“Thrombophilia in Pregnancy: The Clot Thickens…” – with Dr. Andrei Rebarber

Dr. Nathan: Welcome to today’s episode of “Healthful Woman,” a podcast designed to explore topics and women’s health at all stages of life. I’m your host, Dr. Nathan Fox, an OB-GYN and maternal-fetal medicine specialist practicing in New York City. At “Healthful Woman,” I speak with leaders in the field to help you learn more about women’s health, pregnancy, and wellness. All right. Andrei, welcome back to the podcast. How are you doing? 

Andrei: Thank you. My pleasure to be here. 

Dr. Nathan: Andre has been peddling the podcast to everyone he meets. Everyone you meet, you’re just pushing the podcast on people. 

Andrei: I wear my podcast hat on, you know. 

Dr. Nathan: We appreciate it. Thanks for coming back. It is always tough to get the moons to align, that you and I can have an hour in the middle of the day. And we’re going to talk today about thrombophilias. 

Andrei: Yes. Yeah. 

Dr. Nathan: This is something that we go way back on this. 

Andrei: It started with my former associate who I had worked with, a guy by the name of Charlie Lockwood. And he had been at the forefront of thrombophilias, dating back to the early ’90s, looking at what we call acquired thrombophilias at the time, something called antiphospholipid antibody syndrome. And that was sort of the first of these sort of supposed clotting abnormalities that may affect pregnancy outcome. And he sort of first identified a lot of these associations with several other researchers, hematologists, immunologists that he had worked with. And then by the late ’90s, 1999, there was a landmark paper that was published by this guy from Israel by the name of Kupferminc, who actually published this series on women who had genetic clotting disorders, and suggested that they were associated with clotting abnormalities. And that sort of became a tidal wave of sort of belief systems to data, to science, and a mix of…bag of all of that. And we’re still trying to figure it all out in many aspects of life, not just obstetrics but gynecology, contraception uses, whether it impacts on surgical outcomes, orthopedic surgery, so many things where these things can play a role that are not just exclusive to obstetrics. 

Dr. Nathan: Right. And we definitely have to get Charlie on the podcast. We would call him up. 

Andrei: Yeah, it would be great. 

Dr. Nathan: So, our listeners understand when we’re talking about thrombophilia, I mean, the concept is that, you know, we all have, you know, blood in our arteries and veins, and it normally is a nice, smooth liquid that flows nicely. And the thought is that if, let’s say, that gets disrupted, like, we get a cut, we start to bleed, and our body has a very intricate system, where it stops the bleeding, right? It finds the bleeding, plugs the hole, and then it stops plugging the hole. It turns on, then it turns off. And it’s a very delicate system with lots and lots of proteins and enzymes and factors that go into that. And people can have either you call it a disorder, or they may have some predisposition to either bleed too much, or on one end, like hemophilias, things like that, or on the opposite end, where they sort of clot too much. And the main concern, in general, with these always was, well, if someone has a problem, they’re going to get blood clots in their veins, or in their lungs, which could be life-threatening. And then someone said, like, you were talking about, well, maybe these things can affect pregnancy because they clot near the placenta or in the uterus, or whatever it is. And these do exist. But the issue is we’ve identified so many of them, that people are walking around with, and they don’t have any issues, and it’s very hard to sort out who’s going to have a problem and who isn’t. 

Andrei: Even in the…it was late 1800s, Virchow and his triad, people knew that the body clots and unclots. And it’s constant in this balance of clotting and unclotting, and you have a blood clotting system, but you also have a blood unclotting system that actually works in your body. And all of this is controlled to some extent, by certain environmental factors, as well as genetic factors. And the environmental factors we knew about for hundreds of years, like if you’re excessively overweight, you’re going to clot more, if you smoke, you clot more, but, you know, going back to Virchow, and his triad, it was that if blood is moving slowly, then it clots more readily, and blood that moves fast doesn’t clot as much. And so what they call stasis was associated with an increased risk of clotting. So, like, if you’re stuck on bed rest and not moving a lot, then your blood is not moving as much because your muscles actually move the blood…blood flow in the veins that can be associated with clotting and so on. 

So, that’s sort of the background that we’re dealing with. And then you add the pregnancy factor, which is alone because of the hormone environment, it actually increases clotting, which makes sense because delivery can be quite bloody, so, from an evolutionary point of view, it makes a lot of sense that you would have a system where we clot better when you’re pregnant than not because of the fact that…so it induces the liver to produce more chemicals to clot better, but at the same time that can work against you in pregnancy, particularly when people have always treated all ills of pregnancy with bed rest, which is, you know, whether you’re bleeding, you’re cramping, you have preterm labor, you have preeclampsia, the baby is small, everybody gets put on bed rest, which is actually probably a rather dangerous phenomenon for the mother because of the fact that it may increase her risk of clotting, like, clots and so on. 

