Prothrombin G20210A Mutation

As we have written about on several occasions, pregnancy loss is a very traumatic experience for many couples and their families – especially when there are recurrent episodes of loss. It is a basic human need to seek an explanation for such events, partly as a means of gaining closure and partly in the hope of finding a condition that can be treated, thereby improving prospects for another pregnancy. Although evaluation of the couple with pregnancy losses will sometimes identify a specific reason for the losses, in many instances, no concrete etiology is found. During the process of evaluation, it is not unusual to identify factors that may or may not be contributing to the problem, or that might have some other implications for the health of the woman who has experienced pregnancy losses. The reader below may well fit into this latter category and represents the plight of many women who are evaluated for recurrent pregnancy loss…

Karen said...

Dr. T - I am 39 years old. I have a 16 year old son who was born at 24 weeks due to a placental abruption (he is perfectly fine today) and a 3, 2 and 1 year old from my current marriage. We wanted to have one more child and had 2 miscarriages this year. The 2nd miscarriage was at 15 weeks and my OB tested me and we found out I have Prothrombin G20210A gene mutation, a blood clotting disorder. I'm somewhat confused how my last 3 children were born with no problems other than I have an incompetent cervix. At my age, is this clotting disorder a high risk to my health/life? I would love to have another child, but I also REALLY want to be here for the 4 I have now. I'd love to hear your thoughts.

Karen

Kenneth F. Trofatter, Jr., MD, PhD said...

To Karen:
It is less likely the Prothrombin G20210A mutation had anything to do with your two miscarriages in view of your previous obstetrical history apart from the miscarriages. Much more common causes at your age are chromosomal abnormalities of the babies, an intrauterine abnormality such as a fibroid, scar tissue, or polyp, a hormonal abnormality such as thyroid disease, or an autoimmune condition. You have not told me the extent of your evaluation for “thrombophilias” that could contribute to your pregnancy losses, however, I am presuming you were at least screened for the more common genetic and acquired thrombophilias that have been variably linked to pregnancy loss and poor pregnancy outcome based on the fact you were identified as being a carrier of that prothrombin mutation.

About 2% of the population is heterozygous (carrying one dose) of the prothrombin mutation G20210A. This and the Factor V Leiden mutation are the two most common genetic causes of thrombophilia. Having the prothrombin mutation increases the risk of developing deep venous thrombosis (DVT), usually the result of a blood clot in the deep veins in the legs, and pulmonary embolus (PE) - a blood clot that travels to the lungs, usually from DVT - from approximately 1 in 1000 people to 2-3 in 1000 people each year. Having homozygous prothrombin mutations increases the risk even more. However, many people with the prothrombin mutation will never develop a blood clot in their lifetime. Factors that increase risk include age, pregnancy, obesity, family history of DVT/PE, smoking, diabetes, and the presence of other thrombophilias among many others.

So, those are my thoughts. The best thing you have going for you is the OB history of successful pregnancies in the past. If your doctor chooses to treat you during pregnancy to prevent venous thromboembolic events, at this point no more than prophylactic therapy is indicated. Good luck and thanks for writing.
Dr T

Labels: prothrombin mutation, recurrent pregnancy loss, thromboembolic complications and pregnancy, thrombophilias

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Use of Fondaparinux During Pregnancy

I felt the comment below from a reader deserved a more thorough response than could be accommodated under the post upon which it was left and also might be of interest to other readers and providers who frequent this site. Anticoagulation during pregnancy has become more widely used to treat, both prophylactically and therapeutically, women who have had problems with thromboembolic complications, unexplained recurrent pregnancy loss, and those who have been identified as being ‘at risk’ because of acquired or genetic thrombophilias (e.g., antiphospholipid antibody syndrome; lupus anticoagulants; Factor V Leiden; MTHFR polymorphisms; prothrombin mutations,; antithrombin III deficiency; protein C and S deficiencies, etc.). The treatment of choice in recent years during pregnancy has been either unfractionated or low-molecular weight heparins. These are used because of their efficacy and relative safety for both mother and baby (they do not cross the placenta to the fetal circulation).

However, their use is not without risks. Prolonged use of heparins can lead to reduction in bone density (osteopenia and osteoporosis), cutaneous and systemic allergic reactions (accompanied in some cases by decreased efficacy), and heparin-induced thrombocytopenias that may place the patient at risk for hemorrhagic complications. When such complications arise, alternative medications such as fondaparinux (Arixtra) have been offered as alternative therapy. Although very few of us have a vast experience with the use of this drug in pregnancy and, currently, I am not aware of recommended regimens for the same, there is a growing need and a growing body of evidence to support that use when in indicated situations. Following our reader’s comment, I provide general information related to fondaparinux and, specifically, to its use during pregnancy….


jen27 has left a new comment on your post "Tales of Two Thrombophilias":

I am so happy to have found your blog! I have another take on thrombophilia and pregnancy. I am 39 years old, first time pregnancy and presented with bilateral PE (pulmonary emboli) at 8 weeks. Was placed on lovenox--allergic! Then placed on Heparin--allergic! I am now on Arixtra and I seem to be tolerating it well. My concern is with the delivery and also with a possible amniocentesis (of course, I am high-risk for Down's). This is a new drug and my OB is has never used it before. How do we plan for delivery? He is talking about inducing me around 37 weeks to have some control over bleeding. My hematologist has not used this drug with a pregnancy before and is not sure how we should proceed. Also, I am scheduled for a possible amniocentesis in two weeks and have started to worry about internal bleeding. Any advice would be most appreciated!


