See below for an archive of our expert answers.

As an addendum to my question, I would also like your experts to weigh in on what the fetal survivability rate might be, given proper and timely treatment.

Roberta Gold
Encino, CA

The benefit and role of antithrombotic therapy in the prevention of placental mediated pregnancy complications in women with thrombophilia remains controversial.

First, as outlined above, the evidence of an association/causal role for hereditary thrombophilia in these disorders is not strong. Second, trial results have been mixed. One study (Gris et al. Blood 2004) suggested that recurrent late loss in women with the factor V Leiden, prothrombin gene mutation, or protein S deficiency could be reduced by about 60% with low molecular weight heparin (LMWH) prophylaxis compared with aspirin (frequency of life birth 86% vs 29%). However, this study has some important limitations and over the years less importance has been placed on the results. A subgroup analysis of the ALIFE Trial (Kandoorp et al. N Engl J Med 2010) showed no benefit to the use of LMWH plus aspirin, or aspirin in women with recurrent pregnancy losses and thrombophilia. So, at this juncture, there is no general recommendation for the use of LMWH in this setting.

The role of LMWH prophylaxis (added to aspirin) for prevention of other placental mediated pregnancy complications in women with hereditary thrombophilia remains controversial as well, with some studies showing no benefit and some showing a 10% relative risk reduction. Again, there is no consensus on the use of LMWH here.

Studies in women with antiphospholipid antibodies and a history of recurrent pregnancy losses appear to benefit from the combination of aspirin and prophylactic heparin or LMWH, although the degree of benefit varies between studies (from no benefit to a reduction in the risk of subsequent loss from 60% to 20%). 

Associate Professor, Department of Medicine McMaster University  
Director, Division of Hematology & Thromboembolism
Discipline Director for Hematology in Laboratory Medicine

I have a 14-year-old who is 15 months past menarche with von Willebrand disease. She has no history of severe bleeding episodes prior to menarche, but since menarche, has bled almost daily. She did stop briefly with Premarin but has failed multiple doses and types of OCPs, progestins, and multiple combination and doses of estradiol and progestins. She has also failed Amicar and Lysteda. She has a normal pelvic ultrasound with endometrial measurements between 4 and 6 mm. She had a Mirena inserted 3 months ago (with a normal endometrial cavity at that time) and has continued to bleed. We are beginning to add oral estradiol at this time. The family is understandably frustrated since she has been bleeding almost daily for 15 months. She has normal thyroid studies, cbc, and ferritin is in the low normal range. We would appreciate any thoughts to help this young woman and her family.

It sounds like she has tried quite a few hormones (doses unspecified). With a Mirena, irregular bleeding is expected with gradual reduction in bleeding over time. Another option is Depo Lupron to shut her down centrally; however, she may continue to have at least one flare bleed until things down regulate. If she does not respond to these approaches, she may need von Willebrand Factor (VWF) concentrate infusion, particularly if her von Willebrand Disease (VWD) is more severe.

Jennifer E. Dietrich, MD, MSc, FACOG
Associate Professor
Department of Obstetrics and Gynecology and Department of Pediatrics
Baylor College of Medicine
Chief of Pediatric and Adolescent Gynecology Texas Children's Hospital
Division Head Pediatric and Adolescent Gynecology
CME Director Department of Obstetrics and Gynecology

Barbara A. Konkle, MD
Director, Clinical and Translational Research, Puget Sound Blood Center
Medical Director, Hemostasis Reference Laboratory, Puget Sound Blood Center
Professor of Medicine/Hematology, University of Washington


I have a 15-year-old girl with systemic lupus, and psychiatric issues I believe from the Lupus. She has been treated for severe ITP twice (wet purpura, petechiae and heavy menstrual bleeding to hgb 5), and has had bleeding and purpura. She has been on steroids and numerous drugs from her disease including Plaquenil and Belimumab. She has chronic constipation that has required several admissions. She has had bouts of severe itching until she scratches herself until she bleeds and has impressive large purpura. We have been giving her Depo for the last 1.5 yrs because of heavy period. Her medical team is concerned about bone health with all the steroids and Depo Provera. They are suggesting a  subcutaneous implant.  Not sure with her psychiatric component if she would try to scratch the device out. Also, I wanted to confirm from a clotting standpoint that this would be a safe choice. I was wondering if Mirena would give her progesterone, local control of menses without systemic effects, and hopefully, would not be bothered by her propensity to pick scabs and scratch. Yes, she is 15 yrs of age but as you can see she has many other quirks. What is your recommendation for girls with active systemic Lupus who need birth control?

