Recurrent Pregnancy Loss and PAI-1: Thrombosis vs. Hypofibrinolysis as the Pathogenic Mechanism?
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...
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!
Wed Dec 12, 06:38:00 PM 2007