Fondaparinux is not a heparin substance. It is a synthetic pentasaccharide (5-sugar) compound that has been found to be a selective inhibitor of Factor Xa. In the blood-clotting system, Factor Xa functions at the common point at which both the intrinsic and extrinsic clotting cascades come together and, therefore, it is a highly efficient inhibitor of thrombin formation and, subsequently, fibrin formation (which is the foundation upon which blood clotting occurs). Fondaparinux actually binds, quite specifically, to antithrombin III (ATIII) which then facilitates the binding of ATIII to Factor Xa, inactivating it and interrupting the clotting cascade. Interestingly, once the ATIII-fondaparinux complex binds to Factor Xa, the fondaparinux is actually released intact and can then bind with another ATIII molecule to repeat the process.

Fondaparinux is administered by subcutaneous (not intramuscular) injection. It is rapidly absorbed and reaches peak serum concentrations about 2 hours after dosing. “It has a terminal half-life of 13 to 21 h, permitting once daily dosing” and a “linear pharmacokinetic profile which exhibits minimal intrasubject and intersubject variability, suggesting that individual dose adjustments will not be required for the vast majority of the population and there will be no need for routine hemostatic monitoring.” (Bauer, et al., Cardiovasc Drug Rev 2002;20:37-52). The drug also has minimal binding to plasma proteins usually involved in drug binding, therefore, the risk of complications related to drug interactions associated with displacement of drugs that do bind to these proteins is very low. The drug is cleared intact by the kidneys so dosing regimens in patients with renal compromise must be adjusted accordingly.

In studies performed both in vitro (Lagrange ,et al., Thromb Haemost 2002;87:831-5) and in vivo (Dempfle, N Engl J Med 2004;350:1914-5) there appears to be minimal transplacental passage of fondaparinux, placing the baby at low risk for hemorrhagic complications. Furthermore, studies performed in pregnant rats and rabbits at 32 times and 65 times, respectively, the recommended human dose have not shown impairment of fertility or a teratogenic effect on the fetus, resulting in the drug being classified as "class B." However, it should be recognized that pregnant women were excluded from all controlled clinical trials conducted with fondaparinux so there are to date no controlled trials during the first trimester of pregnancy.

Indeed, there are only a few case reports published in the scientific literature (Dempfle, N Engl J Med 2004;350:1914-5; Wijesiriwardana, et al., Blood Coagul Fibrinolysis 2006;17:147-9; Mazzolai, et al., Blood 2006;108:1569-70; Harenberg, Thromb Res 2007;119:385-8; Gerhardt, et al., Thromb Haemost 2007;97:496-7). Although the drug appeared safe and was well-tolerated with no untoward maternal or fetal effects in any of these reports, and none of the few patients described developed recurrent episodes of thromboembolic disease or allergic reaction, it is hard to generalize the safety and efficacy of the drug during pregnancy based on only a handful of patients. Safety of the drug in nursing women has also not been studied to date although, again, in lactating rats, only a small amount were found in breast milk.

With all that said and done, how should fondaparinux be used during pregnancy? None of the case reports agreed on a common regimen. In most of the clinical trials leading to its approval, fondaparinux has been employed only as a prophylactic agent in the perioperative period in ‘at risk’ patients or in the acute management of a thromboembolic condition while the patient was being transferred to warfarin over the course of 5 to 9 days. For both of these indications, fondaparinux has been found to be more efficacious than either heparin or low-molecular-weight heparin and to have comparable safety profiles. It has been found that fondaparinux is associated with hemorrhagic complications if given less than 6 hours after an operative procedure.

In the case reports, various approaches to therapy during pregnancy were described. As examples, Wijesiriwardana and colleagues (referenced above) described the case of a woman who had had deep venous thrombosis in a previous pregnancy who then developed an allergic reaction to low molecular weight heparin after three weeks of therapy during a subsequent pregnancy. She was placed on warfarin until 36 weeks’ gestation and then switched to fondaparinux 2.5 mg SQ daily. The latter was discontinued the day she began induction of labor and then restarted 6 hours after her uncomplicated vaginal delivery while she was transitioned back to a therapeutic level of warfarin. Neither she nor the baby had hemorrhagic complications related to this approach, nor did she develop recurrent thrombosis during the treatment period. In the report by Mazzolai and colleagues (also referenced above), a woman with protein S deficiency, who also had a history of deep venous thrombosis and developed allergies to both heparin and low-molecular weight heparin, was treated successfully, and without complications, for 150 days during pregnancy. Either approach seems very reasonable in the patient at high risk for thromboembolic complications and hypersensitivity to heparin compounds. Indeed, judging from the safety profile of fondaparinux to date, some thought may have to be given to its use as a first-line agent under these circumstances at some point in the future.

I realize that I have been long-winded, so in fairness to our reader, I should try to answer her questions! It would be helpful, however, if I had some more information, specifically, related to her medical history and identified risk factors for her bilateral pulmonary emboli in early pregnancy. Regardless, I would offer the following suggestions: 1) Consider maternal serum screening and a ‘targeted ultrasound’ to reevaluate your risk for Down syndrome and trisomy 18 before proceeding with an amniocentesis based on your ‘age alone’ risk; 2) If you do decide to proceed with the amniocentesis, stop the fondaparinux take your last dose 24 hours before the procedure and then resume dosing 6-8 hours afterwards; 3) Unless you have or develop other risk factors, elective delivery before 39 weeks is probably not indicated (unless you have another amniocentesis to document fetal lung maturity first); 4) Since anticoagulation therapy places you at increased risk for complications related to spinal and epidural anesthesia, and the effects of fondaparinux cannot be readily ‘reversed’ in a short period of time, consider third trimester consultation with an anesthesiologist who can suggest a plan of management in the peripartum period; 5) If an induction is planned, discontinue the drug the day before and resume 6-8 hours following delivery; 6) Consider leg compression boots throughout the time you are not taking fondaparinux before, during, and after delivery to minimize your risks for deep venous thrombosis; 7) Convert to warfarin after delivery while being covered with fondaparinux until a therapeutic INR level is reached.