Paulette Bryant, MD
Charlotte, NC

As long as her platelet counts are not severely decreased there should be no problem with placement and it will help with her menses. As some patients with lupus are prone to thrombosis this should be discussed with her physicians who know her best.

IUD would be a great option for her.  Recommend getting an ultrasound before to ensure uterine cavity large enough.  If at risk for bleeding might consider intraop placement or placing in a controlled setting.

Terry Gernsheimer, MD
University of Washington School of Medicine
Jennifer Dietrich, MD, MSc, FACOG
Baylor College of Medicine

Woman taking drospirenone/ethinyl estradiol oral contraceptive, diagnosed with DVT and PE 18 months prior to pregnancy. Enoxaparin sodium prophylaxis prescribed from start of pregnancy. On-going headache symptoms of CVT from about 16 weeks. CVT finally diagnosed and treatment started at about 22 weeks. (Enoxaparin sodium prophylaxis failure, indicated) Fetal demise resulting from placental clotting at about 26+ weeks. What is the percentage of risk to the fetus that could be determined to have existed at the time the CVT was diagnosed at about 22+ weeks?

It is unlikely that there was any risk to the fetus from the CVT. In all probability this patient has an underlying hypercoagulable disorder that predisposed her to DVT, PE, CVT as well as the fetal demise.


Seeing a patient: 29-year-old wf with ET (?PV). Hx: 3 years ago, plt count 1 million No Tx per heme and no w/u Has had 2 miscarriages Wants to get PREGNANT No bleeding or thrombosis wbc high 12.4 hgb 15.5 (borderline high) plt 850 vw panel Normal (ordered bc high plt but no bleed) ferritin 60 crp nl esr nl jak 2 pos LAP nl epo LOW 2 u/s splenomegaly bmbx: incr megas c/w ET bcr abl neg.  chromo pending (just done 48 hrs ago) no incr blasts or fibrosis

Burton F. Alexander, III MD
Virginia Oncology Associates

We'd like her on low-dose ASA during pregnancy, the intrapartum period and for six weeks postpartum (PP). If she has no other risk factors for thrombosis, I would reserve LMWH for the postpartum period only (i.e., enoxparin 40 mg qd for the first three weeks PP). We'd recommend fetal surveillance (detailed ultrasound in the second trimester, monthly ultrasounds in the third trimester, at least weekly testing in the last two months of pregnancy and delivery at 39 weeks). Although these women have an increased chance of poor pregnancy outcome, there is a good chance things will turn out well.

Andra James, MD, MPH
Director/Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC


In ITP, is it okay to use birth control pills to control heavy menstrual bleeding?

In a woman with ITP who has not had a history of blood clots, we have no objections to birth control pills.  We also have no objections to the levonorgestrel (progestin) IUD which REDUCES menstrual blood flow from the uterus, although it does not prevent ovulation, and ovarian cysts can still form.  We DO object to the copper IUD, which increases menstrual blood.  Most women do not see an effect on their counts and benefit from having their menstrual bleeding controlled when they are not trying to become pregnant.

Andra James, MD, MPH
Director/Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC


Has anyone nationally or internationally done any studies of apixaban, a direct oral factor Xa inhibitor in pregnancy or postpartum? Not sure if it crosses the placenta or not.

