Friday, July 21, 2017
Friday, July 21, 2017
Kenneth F. Trofatter, Jr., MD, PhDPregnancy and Childbirth

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

Kenneth F. Trofatter, Jr., MD, PhD
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!)...

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  • At Fri May 02, 06:43:00 AM 2008, Anonymous Anonymous said…

    I lost 2 baby girls in the past year. After the first loss, a placental abruption at 20wk5d, we learned I had a homozygous PAI-1 deficiency. Early in the second pregnancy, I was started on Lovenox 60mg BID. I started bleeding around 9 weeks so the dosage was reduced to 60mg QD. At 23wk6d I went into preterm labor and presented with hourglassing membranes. The baby was born at 24wk2d. The specialist feels the dosing may have been to much for me as evidenced by the early bleed. There is some question regarding a possible abruption as well.
    I am just wondering your thoughts on dosages with Lovenox during pregnancy. Any information you can offer would be helpful.

  • At Fri May 02, 05:19:00 PM 2008, Blogger Kenneth F. Trofatter, Jr., MD, PhD said…

    To anonymous May 2: What other 'thrombophilias' were you screened for and do you have any other mdical problems? I would probably suggest going with a baby aspirin (81 mg) and a 40-60 mg/day dose of Lovenox (depending on your weight)on a prophylactic basis rather than therapeutic dose. Throw 2-4 mg/day of folic acid into the mix as well.

    I am somewhat concerned by your hoitory that you may also have an incompetent cervix. That can lead to premature cervical change followed by an ascending infection and then placental abruption. Talk with your doctor about this possibility. Thanks for writing and I am sorry you have had such a rough time of things. Dr T

  • At Mon May 05, 01:18:00 PM 2008, Anonymous Danielle M said…

    I am Danielle, the anonymous post from May 2! I wanted to give a little more info to further clarify my situation. Last year, a complete clotting panel was drawn. Some of the test were: antithrombin III act, ANA, Protein S, Protein S free, Protein C act, Protein C AG, viper venom, lupus anticoagulant, Cardiolipin, Homocystine. Several were repeated 6 weeks after the loss this February- for sure cardiolipin, lupus anticoag, ANA.

    My OB was checking my cervix on a weekly basis (Tuesdays) due to my history. I was admitted around 3am on a Monday morning, 23wk6d, so I am not sure about my cervix leading up to that day. I do know I was having contractions from at least 18wks but thought they were Braxton Hicks due to the lack of cervical change. US was "perfect" at 20 weeks. No cervical changes noted.

    I was on and terbutaline and magnesium for 2 days in the hospital. After 2 doses of steroids were administered, for the baby's lung development, the mag was stopped. Procardia was then started. Spiked a temp on Thursday and MFS felt it was in our best interest to deliver. She was just too young.

    I was on 600mg of amoxicillian, prophylactically, this pregnancy because the placenta was positive for infection after the first delivery in '06. I was/am also taking 81mg of baby aspirin since dx of PAI-1 deficiency. I have also increased folic acid.

    I am RH-. Otherwise, I am a healthy 5'8", 135# (pre/post pregnancy) female. Per my OB, I look like an easy obstetrical patient but, in actuality, am quite complex!

    My OB and MFS have a "plan" for a future. While I respect and trust them completely, it is comforting to hear the same recommendations from someone else. They are also planning progesterone starting 16wk and weekly US from 20wk on (I think) to monitor my cervix. No prophylactic cerclage due to risks and "lack of" cervical insuff.

    Thank you for your time and consideration. I know I have written a book and have probably exceeded my question limit! Please know that your willingness to share your thoughts has been greatly appreciated.

    Danielle M.

  • At Tue May 06, 03:45:00 PM 2008, Blogger Kenneth F. Trofatter, Jr., MD, PhD said…

    Hi Danielle: Thanks for the update. I will be pulling for you throughout this pregnancy! Please let us know how things turn out along the way. Dr T

  • At Fri Jul 04, 12:43:00 PM 2008, Blogger Blake & Danielle said…

    Apparently you knew something i didn't with the last post. I did not know I was pregnant at the time but was. I am now 10wk3d and have had complications already. I began taking 40 mg of Lovenox on June 4th. I noticed trace bleeding by the 7th. I held the Lovenox that night and for the next few days. I did not resume until the spotting was comletely gone.
    Within 5 days of going back on the Lovenox, the spotting started again. I went back off the Lovenox and within 72 hours had a significant amount of bleeding. 2 vaginal ultrasounds over the course of a week revealed no bleeding/clots around the baby. However, a week and a day after the fact, a retrochorionic clot was seen. It was determined to be "small".

