Maternal Floor Infarction (MFI) demystified?

I was pleased to see that the paper on LCDH mutations and maternal floor infarction was finally published[1]. The material had been presented at the Philadelphia SPP meeting. This is a paper of courage and persistence in tracking down a long shot based on a single case report.

By now everyone agrees that maternal floor infarction is a misnomer at least for most of the cases so labeled. The pathology is a diffuse increase in peri/inter villous fibrinoid and usually with some intervillous thrombi. To understand the lesion, the conditions in which perivillous fibrinoid forms must also be understood. I think this understanding can be achieved following the advice of Yogi Berra “You can observe a lot just by watching”.

We see fibrinoid at the edges of old infarctions. The center of the infarction has lost all  blood flow and shows a collapsed intervillous space and complete coagulation of the villi, outside of which is a shell of perivillous fibrinoid with entrapped villous cores, and then villi adapting to low blood flow that are narrow with increased syncytial knots (yet another misnomer) and capillary syncytial membranes.  A similar pattern can be seen around old intervillous thrombi. There are stalactites of fibrinoid dripping from the subchorionic plate where they seem to follow the likely low flow areas from the fountain like spiral artery perfusion of the intervillous space. To me the common factor in all of these locations is an intermediate degree of hypoxia between coagulation necrosis of syncytium and syncytial adaptation.

The next relevant observation is at the edges of intervillous fibrinoid particularly in areas of massive perivillous fibrinoid deposition. The edges show apoptotic appearing condensation of the syncytial nuclei and apparent peeling off the syncytium.  The result is an exposed surface of the villous stroma with preservation of the subsyncytial Langhans cytotrophoblast . The process might be an overly exuberant expelling of synctytial knots. The end result of such exposure is cytotrophoblast proliferation and production of surrounding extracellular matrix and the layering of fibrin from the intervillous space. If isolated the villous surface is “re-epitheliazed”  by syncytium,  but in rapidly forming deposition the matrix and fibrin contact the surface of another denuded villus and the area of fibrinoid deposition enlarges.

Okay, so this is a lot of speculation based on some still H&E pictures, but it is does provide the basis for a consistent hypothesis about the formation of massive perivillous fibrinoid deposition. The theory is that anything that kills the synctytial surface of the villi but leaves the cytotrophoblast intact can produce massive fibrinoid deposition. Antibodies to anti-paternal antigens, or even autoantibodies, on the syncytial surface could result in syncytial death. Repetitive hypoxia that can propagate itself as I saw in a case of multiple sickle cell crises might produce the same lesion. In rats a similar lesion can occur with an oxidative poison. Which brings us back to the recent  paper.  I would like to think that the mutation in beta oxidation of lipid simply leaves the syncytium energy depleted. Normally it is the most intense consumer of oxidative metabolism of glucose in the body, presumably because of the transport needs of the fetus.

This would make such a neat theory, but there is a major wrinkle. The mutations in HADHA in the MFI cases were a strange mix of novel mutations. Is there a common thread among these mutations?  Beats me.  MFI is not, to my knowledge or experience, associated with acute fatty liver of pregnancy or HELLP syndrome. There is something unexplained going on here that begs for more analysis. I have offered to submit some blocks to Linda Ernst, and I know others have also volunteered.  The problem as I understood it some years ago was funding. Is there no kind soul out there who can undertake the possibly frustrating task of sequencing the HADHA gene from formalin fixed tissue blocks?

A prospective study of MFI measuring the metabolism of living villi in vitro with known could test the hypothesis.  I was involved in the paper by Mandsager showing that the diagnosis of MFI can be made prenatally, so there would be time to set up the experiment up[2].

References:

For a more complete literature review see our group’s website www.pediatricperinatalpathology.com, under placenta

1.            Griffin, A.C., et al., Mutations in long-chain 3-hydroxyacyl coenzyme a dehydrogenase are associated with placental maternal floor infarction/massive perivillous fibrin deposition. Pediatr Dev Pathol, 2012. 15(5): p. 368-74.

2.            Mandsager, N.T., et al., Maternal floor infarction of the placenta: prenatal diagnosis and clinical significance. Obstet Gynecol, 1994. 83(5 Pt 1): p. 750-4.