Even More Reasons to Prevent Pregnancy Loss

Lipoprotein(a) or Lp(a) is a prothrombotic low density cholesterol that has been underappreciated by clinicians and therefore has not been given much attention until recently. Lp(a) is now known to be an independent risk factor for adverse cardiovascular diseases such as heart attack, stroke, pulmonary embolism and valvular disease. Researchers have demonstrated that Lp(a) has a two-fold mechanism in which it causes 1. atherosclerosis within the walls of blood vessels and 2. thrombosis or increased blood clots within the lumen of blood vessels through its similarities to a protein called plasminogen which inhibits fibrinolysis (the process of breaking down blood clots).

Pregnancy in itself is inherently a prothrombotic state. The combination of pregnancy with any of the “known” thrombophilias increases a women’s risk for adverse pregnancy outcomes. When we consider Lp(a) as a previously “unknown, unrevealed or even unimagined” thrombophilia, there may be evidence that an elevated Lp(a) level could further compound the development of poor pregnancy outcomes such as miscarriage and stillbirth. Lp(a) is not part of routine laboratory screening and therefore is not often readily identified. Lp(a) is now regarded as the silent threat that clinicians have been oblivious to for far too long. In my presentation, I will explore a clinical case history that details one woman’s experience with an elevated Lp(a) and recurrent pregnancy loss.

Dr. Yolanda Marie Archibald is a medical school graduate and aspiring Obstetrician/Gynecologist. She received her medical degree from the Universidad Autónoma de Guadalajara School of Medicine in Guadalajara, Mexico. She currently works closely with physicians at Adefris & Toppin Women’s Specialists M.D.P.C. in Woodbury, Minnesota under the mentorship of Dr. Barbara C. Toppin. She will be applying to medical residency this year and is eager to practice medicine in the field of women’s health care. She has developed a profound interest in identifying preventable factors that contribute to recurrent pregnancy loss and managing them to decrease the burden of loss on women who repeatedly experience adverse pregnancy outcomes.

Dr. Toppin has disclosed that she does not have any real or perceived conflicts of interest in making this presentation.

Sabrina Cali: Dr. Yolanda Archibald is a medical school graduate and aspiring obstetrician/gynecologist. She received her medical degree from the Universidad Autónoma de Guadalajara School of Medicine in Guadalajara, Mexico. She currently works closely with physicians at Adefris & Toppin Women’s Specialists. She will be applying to medical residency this year and is eager to practice medicine in the field of women’s health care. She has developed a profound interest in identifying preventable factors that contribute to recurrent pregnancy loss and managing them to decrease the burden of loss on women who repeatedly experience adverse pregnancy outcomes. Dr. Archibald’s presentation is titled, Lipoprotein the New Thrombophilia: Could it be an Unanticipated Relevant Risk for Recurrent Pregnancy Loss?

Dr. Yolanda Archibald: Hello, everyone. My name is Yolanda Archibald, and I’m a medical school graduate. I’m currently studying for my medical licensing exams and I’ll be applying to obstetrics and gynecology residency programs so that I can care for patients in the field of women’s health care. I currently work at Adefris & Toppin Women’s Specialists. We’re located in Woodbury, Minnesota. It’s a private practice OB/GYN group. I work there along with Dr. Barbara Toppin and her partners. Dr. Toppin is presenting today as well, so please stay tuned for her presentation. The clinical case that I will be discussing with you today is actually one of her patients that she sees in clinic. You will want to listen to her talk as well.

I’m very happy that I get the opportunity to be here with all of you today. Miscarriage and stillbirth are two very important topics in women’s health care, and I’m committed to contributing in any way possible to finding ways to lower that curve for women and families. I, myself, am the daughter of a mother who experienced four losses and I was old enough to remember at least two of those losses and remember being very excited about being a big sister and then all of a sudden there were no babies that came home.

I’m very optimistic and I truly believe that through awareness, research dollars, and plain old grassroots efforts to really get the word out to women and clinicians about these sort of emerging ideas and prevention, and that one day we could maybe even see a world where miscarriage and stillbirth are essentially a thing of the past.

Today I’d like to talk to you briefly about a protein that can be detected in the blood. It’s called lipoprotein (a), and we’ll see in just a little while that lipoprotein (a) is a form of bad cholesterol, and I’m going to present to you a clinical case that might suggest that lipoprotein (a) could be used essentially as a biomarker to identify women who might be at an increased risk of experiencing recurrent miscarriages and even stillbirths.

