUTION 1: Reclaiming my periods (mostly)

I had never even considered an IUD. I vaguely have heard negative things about it, and I wasn't all that interested in having a device in my uterus. Plus, the pill just always seemed an easier way to control my periods and provide birth control. (My doctors still do not agree if the pill actually triggered these most recent clots, since the pill is more commonly associated with the risk of unprovoked, life-threatening clots.  My clots were provoked by, presumably, my misbehaving veins. To be safe, we decided I won't take estrogen-containing pills again.)

14 days into Xarelto, I didn't care. I just wanted the menstrual bleeding to stop.

Despite there being many progestin-only options (here's a nice overview), the IUD seems to be the crowd favorite. "An advantage of the levonorgestrel IUD is that there is very little systemic absorption of the progestin. Nonetheless, menstrual blood flow is reduced 71% to 95%. Reduced menstrual blood flow has been confirmed in women with bleeding disorders and in women on anticoagulation." (source)

I met my (brand-new, internet-searched) gynecologist on a Tuesday; my Mirena was placed on that Friday during my lunch hour -- I returned to school and finished teaching that day.

My second period (post-IUD) was also 10 days long, but with slightly fewer clots. The third period (after a full month with the IUD) was only 5 days, I was bleeding less, and felt much less light-headed! However, the intermenstrual bleeding (presumable from ovulation, or as a side effect of the IUD) was pretty constant, I basically had my period all but 14 days over a 3-month time frame. It got old, let me tell you.  But, it also was a tolerable "new normal."  I even got to joking about it.

If you decide to go the IUD route, I also recommend not Googling "IUD insertion" before you go -- some women, especially those who have never had children, describe it as the "worst pain in their life" (What Getting an IUD Really Feels Like, According to 13 Women) whereas the mommy-blogs rate the pain a 1-2 on a scale of 10. (Not sure if that's due to physical changes in the cervix, but I suspect that, once you have a child, your pain scale is significantly and permanently altered.)

The insertion wasn't pleasant, but it wasn't that bad (for me). Through the insertion process, only the last step was biting-sharp, but over quickly. I also couldn't take the recommended dose of 600 mg of ibuprofen before insertion, so that was a bummer. My doctor also took a vaginal ultrasound to rule out uterine perforation--this would be bad news on blood thinners! As mentioned, it was quick and I went back to work that day. I even helped a friend pack on Saturday. It is still not always 100% comfortable, but it is better than bleeding all the time.


SOLUTION 2: Reclaiming my independence

After almost two months of worrying, I told myself I couldn't live like this. I picked up some gauze pads and bandage rolls and threw them in my bike bag, in case of a spill.

I also ordered a medical ID bracelet (here is the one I chose) to wear when I was out alone. Again there is not that much out there for younger, active folks, but I figured it couldn't hurt in the case of an accident. I choose "blood thinner" on the outside, since "Xarelto" is probably not a recognizable name. I added a label to the inside with the dosage, in case I was ever in need of emergency responders.




Finally, I switched my dosing to nighttime. After the initial 2x dosing, I continued to take my once-a-day in the morning, since the meds had to be taken at the same time each day, and with food. For convenience, I was taking it in the morning and the doctor said that wouldn't be a problem. However, with the periods, I would have liked to have been told that "maximal anticoagulant potency might be better tolerated during night, when the risk to experience accidents or injuries" (or perhaps menstrual bleeding?) "is lower." (source)


CONCLUSION

My clots dissolved and I had the ablation done earlier this month--I could write a whole other post about dealing with health insurance. The bruising (internal bleeding) was extensive but I now have been off blood thinners for the last few weeks and the bruises have just about faded. (My ultrasound tech said, three days after the procedure, that "You are lucky, some folks on Xarelto look like they've been hit by a truck after ablation!")

I still have the Mirena IUD and it will be interesting to see how it manages my periods long-term. So, far I am enjoying my 10th day in a row without bleeding.

Looking back, once the periods were under control, I had less light-headedness and, presumably, less anxiety. In fact, by the 2 month mark, it just became a "new normal." I feel fortunate that my experience was short-term and I hope my research can help other menstruating people learn about heavy menstrual bleeding and anticoagulation (periods and blood thinners!).

If you've read this far, you might also be interested in this other blood-clot-related news, published about one week after I got off blood thinners: Doctors Aren’t Sure How This Even Came Out of a Patient: somehow, a man coughed up an intact blood clot shaped like a lung passage (Atlantic, Dec 6, 2018)

Bodies are fascinating.