Thanks for a great comment Jen and best wishes for the rest of the pregnancy! Please let us know how things turn out.
Dr T

Labels: fondaparinux, heparin, lovenox, thromboembolic complications and pregnancy, thrombophilias

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When to Start Anticoagulation Therapy for Recurrent Early Pregnancy Loss

For many years now, we have placed women with recurrent early pregnancy loss on low-dose aspirin (81 mg) and heparin, or low molecular-weight heparin such as lovenox, to help them improve their prospects for pregnancy outcome. In some instances this regimen is used because an acquired (e.g., lupus anticoagulant; antiphospholipid antibodies) or genetic (e.g., Factor V Leiden; MTHFR polymorphism; protein C, protein S, and antithrombin III deficiencies; prothrombin G20210 mutations, etc.) ‘thrombophilia’ (tendency to form or maintain blood clots) has been identified. In other instances it is used simply as ‘empiric therapy’ because no particular reason has been identified and, quite frankly, we know that we do NOT have all the answers, because patients request that “anything be done that can be,” and because on the whole it is a fairly safe regimen, although it can be somewhat expensive.

Under these circumstances and, particularly, when used as ‘empiric therapy’, even when a successful pregnancy results, we cannot be entirely sure if our treatment was the deciding factor or it if was simply the result of chance. The original thinking was that somehow the anticoagulation properties of these agents prevented abnormal clotting of the placenta that was preventing the early pregnancy from developing normally. In recent years, we have discovered that other factors may be equally, if not more, important in early growth and development of the placenta as I allude to in my response to our reader’s questions below…

• At Sat Jan 19, 02:46:00 PM 2008, ONE OUT OF SIX said…

Dr. T - what are your thoughts on starting lovenox prior to implantation - either right before, or right after ovulation? And is your opinion the same in regard to a natural cycle as opposed to an ovulation induction cycle in which ovulation is then triggered with HCG? Also - does the patient already being on a daily baby aspirin have an impact one way or the other?

It has been suggested to me that being on both baby aspirin and lovenox (40mg/once a day) could actually inhibit implantation by causing a bleed at implantation site.

Others have said this is not the case at all - and in fact the opposite is true - healthier blood flow to uterus will assist with implantation (that may have been prevented in the past by diagnosed clotting disorders - homo MTHFR C677T and hetero Factor V.)

Last question - can you move to Pittsburgh, PA so I can become a patient? ;-)
Thanks for your insight.

• At Fri Jan 25, 10:53:00 AM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To One out of Six: Flattery will get you an answer EVERY TIME! Personally, I rarely will start lovenox or heparin before midway through the luteal phase after spontaneous ovulation or ovulation induction (about day 20-21) unless you have documented antiphospholipid syndrome or another condition that requires chronic anticoagulation. The reasons for that are it may increase bleeding from the ovarian ovulatory site (and, personally, I have taken two young women, who were not even on lovenox or aspirin, to the operating room in the past month with bellies full of blood from that very thing) and I sincerely doubt it does much good until the embryo has reached the uterine cavity and attachment has actually taken place. With all that said and done, on prophylactic doses of lovenox such as you are taking, it probably would not hurt or put you at much risk.

With regard to recurrent early pregnancy loss, however, the anticoagulation properties of lovenox and aspirin may be LESS important than their roles in improving trophoblast invasion and migration! This may be especially true under those circumstances in which 'thrombophilic antibodies' such as lupus anticoagulants, antiphospholipid antibodies, and anti-β2-glycoprotein-1 antibodies are present. These antibodies can bind to the trophoblasts in association with β2-glycoprotein-1 and impair both trophoblast invasion and migration that are necessary for early pregnancy success. Interestingly, heparin and lovenox can reverse the effects of these antibodies by blocking their binding to β2-glycoprotein-1. Anyway, I will put your question and my answer into a brief post on this subject soon (and perhaps a larger series later on) so, thanks for reading, for the excellent questions, and best of luck!

Dr T

Labels: heparin, lovenox, recurrent pregnancy loss, thrombophilias

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Plasminogen Activator Inhibitor-1 (PAI-1): Role in Adverse Pregnancy Outcome? - 2 - Late Pregnancy Complications

In our last post, we discussed the role of plasminogen activator inhibitor-1 (PAI-1) in helping to maintain the balance between the clotting and fibrinolytic (clot-dissolving) sides of the coagulation system. The primary function of PAI-1 is to inhibit plasminogen activators (t-PA and u-PA) from converting plasminogen to plasmin which is responsible for initiating fibrinolysis. The premise is that if there is too much PAI-1 activity, clots will tend to hang around longer and if there is too little, the individual would be at increased risk for bleeding problems. Before we can address possible roles of abnormalities of PAI-1 production and activity in adverse pregnancy outcome and recurrent pregnancy loss (RPL), it would be helpful to understand changes that might occur in these parameters during normal pregnancy.

Kruithof and colleagues (Blood 1987;69:460-6) reported that both plasminogen activators (t-PA and u-PA) and plasminogen activator inhibitors increased during pregnancy. t-PA and u-PA increased 50% and 200%, respectively, throughout normal pregnancy. They also found that PAI-1, produced predominantly by endothelial cells lining blood vessels, increased nearly 10-fold by term over that found in nonpregnant women and a second plasminogen activator inhibitor, PAI-2, not found in nonpregnant women, but produced by the placenta, was present in very high concentrations by term. The increase in both activators and inhibitors appeared to maintain the balance between the clotting and fibrinolytic systems during normal pregnancy because no changes in plasminogen or the overall fibrinolytic activity were found. Within “three to five days after delivery most parameters of the fibrinolytic system were normal again.”