I’d like to start by discussing the clinical case and then expanding on some important concepts pertaining to lipoprotein (a) as we go along. Our patient is a 35-year-old healthy female who presented to clinic two weeks after experiencing her third miscarriage. She had no living children up to this point and she was searching for answers in determining the cause of her recurrent pregnancy loss.

After having had multiple miscarriages, her obstetrician gynecologist, or OB/GYN physician assessed her for the most common causes of recurrent pregnancy loss, and there were no chromosomal abnormalities with any of the three fetuses. Her thyroid hormone and other hormone levels were normal. She had no known blood clotting disorders– and we’ll come back to this in just a few minutes, because this really is the crux of our discussion on lipoprotein (a).

Our patient also had no structural disorders of the uterus or of the cervix. For all intents and purposes, up to that point, there was no explanation for her losses. Her OB/GYN diagnosed her with recurrent unexplained pregnancy loss. But she wasn’t willing to accept that answer. At that point she decided to change physicians and she found Dr. Toppin, and with our new OB/GYN, she underwent an extensive workup and she was found to have a significantly elevated lipoprotein (a) level. No other clinically significant abnormalities were found.

She was instructed by her physician to take two tablets of 81 milligram or low dose aspirin by mouth starting at day 14 or ovulation day of her next menstrual cycle. She became pregnant again, and this was the first of her four pregnancies that she carried to term and she delivered a healthy baby at the end of that pregnancy.

A few years later, she and her husband planned pregnancy again. She consulted with her OB/GYN and she resumed the low dose aspirin regimen that she had been prescribed previously. She became pregnant and she gave birth to another healthy baby at term, and this was her fifth pregnancy and second living child.

A few years after that, she became pregnant again. However, this was not a planned pregnancy and therefore she was not on the low dose aspirin regimen at the time. Sadly, she suffered a miscarriage with her sixth pregnancy, but that miscarriage prompted her and her husband to desire another child. She consulted with her OB/GYN and she went back on the low dose aspirin regimen and she achieved her seventh pregnancy. That pregnancy also resulted in her delivering a third healthy baby at term.

What we learn is that for this patient, when she was taking the low dose aspirin regimen that was prescribed to her by her physician, she was successful at carrying her babies to term and giving birth to live healthy babies. It was only while not on her aspirin regimen that she suffered those recurrent adverse pregnancy outcomes.

Let’s talk briefly about cholesterol. There are two main types of cholesterol in the human body. There’s high density lipoproteins known as the good cholesterol and there’s low density lipoproteins often referred to as the bad cholesterol. Cholesterol makes up the membrane of pretty much every cell in the human body. It’s like a wall or a barrier that keeps what’s supposed to be on the inside of our cells in, and what’s supposed to be on the outside of our cells out. Cholesterol does have a pretty important function in the human body.

Cholesterol is also used as a starting point for the production on the naturally occurring steroid hormones that we have in our body, as well as the production of sex hormones like testosterone in men and estrogen and women. These are the hormones that produce the characteristics that make men, men, and that make women, women.

Cholesterol also forms plaque within the walls of blood vessels, and this is what makes cholesterol not so good. Because these plaques, they build up over time and can cause blockages of blood vessels. When that happens, blood is unable to freely flow past the blockages to supply the tissue that those particular blood vessels were designed to supply. It’s this plaque buildup that causes conditions such as heart attacks, if we’re talking about the buildup of plaques within arteries in the heart. Or strokes, if we’re talking plaque buildup in the blood vessels in the brain. Or pulmonary embolisms, if we’re talking plaque buildup in the blood vessels of the lungs.

All physicians are aware of the dangers of cholesterol plaques on specific organ systems that we just talked about. Even the general public knows that increased cholesterol causes heart attacks and strokes. Just going back to the patient in our initial discussion. The second physician that she had seen was aware that having an elevated level of lipoprotein (a) put her patient at an increased risk for the development of blockages in blood vessels not only due to plaque buildup, but also buildup of blood clots, and that this could be playing a role in the development of her recurrent pregnancy loss.

