Expires July 2023
Ariela Marshall, M.D., is an Assistant Professor of Laboratory Medicine and Pathology, Assistant Professor of Medicine, and a Senior Associate Consultant in the Division of Hematology at Mayo Clinic in Rochester, Minnesota.
Contact us: MMLHotTopics@mayo.edu.
Hi, I’m Matt Binnicker, the Director of Clinical Virology and Vice Chair of Practice in the Department of Laboratory Medicine and Pathology at Mayo Clinic. Did you know that venous thromboembolism, or blood clots, is one of the leading causes of death among pregnant women? Fortunately, this condition can be successfully managed if identified and treated appropriately. In this month’s Hot Topic, my colleague, Dr. Ariela Marshall, will provide an overview of venous thromboembolism in the pregnant population, including its risk factors, treatment, and prevention. I hope you enjoy this month’s Hot Topic, and I want to personally thank you for allowing Mayo Medical Laboratories the opportunity to be a partner in your patients’ health care.
Thanks so much for the opportunity to speak today. My name is Ariela Marshall. I’m one of the Senior Associate Consultants in the Division of Hematology at Mayo Clinic in Rochester and a member of the coagulation and our core and consultative Hematology groups. One of my specific interests is coagulation and bleeding disorders in women’s health, so I’d like to talk about that today.
I do not have any disclosures.
So, looking at the presentation overall, we’d just like you to consider some of the following important points about how testing and diagnosis are used in management, when should tests be used, and how will results of testing impact patient management.
I’d like to start with a case. This is a 31-year-old woman whom I saw in our coagulation clinic. She has a history of venous thromboembolism (VTE), and she wishes to become pregnant for a second time. So, she’s 31, she’s previously been pregnant, she’s premenopausal, and she does have a history of polycystic ovarian syndrome (PCOS). In 2011, she presented with acute right leg pain and swelling after a long drive. She was also an active smoker at the time and was using a Nuva-Ring for contraception. She did not have imaging that we’re aware of; this was all diagnosed at an outside facility, but she was treated empirically for a possible DVT with enoxaparin, and her symptoms resolved. She did well between 2011 and 2015. During this period of time, she used both the mini-pill, which is a progestin-containing contraceptive, as well as combined oral contraceptives containing estrogen. In 2015, she had a successful pregnancy; and after her pregnancy, she restarted the Nuva-Ring, which is an estrogen-containing type of contraceptive. Three weeks postpartum, she awoke with lower extremity pain and dyspnea on exertion. She was diagnosed with a left lower extremity DVT as well as bilateral pulmonary emboli. She was transitioned to lovenox and then to warfarin. She did undergo thrombophilia testing at that time; it was essentially unremarkable, so negative for factor V Leiden and prothrombin gene mutations, negative for antiphospholipid antibodies, as well as did not show any evidence of deficiencies of proteins C, S, or antithrombin. At the time she saw us in the clinic, she had been on warfarin for one month. She also noted some increased menstrual bleeding but was otherwise tolerating it well, and she wanted to discuss the role of her anticoagulation therapy and her risk of VTE in future pregnancies, including what to do about the risk of hormone stimulation, if she needed it, for infertility related to her PCOS, as well as the role of prophylactic anticoagulation.
So talking about venous thromboembolic disease in pregnancy, in general, about 1 to 2 per 1,000 pregnancies are complicated by VTE. The risk is higher in all pregnant women, but there’s a difference between antenatal and postnatal periods. So, in the antenatal period, the risk is about 5-fold higher than in non-pregnant women, and DVT is more common. However, in the postnatal period, the risk was actually increased up to 20-fold higher compared to non-pregnant women, and this is the time when pulmonary emboli are more common. In terms of consequences, pregnancy-related VTE is one of the leading causes of pregnancy-related death in the developed world, and the mortality is as high as 1 in 100,000 in the United States and Europe.