In 1989, Estelles and colleagues (Blood 1989;74:1332-8) reported that women with severe preeclampsia in third trimester had significantly higher levels of PAI-1 than nonhypertensive women. Interestingly, PAI-2 levels were significantly lower in the preeclamptic women and a positive correlation between birth weight and PAI-2 levels was found (in other words, the higher the PAI-2, the greater the birth weight); and birth weight was inversely correlated with PAI-1 levels (higher the PAI-1 activity, the lower the birth weight). The presumption is that the lower PAI-2 levels correlated with a decreased placental mass or function in preeclamptic women. Regardless, the high levels of PAI activity in severe preeclampsia appear to be solely related to the increased activity of PAI-1. And, as many of our readers are aware, this might account in part for the coagulation abnormalities frequently accompanying the more severe forms of preeclampsia.

Unfortunately, these observations late in pregnancy don’t really tell us whether elevated levels of PAI-1 in preeclampsia are a cause, an effect, a response, or a contributor to the disease process itself. Based on several observations by other investigators, and the putative role of PAI-1 in placentation early in pregnancy (which we will eventually get to here), perhaps it is all the above. There does appear to be a genetic predisposition/association with abnormalities in PAI-1 production and later pregnancy complications. Yamada and colleagues (J Hum Genet 2000;45:138-41) evaluated the association between preeclampsia and deletion/insertion polymorphisms (4G or 5G) in the promoter of the PAI-1 gene. The 4G/5G polymorphism was assessed in 115 women with preeclampsia, 210 normotensive pregnant women and 298 nonpregnant controls. The frequency of the 4G allele (which results in increased production of PAI-1) and of 4G/4G homozygosity was significantly higher in the preeclamptic women than either the normal pregnant or nonpregnant controls, suggesting that the presence of 4G is one risk factor for preeclampsia and perhaps more severe manifestations of the disease.

Along the same lines, Glueck, et al. (Metabolism 2000;49:845-52) evaluated complications in 133 women with at least one pregnancy, and found a significant association of the 4G/4G PAI-1 polymorphism with prematurity, intrauterine growth restriction (IUGR), and “total complications of pregnancy” that was independent of the presence of other genetic thrombophilias (factor V Leiden, MTHFR C677T, and prothrombin G20210A mutations). In a subsequent study (Glueck, et al., Obstet Gynecol 2001;97:44-8), they reaffirmed the presence of the 4G/4G genotype as a risk factor for IUGR and extended their findings to include associations with severe preeclampsia, placental abruption, and stillbirth. They also reported that “the hypofibrinolytic 4G/4G mutation of the PAI-1 gene…is frequently associated with the thrombophilic factor V Leiden mutation” which would further increase the risk of problems related to clotting.

Over the years, PAI-1 made by vascular endothelial cells was found to be induced by angiotensin II which is produced by the action of the angiotensin I-converting enzyme (ACE). In a fascinating paper published in 2003, Xia and colleagues (J Soc Gynecol Invest 2003;10:82-93) reported that 18 of 20 women with severe preeclampsia were found to have IgG antibodies to the angiotensin II type 1 (AT1) receptor. None of 18 normotensive pregnant women had these autoantibodies. They also found that the serum from the same 18 of 20 women with these AT1 receptor autoantibodies stimulated PAI-1 secretion by trophoblasts (placental cells) in culture. Activation of the trophoblast AT1 receptors was also correlated with decreased trophoblast migration and invasion in tissue culture models and this, too, was directly correlated with PAI-1 production. We will return to this point in our subsequent discussion of the role of PAI-1 in recurrent early pregnancy loss. Bobst and colleagues (Am J Hypertens 2005;18:330-6) further reported that AT1 receptor autoantibodies found in preeclamptic patients stimulated PAI-1 (and the cytokine IL-6) production by human kidney (mesangial) cells in culture. Reversible ‘damage’ to the kidney is one of the events which characterize preeclampsia and the more severe the kidney impairment, generally, the more severe the preeclampsia with regard to hypertension and decreased urine production...(more to follow!)...

Labels: IUGR, PAI-1, preeclampsia, thrombophilias

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Plasminogen Activator Inhibitor-1 (PAI-1): Role in Adverse Pregnancy Outcome? - 1 - Introduction

In a post at the end of September, we summarized a series of questions from a 26 year old, otherwise healthy, reader who had had recurrent early first trimester pregnancy losses. Her ‘work-up’ to date had been relatively unremarkable, however, she was found to be a carrier for the plasminogen activator inhibitor-1 (PAI-1) 4G/4G polymorphism and her queries revolved around the possible role of PAI-1 polymorphisms in recurrent pregnancy loss (RPL), options for ‘therapy’, and the utility and safety of such therapy. In the last comment from her cited in that earlier post, she notified us that she had actually conceived again, but unfortunately, a few days later, she again miscarried. Is her PAI-1 polymorphism contributing to her early losses? To be honest with you, I don’t know at this point. I can think of other possibilities that may be just as likely, but her questions are very good ones, and it was well worth my time to look into the literature on the issue and perhaps draw some conclusions that may help her or another reader who is in a similar situation...

First of all, what is PAI-1? The best way to explain PAI-1 is to describe what it does. The blood clotting system is made up of many different factors, some which cause a clot to form and others which cause the clot to breakdown, and these coexist in a very delicate balance. When the blood clotting pathways are activated, fibrinogen, a soluble plasma glycoprotein, is polymerized to form fibrin which is then cross-linked by the action of factor XIII to form the ‘clot’. Under normal circumstances, as soon as a clot forms, it begins to be broken down by other plasma factors. Specifically, a substance called tissue plasminogen activator (tPA) converts an inactive plasma protein, plasminogen, to the active substance, plasmin, which then plays a critical role in the breakdown of fibrin (fibrinolysis), thereby ‘dissolving’ the clot. (Interestingly, and perhaps germane to our discussion at some later point, plasmin also plays important roles in ovulation, cell migration, and epithelial cell differentiation).