So, that’s sort of the background that you have sort of this balance. And then in the background of this, there are certain conditions, some are what we call acquired, which means some occur throughout your lifespan. So, like their medical conditions, autoimmune disorders, that can be acquired, that you get more…you’re hypercoagulable, or you clot more, and that immune function is altered. And that has to do with something called antiphospholipid antibody syndrome or anticardiolipins, and we can go into that later. And then you have the genetic thrombophilias, or thrombo, Latin “philia,” clot love, love to clot, essentially. So, they are genetic predispositions, but all they are just really predispositions. And so their predisposition to clotting. And what we found is, at least of the known genetic thrombophilias, and this really is very important that it’s only identified in certain populations. So, there’s certain populations that, you know, again, we have not identified they are genetics thrombophilias. So, particularly in European Caucasian population, the current battery of tests identifies some of the genetic predispositions. But if you take other ethnic groups in other parts of the world, we don’t have those. We didn’t identify what mutations affect their protein. 

So, they found these particular what we call point mutations or errors that are passed on from parent to child over generations. And they could be silent. And they basically alter this balance or this sort of clotting to unclotting phenomenon. So, you are a little more tipped towards the balance of clotting. But what seems to be evident is that you need multiple things aligned, not just the genetic predisposition alone, to create a disease state, which is the blood clot itself, or worse, as you said, the embolism to your lung or something like that, which could be catastrophic. So, there are a lot of people who walk around with these genetic predispositions. Most people have no problems. And the big question is, how do I identify those people, particularly in pregnancy, because now the pregnancy increases your risk for clotting? So, that’s kind of the second hit, essentially, of this genetic predisposition and the pregnancy. But again, the problem becomes, when you’re looking at the condition itself, who do we treat? Why should we treat everybody? The majority of people will never have a problem. And part of that is that we’re seeing the tip of an iceberg. And basically, you’re not mapping out the whole genetic profile of all of us to say, what are our genes for unclotting? What are our genes for clotting? And how is that full balance? What we’re identifying is just the tip of the iceberg following along. And underneath, you really don’t understand in that individual patient, just more statistics and data from numbers, from other people necessarily how aggressive that clotting factor is, essentially. And that’s been the challenge. And that’s why the data is all over the place, in my opinion. 

Dr. Nathan: Yeah, I mean, if you look at some of the older studies, what they would do is they would take, let’s say, you know, 100 people who in the hospital had blood clots, right? They came into the hospital because their leg was swollen and they had a blood clot, or they’re short of breath, had a blood clot in their lungs. And they would test them and say, how many of these people had the genetic predispositions compared to 100 people who didn’t have blood clots? And it was way higher, right? Let’s say, I don’t know, 40% of them or something, versus almost none. And, like, whoa, but if you look at it the other way around, if you take, you know, 100 people walking around, or 1000 people walking around and test all of them, you know, what we find is based on the population, let’s say somewhere between like 3% to 10% of people are going to carry one of these things. But the vast majority of them are never gonna have a problem in their life because again, there’s other things that go into it, whether it’s genetic, whether it’s environmental, whether it’s their own health. 

I mean, there’s a lot of other things that can factor into that. And what happens is sort of practically is, you know, there’s a lot of women coming either with a diagnosis, like someone has tested them and found one of these things, or we’re trying to decide with her, should I send these tests, or should I not send these tests. And the reason we really care about these, like primarily is for the health of the mother, we’re worried about her getting a blood clot during pregnancy. But when it sort of open the can of worms of maybe this can affect things, like risk of miscarriage, risk of preterm birth, risk of stillbirth, all of that, it exploded in who got tested and who got treated. And that’s why it’s so hard. And there’s so much we’re trying to sort through and it’s not like a clean thing where we get to decide who gets tested, and who gets treated. People come in with tests already done, people already counsel them, maybe in a different way than we would or someone else would. And there’s a whole lot of unsorting that has to get done before we could put it back together. 

Andrei: It’s very complicated. So, first of all, most physicians or national organizations have suggested not to test anybody for any obstetrical complication or problems. So, they solve that problem because the data is not robust on who needs to be tested. And it’s even more complicated or limited to suggest that treatment works to prevent the adverse outcomes in pregnancy. The data is pretty good that patients who actually have a clot themselves in the sense of a leg clot or an embolism, they can get tested to define their risk, but the treatment probably doesn’t change too much per se. So, that’s sort of where we’re at. The testing, however, is being done so much now by so many people, because there’s a lot of myths and misconceptions about it. And the problem with the test is even how people are counseled because it is not explained to people that they have a genetic predisposition. What is explained is they have a disease… 

Dr. Nathan: Right. Disorder. 

Andrei: Disorder. It’s a genetic disorder, which it isn’t. It’s not a genetic disease. It’s not a genetic disorder. It is a predisposition that we’re identifying. And it may or may not manifest at all throughout your whole lifetime. And in fact, the majority of people, it never affects your whole life. And so that’s the problem. But when people see a lab test, and it says abnormal on it, it obviously creates a lot of anxiety and stress. And hematologists, particularly as it relates to my field, pregnancy, hematologists are testing for this, you have maternal-fetal medicine specialists doing it, OB-GYNs are doing it, midwives are doing it, and… 

Dr. Nathan: Fertility doctors are doing it. 

Andrei: Fertility doctors are doing it, reproductive endocrinology and fertility specialists. And so it’s permeated through our culture in the sense of now a good 25 years of being capable to do this testing, that it’s what they call the thrombophilia panel, and they just run a lot of the stuff. And I think that that’s been problematic. Now, that’s sort of where we’re at. Often, when people come to see us, we end up filtering through and really taking a cone-down view of their…why they got tested. And I think that’s really important. Is it because of their family history? Is it because of their personal medical history? Is it because of their personal obstetrical history? And these three categories really help to define the significance of these findings. So, that’s important. And additionally, it helps guide us as to how much we’re going to treat. And taking good histories, understanding what obstetrically happened to them, sometimes looking at things like the placenta pathology report after an obstetrical complication, what the pathology, what the placenta looked like, where they have damaged placentas, where the baby really significantly affected, may help. But even that is pretty controversial as far as its association. 