    This happened around the same time with my last pregnancy but I was on 60mg BID at that time. MFS felt the early bleed played a significant role in preterm labor last time. I now find myself in the same position. It is planned for me to begin progesteron injections at 15/16 weeks.

    I am concerned about going back on Lovenox, as it only seems to make me bleed. I am only taking 1 baby aspirin daily at this time.

    Any thoughts you have to offer would be greatly appreciated.

  • At Sat Jul 12, 08:02:00 PM 2008, Blogger Kenneth F. Trofatter, Jr., MD, PhD said…

    Danielle: I agree, it might be better to stay off the lovenox completely. They are also going to follow your cervix carefully this pregnancy, right? Best of luck. I will be oulling for you. Let us know how things develop along the way! Dr T

  • At Wed Oct 15, 06:03:00 PM 2008, Blogger Blake & Danielle said…

    Well, it is me again! I am now at 25 weeks, which is quite a milestone. I have managed to carry this little guy longer than either of his sisters!
    I currently have weekly progesterone injections and ultrasounds to monitor my cervix, although cervical insufficiency was never really thought to be the issue. I was put on bed rest at 17 weeks due to shortening of the cervix, noted while having a contraction during an ultrasound. (37mm to 25mm, returning to lower 30's as contraction relaxed) Until this past week my cervix has remained in the upper and mid 30's. On Tuesday, I began to contract when the probe was being inserted. By the time she took her initial measure, it was 27 mm but plummeted to 10 with the contraction. Funneling was noted before and after with my cervix only returning to 20 during the time frame observed.
    I have been having frequent contractions since 16 weeks and have most recently been using terbutaline (2.5mg) PRN when I have 4 or more contractions in an hour. Most weeks have I have only taken 1 pill, 3-4 days a week. Due to this weeks findings, I have started taking it every 8 hours. I still have some break through contractions but they are not regular at this point. Pending no changes, I will return to my OB on Tuesday and MFM on Wednesday.
    Hospital admission and preterm birth seem inevitable for the future. I would love any thoughts you have on the treatment of preterm labor. I know there are mixed opinions on how long one should be kept on magnesium sulfate, pending no other complications. I also used Procardia in the past and expect to see it again.
    I know it is difficult to give insight on cases that are not your own. That being said, I value any opinions/recommendations you can offer. Any guidance you can give will help with my peace of mind as we make decisions in the upcoming weeks. Thanks so much for your time and consideration!

  • At Sat Nov 01, 09:20:00 AM 2008, Blogger Kenneth F. Trofatter, Jr., MD, PhD said…

    To Danielle: Well, hello again. Sorry but I just got this in my mailbox. I hope it finds you still pregnant. With all the problems you have had, you really might benefit from a cerclage in your next pregnancy. Personally, I am not a big fan of oral terbutaline but if it works for you, so be it! I would rather give it by subcutaneous pump if that seems to be the drug of choice. I have become much more of a fan of procardia, although both drugs carry with them some unpleasant side-effects. Prior to 30 weeks, I frequently couple these drugs with a short course of indomethacin and sometimes follow-up with fairly high-dose ibuprofen until 32-34 weeks. I still aggressively use magnesium sulfate as an initial drug to 'break' acute pretem labor and then add the others depending on which seems to work best with each patient. Anyway, I hope you are doing well and wish you the best for the rest of the pregnancy. Let us know how things turn out! Dr T

  • At Thu Nov 13, 11:02:00 PM 2008, Anonymous Anonymous said…

    after losing one child at 28 weeks w/ no explaination and trying for 18 months we got pregnant again and wax dx w/ PAI i took heprin shots 2x a day to thwart the clots. due to unforeseen reeasons we has to relocate from Fl to Il well 6 days after arriving home the ultrasound tech found the blood flow to the placenta to baby was stopping we had and emergency c section and my son was born at 30 weeks wt of 3# .06 ozs.....he is now a very active 3 yr old my only child due to too much risk anymore... hopefully you and baby make it......count your blessings cuz mort rate for child is 75% and 50% for you... I'm praying for all who have to endure the stress knowing there is nothing they can do but hope God is kind!!!!!! I Thank god everyday for my son and the doctors who fought so hard to give me him w/ as little complications as possible