PAI-1 fits into this balance as the primary inhibitor of tPA and other ‘plasminogen activators’ in the blood. To put its role in perspective, by inhibiting tPA, PAI-1 prevents the activation of plasminogen, thereby controlling the rate and extent of fibrin degradation (clot break down, or fibrinolysis) that occurs. Overactivity of PAI-1 will therefore lead to a tendency to form (or maintain) clots and an underactivity will result in an increased risk for bleeding. (With regard to other known functions of plasmin mentioned above, overactivity of PAI-1 might then also impair ovulation, cell migration, and epithelial cell differentiation).

Control of PAI-1 production is complex, but it is at least partly determined on a genetic basis. Certain polymorphisms of PAI-1, 4G/4G and 4G/5G, are associated with increased blood concentrations of PAI-1. Elevated PAI-1 levels have been correlated with risk for both arterial and venous thromboembolic conditions (e.g., deep venous thrombosis, pulmonary embolism, and stroke) and atherosclerotic disease (.eg., coronary and carotid artery disease), especially if other genetic (e.g., factor V Leiden; prothrombin G20210A; MTHFR polymorphisms; protein C, protein S, and antithrombin III deficiencies) or inherited (e.g., antiphospholipid antibodies; lupus anticoagulant; anti-beta-1-glycoprotein) thrombophilias are also present. Individuals with insulin resistance syndromes and diabetes mellitus frequently have elevated PAI-1 levels. Obesity and hyperlipidemia are also associated with elevated PAI-1 and under certain circumstances, weight reduction and/or reduction in cholesterol and triglycerides, can lead to reduction in PAI-1 levels.

In our next post on this subject, we will begin to explore the possible association and mechanisms of PAI-1 activity with adverse pregnancy outcome and recurrent pregnancy loss…

Labels: PAI 1, pregnancy loss, thrombophilias

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Retinal Arteriole Occlusion in Early Pregnancy

The comment below was left on a recent post regarding "Readers' Questions Related to MTHFR Polymorphisms." The reader presents a very unusual complication early in her first pregnancy - retinal arteriole occlusion - and the response to her query does not have a ready answer, but it sure was fun to try to come up with one!

I'm now pregnant with my first child. At 9 weeks I developed an arteriole occlusion in the retina of my right eye with some vision loss. My OB did quite a lot of testing and I was found to be positive for homozygous MTHFR. My homocysteine level (not fasting) was normal and my doc doesn't think I need Lovenox or Heparin. I'm on baby aspirin alone but questioning if I should be on additional therapy or seek a second opinion. Any suggestions? Of note, I'm an otherwise healthy 29 year old with no history of lost pregnancies or other clotting problems.

One of the hardest things about responding to a question like this from afar is inadequate information and the inability to question the patient in person and to perform an adequate examination. The obvious concern is why did a “healthy 29 year old” pregnant woman develop occlusion of a retinal arteriole to begin with. We are told that she had “quite a lot of testing done” but without knowing what tests were done, it is hard to know what other tests should be done so that our reader’s question might be best answered.

Retinal arteriole occlusions are most common in older individuals, typically in their 70’s, and in that group, they are usually the result of embolic events – most often cholesterol emboli from atherosclerotic disease in the aorta or carotid arteries, calcific emboli from valvular disease in the heart or atheromatous plaques, and platelet/fibrin emboli from foci of thrombosus in the heart or vascular tree. It has been estimated that less than 1 in 50,000 patient visits to an ophthalmologist will be for the indication of retinal arteriole occlusion in someone less than 30 years of age (Greven, et al., Am J Ophthalmol. 1995;120:776-83).

Indeed, causes of retinal arteriolar occlusion in younger folks are typically NOT related to embolic events, although there are still circumstances when they still can be. Conditions that may increase the risk in this age group include sickle cell hemoglobinopathies, smoking, diabetes, hypertension, genetic and acquired thrombophilias (e.g., antiphospholipid antibodies, lupus anticoagulant, anti-β-2-glycoprotein-1, factor V Leiden, antithrombin III deficiency, protein C and S deficiencies, prothrombin mutation, hyperhomocysteinemia, and, perhaps MTHFR polymorphisms and plasminogen-activator-inhibitor-1), hyperlipidemia, cocaine and IV drug use, cardiac arrhythmias (e.g. atrial flutter) and valvular disease (e.g., bacterial endocarditis), hyperviscosity syndromes, as well as pregnancy and use of hormonal contraceptives. Other conditions that should also be considered are HIV infection, use of certain herbal products and prescription medications such as sildenafil citrate (Viagra) to increase libido, Behcet’s disease, and a host of less common infectious/inflammatory diseases. A history of migraine headaches is also very common among younger women who develop retinal arteriole occlusion.

So the first thing we need from our reader is a very good history, including family, dietary, and social, to query for risk factors and to select for further evaluation from the myriad of possible causes for this condition in women of her age detailed above. She needs a thorough physical exam with blood pressure, cardiac, vascular, and ophthalmologic evaluation, the latter of which she most likely has already had. Serious consideration should be given to both an electrocardiogram (or Holter monitoring) and an echocardiogram to evaluate the rhythm and structure of her heart. Unless some other physical finding such as carotid bruits dictate, carotid Doppler studies are probably unnecessary at her age. Consideration should be given to screens for syphilis (remember, false-positive results are associated with thrombophilias), general autoimmune disease (e.g., ANA, rheumatoid factor), selected genetic and acquired thrombophilias (choose from above!), homocysteine (although if she is on supplemental folic acid, or was at the time her initial homocysteine level was performed, this will probably be 'normal'), complete blood count with platelet count, hemoglobin electrophoresis, diabetes, lipid profile, HIV, and perhaps even blood cultures for bacteria that might be associated with endocarditis and valvular disease.