But I think you really need to be careful on who you test, explain to people what we call sort of a pretest counseling about the importance of this, the genetic testing, and what its significance may or may not be. And particularly as a patient, I would ask, how would you treat me different if I’m positive for this or not, and what’s the evidence to support that before you get tested because otherwise, the question is like with any genetic test, if you’re not going to do anything about it, and it doesn’t change anything in the medical management, and it can only affect you psychologically and emotionally in a negative way without necessarily being productive in your life in any fashion. So, you want to have a clear idea from the person testing you, why they’re sending it, what’s the proof that it’s going to make any difference in your management or outcome, and what are the treatments that would improve it. 

Dr. Nathan: Right. And also, even if a decision is made that we do need to test, there’s also a variation of what we should be sending. So, for example, you know, the genetic ones that we’re referring to, the most famous ones, there’s Factor V Leiden, named after the place in Europe, in which it was discovered. And then there’s the prothrombin gene mutation, and then there’s your Protein C and your Protein S levels. And that’s a little bit complicated because Protein S actually drops when you’re pregnant. So, if you send it during pregnancy, someone’s going to be potentially falsely diagnosed as having a problem. And in fact, that’s a normal finding for it to be low on pregnancy. 

Andrei: Protein S notoriously is a problem because it can function like an acute phase reactant. So, you actually have inflammatory processes, it can alter your Protein S level and lower it if you had an infection at the time. If you’re on oral contraceptives, you can affect Protein S levels, and pregnant state affects dramatically the Protein S levels. So, testing for Protein S, you have to ask specific questions before you can even test people for that, and also the labs vary in their accuracy. So, what happens is particularly Protein S can be divided into three categories. You have a total Protein S level, you have the functional Protein S, and you have what’s called the antigenic or the free portion of Protein S that’s floating around. And so these three different types and their levels actually affect the type of Protein S deficiency you have, of which there are at least three…four types because there’s Type 1, Type II and Type III A and B. And so the reality is that there are different subtypes based on the ratio. And the effects are varied based on severity. So, Protein S is notoriously problematic. It’s mainly been false positives in a lot of cases that people come to us. And we end up retesting. And I think that’s really important because getting a label of a thrombophilia in your chart, in your medical chart, does have implications on use of oral contraceptives, has implications for surgery, and surgeons, anesthesiologists get nervous about it. And you may be falsely told that you have this condition that you really don’t have, because of false positives on testing that occurred. 

Dr. Nathan: Yeah. And there’s one more antithrombin. But all of these, these inherited ones, as far as we know, and the current evidence don’t seem to be strongly associated with pregnancy outcomes, like miscarriage, like preterm birth, like small babies, like preeclampsia. There might be some cases where they are, but they’re not as strongly associated. So, there were times when we were sending these routinely on people for any of those issues, and it does not seem to be correct. But on the other hand, there’s the inherited ones that you were talking about before, the antiphospholipid antibodies… 

Andrei: The acquired. 

Dr. Nathan: Right, the acquired. The acquired ones, which have a stronger association with things like stillbirth and preeclampsia and fetal growth restriction, and recurrent miscarriages of certain types. And so we may have a situation where we see someone and say, “Okay, I’m going to test you just for the acquired, just for the antiphospholipid, but not for the others.” And the final one is one of the really fascinating tests that gets sent all the time nowadays, even though for 20 years we’ve been saying don’t send it, is the MTHFR mutation, which, I mean, 20 years ago, we were saying, why are we sending this and it’s still getting sent, like, on everybody and freaking everybody out. So, what is the MTHFR? 

Andrei: So, MTHFR stands for methylenetetrahydrofolate reductase. It’s an enzyme that assists in the metabolism of homocysteine, which is an amino acid. And hyperhomocysteinemia, or an excess amount of this, if the mutation in the methylenetetrahydrofolate reductase can impair its function as an enzyme to do this conversion. And so you get a buildup of homocysteine. And so there are people who have hyperhomocysteinemia. And what they found is in those patients that are particularly high, above 15 to 20 levels, there’s a stronger association with early heart attack and heart disease and cardiovascular disease, stroke events. The data is more problematic in pregnancy, whether that correlates. And additionally, there’s some data that MTHFR, particularly fetal MTHFR mutations can be associated with neural tube defects and other issues. 

But, again, in general, we do not recommend screening or testing. And the reason for that is there are different mutations that people are testing. So, the Class 6 mutation that had been associated with adverse outcome was the C677T mutation. But there’s also the benign variant, the A1298C mutation, and the MTHFR A1298C mutation is a benign variant, or what we call polymorphism, and has no impact on affecting enzymatic function, whereas the C677T mutation does diminish it. But in the presence of folic acid, B6, B12, you’re actually…the enzyme works quite fine. And so at the end of the day, the enzyme can be upregulated with certain environmental cofactors as well. And so the simplistic answer is, it shouldn’t be tested. Thirty to 40% of people are walking around what we call heterozygous for MTHFR, 10% are what we call homozygous MTHFR for that C677T mutation. In and of itself, that means 1 out of 10 people have this homozygous state, and more have obviously one of the variants. But it is not a condition. It’s what’s called a polymorphism. It shouldn’t be tested. It’s benign in 99.99% of people… 

Dr. Nathan: And the treatment is folic acid. It’s not blood [crosstalk 00:19:20]. 