Jeffrey Kuller, MD Professor Obstetrics/Gynecology / Maternal-Fetal Medicine
Duke University School of Medicine Durham, NC

The four new oral agents for long-term anticoagulation, the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban have not been studied in pregnancy. Two of the four have been approved by the United States Food and Drug Administration (FDA) - dabigatran for the treatment of atrial fibrillation and rivoroxaban for VTE prophylaxis after orthopedic surgery. There are no published data on edoxaban. For apixaban, unpublished animal studies do not yet indicate direct or indirect harmful effects.[1]  Rivaroxaban reportedly crosses the placenta in animals.[2]  For both rivaroxaban and dabigatran, while there were no structural malformations in rats or rabbits, post-implantation losses were noted in rats.[2,3]  The therapeutic formulation of dabigatran, however, is polar, and prevents it from crossing membranes. The drug has not been found to cross the placenta in the mouse, rat or rabbit (from drug development research). Therefore, while dabigatran does not necessarily need to be stopped prior to conception, there are, nonetheless, insufficient data to justify continuing its use during pregnancy. Even in a non-continuing pregnancy, the lack of a reversing agent for these anticoagulants would preclude their use.

With respect to the four new oral agents for long-term anticoagulation, a high milk to plasma ratio in rats suggests active transport of apixaban into breast milk.[4]   There are no data about the presence of edoxaban, rivaroxaban or dabigatran in breast milk. 

1. ELiquis: summary of product characteristics.  2011  [cited 2011 November 18, 2011]; Available from: http://www.eliquis.com/PDF/ELIQUIS®SmPC.pdf.

2. Prescribing information for Xarelto (rivaroxaban) tablets for oral use.  2011  [cited 2011 November 18, 2011]; Available from:http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf#zoom=100.

3. Pradaxa prescribing information.  2011  [cited 2011 November 18, 2011]; Available from:http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf.

4. Wang L., et al. Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos, 2011. 39(2): p. 256-64.

Andra James, MD, MPH
Director/Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Associate Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC


Having difficulty with success recommending the levonorgestrel-releasing IUD. Several women with VWD have had them removed shortly after placement because of a dramatic increase in bleeding for several weeks after the procedure. Any suggestions? These were women without success using various birth control pills (BCPs). Parenteral hormonal therapy in preparation? Aminocaproic acid?  

Richard Lipton, MD, Physician-In-Charge, Hemophilia Treatment Center
Long Island Jewish Medical Center, New Hyde Park, NY

I would like to think that women could be encouraged to persevere during the first few weeks/months with the levonorgestrel-releasing IUD when a pre-existing thickened endometrium may be shedding.  If women/girls continue to have irregular bleeding with a levonorgestrel-releasing IUD, we can cycle them with low-dose estrogen or a low-dose birth control pill (BCP), such as norethindrone/ethinyl estradiol, with only three days off of hormone. 

Before starting aminocaproic acid, we would suggest starting the new oral tranexamic preparation, which we believe is better tolerated than aminocaproic acid. This can be used with levonorgestrel-releasing IUD in place or in lieu of levonorgestrel-releasing IUD.

I hope this helps.

Andra James, MD, MPH
Director/Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Associate Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC


It has been brought to my attention from the pathologist in our system who was asked to review data on a 28-year-old woman who had one viable pregnancy, one blighted ovum, and one first trimester missed abortion. There was no prior history of DVT (deep vein thrombosis) or VTE (venous thromboembolism). There is no family history of such. The patient had significant testing done. The pertinent findings are a homozygous MTHFR C677T mutation with a normal homocysteine and the fact that she was heterozygous for a prothrombin mutation. The pathologist has referenced an article by Altomare from the Thrombosis Journal, 2007;5:17. There is a suggestion in this article of patients with early fetal demise who have the MTHFR mutation. The prevailing thought is that the MTHFR mutation is not thrombogenic; however, this patient, as well as this article, does raise some questions. Therefore, I would appreciate if you would forward this note to experts in your foundation for their opinion regarding: Is MTHFR mutation thrombogenic and is it worthwhile doing the test? Is there a role for the MTHFR mutation in fetal demise? If such, what are the recommendations if any for anticoagulation? Is the prothrombin mutation in the patient referenced above the real culprit here instead of the MTHFR mutation? I appreciate your help and insight in this matter. I will be looking forward to your review and discussion.

Kenneth Krupp, MD
Promedica Cancer Center Sylvania, OH

Dear Dr. Krupp:

Thank-you for your question.