Because of that, as part of her workup, she ordered the Cardio IQ Advanced Lipid Panel, which is a complete cholesterol test, sometimes called lipid panel or lipid profile. This is a blood test that can measure the amounts of cholesterol and triglycerides in your blood, but not only does it measure total cholesterol, HDL and LDL, but it also measures the modified proteins such as lipoprotein (a) in the blood.

When our patient’s lab work came back, we see that she has an elevated total cholesterol, low density cholesterol, LDL, which is the bad cholesterol. Then if we look at her lipoprotein (a) level, it’s really high. Significantly elevated at 194 nanomoles per liter, when normal should be less than 75.

What exactly is lipoprotein (a)? Lipoprotein (a), or the shortened version, Lp(a), is a modified version of low-density lipoprotein or LDL, which as we’ve said, is the bad cholesterol. It’s bad in that this form of cholesterol gets transported to places in the body where instead of being useful essentially it becomes harmful. Lipoprotein (a) is essentially, as we said, bad cholesterol with a component that is similar in structure to a plasma protein called plasminogen, and plasminogen is designed to dissolve blood clots when it’s in its active form.

For all the non-clinicians in the room, I know that this talk is a bit technical, but please stay with me because the structure of this protein is important for our discussion. We’ll talk a little bit more about plasminogen again in just a little while, but the fact that a portion of lipoprotein (a) is similar to plasminogen is actually the key to the mechanism by which lipoprotein (a) has the potential to contribute to blood clots and therefore recurrent miscarriages and stillbirths.

On a molecular level, lipoprotein (a) is important for wound healing, tissue repair, and vascular remodeling. As we’ve said, we know that it increases the risk of cardiovascular events. We see that it does this through oxidative modifications that it undergoes, which cause it to become pro-atherogenic, pro-inflammatory, and prothrombotic.

What does that mean? Well, when there’s damage to the wall of a blood vessel a cascade of events is initiated and lipoprotein (a) comes along to help heal and repair the damage along with some other proteins. Lipoprotein (a)’s pro-atherogenic effects are what causes atherosclerosis, which is simply a buildup of plaque within the wall of blood vessels such as arteries. We see in the image here on the left side of the slide an example of plaque building up on the wall of this blood vessel and it narrows off the flow of blood so that the red blood cells are forced to squeeze through that blockage.

As the plaque grows, it’s going to cause even further narrowing of that blood vessel. Its pro-inflammatory effects are what cause inflammatory cells to accumulate within the wall of blood vessels when this process is happening. Then it’s prothrombotic effects– and thrombotic is just another way of saying increased blood clotting, and that’s due to the inactive plasminogen component of lipoprotein (a).

Really, lipoprotein (a) has the potential to cause blockages in blood vessels by not one but two mechanisms. Its ability to cause atherosclerosis that blocks blood vessels as we’ve said, and then the inactive state of its plasminogen component that leads to the accumulation of blood clots that are made up of platelets and red blood cells that are then stabilized by another protein called fibrin. The platelets, red blood cells, and fibrin, those are components of the blood clotting system and they come to the site of an injury to stop bleeding that happens when a blood vessel gets injured.

This is called hemostasis. Just to reiterate, hemostasis is what happens when inside of our body, a blood vessel is injured and is actively bleeding, which can happen for a number of different reasons. The implantation of an embryo inside the uterine cavity is one reason that a blood vessel could bleed. There are many other reasons as well. The body basically heals itself and the injured blood vessel is quickly sealed over through the process of hemostasis which as we’ve already said involves platelets, red blood cells, and fibrin sealing off that injured portion of the blood vessel. Then blood clotting factors arriving at the area to strengthen that seal. Because of how quickly that happens, many times we’re never even aware that there was a blood vessel briefly bleeding within the body.

In image (a), we see a cartoon image of a blood vessel, and we see the damaged wall of the blood vessel at point 3 in the image. We see number one is platelets, two are red blood cells. In image (b), we see those components are bound together, forming a clot represented by the number four in the image. It’s wrapped tightly together with fibrin particles which are the yellow lines represented by the number five. This seals off that section of the damaged blood vessel and stops the bleeding.

Now, there’s always balance, and so just like everything else in the body, the process of blood clotting or hemostasis has an opposite. That opposite is mediated by the fibrinolytic pathway which basically serves to break down fibrin and blood clots which is what we’ve just described on this slide. However, if the fibrinolytic system is inactivated for whatever reason, the body will be unable to break down blood clots. This is where plasminogen comes into play.