Andrei: And the treatment, if anything is… Correct. And we don’t even know… 

Dr. Nathan: Which we give in pregnancy. 

Andre: It’s even a question mark whether folic acid…I mean, supplementation may help fetal outcomes, but whether there’s maternal benefit to this, it’s unclear. But I think if you’re going to do anything, you can consider looking at a fasting homocysteine level, but that is probably maybe in patients who have family history of coronary disease and early heart attacks and strokes combined with adverse pregnancy outcome. Some people might consider that, but even then, the problem becomes, you know, what do you do with that? And there’s other workups and treatments. 

Dr. Nathan: Right. So, MTHFR, that’s out. Now, you wanted to talk about the acquired thrombophilias and antiphospholipid antibody syndrome? 

Andrei: Right. That’s an interesting phenomenon because it is an autoimmune condition. So, things like lupus, systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s, these are all autoimmune conditions where your immune system, it gets out of balance and creates these antibodies that start to attack yourself essentially, attack self-antigens or self-proteins. And so lots of people develop these things over time. We don’t exactly know why people have that. 

Dr. Nathan: Frequently they’re young women. 

Andrei: Right. More likely women. And also they tend to run in families. So, Hashimoto’s thyroiditis, for example, is one autoimmune disorder, and then you can get into phospholipids. And so they cluster in one patient with more conditions. The particular condition, antiphospholipid antibody syndrome, however, has very particular criteria. And why I’m saying that is that anticardiolipin antibody or lupus anticoagulant are the blood tests that we order. But the syndrome has a very specific definition because a lot of us are walking around with these antibodies being present. That doesn’t mean you have the disease or the condition. So, when actually, Lockwood did work when he was actually a fellow up at Yale years ago, and this was a classic paper, I think it was 1989, 1990, he showed that 1 out of 10 people have anticardiolipin antibody-positive. But they’re low positive and certain, what we call subtypes, IgG or IgM, mostly IgM, and they’re generally not associated with the disease state. 

Dr. Nathan: Right. And they’re transient. They usually come and go. 

Andrei: And they’re transient, and they come and go. But true disease state that is associated with patients who have persistently positive cardiolipin antibodies or lupus anticoagulant on 2 separate occasions, at least 12 weeks apart. And ideally, the antibodies have to be high positive or moderate positive, in mostly IgG subtype, and you also have to have a clinical picture. So, you don’t just need a blood test, but you also need a clinical history. And the clinical history is either very complicated obstetrical history of stillbirth or abruption or something along those lines or an arterial or venous thrombosis. And I think this is very important that antiphospholipid antibody syndrome is not just venous thrombosis, or thrombosis like a leg clot, or the potential for lung embolism, but you can get strokes with antiphospholipid antibody syndrome. So, you have arterial system as well as venous system. It is much more aggressive in its risk of thrombosis for some people. And truly those patients that have this, if untreated, have…pose significant risks to themselves in their pregnancy. So, this is significantly different, if it is present, and it meets the criteria that were defined internationally by organizations. And it is important for patients to actually consider testing and treating in that setting and proper counseling about how that pregnancy should be managed. So, true anticardiolipin antibody-positive syndromes, or antiphospholipid antibody syndrome, these patients should be seen and consulted by a maternal-fetal medicine specialist. They should have regular surveillance and monitoring in their pregnancy. And they generally should be treated with anticoagulation, if they truly have the disorder condition for their own mitigating risks. 

Dr. Nathan: Seriously, because it has a much higher risk, both for the mother and for the baby with antiphospholipid syndrome. And it’s something that’s interesting because with all the testing that goes on for these blood clotting disorders, most people are just sending the inherited ones, like Factor V Leiden and prothrombin because they are more famous. So, you know, someone comes into an emergency room and has a blood clot-driven arterial blood clot, a lot of times these antiphospholipids don’t get sent. It’s not sort of in the common knowledge of all medical specialties for some reason, and we’ll see them, and you see, you know, a 40-year-old woman with a history of a stroke and then it’s like, well, they checked you for Factor V Leiden, which is pretty unlikely but have they check you for antiphospholipid, and she is like, “No. I’ve never heard of that.” And so that’s really an important one that for whatever reason, is always on the mind of obstetricians and maternal-fetal medicine specialists and, you know, sometimes hematologists, but in the world, people don’t always know about this one. 

Andrei: It’s actually a misnomer. Even to test a lupus anticoagulant suggests that it’s an anticoagulant that actually prevents clots, but the test is actually the reason why that came about was because in the lab, it actually prolonged clotting time, so they called it an anticoagulant, but when it’s in your bloodstream, the lupus anticoagulant actually promotes clotting. And so the test itself is a misnomer. 

Dr. Nathan: It’s double confusing because you don’t need lupus to have it, that’s number one. And number two, it’s not an anticoagulant. It’s like [crosstalk 00:25:00] twice. 