So, the risk factors primarily are what we’ve all learned about in terms of Virchow’s triad. So, the first being stasis. So, this is a May-Thurner physiology with compression of the left iliac vein by the right iliac artery or ovarian artery. This situation is actually exacerbated in pregnancy by compression due to the gravid uterus; and in pregnancy, this explains why we see about 90% of DVTs on the left side versus essentially equivocal between left and right in non-pregnant women. We also see a predilection toward more proximal VTE in pregnancy. So, 70% of DVTs are actually in iliofemoral veins or more proximal veins versus only about 10% in the non-pregnant population. Less than 10% of VTE in pregnancy are isolated calf DVTs versus a much higher proportion in the non-pregnant women.
There is also hypercoagulability and endothelial injury. In terms of hypercoagulability, we see increases in many of the coagulation factors that predispose towards thrombosis. We also see decreased anticoagulant factors, so decreased protein S and acquired resistance to activated protein C. Furthermore, there is reduced fibrinolysis via reduced tPA and increased plasminogen activator inhibitor, which is placental. There is also an acquired antithrombin deficiency. This can be seen in the setting of preeclampsia leading to proteinuria and loss of antithrombin that way. In endothelial injury, we see compression by the uterus as well as edema during pregnancy; and finally during delivery, there is actually quite a bit of vascular damage that occurs.
There are multiple other risk factors varying both between the antepartum and the postpartum period. So, antepartum, we do see that advanced age in terms of the mother as well as gestational diabetes, and, in some cases, assisted reproduction can lead to increased risk. With assisted reproduction, this is primarily due to ovarian hyperstimulation syndrome, which we see in women who are given hormones to promote ovulation. In the postpartum period, we see VTE related to things that have essentially happened during delivery, so preeclampsia and eclampsia, placental previa, and abruption, as well as either planned or emergency C-sections can all increase the risk of VTE. And finally, we know that women who have hereditary thrombophilias and also any woman who has had a prior VTE before the current pregnancy, these are risk factors for VTE at all times during pregnancy.
In terms of treatment, for women in general who are pregnant and have VTE related to pregnancy, we would prefer use of low molecular weight heparins. Unfractionated heparin and fondparinux are other alternatives. We do avoid warfarin due to the risk of fetal malformation. And at this point, we are actually recommending against the use of the direct oral anticoagulants, and this is because we don’t have enough evidence for their safety and efficacy in pregnancy. We have some of the recommended doses here in terms of prophylactic and therapeutic dosing.
So in terms of prophylaxis after a woman has had a prior VTE, we know that any patient with a prior VTE is at a higher risk of recurrent VTE in subsequent pregnancies. Interestingly, a woman’s lifetime risk of recurrent VTE is lower if her first VTE was pregnancy-associated, but the risk is actually higher in subsequent pregnancies if her first VTE was pregnancy-associated. And this happens because estrogen was likely the provoking risk factor, so any situation in which the woman is exposed to estrogen again would increase her risk of a future VTE.
So these recommendations here are for women who do not a known hereditary thrombophilia. So this is for a woman who has a prior history of VTE. If it was provoked in a non-estrogen-associated situation, and this would be things like surgery or trauma, in the antepartum setting, we recommend clinical vigilance but no prophylactic anticoagulation; whereas in the postpartum setting, we do recommend prophylactic anticoagulation. For a woman who has had a prior VTE which was estrogen-associated, and this could be a prior VTE related to pregnancy or to oral contraceptives, we recommend both antepartum as well as postpartum prophylaxis. And this is also true for women who have had a prior unprovoked VTE. And women who are on warfarin at baseline, for instance, for a mechanical heart valve are switched to low molecular weight heparin during the antepartum setting and restarted on warfarin in the postpartum setting.