  • At Fri Nov 28, 08:52:00 AM 2008, Blogger Kenneth F. Trofatter, Jr., MD, PhD said…

    To anonymous Nov 13: Thank you for reading and for your comment. Best wishes. Dr T

  • At Tue Dec 09, 11:39:00 AM 2008, Anonymous Anonymous said…

    Just like Danielle, I have lost two baby girls in the past year. I delivered the first baby July 29, 2007 at 26wks because of me being diagnosed with preclampsia. The shot for the baby's lung development was administered and the baby lived until August 22, 2007. She was too early to survive. The second delivery was at 22wks because I developed preclampsia early and the baby could not survive in the womb and she was a stillbirth.
    After several lab test I learned I was deficient in PAI-1. I was told to take an 81mg aspirin per day and that Lovenox would be another suggestion after becoming pregnant again. I am already on Clonidine 0.2 mg daily for hypertension and 20mg Prednisone for too much protein in my urine.
    I want to get pregnant again, but I wanted to know are these drugs safe and what other drugs or preventive methods should I use to have a safe delivery and a healthy baby?

  • At Tue Apr 28, 10:19:00 AM 2009, Anonymous Anonymous said…

    Hi -
    I am responding because I tested postive for a PAI-1 deficiency after two miscarriages. I have been tested for a battery of other disorders, and the only other result of note is a postive 4G/5G. The first miscarriage was at 9w4d, the second 11w5d. In both pregnancies I developed subcorionic (spelling?) hematomas, which my doctors felt was an indication of either a bleed or a clot. In both situations, I was also spotting by week 8. In the second pregnancy, I took 81mg baby asprin daily, along with increased folic acid. This did not help sustain the pregnancy.
    In my third pregnacy (which was successful!), I also developed a subcoronic hematoma. However, in this pregnancy I was talking 100mg oral progesterone/2x daily & folic acid at the advice of a specialist who focused on recurrent pregnancy loss. At 9wks, my PAI-1 deficiency was diagnosed by a hematologist, and I began taking Amicar (6g)/6hrs tablet or 12ml /6hrs liquid form. Aminocaproic acid works as an anti-fibrinolytic or anti-proteolytic. My hematoma subsided around 12 weeks. (For me, the hematomas were casued by bleeds.) Throughout the pregnancy, I was sonogramed basic. every 2 weeks to monitor the growth of the baby and the health of the placenta. No issues developed, and I had an otherwise healthy pregnancy. For delivery, my son was taken via c-section at 37 weeks, under general anesthesia. The baby was taken early to prevent any abruptions or tears was the baby gained weight and the placenta aged. The reason for general anesthesia was because there is a theoretical risk of a hemmorage when using spinal anesthetic. My doctors, and my husband and I all agreed, why introduce even a theoretical risk. The thinking was also that a c-section, while major surgery, presented the most controlled situation.
    Interestingly, during my final trimester, my PAI-1 levels were detectable and measureable. My PAI-1 level was unmeasurable in trimesters 1 & 2. The theory here is that it was actually my PAI -2 level that the testing picked up, However, within 3 weeks post delivery, they returned to my normal level - undetectable.

    Prior to the pregnancies, I had never experienced any bleeding issues- with tooth extractions or with a d/c. My doctors feel that in my situation, this is a pregnancy related issue ONLY. If my husband and I decide to have another child, the same plan will be followed, except with starting the Amicar as early as possible. Just a note, I was told to steer clear of both asprin & Lovenox/Heparin during pregnancy b/c by my ob & hematologist - these medications would only exacerbate my problem.
    Hope this helps someone!

  • At Tue Dec 01, 11:51:00 AM 2009, Anonymous Anonymous said…

    Hi, ive had 3 miscarriages and rectly found out i had the genetic mutation PAI-1. What exactly does this mean and what shouls i do for future pregnancies?


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