Andrei: [inaudible 00:25:00]. Exactly. That’s right. Though, patients with antiphospholipid antibody syndrome, the true syndrome, 30% of them lifelong go on and develop over systemic lupus. And so they’re at lifelong risk for that and should be monitored by a rheumatologist. 

Dr. Nathan: Who do we actually test for these things? And I sort of broke it down. The first is, if a woman herself has a history of a blood clot, right, particularly one that’s unexplained, right? Explained would be like, I was in a car crash, and I was in a full-body cast and on bed rest for six weeks, and you get a blood clot, we still might test it, but there’s a very good chance that it was just due to the fact that you’re lying still for six weeks. But certainly unexplained, we will send the thrombophilia or frequently some other doctor will and we would include both the inherited ones and the antiphospholipid and we would not include the MTHFR. 

Andrei: Correct. 

Dr. Nathan: And that’s the most important because she’s the woman who has risk in her pregnancy of developing another blood clot, and particularly if one of these things is positive, and if so, we’re much more likely to give her blood thinners, anticoagulation in the pregnancy. Sometimes even if she doesn’t have one, we’ll give it to her. But it depends on the circumstances and, you know, exactly, but certainly, if she has one of these things, we’re gonna do it. What about people who have a family history of a blood clot? 

Andrei: Yeah, I think that particularly those with two first-degree relatives, it would be somebody I might consider testing for genetic thrombophilia. It doesn’t mean I would put them on anticoagulation during the pregnancy. But for those patients, if they end up in a C-section, I might actually give them anticoagulation postpartum, because there’s an increased risk of clotting at…with a C-section postpartum. And so this would only enhance their risks. So, testing may actually be helpful to define your management postpartum if they wound up with an operative delivery like that. And then sometimes just knowing, because if they do have two first-degree relatives, and they have this, it would certainly limit contraception uses and choices. Any estrogen-containing contraceptive device would be contraindicated in somebody with a thrombophilia. Even a family history, it’s something alone that may give pause to a gynecologist to prescribe medicine. But often people don’t elicit these questions, and they do know the thrombophilia. So, that can provide some insight for people. 

Dr. Nathan: Because again, it’s unusual to have first two first-degree relatives with a blood clot. And like you said, we know some of the genetic predispositions, but we clearly don’t know all of them. So, even if everyone tests negative, it’d be weird. It’s the same thing, like, if someone has three relatives who have cancer, and we can’t find a cancer gene, we don’t say, “Oh, you don’t have any risk.” It’s still you probably have risk, we just don’t know it yet. We can’t figure that out. And so the same is true for blood clots. And then, in terms of women with a history of obstetrical problems, our threshold is definitely different for sending it, like, we said before, with certain sort of very profound outcomes, like stillbirth or very early delivery because of…for preeclampsia, or growth restriction, or very…an unusual history of pregnancy losses, like late losses, or multiple losses, we’re much more likely to send the antiphospholipid antibodies and only in, I would say, individual patients with specific circumstances might we consider the inherited ones, because sending them sort of on all these women, you’re probably going to find more coincidences than causes. 

Andrei: Yeah, we’ve pulled back a lot on who we test. I probably tend to, you know, be more of the over-tester in the group than the other doctors anyway because if you look at the most common reason people are tested, it’s actually the most common misconception. And the recurrent pregnancy loss, there’s really no data that under 10 weeks, that that really is associated with thrombophilia. In fact, the whole premise of thrombophilias are that, you know, blocking off maternal arterial vessels, and that, basically prevents oxygen from getting to the early fetus. But if you actually look at what the early fetus means, actually the early fetus for development, and particularly the early placenta, needs a relatively hypoxic state to develop. And so giving too much oxygen in that environment is not a good thing because they really can’t handle oxygen free radicals and it causes damage to the…invading trophoblasts. So, the reality is that it’s not good to give a high oxygen concentration at the early fetal-maternal interface during first trimester. And there’s no…little data to suggest that it’s associated with miscarriages, and so, certainly, when we’re talking about genetic thrombophilias. And that’s the most common I end up seeing. People are sent after one or two miscarriages and they send these panels and they put people on blood thinners and all that. They put them on…they send these panels for implantation failure through IVF and saying, “Oh, the baby’s not attaching because you have a blood clotting disorder.” None of these things are really based on good evidence-based science, in fact, the data points the opposite. 

Dr. Nathan: Yeah, there’s a great study out of NYU, like 15 years ago-plus, where they looked at women having IVF. And the ones who had the genetic predispositions to clotting did better. 

Andrei: Yeah. Exactly. 

Dr. Nathan: Because you want…I was [inaudible 00:30:17] the fetus, the early, early embryo phase wants like a sticky environment and wants, you know…because it attaches [inaudible 00:30:22] 

Andrei: And it certainly doesn’t want…it doesn’t need oxygen. It needs very little oxygen state. It needs nutrients. It will get its supply through a different…it’s not direct vascular content. The actual maternal-fetal interface and that sort of invasion to get near the maternal blood vessels doesn’t even happen until 12 to 14 weeks. So, when you have that secondary invasion of the placenta, so it biologically makes little sense that blood thinning is going to be the way to go to optimize implantation. Having said that, there are other theories to how Lovenox may work as…in decreasing inflammation. There’s also, I want to separate, this is more genetic, the acquired thrombophilia, like antiphospholipid antibodies, they actually work through different mechanisms. It isn’t pure clotting. There’s actually phospholipid antibodies that have a direct cytotoxic effect on the trophoblast. And they cause damage to the invasion of the trophoblast. 

