LAUSR

Massive perivillous fibrin deposition (MPVF), sometimes known as maternal floor infarction or diffuse perivillous fibrin(oid) deposition, is a rare idiopathic placental lesion centered on the intervillous space, a maternal blood compartment bounded by fetally derived villous syncytiotrophoblast. It is characterized by a latticework of anastomosing bands of fibrin, representing inappropriate activation of the maternal coagulation cascade, and fibrinoid extracellular matrix which is synthesized by an accompanying abnormal accumulation of intraplacental extravillous trophoblast. This fibrin/fibrinoid material surrounds gas-exchanging distal villi leading to a variety of adverse outcomes ranging from growth restriction and preterm delivery to miscarriage and stillbirth. Interestingly, localized lesions resembling MPVF, known as perivillous fibrin plaques (localized perivillous fibrin deposition), are common and have little or no effect on pregnancy outcome suggesting that MPVF could represent a pathologic feed-forward loop, wherein affected mothers are unable to control the spread of localized coagulation and extracellular matrix deposition. In a significant number of cases, MPVF shows histologic overlap with a condition known as chronic histiocytic intervillositis (CHI) which is defined by diffuse infiltration of the intervillous space by maternal monocyte-macrophages. Intriguingly, the pure forms of CHI and MPVF without overlap share the same high recurrence rate, clinical risk factors, and types of adverse pregnancy outcomes. MPVF recurs in most or all of the subsequent pregnancies in a relatively high percentage of affected mothers. This variability in and often very high frequency of recurrence is not consistent with a Mendelian inheritance pattern related to the fetus, but rather suggests a genetic or acquired abnormality in the mother. Although MPVF has previously been considered a single-disease entity, more intensive study over the past 20 years has revealed that it is more properly considered an abnormal tissue reaction pattern likely triggered by a variety of underlying conditions, not all of which are necessarily associated with recurrence. Risk factors that may be associated with recurrence include maternal autoimmune disease, antiphospholipid antibody syndrome, other acquired or genetic thrombophilic conditions, and maternal heterozygosity for long chain fatty acid deficiency. Several of these conditions have an underlying immune etiology, and this pathogenesis is supported by the finding of C4d deposition on affected trophoblast in recurrent miscarriages with MPVF and the occasional overlap of MPVF with CHI. One unifying hypothesis is that fibrin deposition and intervillous inflammation represent distinct, but overlapping, responses to trophoblast injury. Both are usually limited in extent, but in the face of a dysfunctional maternal inflammatory response, both may progress to involve a large portion of the intervillous space resulting in pregnancy loss. Hematogenous maternal infections during pregnancy can also activate the coagulation and innate immune systems and are often centered in the intervillous space where circulating organisms can bind and cross to the fetus through villous syncytiotrophoblast. It is therefore not surprising that a few cases of MPVF have been documented in association with chronic intrauterine infections caused by Coxsackie A and other enteroviruses. Two new case reports in this issue of Pediatric and Developmental Pathology extend and provide additional nuance to the putative association of