Interestingly, despite the association of the thrombophilias with venous and arterial thromboembolic disease, I am not aware of any good study that has correlated MTHFR polymorphisms (even in the homozygous state) with retinal arteriole occlusion. Lowenstein and colleagues (Am J Ophthalmol. 1997;124:840-41) were the first to demonstrate the presence of the MTHFR C677T polymorphism in a patient who presented with retinal vein occlusion. In a subsequent study (Ophthalmology 1999;106:1817-20) they reported that among 59 patients with retinal vein occlusions, 44% were heterozygous and 11% were homozygous for the same polymorphism. Around the same time, Saloman and colleagues (Blood Coagul Fibrinolysis 1998;9:617-622) reported an association between MTHFR C677T homozygosity and retinal vein occlusion in 102 patients (OR 1.9; 95% CI 0.95-3.81). However, a retrospective study of 174 patients in Ireland demonstrated no association between MTHFR homozygosity and either retinal vein or arterial occlusive disease (Cahill, et al., Br J Ophthalmol 2001;85:88-90). I am also unaware of any studies that indicate elevated homocysteine levels are associated with retinal arterial occlusion. Indeed, one study from Scandinavia found no association of either the MTHFR C677T polymorphism or homocysteine levels among 116 patients even with retinal vein occlusion (Larrson, et al., Acta Ophthalmol Scand 2000;78:340-343.

So, how do we counsel our reader. I suppose if nothing other than the homozygous MTHFR C677T polymorphism is found, most likely the baby aspirin, supplemental folic acid and prenatal vitamins may be adequate therapy. If some other risk factor is found upon subsequent evaluation, then her treatment should be adjusted accordingly. Admitting our limitations in current medical understanding due to the ‘unknowns’ that might have led to her retinal arteriole occlusion, and since this is such an unusual condition in young women, her pregnancy should be followed very carefully for evidence of complications related to abnormalities of placentation. Remember, thrombophilias in particular are associated with intrauterine growth restriction, fetal loss, pregnancy-induced hypertensive disorders, and early delivery.

I would suggest she have maternal serum screening done at 16 weeks, a ‘targeted sonogram’ at about 20 weeks, and a follow-up assessment of fetal growth and Doppler flow studies at 26-28 weeks. Understand, there is no standard of care here, but such an approach might help anticipate fetal complications and, thereby, allow for antepartum testing that might reduce her risks for an untoward outcome. She must also be made aware that retinal arteriole occlusion is associated with long-term risks for both cardiovascular disease and stroke and if she does have an underlying thrombophilia as the cause, other thromboembolic complications.

Thanks to our reader for sharing her story and for a most challenging question!
Dr T

Labels: MTHFR, retinal arteriole occlusion, thrombophilias

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Plasminogen Activator Inhibitor 1 (PAI 1) and Recurrent Pregnancy Loss

Back in June, a reader I.R. left a comment on my post "Recurrent Early Pregnancy Loss - 7 - Immunologic a...". Her specific question related to the possible role of plasminogen activator inhibitor 1 (PAI 1) activity and polymorphisms in recurrent pregnancy loss. The question interested me so much at the time, that rather than answering it in cursory fashion, I promised her I would review the current literature and devote a full post to the issue “in the near future.” Despite my having been, repeatedly, sidetracked, I.R. has remained a loyal reader, and insightful patient, and updated me regularly on her progress. Today, in the paragraphs below, I am going to summarize (and modify for clarity) her story with excerpts from her comments and then summarize my thoughts on the issues she has raised in a follow-up post ….

Dr. Trofatter, I have been diagnosed with Recurrent Pregnancy Loss. I've lost three early pregnancies- 6 weeks, 7 weeks, and 4 1/2 weeks- over the last year. After the third loss, my husband and I went through testing in March 2007 and it's been determined that I have a PAI 1 (4G4G) genetic mutation… I am a healthy 26 year old. I have found a wonderful hematologist that goes above and beyond for me. However, I'd like to know your perspective of how PAI 1 correlates with early first trimester miscarriages… I am having a difficult time finding much information on PAI 1 and miscarriages. It seems that most blood clotting disorders cause second trimester miscarriages; however, I feel that scientists and doctors are still building correlations between clotting and early first trimester losses. Thanks for any advice! I.R.

In August, this was followed by another comment on my post "Diabetes in Pregnancy - 2 - Glucose Metabolism and...":

Dr. Trofatter, I have yet another question. My last miscarriage was in February. I have been trying to get pregnant all summer…using ovulation sticks. Does PAI 1 have anything to do with me not being able to conceive? I've mentioned to two of my doctors the connection of PCOS (polycystic ovary syndrome) and PAI 1 and they all agree that I do not fit any of the typical picture of PCOS; however, after asking for a glucose/insulin test, I am now scheduled to get one. Do you think this is a good step? I know that PAI 1 has something to do with insulin which has to do with the endocrine system which can affect ovulation. I've never had issues in the past getting pregnant, just maintaining my pregnancies. I do not have diabetes. Any advice would be greatly appreciated! No matter how much I try to research PAI 1 and recurrent pregnancy loss, I can’t seem to understand it. Thanks so much for your time! I.R.