And so at the end of the day, the mechanism of how antiphospholipid antibody syndrome works is much more complex than a simple clotting, as well. But certainly, from the genetic thrombophilia perspective, that probably has a little role in IVF failure or early losses under 10 weeks. And then even later losses, second to third trimester losses, very limited data suggesting association. And if it is, it’s weak, at best, and it depends on the population studied. And the biggest problem is that it really doesn’t take into account a lot of confounders. All of these studies, it’s complex to study this one factor, and these studies don’t take into account all the confounders that could impact on these outcomes as well. And so that becomes problematic with these studies. Having said that, stillbirth, placental abruption, growth restriction, early-onset preeclampsia, those were all traditionally associated with these thrombophilias. The current American College of OB and GYN guidelines suggest no one should be tested for these thrombophilias for obstetrical conditions. The only one is early-onset preeclampsia, and/or severe growth restriction, you may consider antiphospholipid antibody syndrome, but that’s about the only one that people are doing. 

Dr. Nathan: When we see women who have one of these, right, whether it’s inherited, whether it’s acquired, and we’re trying to decide what to do with them during pregnancy, and it may differ during pregnancy versus after delivery, again, based if they have a cesarean or not, essentially it comes down to about four options, right? Option number one is we do nothing. We say we’re just going to watch and wait, you look fine. Option number two is very, very benign, take a low-dose aspirin, a baby aspirin, which is 81 milligrams once a day. Again, really almost no downside to that… 

Andrei: Which we are telling everybody to take it anyway, no matter what [inaudible 00:33:10]. 

Dr. Nathan: Yeah, it may be good for everybody. Then the next option is some sort of an injectable blood thinner. There’s either heparin or low molecular weight heparin, one of the brand names is called Lovenox that a lot of people get put on. And that’s given as am injection and either once a day for the Lovenox or maybe twice a day for the unfractionated heparin. And then the fourth option is the same thing with injectables, but at a higher dose, right? Meaning either just a higher dose, in terms of how many units you’re going to give or whether it’s, you know, how many times a day. How do we decide which one of those four it’s going to be? I mean, there’s no way to just lay out exactly how we do it. But what are the variables that go into it when you’re deciding whether to do nothing, baby aspirin, or a small amount of the anticoagulation, or a high amount? 

Andrei: In general, we rarely put people on high anticoagulation. Exclusive indications are, for high anticoagulation, would be actual DVT or PE, deep venous thrombosis or pulmonary embolism in the pregnancy itself, or… 

Dr. Nathan: At that time? 

Andre: At that time, or patients with heart valves that are artificial heart valves, which we don’t see that much anymore. Those are the indications for…and so a mechanical heart valve. And then the majority of others are probably 90% are do nothing or baby aspirin. And the baby aspirin I often will give people because people don’t want to do nothing after they’ve had a bad thing happen. Like, what do you mean you’re not gonna do anything? And there is data to suggest that things like preeclampsia more likely are in patients with prior obstetrical histories that are complex, for some unknown reason, that…something with the placenta. And there’s pretty good data that a baby aspirin, anywhere from 81milligrams to 150 milligrams dosage of aspirin may be preventative for the development of preeclampsia and may optimize some placental invasion around that 12 to 14-week period. So, having baby aspirin on board, around 12 to 14 weeks seems to be very important, and particularly under 20 weeks. After that, it probably may not…you know, there are some people who do it up to 28, but I think it probably has little biologic sense, [inaudible 00:35:19] 

Dr. Nathan: And there’s essentially, for the 81 milligrams for sure, there’s essentially no risk. I mean, they looked at this in 30,000, 40,000, 50,000 and not an increased risk of things like bleeding or whatever complications. 

Andrei: It does not increase your risk of adverse outcome. 

Dr. Nathan: It doesn’t hurt the mom, it doesn’t hurt the baby. Right. 

Andrei: Correct. And this is data spanning 30 years, actually. 

Dr. Nathan: Yeah. 

Andrei: So, it’s gone back and forth on should everybody get it, which population should get it. And the population of who should get a baby aspirin over the last decade has been expanding ever so much all the time. So, in general, patients who come and get these tests done often are coming with some problem. In the past, the baby aspirin seems reasonable. The patients with a prior history of a leg clot themselves, particularly in association with one of these genetic thrombophilias, should probably get the Lovenox. And that’s probably very clear. And then the one subpopulation that we’re left with that we don’t often know exactly what to do with are patients who have a bad history, find the genetic thrombophilia, and then you figure out, okay, do I put them on heparin or just the baby aspirin? And, you know, because even if you wouldn’t have tested them in the beginning, in the first place, now, they are already coming to you for an opinion, and they’ve been tested. And I think that it really depends on the type of problem. Like I said, early losses under 10 weeks, little data to suggest benefit of and any role. Prior history of severe growth restriction, a placenta that suggests infarction, infarcted and damaged placenta, so, abruption, stillbirth, IUGR, possibly, you know, I do less and less of it, but I think that there’s, you know, maybe some role in a small population of patients. But again, that really has to do with the subgroup of patients that you’re studying. And, you know, I tell people that that’s still considered very experimental and the large portion of data suggests not much benefit. 

