M a t e r na l F l o o r I n f a rc t i o n a n d Massive Perivillous Fibrin Deposition Ona Marie Faye-Petersen, MDa,*, Linda M. Ernst, MDb KEYWORDS  Maternal floor infarction  Massive perivillous fibrinoid  Placental infarction  Perivillous fibrin  Placental fibrin  Placental ischemia M aternal floor infarction (MFI) and massive perivillous fibrin deposition (MPVFD) are pathologically overlapping placental disorders with characteristic gross and shared light microscopic features of excessive perivillous deposition of fibrinoid material. Although rare, they are associated with high rates of fetal growth restriction, perinatal morbidity and mortality, and risks of recurrence with fetal death. The cause of the extensive fibrinoid deposition is unknown, but evidence supports involvement of maternal alloimmune or autoimmune mechanisms. This article presents an updated discussion of features, placental histopathologic differential diagnosis, possible causes, clinical correlates, and adverse outcomes of the MFI/MPVFD spectrum. OVERVIEW Maternal floor infarction (MFI) and massive perivillous fibrin deposition (MPVFD) are rare (incidence 0.028%–0.5% of deliveries),1–4 closely related placental lesions of unclear etiopathogenesis but associated with high perinatal morbidity, mortality, and recurrence risks. MFI5 refers to a lesion grossly characterized by a yellowish, thickened maternal floor, and, histologically, by extensive, basal rindlike depositions of fibrin material. Although its appearance is grossly suggestive of laminar infarction, microscopically, chorionic villi in MFI are atrophic and widely separated by cloaks of this fibrin material, instead of displaying a predominant pattern of ischemic injury (ie, villous crowding, excessive syncytial knot formation, and necrosis). Thus, the term, infarction, is a misnomer. Also, perivillous fibrinoid deposition often extends beyond the basal plate, variably entrapping villi and obliterating the intervillous space. Fox and Elston6 proposed the descriptive term, MPVFD, to denote this constellation of features, and Katzman and Genest7 provided useful semiquantitative diagnostic criteria. Their subclassifications enable diagnostic uniformity and more meaningful, comparative clinicopathologic and outcomes studies between MFI/MPVFD and other entities showing excessive perivillous fibrinoid deposition. As discussed in this article, the composition of the perivillous fibrin and/or fibrin-like complex (fibrinoid) is incompletely understood, and its deposition likely progresses during gestation. The terms, MFI and MPVFD, are often used interchangeably in the literature, because most investigators5,8 consider them variants of a common pathologic spectrum. Thus, for the purposes of this discussion, MPVFD is used to refer to the spectrum of changes of MFI and MPVFD, and fibrinoid to refer to the perivillous material. GROSS FEATURES MPVFD typically results in a small-for-gestational date, dense (stiff) placenta with a firm, yellowwhite, thickened-appearing maternal surface (Fig. 1). Serial sections of classic forms exhibit a yellowish basal layer or rind of fibrinoid (Fig. 2). More commonly, fibrinoid deposition is more diffuse, with vertically oriented, pale trabeculae a The University of Alabama at Birmingham, 619 South 19th Street, Birmingham, AL 35249-7331, USA; Northwestern University, Olson 2-454, 303 East Chicago Avenue, Chicago, IL 60611, USA * Corresponding author. E-mail address: onafp@uab.edu b Surgical Pathology 6 (2013) 101–114 http://dx.doi.org/10.1016/j.path.2012.10.002 1875-9181/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved. surgpath.theclinics.com ABSTRACT 102 Faye-Petersen & Ernst Key Points OF MPVFD 1. MPVFD is also known as MFI 2. MPVFD is a rare but important lesion of unknown cause but strong evidence for involvement of auto/ alloimmune mechanisms in most studies; other etiologies possible 3. The Classic prenatal ultrasonographic findings are fetal intrauterine growth restriction, oligohydramnios, and dense hyperechoic placenta 4. MPVFD has a high morbidity and mortality rate, with high risks of neurologic injury and of recurrence 5. The placenta is usually small and dense with friable, granular trabeculae of fibrinoid deposition 6. The predominant histopathologic feature is basal deposition of abundant fibrinoid with variable upwards extension to middle and suchorionic zones of latticework perivillous fibrinoid; villi appear choked off by thick layers of fibrinoid that obliterate the intervillous space. extending from the basal zone, into the middle and subchorial zones, in a lattice-like network. The parenchyma of MPVFD is friable, granular appearing, and dense versus the spongy and compressible texture of normal villous tissue (Figs. 3 and 4). Although most MPVFD results in low placental weight, due to the loss of functional and blood-filled chorionic villi, it may also be associated with a normal or even increased weight for dates. Heavy MPVFD is generally due to the presence of abundant fibrinoid and/or proliferation of extravillous cytotrophoblast.1,5 All forms may have regions of true chorionic villous ischemia or infarction consistent with sequelae of altered blood flow patterns and sluggish, eddy-like regions in the intervillous space, due to pathologic perivillous fibrinoid deposition. Presumably, these altered blood flow patterns also