We see in the diagram on the right side of the page at the bottom that plasminogen gets converted to plasmin, which breaks down the newly formed platelets, red blood cell, fibrin blood clot that we made on the previous slide. It breaks them down into fibrin breakdown products also called fibrin degradation products.

But if this plasminogen is never converted to plasmin, then plasminogen remains in its inactive state and it will not function to break down those blood clots. If a patient has an increased propensity to form blood clots, and they’re not being broken down, then those blood clots can become problematic. This can lead to miscarriage and stillbirth, what you’ll see on the next slide.

As we’ve said, the inactive plasminogen component is the exact mechanism that gives lipoprotein (a) the ability not to increase the production of blood clots, but if blood clots are present for some other reason like pregnancy, then those blood clots will not be broken down the way that they should. Again, this can lead to miscarriage and stillbirth.

Why is this important for pregnancy? Well, the title of this slide is Pregnancy: The Hypercoagulable State. Hypercoagulable just means increased ability to coagulate or clot in reference to blood clots. It’s just another term used to mean the same thing. There are many different physiologic changes that occur in a woman’s body during pregnancy.

During pregnancy, the liver will upregulate the production of proteins, and this is done to support the mother and baby. The increased production of blood clotting factors is thought to be a mechanism that the body developed to prevent hemorrhage at the time of delivery. We know that delivery is a time when there is some blood loss but this mechanism prevents any major blood loss.

With the increase in blood clotting factors onboard, occasionally women will develop blood clots during pregnancy, which is not good. Therefore, we know that pregnancy itself is hypercoagulable or prothrombotic state, and thrombotic just means the same thing. Thrombo is another word for clot, and these words are used interchangeably clinically, and in the literature, to simply mean an increased tendency to develop blood clots.

Most commonly, clinicians see blood clots develop in the deep veins of the lower extremities which are the legs. When this happens, it’s called deep vein thrombosis, and it can be dangerous, especially, if blood clots that originally develop in the deep veins of the legs, if they break away and travel to the lungs where they can cause a pulmonary embolism. Pulmonary embolism is basically a blood clot or clots lodged in a vein or in multiple veins of the lungs.

There are some genetic conditions that are inherited. In other words, passed down in families. You may see them in multiple generations of the same family and they’re known to cause increased production of blood clots in patients, and collectively these disorders are referred to as thrombophilias. Some of the relatively common thrombophilias in populations around the world in both men and women are antithrombin deficiency, Factor V Leiden mutation, protein C or S deficiency, prothrombin mutation, and antiphospholipid antibody syndrome.

Now, what happens when you have a woman with one of these inherited thrombophilias who gets pregnant? Well, if you add pregnancy on top of one of the thrombophilias, things can get a bit tricky because a woman with a known thrombophilia who becomes pregnant has an even greater risk of developing blood clots due to her double or dual hypercoagulable state, if you will. That’s because as we just described, pregnancy itself is a hypercoagulable state, and now we’re adding a hypercoagulable condition on top of that. We know that because it’s well-documented that the more high risk thrombophilias can cause a miscarriage and stillbirth in pregnant women.

Now that we covered the most common inherited thrombophilias and we discussed how they affect pregnancy outcomes, let’s bring lipoprotein (a) back into the discussion. First, notice that it was not on the list of the common thrombophilias and that’s because the data is really lacking in terms of lipoprotein (a) and how its thrombotic potential contributes to anything other than cardiovascular disease.

The verdict is in. Lipoprotein (a) is prothrombotic and there are many recent articles confirming lipoprotein (a) and how it contributes to cardiovascular disease. There was also even a study that looked at lipoprotein (a) as a risk factor for the development of venous thrombosis and pulmonary embolism in patients younger than 50 years old. And so there is research on lipoprotein (a) and its ability to play a role in blood clotting in patients.

However, there’s not been much research in terms of the effects that lipoprotein (a) have on pregnancy outcomes since about 2012. There was a literature review that was conducted in 2012 to assess the status of lipoprotein (a) in pregnancy at that time. There were multiple studies in that review and they looked at the time period from 2003 up to 2012. Those studies indicated that lipoprotein (a) may play a role in the pathologic processes in pregnancy and in pregnancy outcomes such as the recurrent unexplained miscarriage and intrauterine growth restriction, which can lead to stillbirth.