Dr. Nathan: Well, let me ask you this, what’s the downside, right? So, we’re trying to decide whether to put her on a baby aspirin or give her a small amount of the injectables, you know, Lovenox, or heparin. And she would say, “Well, what’s the downside of getting the injectables? Are they dangerous to the baby?” No, they’re not dangerous to the baby. So… 

Andrei: They don’t cross the placenta. The molecule is too large. 

Dr. Nathan: Right. Right. So, what’s the concern that you might have other than maybe just academically being wrong? 

Andrei: Beyond the academics, there’s easy bruising. I actually just did a consult on a patient who was put unnecessarily on Lovenox by a doctor who does all these, like, recurrent pregnancy loss. 

Dr. Nathan: Right. They look like they’re…they just got out of, like, a cage match, all bruised up. 

Andrei: Not just bruised up, she actually had big welts that took two weeks to heal. They told her just keep doing it and keep doing it and for two weeks, and then she had welts all over her, huge inflammation. And she ended up with an allergic reaction to it. There was some scarring in some of the area because of the shots. So, while that’s the really, I don’t know, maybe under five patients I’ve ever heard of having such a significant allergic reaction to the Lovenox, there are allergic reactions. Second, there’s bruising. The third, really their long-term Lovenox use may affect bone demineralization and weaken bones. And particularly for patients who might have risk for osteoporosis, it may not be ideal. Lovenox does less than heparin. Heparin is notorious for doing that. And that’s why we don’t put people on heparin anymore, and we put them on Lovenox. It lasts longer in the bloodstream, so it’s basically single…once a day dosing rather than twice a day. And that’s one. And then the bone effects are less. 

Dr. Nathan: And also it’s a little bit easier. Lovenox comes prefilled. Heparin, you have to drop it yourself. I tell people, there’s a cost, money potentially. It’s annoying, right, to inject yourself. It can be painful. There’s the bruising. There are rare complications like allergies. Sometimes it can affect, like you said, bone loss. Sometimes their platelets can drop. That happens. And I think also people…there is a practical implication, potentially, if they, let’s say, fell and hit their face, and they’re gonna get a nosebleed, they’re gonna bleed more, right? They’re on a blood thinner. It doesn’t have to be life-threatening or anything but annoying. And then there is a definite issue towards the end of pregnancy when people are on blood thinners. And this is we have to sort of, if we think they need to be on it, we manage it and switch them into this because if someone shows up in labor, and they’re on a blood thinner, number one, they could bleed more when they deliver. But number two, which comes up more practically, is they may not be a candidate for an epidural if they’re on a blood thinner because the anesthesiologist is concerned that if he or she places an epidural, and someone who has thinner blood is anticoagulated, there may be bleeding near their spine that they can’t see or treat, and they can potentially become paralyzed. So, they really, really won’t do it unless they’re confident the blood isn’t anticoagulated. So, if they’re on Lovenox, you really can’t get an epidural, if you’re within 12 or 24 hours based on your dose. If you’re on the unfractionated, there is a way you could do it but it could delay it. And not everyone realizes this when they’re put on these blood thinners that if they show up in labor, you know, earlier than expected, or whatever it is, they may have to labor without an epidural, right? And some people don’t want an epidural and that’s fine. But if they want one, they may be disappointed. 

Andrei: Right. And I mean, again, the reason is that the Lovenox is very specific in its anticoagulant effect on factor X. And so an anti-factor Xa level can assess the level of anticoagulation in your bloodstream of the medicine and you cannot get that test readily on a labor floor. 

Dr. Nathan: You can find it out after you deliver if it was okay to get it, but [crosstalk 00:40:49] 

Andrei: Right, because it takes 24 hours. Whereas something called a PT/PTT level, where prothrombin and partial thromboplastin time, the PTT can be affected by heparin, full heparin, not low molecular weight heparin. And so we ended up switching to heparin and then measuring PT/PTT levels, particularly to make sure that they’re not high, and that you can get so that when the patient comes in the labor floor, if the anesthesiologist is concerned, they would get a PTT level, and make sure that’s normal, and that can turn around as in, in a couple…I guess, 30 minutes to an hour, and then they can place an epidural more confidently that the level of anticoagulation is not significant. And there are reports of epidural site hematomas. If the hematoma is in the spine, you actually need surgery to evacuate the clot. 

Dr. Nathan: Yeah. 

Andrei: Because otherwise, you can get nerve injury and compression. And there are case reports of patients on Lovenox where this has happened nonpregnant. There are people who got spinals or epidurals with that Lovenox and didn’t…you know, and nothing happened, the majority won’t. But it is a theoretical concern that the anesthesiologists are worried about. So, at 36 weeks, for those patients that are on Lovenox, we switch them to heparin so we can measure the level when they come in labor, so they can still be candidates for epidural. 