I'm not sure why this patient was tested for an underlying thrombophilia after a single early pregnancy loss. This would not have been my practice. Although these events are very sad; they are very common and do not necessarily indicate any underlying pathology. Most affected women go on to have a subsequent normal pregnancy without any intervention.

The data regarding the role of hereditary thrombophilia in pregnancy loss (even recurrent or late loss) is by no means definitive. This is very much the case with respect to the two thrombophilias you mention. Available data are inconsistent. Even when positive associations have been reported, they are weak - e.g., odds ratios of less than two in case control studies. Case control studies almost always exaggerate the strength of association so that when methodologically stronger cohort studies are conducted, the association invariably becomes weaker or even disappears. The available data have not
convinced me that that either of the MTHFR or the prothrombin gene mutation is associated with an increased risk of pregnancy loss. There are no good studies demonstrating benefit to intervention with low molecular weight heparin (LMWH) in women with a single early loss, regardless of the presence of absence of thrombophilia.

As you have mentioned, homozygosity for the MTHFR mutation is not considered thrombophilic (in the absence of elevated homocysteine levels). We no longer offer routine testing for this thrombophilia at our centre.

In the absence of a personal or family history of VTE, there is no role for either antepartum or postpartum prophylaxis in asymptomatic women with thrombophilias other than those considered high risk (e.g., homozzygosity for factor V Leiden).  I would not consider this patient's thrombophilia to be high risk.

Therefore, unless I have missed something, I do not see any role for antepartum or postpartum LMWH in this setting. This patient should ensure that she is taking appropriate folate supplementation during any subsequent pregnancy. As for any pregnant woman, she should be vigilant for signs and symptoms of venous thromboembolism and seek medical attention urgently should they occur. Her need for thrombosis prophylaxis should be re-evaluated if intervening risk factors develop.

I hope that is of some help.

Best regards,

Shannon

Shannon M. Bates, MDCM, MSc, FRCP(C)
Associate Professor, Department of Medicine
McMaster University
Director, Division of Hematology & Thromboembolism
Discipline Director for Hematology in Laboratory Medicine
Telephone: 905-521-2100, ext. 73928
Fax: 905-521-4997
E-mail: batesm@mcmaster.ca


We have a young woman diagnosed with VWD who has very heavy menstrual cycles and is not able to tolerate any hormonal support, including levonorgestrel IUD. She also has endometriosis. She has had five periods in the last eight weeks and will use desmopressin beginning tomorrow, one spray to each nostril for two days. She is so ill from her periods she has had to quit her job and suspend schooling. She will be having further lab testing including FXIII, dense platelet granules and plasminogen. We would like to start her on tranexamic acid if her insurance will cover it. Any other suggestions?

Carolyn Solomon, RN, Nurse Coordinator and Pediatric Thrombosis Coordinator and Hemophilia Nurse
Michigan State University Center for Bleeding and Clotting Disorders

In our evaluation, we would want to know how old this young woman is, how severely affected she is with VWD and how far from menarche she is. We would be interested to know the hormonal treatments that have been attempted and the extent to which a gynecologist has been involved. We do know she has failed hormonal treatments, including the levonorgestrel IUD, and you are trying desmopressin.

We would be interested to know her thyroid function, her current hemoglobin, and a current assessment of her iron stores. With eight periods in two months, she is having irregular bleeding, not just heavy bleeding, and we would not expect that her bleeding is going to respond to hemostatic therapy alone; it will likely require the joint efforts of the hematologist and the gynecologist. She will need cycle control and hemostasis. It is not clear that all potentially tolerable hormonal manipulations have been tried, such as monthly short courses of progestin to induce withdrawal bleeding. This may give her cycle control, especially when used in conjunction with desmopressin or antifibrinolytic. 

Concerning tranexamic acid, there are no clinical trials in adolescents.  As far as the dosing, if she is adult weight/size, then we would expect the same dose as that for an adult woman. In a young woman with VWD, when cycle control is achieved, and antifibrinolytics and desmopressin have failed, we have no reservations about using VWF concentrates to achieve hemostasis.

Andra James, MD, MPH
Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Associate Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC