Recurrent Pregnancy Loss and PAI-1: Thrombosis vs. Hypofibrinolysis as the Pathogenic Mechanism?
Wednesday, December 12, 2007
Kenneth F. Trofatter, Jr., MD, PhD
Below is a great comment from a reader who had the motivation (and fortitude) to tackle my recent series regarding polymorphisms of plasminogen activator inhibitor-1 (PAI-1) and poor pregnancy outcome. I am offering my response to our general readership because it summarizes concisely the major point of enlightenment I had myself during my reasearch on this subject...
Anonymous said...
Dr T.,
Thank you for this very interesting series on PAI-1. From my own personal experience with this defect (4G/4G mutation), I have found that most doctors are still not sure what to make of the experimental data to date. In general, I have received the following comments: 1) I don't think you have a blood clotting problem because you have no history of blood clotting even when you were on birth control pills. 2) I don't test for PAI-1 because regardless of the result I would suggest a person with repetitive miscarriages of your type try Lovenox therapy. 3) I think you do have blood clotting concerns but I don't think this is because of PAI-1. I suspect you have a yet-to-be-discovered variant of Factor V Leiden.
As for the first comment, my only thoughts are that somehow the interaction of PAI-1 and PAI-2 might be responsible for the blood clotting concerns during pregnancy. During one prior miscarriage, it was documented that my Protein S level plummeted in the early weeks of pregnancy, suggesting clotting activity was occurring. I continue to watch for news about PAI-1 and other clotting-related causes of pregnancy loss. I am hopeful that your series will encourage others to look more closely at this interesting gene.Fri Dec 07, 04:20:00 PM 2007
Kenneth F. Trofatter, Jr., MD, PhD said...
To Anonymous Dec 7: Thank you for your thoughtful response. What led to your being tested for PAI-1 in the first place? Was it repetitive early pregnancy losses or other pregnancy-related complications? Anyway, one of the things that dawned on me while writing this series is that the issues related to thrombosis (clotting) and those related to hypofibrinolysis, though related, may actually be SEPARATE issues when it comes to pregnancy complications. What I tried to point out is that even though hypofibrinolysis can lead to thrombosis, it might also lead to other defects (impaired ovulation and/or implantation) that are not related at all to thrombosis! I think this is a subtle point that most providers have missed. Of course when both occur, you've got the double whammy to contend with regard to suboptimal pregnancy outcome.
Incidentally, your doctor may be correct - you could have some other problem that we have not gotten smart enough yet to figure out and, he/she is also correct that an empiric course of therapy is often warranted even if we don't know what we are treating! By the way, protein S levels usually do drop, even during normal pregnancies, although usually this is after the first trimester. You might want to read a post that I wrote earlier this year regarding my first experience (many years ago) with a patient with repetitive miscarriages who only developed a 'lupus anticoagulant' after she conceived. After she got over that 'immunologic hurdle', she did just fine. I have often wondered if activation of the clotting system and the complement system early in pregnancy reflects a suboptimal immune response to pregnancy that can be overcome with time. Could that be your problem as reflected in the rapid drop of protein S activity? Again thank you for reading and best of luck to you!
Dr T
Wed Dec 12, 06:38:00 PM 2007
Labels: PAI-1, recurrent pregnancy loss
5 Comments:
At Sat Dec 22, 06:43:00 AM 2007,
knwd said…
Dr. Trofatter,
First of all let me say thanks for taking so much of your time to post information here. This site is one of the best sources I've found so far, and I've been doing a LOT of research on the web in the last 6-8 weeks.
I just turned 34, and I have had two miscarriages this year. The first was at 8 weeks, and the second was at 13.5 weeks. Since then, I've been to see both a Hemotologist and a Reproductive Endocrinologist, who have put me through several rounds of testing. This is what we know so far:
I am compound heterozygous (C677T & A1298C) for MTHFR, but my homocysteine level was 6. I also had two positive tests for anticardiolipin IgM antibodies (18 & 26) and an elevated level for PAI-1. I'm still waiting on the results from the genetic testing to find out if I am 4G/4G or 4G/5G.
I am currently taking a prenatal vitamin, Folbic (2.5 mg of Folic Acid plus B6 & B12), and baby aspirin every day. I also take Labetalol twice daily for my blood pressure.
I have a couple of questions. The first one (obviously) is what treatment you would recommend for pregnancy, and also what these conditions mean for the rest of my life.
My second question is around my family-- Who else is at risk, and for what? How do we find out? My mom has had clots in her legs, and there is strong history of high blood pressure on her side of the family. (My mom, uncle, and grandmother all have it, and they're all otherwise healthy and not overweight.) My dad had a brother who died of a heart attack at 50, so I'm worried about his health risks as well.
I also have a younger full-sister, half-sister, and half-brother, so I supposed that if I inherited these conditions from my mom, they would also potentially be at risk. My doctor's office said that most insurance companies won't pay for the genetic testing, which is frustrating.
At Tue Jan 01, 12:09:00 PM 2008,
knwd said…
Dr. Trofatter - Thanks very much for summarizing so much information regarding PAI-1 and other causes of miscarriage!
After two miscarriages, at 8 weeks and 13.5 weeks, I have been diagnosed as being compound heterozygous (677T and 1298C) for the MTHFR gene as well as homozygous (4G/4G) for the PAI gene. (My homocysteine levels were normal, but my PAI-1 levels were very high: 156.) I am not obese, I don't have symptoms of diabetes or PCOS, and I haven't had trouble conceiving.
I am currently taking prenatal supplements, Folic Acid / Vitamin B supplements, and baby aspirin every day, in addition to my blood pressure medication. My RE and I have already discussed starting heparin or Lovenox when I get pregnant again, and she also suggested metformin / Glucophage.
I understand that metformin seems to be helpful in regulating PAI-1 levels for people who have PCOS or diabetes, but do you know if there are any studies that have been performed outside of these conditions? Given that there aren't long-term studies on its safety, I'm not sure how to consider the risk vs. benefits of the drug. I am assuming that my PAI-1 levels are driven by genetics rather than another medical condition, so I'm wondering if metformin addresses the root cause or just the secondary mechanisms that cause elevated PAI-1 levels?
-knwd
At Thu Jan 17, 10:59:00 AM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To knwd Jan 1: I apologize for my delay in answering your question, but 'etecnical difficulties and pure volume of queries has had me playing catch-up for awhile. Anyway, I would recommend going with the metformin myself. It doe sget at the underlying metabolic difficulties associated with a genetic predisposition to elevated PAI-1. By reducing insulin resistance, even if you are not heavy or diabetic, yoou can reduce the production of PAI-1 at a transcriptional level. I would still couple that with a baby aspirin to help reduce contribution of PAI-1 production as the result of platelet activation in people who are programmed to be over-producers of PAI-1 as well. Metformin seems to be relatively safe to use throughout pregnancy, but in your caes, once you got into midtrimester, you could probably stop it and things will be just fine. Good luck, thanks for reading and let me know how things turn out! Dr T
At Wed Oct 22, 10:58:00 AM 2008,
Anonymous said…
Dr. Trofatter,
My son was stillborn at 35 weeks. I am 41 and this was my first pregnancy. I had difficulty conceiving, and only got pregnant after surgery to remove a fibrod and starting Clomid. I am overweight but did not have any medical problems during the pregnancy. I went in for a routine appointment and they could not find a heartbeat. I had no warning signs that there was a problem. I was tested and found to have a problem with the PAI-1 4G/5G. There was some minor problems with the placenta ( a few nodules I think, but I don't fully understand). I am still waiting to be tested for protein C and S deficiencys ( it has not been 12 weeks since delivery yet).
I have been researching trying to understand what happened to cause my baby's death and how to prevent it from happening again. My doctor has talked about staring me on Heparin or Lovenox when I get pregnant again.
My questions are: is there more that I can do to prevent another loss besides the Heparin? Will the heparin work, because I cant' face another devasting loss. Are there any tests or warning signs that a clot is forming to give us a heads up so I could have the baby before the clot kills it. My baby was far enough along at 35 weeks to have survived if we had known and delivered early.
Any information would be appreciated.
At Thu Oct 30, 03:29:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Oct 22: I am so sorry for your loss. What did the baby weigh when he was born? Did you have any hypertensive complications? What was the fluid like around the baby? Regardless, I do not know if heparin or lovenox will help you because I am not sure we understand why you actually lost your baby. If you had had fibroid surgery, it is possible the placenta implanted at a suboptimal site and the baby simply outgrew its placenta by 35 weeks. There is also the possibility that a 'cord accident' occurred, but those are fairly unusual unless the cord is abnormally developed or very thin as is seen sometimes with abnormalities of placentation and intrauterine growth restriction. Certainly heparin or lovenox at a 'prophylactic' dose level would be safe enough to use under the circumstances, but another pregnancy should be followed by serial assessment of fetal growth and Dopplers and then regular antepartum testing once you get past 28 weeks, hopefully, to detect evidence of fetal compromise before the baby is in serious trouble. Thankd for writing and kind regards, Dr T
Post a Comment
<< Home