Dr. Nathan: Right. But it’s definitely part of the discussion when we’re trying to decide whether to put someone out or not. And, you know, if we have this discussion with patients, and some women are more comfortable being sort of aggressive with treatments, saying I’d rather, you know, take the Lovenox and take on those risks, and some women are the opposite, saying, I really only want it if you’re certain I need it. And that’s fine. Like, since there’s a lot of uncertainty here, there’s leeway with how you make these decisions. And it’s a conversation. And I think, sort of as a summary, I think what’s important for people to know is that these predispositions, these thrombophilias, some people call them, you know, clotting disorders, which I think we said is a misnomer, they’re very common. A lot of people have them. Again, probably 5% to 10% of people, you know, 5% to 10% of you listeners out there probably have one of these and most likely don’t know about it, and most people that have them, nothing’s gonna happen in life [inaudible 00:42:58] 

Andrei: There are probably more of us, and that, because we just haven’t identified all of them, and depending on which ethnic group. You know, this prevalence is mainly in a Caucasian European population of somewhere in the order of 8% to 10%. The take-home message is make sure you know what you’re getting tested for. 

Dr. Nathan: Exactly. 

Andrei: Figure out why they’re testing for it, whoever’s testing you for these conditions, and if there’s significant value to them, besides just knowing, and understand what the implications might be if you have a positive versus a negative test. And I think that’s really important for any genetic test that is being run now, that people are often sending tests, but the patients are not necessarily fully aware of what the implications are, and how that changes management because ultimately, if it doesn’t change your management, it may not be worthwhile to do it. For pregnancy, in particular, I think that the large body of evidence suggested that these are not tested, are clearly associated with adverse pregnancy outcome. But if there’s family history of clotting, leg clotting, embolism, things like that, there may be a role to testing, and again, except in rare circumstances. And ideally, you want to get a counseling session, if you come up positive for it, and you happen to be pregnant or planning to be pregnant with a maternal-fetal medicine specialist or a hematologist, or an OB-GYN who has an area of interest or expertise in this that can explain to you the particular clotting issue, what the concerns have been reported with it, and how they feel the best treatment would be about it. 

Dr. Nathan: Yeah, I think that ideally, you could have a conversation with one of those people before you get tested, right? If there’s a thought about testing, you may want to just… You know, if it’s pregnancy-related, again, maybe a maternal-fetal medicine specialist, maybe it’s a hematologist who has an interest in pregnancy, many do, some don’t, but many do. Again, a lot of hematologists focus only on cancer because they do hematology-oncology, but ones that do a lot of hematology blood disorders, many of them like to see women in pregnancy or before, or an OB-GYN, again, who has a lot of interest in this. If you’re already tested, and you have one of these, again, the same thing for pregnancy, you want to make sure that you’re seeing someone who’s comfortable and understands, that can talk intelligently about this with you and give you options. And if you’re not pregnant, or you’re not gonna get pregnant, the same thing, you want to either see a hematologist or a good primary care doctor who has an understanding of these and will tell you what are the implications, what do you need to know for your life, you know, how might this affect your health moving forward. This is certainly not something where you want to rely on Dr. Google because there’s so much variation based on your specific circumstances, your specific test results, your other health conditions where you can have the exact same call it mutation as a friend of yours, and you may need to be on lifelong anticoagulation, and he or she may need nothing the rest of their life. 

Andrei: Correct. The mutation is only one piece of the puzzle. And I think that’s key, the clinical context of testing, the clinical context of the conditions, your history or individual, and each one are specific clues to put the picture together. It isn’t one of those kind of tests where you test positive, then you get this, and test negative, you get that, you really have to put the whole story together. But I think one of the hardest things we end up facing often is trying to take people off of this medicine. And so I have always joked that the last decade of my career…first decade of my career was putting people on heparin, then we figured out it didn’t do that much. And then now the last decade has been trying to take people off the heparin, and that usually is a lengthy conversation. And I sort of explain to people, people are very sold on the concept because it has some biological plausibility, like makes sense to people, blood thinners, more blood flow, better oxygen, baby’s gonna do better, and so in a simplistic way, though not in an actual medical way. And then, the other is that since…if they’ve had successful pregnancies, taking them off is even more challenging. And, you know, I tell people, look, no matter what we do in obstetrics, in…across various interventions, most people do fine with or without us. So, the reality is that we’re there to tweak the system and maybe improves your chances statistically, but, you know, some of these treatments, and that’s really the problem with it, is that when the doctor gives the medicine, and they do great, at the end of the day, people think it must be the medicine that did everything. And so they feel thankful, and they’re exceptionally grateful patients that, you know, we fixed the problem. The reality is that a lot of times you will probably have the same outcome with or without the intervention. And I think that that’s always a challenge in our field as obstetricians when to intervene, who to treat, and who will do just fine without anything. And that’s really the challenge. 

Dr. Nathan: Thanks for coming around talking about thrombophilias. 

Andrei: Pleasure. 

Dr. Nathan: Have a good one. I’ll probably see you around. 

Andrei: The clock thickens. 

Dr. Nathan: Oh, my God. Thanks, everyone. Thank you for listening to the “Healthful Woman” podcast. To learn more about our podcast, please visit our website at www.healthfulwoman.com. That’s healthfulwoman.com. If you have any questions about this podcast or any other topic you would like us to address, please feel free to email us at hw@healthfulwoman.com. Have a great day. The information discussed in “Healthful Woman” is intended for educational uses only. It does not replace medical care from your physician. “Healthful Woman” is meant to expand your knowledge of women’s health and does not replace ongoing care from your regular physician or gynecologist. We encourage you to speak with your doctor about specific diagnoses and treatment options for an effective treatment plan.