A few weeks later, I.R. left another comment on the same post…"Diabetes in Pregnancy - 2 - Glucose Metabolism and..." (sometime I have really got to finish up that series too!)…

Hi Dr. Trofatter, Low and behold, after a few months of asking for an insulin/glucose test, my wish was granted last week. I received my results yesterday and both fasting tests were normal and my two hour glucose was normal as well; however, my two hour insulin levels were elevated which is evidence of insulin resistance…I have mentioned the correlation of PAI 1 and insulin to my doctors a couple of times before but was essentially dismissed because I don't fit the "criteria" of a person who has insulin resistance. I'm not overweight at all and I'm not inactive…I start glucophage with hopes of increasing the quality of my ovulation. I do ovulate "regularly" on CD 15. What are your thoughts of taking glucophage (Metformin) while pregnant?...I know that it is controversial either way. I would appreciate any insight about the connection of PAI 1 and early trimester pregnancy loss as well as its connection to insulin.
Hope you're doing well! IR

I actually did respond briefly to this query and my comment included the following thoughts: There indeed appears to be a need to increase insulin sensitivity in first trimester to aid in proper implantation and placentation...I bet you will be home free from the baby's standpoint if you can get past twelve weeks...You will still be at increased risk for gestational diabetes...While you're at it, why don't you throw the progesterone support, baby aspirin, extra folic acid, and heparin or Lovenox into the mix as well...The latter I would not begin until a pregnancy is confirmed chemically (just about the time you miss a period)... Hang in there girl. I wish you the best on this and think you are going to be a great MOM! Dr T

Then, within two weeks of the above, the following comment was received from I.R.…

Hi Dr. Trofatter, I am on calendar day (CD) 31 and had a positive pregnancy test on CD 27. :) I started Lovenox and am continuing low dose aspirin, my prenatal vitamin and because of the insulin resistance diagnosis, I began glucophage on CD 23. I talked with my nurse today about a calcium supplement and also mentioned the glucophage. She talked with my doctor and she said that he wants me to stop taking glucophage. According to him, since I never made it to the maintenance dose (the 3 pills each day), then it isn't doing anything to help me. I've read elsewhere though that it can help prevent MC. She said that they only wanted me on it to regulate my ovulatory pattern, which does make sense to me, even though I do ovulate regularly just at a later day than 14. My question/concern is that my doctor isn't giving any thought to his decision of stopping glucophage and my diagnosis with PAI 1. This is such a big deal to me…I want to call again tomorrow, but would like a second opinion about my feelings as to whether they're rational or not! I really do like my RE (reproductive endocrinologist) and know that he's performed miracles for many women… Thoughts??!! Thanks again for your insight and time! It means so much! I.R.

To summarize I.R.’s many questions and to throw in a few of my own…
1) What is PAI 1 and what are its roles?
2) What is the association between PAI 1 activity and recurrent pregnancy loss?
3) Should screening for PAI 1 be a part of our regular evaluation of the couple with recurrent pregnancy loss?
4) What is the association between PAI 1 activity and insulin resistance?
5) Could PAI 1 activity be associated with infertility?
6) What role might glucophage play in the management of women with recurrent pregnancy loss and abnormalities of PAI 1 activity?
7) If glucophage is used in women with ‘insulin resistance’, is there a benefit to continuing it during pregnancy or should it be stopped, and when?
8) In the absence of clinical indication other than recurrent pregnancy loss, should the other medications (Lovenox and aspirin) be continued or stopped and when?

Actually, if I had all the answers to the above questions (and I am sure I will come up with a few more as I try to answer these), I would probably be quite famous, but in our next post on this subject, I will at least give you my thoughts! And, to I.R., thanks for your loyalty and your patience and best of luck with this pregnancy!

Labels: diabetes; insulin resistance, glucophage, lovenox, PAI 1, PCOS, plasminogen activator inhibitor 1, recurrent pregnancy loss, thrombophilias

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Comment Regarding Prednisone Therapy for Recurrent Pregnancy Loss

Below are excerpts from a comment/query that appeared recently on my post Recurrent Early Pregnancy Loss -6- A Special Patient. In this post, I recount my first experiences with a woman who had pregnancy complications (miscarriages and severe preeclampsia) associated with a 'thromobphilia' - in her case, lupus anticoagulant. Her fascinating medical history stimulated my interest in both recurrent pregnancy loss and the role of an appropriate immune response in pregnancy success. The reader's comments below reminded me how far we have come in our quest to understand factors that contribute to pregnancy loss...and also, how far we still have to go...

Anonymous said...
I was happy to read your thoughts on the immune/thrombophilic connections to recurrent pregnancy loss. I have had 3 miscarriages and 1 ectopic pregnancy causing emergency laproscopy and the loss of my right fallopian tube. We have been trying to conceive for 2 years...I recently saw a specialist in NYC... who diagnosed me with high antinuclear antibody (ANA) 1:320, speckled. I am now trying o conceive for the first time since the diagnosis and am nervous about taking prednisone. Have you noticed any severe side effects from this? I was also advised to take one baby aspirin (81 mg), 40 mg of Lovenox twice per day (I have homozygous MTHFR, homozygous PAI-1, heterozygous factor XIII V34L), Vitamin E, Metanx(a Folgard-like drug), progesterone(always had low progesterone around 7 after ovulation). I will probably take Clomid because in the past, it has helped raise my postovulatory progesterone levels...I have high CD 19 and CD 19+ cell, CD5+ on the NK (natural killer) cell assay...

Kenneth F. Trofatter, Jr., MD, PhD said...
To Anonymous Sept 20: You are a mess, Girl! Just kidding. I have seen much worse! It sounds like you are in pretty good hands. Did your doctors find any specific autoimmune antibodies known to be a problem in pregnancy, ie, anticardiolipin antibodies, lupus anticoagulant, anti-Ro(SS-A), or anti-La(SS-B)? Not that any of those would change your therapy at this point very much.