The article concluded by suggesting that further research was needed to investigate the association between lipoprotein (a) and adverse pregnancy outcomes, and I must say that I agree. Especially in light of the clinical case that I presented at the start of this presentation, the patient in our clinical case had an elevated level of lipoprotein (a) and she experienced a total of four miscarriages when she was not being treated with the low dose aspirin anticoagulation treatment regimen. Yet, when she was on that regimen, she had successful pregnancy outcomes.

There was a case-control study that was done in 2005, and the authors found higher levels of lipoprotein (a) in subjects with recurrent pregnancy loss. In that study, the authors postulated that it could be due to the association of lipoprotein (a) with a hypofibrinolytic state promoting thrombosis and therefore miscarriage. This is exactly what we talked about a few sides ago. It’s the mechanism by which the inactive plasminogen component of lipoprotein (a) prevents the breakdown of blood clots which essentially can lead to miscarriage and stillbirth.

How do we manage pregnant patients who have thrombophilia disorders? Well, the decision to provide thromboprophylaxis, which is providing treatment to prevent the development of thrombo or blood clots is called. The decision to provide that treatment to pregnant patients usually depends upon a couple of things.

The presence of a thrombophilia that’s considered high risk for the development of a venous thromboembolism and a patient’s personal and or family history of a previous venous thromboembolism. If a clinician does make the decision to provide treatment to a patient, based on American College of Obstetricians and Gynecologists guidelines, the treatment usually entails a low dose aspirin, low molecular weight heparin or a combination of the two drugs.

The patient in our clinical case review was treated with two 81 milligram low aspirin from the time of ovulation or day 14 of her menstrual cycle. I wanted to cover the anticoagulation or anti-clotting or some refer to it as blood thinning mechanism of action of aspirin. Aspirin irreversibly inhibits an enzyme called cyclooxygenase.

By inhibiting that enzyme, it effectively decreases the synthesis of a molecule called thromboxane A2. Thromboxane A2 is made by platelets, and it’s important for the aggregation of platelets during hemostasis. When platelets are coming together and binding with other platelets and with red blood cells and then fibrin to form that blood clot in order to stop the bleeding of the damaged blood vessel. We’ve seen this earlier in our discussion. Aspirin essentially blocks the process of platelets coming together to participate in the formation of a blood clot, and that’s a very important step.

I know that aspirin which is sold over the counter seems harmless and you may even know someone who’s taking it prophylactically to prevent heart attacks and strokes. However, there are side effects, as well as people who may have an allergy to aspirin or who may be taking other medications, which interacts negatively when combined with aspirin. I just wanted to add this disclaimer that it’s very important to consult with your physician before taking any medications, including over the counter medications such as low dose aspirin.

I wanted to share this clinical case with you today to bring awareness to lipoprotein (a) in terms of adverse pregnancy outcomes, and to shed light on the need for further advancements in research to determine the precise connection between an elevated lipoprotein (a) level and recurrent pregnancy loss.

In conclusion, there is evidence that an elevated level of the prothrombotic lipoprotein (a) may be a risk factor for recurrent pregnancy loss and intrauterine growth restriction, which can lead to stillbirth. With more research and a better understanding of the connection between lipoprotein (a) and adverse pregnancy outcomes, in the future, we may be able to use lipoprotein (a) levels as a biomarker to identify patients who are at an increased risk for adverse pregnancy outcomes, such as miscarriage and stillbirth. It has been well-documented that a history of recurrent miscarriage is associated with future cardiovascular disease in women. My hypothesis is that this association may actually be the link between an elevated lipoprotein (a) level and recurrent pregnancy loss.

With that, I just want to say thank you all for your time, and for listening to my talk. I want to say thanks to Star Legacy for giving me the opportunity to speak with you all today. With that, we arrive at the end of the talk.

This presentation was part of the Stillbirth Summit 2021.   This individual lecture will be awarded .75 hours of continuing education credit to include viewing the lecture and completing evaluation and post-test.  Once received a certificate will be emailed to the address you provide in the post-test.  If you did not register for the Summit WITH Continuing Education, you can purchase the continuing education by clicking here.  This purchase will provide you access to all Stillbirth Summit 2021 lectures including continuing education credit. There is no charge for viewing the presentation.

To receive continuing education credit for this lecture, the participant must complete the evaluation and post-test.