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Bleeding and Clotting Disorders

PAI 1 G4/g5 & MTHFR A 1298C One Copy Mutation



Hi My husband was recently tested for blood clotting disorders and came out positive for one copy of MTHFR 1298C and PAI 1 G4/g5 mutations. He has never had any thrombophilic event ever. He just went in to consult with a heamatologist today, who refused to see him, in absence of any history of clot or blood disorder. Now he wants us to wait till anything of this nature arises in future. I want to know, if its okay to take extra folic acid or a blood thinner like BA. I too have MTHFR A 1298C homozyogous mutation, and my perinatologist feels that I should take extra folic acid throughout my life. Need your help in understanding the risk factors associated with PAI 1 mutation and if there is anything he can do to avoid these risks. Thanks


My first question would be, "Why was your husband tested?" if he has never had a thrombotic event.  I suspect he was tested in the context of pregnancy, given that it sounds like you are seeing a high-risk specialist and have had a thrombophilia workup yourself.  If this is the case, and he is asymptomatic and healthy, I would absolutely agree that no action needs to be taken (in terms of his treatment) based on these results. 

With our current level of knowledge, there is no evidence to suggest that PAI 4G/5G (a heterozygous PAI mutation) or that MTHFR heterozygous A1298C increase the risk of thrombosis (blood clots).  Years ago, when we had more limited research, there was concern that MTHFR homozygous mutations may lead to elevated homocysteine levels, and elevated homocysteine levels were associated with a higher risk of blood clots and certain complications of pregnancy (miscarriage, preeclampsia, placental abruption, small-for-gestational age babies.  People were often treated with baby aspirin and/or folate/B6/B12 vitamins in an effort to "counteract" the potential effects of the mutation, and to lower homocysteine. 

The problem is that we now know that MTHFR mutations do not really cause problematic homocysteine levels.  This is because our diet in the US is so fortified with B vitamins already that very few people will develop homocysteine elevations, even when they have these mutations.  The original studies that showed that MTHFR led to elevated homocysteine were done in Europe, before the fortification.

To double check this, one could have their homocysteine checked.  If it is normal, this provides further evidence that there is no need to treat.  Even if homocysteine IS slightly elevated, there is now debate about treating that, since we now know that lowering homocysteine doesn't seem to help prevent blood clots.

The evidence around PAI is even more scarce, but current recommendations do not support testing, or treating, this mutation, especially in the heterozygous state.  I hope this helps.  

Best of luck to you.

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Response by:

Elizabeth A Varga, MS, CGC
Clinical Assistant Professor of Pediatrics
College of Medicine
The Ohio State University