Your primary question seems to be related to the prednisone therapy - how much are you taking each day? Many years ago, prednisone was the foundation of our therapy for women suspected of having an immunologic basis for their recurrent pregnancy loss. Over the years, the literature has shown no great benefit of that, and potentially some harm, over anticoagulation therapy with unfractionated and low-molecular weight heparin (Lovenox). I usually reserve the prednisone for women with diagnosed autoimmune conditions such as systemic lupus erythematosus (SLE), who need to be treated for acute flares in their disease, and for women who decline heparin therapy because of the need for daily injections. Incidentally, despite the "high ANA," you do NOT meet the criteria for SLE (from what you have told me so far) and, indeed, many individuals who have modestly elevated ANA have no identifiable autoimmune or pregnancy-related problems whatsoever!

Prednisone therapy during pregnancy is associated with increased risk for gestational diabetes, infectious complications, premature rupture of membranes, and early delivery. It also increases your appetite (and weight) and fluid retention at high enough doses. If you absolutely don't need prednisone, try to get off of it by 20 weeks gestation. It probably isn't going to help much beyond first trimester in your case anyway.

Incidentally, I have also found that women in your situation with homozygous PAI-1 are insulin resistant and often benefit from therapy with glucophage (metformin) prior to and during their pregnancies. Anyway, thanks for reading and writing and I wish you the best of luck!
Dr T

Labels: recurrent pregnancy loss, thrombophilias

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Another Late Midtrimester Pregnancy Loss

Soumya has left a new comment on your post "Recurrent Early Pregnancy Loss - 6 - A Special Pat..." (I have modified/revised her comment somewhat to the best of my understanding of her concerns)...


Hi I lost my pregnancy at 24 weeks on July 17. Actually I didn't have any complications during pregnancy. When I didn't feel any movements for 5 days, I went to the hospital and they didn't find my baby's heartbeat. My doctor said that blood results are showing protien C and protien S deficiencies and an MTHFR abnormality. She told me that perhaps these abnormalities caused the blood to clot in the placenta and that I should see a high risk specialist before another pregnancy so that he can give me treatment to help overcome these problems. She also said that after delivery protein C and protein S generally will be reduced.... When I lost my baby I didnt have any other symptoms like bleeding or stomach pain except when the baby moved. There is no family history of blood clotting problems. Can you tell me what would be the reason and if so what will be the treatments for blood clotting? Should I start the medication before another pregnancy or only after getting pregnant?
Fri Aug 10, 11:14:00 PM 2007

Kenneth F. Trofatter, Jr., MD, PhD said...

To Soumya: I am sorry for your loss. The most common causes of late midtrimester fetal demise are fetal chromosomal abnormalities (and, less commonly, genetic abnormalities), infection, congenital birth defects, and abnormalities of placentation (that may be associated with "blood clots," sterile inflammatory changes, and fetal growth restriction). The latter are also often associated with maternal pregnancy-related hypertensive disorders and premature placental separation (abruption).

Usually during pregnancy, protein S levels decrease and protein C levels remain the same or are only slightly lower, so from what you have told me, I cannot be sure the results you describe above are actually 'abnormal' or simply related to the pregnancy itself. It would help me if I knew what tests were done to measure protein S and protein C, the actual test results, and the 'normal' range of test results in the laboratory that did the studies. It would also be helpful if you could give me more specific information regarding the MTHFR abnormality (the specific 'polymorphism(s)' and whether this is heterozygous (one dose), homozygous (two doses), or complex heterozygous (two different abnormal genes)).

Now that you are no longer pregnant, you should go to the specialist BEFORE you get pregnant again to be tested for these and other factors that are associated with pregnancy losses and increased risk for blood clots. The best way to test for protein C and protein S deficiencies is to have a test for "functional protein C and S activity" (don't ask me to explain that here!) BEFORE you get pregnant again. Other studies that can be done to look for autoimmune or genetic thrombophilias (factors that increase your risk for either making blood clots or not breaking them down efficiently) include: antiphospholipid antibodies; lupus anticoagulant; antithrombin III levels; factor V Leiden mutation; factor II (prothrombin) G20210A mutation; and homocysteine levels. On rare occasions, mutations in the plasminogen activator inhibitor-1 (4G/4G) are also associated with increased risk for blood clot formation and pregnancy losses.

Ask the doctor who delivered your baby if the placental pathology showed any specific evidence of infection or blood clot formation (either placental abruption or evidence of vascular abnormalities or inflammatory changes). Without abdominal pain or bleeding, it is unlikely that you had a placental abruption. Was the placenta normal size? Did the baby appear normal and was it a normal size for 23-24 weeks (i.e., what did the baby weigh)? Was there any evidence of the baby having a chromosomal abnormality (and were chromosomal studies sent) or an infection (bacterial, viral, or parasitic)? Did you have any evidence of infection when you were admitted to the hospital (high white blood cell count, fever, bladder infection)? Did you have cultures sent for Group B Streptococcus? Were you or the baby tested for cytomegalovirus or toxoplasmosis infections or other organisms that are known to cause problems in your country?

If any blood clotting problems are found, a specialist in high risk obstetrics or hematology can counsel you regarding the best ways to reduce the risk for a pregnancy complications for both you and the baby. Sometimes this means simply having to take extra folic acid (2-4 mg per day) and/or a baby aspirin (81 mg). In other situations, it may be best to treat you with either prophylactic or even therapeutic levels of anticoagulation therapy (by self-injection of heparin or low-molecular weight heparin) for part or all of the pregnancy. Before you get pregnant again, you might also consider sitting down and talking with a genetic counselor who might help identify risks that may not be so obvious and help you to better understand some of your risks based on the findings of your doctors. I do hope things turn out better for you the next time. Let me know, okay? Thanks for reading and for the good question! Dr T
Fri Aug 17, 12:26:00 PM 2007

Labels: MTHFR, pregnancy loss, thrombophilias

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