Now I’d like to talk a little bit about the hereditary thrombophilias. So we know that about 50% or an even higher percentage of women who have VTE in pregnancy have at least one inherited thrombophilia. And so there is a difference in management for these women who have the inherited thrombophilias in terms of antepartum and postpartum prophylaxis compared to women who do not have these thrombophilias. And this really depends not only on the woman’s personal history but also on the specific thrombophilia that she has as well as her family history. So there’s many different situations that I’ll talk through. And I think really for most of them, we do recommend postpartum anticoagulation. And the differences are more in whether we recommend antepartum anticoagulation or not.
So the high-risk situation is a woman who has a homozygous factor V Leiden or prothrombin gene mutation. Also in the high-risk situation we would consider women who have compound heterozygosity for factor V Leiden and a prothrombin gene mutation. So these are the highest risk for pregnancy-associated VTE. And so if a woman has one of these high-risk mutations, does not have a prior history of VTE, but has a family history of VTE, we recommend both antepartum and postpartum anticoagulation. If a woman has these high-risk mutations but does not have a personal or a family history of VTE, we would recommend antepartum clinical vigilance and postpartum prophylaxis. For prior VTE in women who have homozygous factor V Leiden or prothrombin gene mutation or compound heterozygotes, because they’ve had a prior VTE, regardless of family history, we would recommend both antepartum and postpartum prophylaxis. For all of the other thrombophilias, and this would be protein C or protein S deficiency as well as heterozygous for factor V Leiden or prothrombin gene mutation, if the woman has a family history of VTE, we would recommend postpartum prophylaxis; and if there’s no family history of VTE, we’d recommend clinical vigilance both antepartum and postpartum. And for any woman who’s had a prior VTE or any other thrombophilia, we recommend antepartum and postpartum prophylaxis, and this is really for the history of prior VTE more so than for the thrombophilia itself. I would like to mention that these, are official recommendations. However, in the “real-world clinical setting,” there are variations among practitioners; and if a woman has a high-risk thrombophilia . . . . . . so for instance, homozygous for factor V Leiden, even if there’s no family history of VTE, many practitioners would use antepartum prophylaxis for these women. And similarly, even a woman with a somewhat lower-risk VTE, such as a factor V Leiden heterozygosity, if there’s a family history of VTE, some practitioners would recommend antepartum as well as postpartum prophylaxis. So it’s really a very kind of practitioner-dependent situation and one that requires careful discussion with the patient about risks and benefits of antepartum prophylaxis.
So returning to our case, kind of summarizing the findings here, we felt that this patient’s first DVT was likely provoked in the setting of hormone exposure as well as smoking and physical inactivity. Her second DVT and the pulmonary emboli, we felt, were likely provoked in the postpartum setting, so in the setting of estrogen exposure. Going forward, she does have this history of polycystic ovarian syndrome and needing hormone therapy to become pregnant. So we recommended considering full-dose warfarin or direct oral anticoagulant during this time of hormonal stimulation. This is based on evidence that was published recently that suggests that women who are on therapeutic anticoagulation do not have an increased risk of recurrent VTE when they’re exposed to hormones even if they do have a hormone-related VTE historically in the past. Once pregnancy is attained in the future, we did recommend antepartum prophylaxis with enoxaparin for the complete duration of pregnancy as well as postpartum prophylaxis with enoxaparin or with warfarin therapy for at least six weeks after delivery. And some practitioners would actually recommend up to 8 weeks if a woman had a Cesarean section because this would give additional risk factors for VTE.
So kind of summarizing the overall thoughts about pregnancy-related VTE, I would say that one of the most important things to consider are what an individual patient’s risk factors are for thrombosis. What we are going to test for if there’s a family history of VTE, you might consider testing for hereditary thrombophilia since this would have impact on recommendations for prophylaxis in the future; and depending on results of thrombophilia testing as well as a woman’s personal and family history, making specific recommendations about antepartum and postpartum prophylaxis. And certainly, we’d also want you to take into account the method of delivery, the woman’s other risk factors, and the specific situation that she may have had a VTE in the initial situation. So that is what I wanted to talk about today, and I hope this was helpful for everyone.