explain the Fig. 1. Maternal surface in MPVFD. Gross image of maternal surface of placenta with MPVFD. Note the yellow-white, thickened appearance of the maternal surface. Massive Perivillous Fibrin Deposition Fig. 2. Classic MFI. Gross image of cross-sections of classic MFI with yellowwhite rind of fibrinoid material seen predominantly along the basal (maternal) surface of the placenta. Note that there is also focal extension of the fibrinoid maternal into more central and subchorionic regions. (Courtesy of Stewart Cramer, MD, University of Rochester, Rochester, NY.) characteristic increase in extravillous trophoblast cysts (X-cell cysts) and intervillous, thrombohematomatous formation within the parenchyma (Fig. 5).1 Formalin fixation highlights the pathologic fibrinoid latticework, atrophic portions of the villous tree, X-cell cysts, and thrombohematomas (see Fig. 5). MICROSCOPIC FEATURES MPVFD is characterized by marked increase in perivillous fibrinoid deposition in the intervillous space adjacent to the basal plate with varying degrees of upward extension into the midzonal and subchorionic regions (Fig. 6). Chorionic villi appear to stand apart, due to their circumferential sheaths of amorphous to laminated, eosinophilic fibrinoid and display varying degrees of atrophy, with loss of syncytiotrophoblast, villous vascularity, and stromal histologic detail. Although grossly, the maternal floor has a blanket-like distribution of fibrinoid, microscopically, the pathology is often discontinuous. Basal, encased, individuated villi and villous clusters, however, are matted together (so-called gitter infarct) and seem to provide scaffolding for further fibrinoid deposition (Fig. 7). A more extensive upward distribution is more common in placentas from later, third-trimester deliveries and is compatible with a progressive process. Excessive extravillous cytotrophoblast (X-cell) proliferations (nodular or confluent aggregations) and X-cell cysts are common, or even the Fig. 3. Cut surfaces of placenta, normal (A) versus MPVFD (B). Gross images of cross-sections of placenta showing pale, granular and dense appearing parenchyma in MPVFD (B) compared with age-matched control (A) with more spongy and red parenchyma. Also, note intervillous thrombus (arrow) and chorionic cyst (arrowhead) within parenchyma of placenta with MPVFD. 103 104 Fig. 4. Cut surfaces of placenta with MPVFD, after fixation. Closer views of gross of cross-sections of placenta showing pale, granular, and dense-appearing parenchyma in MPVFD. Fig. 5. Cut surfaces of placenta with MPVFD, after fixation. (A) Note the vertically oriented trabeculae of fibrinoid extending through the parenchyma. (B) Closer inspection reveals the coarse granularity of the parenchyma and an intervillous thrombus is seen (arrow). Massive Perivillous Fibrin Deposition Fig. 6. Low-power photomicrograph of the basal surface (lower surface) and overlying placental parenchyma. Note the extensive perivillous fibrin deposition characterized by amorphous eosinophilic deposits that surround and choke the chorionic villi. In this image, the perivillous fibrin extends in vertical bands toward the chorionic plate (hematoxylin-eosin, original magnification 20). dominant, feature (Fig. 8). X-cell proliferations, cysts, and occasional foci of chronic chorionic villous ischemia and infarction are likely linked to development of abnormal blood flow patterns in the maternal space and sites of relative secondary ischemia. Not surprisingly, intervillous thrombohematomas may coexist or merge with areas of perivillous fibrinoid deposition. Inflammation, when present, is a minor component. Scattered lymphocytes and monocytes/histiocytes (Fig. 9), but not plasma cells, may be present within or adjacent to the villi. Degenerating villi may also elicit perivillous neutrophilic reactions. Lymphoplasmacytic deciduitis may occasionally be seen.1,5,9–11 Fig. 7. Progression of MPVFD. This series of images illustrates how MPVFD is initiated near the basal surface of the placenta (A) and progresses toward the midzonal (B, C) and subchorionic regions (D). Notice how the villi in the basal zones ([A] and [B, C (lower)]) are more sclerotic than those in the midzonal region (B, C [upper]) and subchorionic region (D). The villi in the subchorionic region are only partially surrounded by fibrinoid and still maintain some fetal capillaries (hematoxylin-eosin, original magnifications [A] 20, [B] 100, [C] 200, and [D] 100). 105 106 Faye-Petersen & Ernst Fig. 8. Perivillous fibrin deposition with prominent proliferation of extravillous trophoblast cells (X-cells) (hematoxylin-eosin, original magnification 400). DIAGNOSIS The diagnosis of MPVFD should be suspected when the placenta is small for the gestational period, is diffusely firm, and shows a maternal surface that is pale yellow-white and granular, and serial sections display basal deposition of granular fibrinoid material that extends upward, toward the chorionic plate in a matted and/or trabecular network. Light microscopically, basal Fig. 9. Chronic inflammatory infiltrates in MPVFD. Microscopic image of lymphohistiocytic cells within the intervillous space adjacent to areas of MPVFD. No significant chronic villitis or plasma cells are seen (hematoxylin-eosin, original magnification 20). Massive Perivillous Fibrin Deposition chorionic villi show encasement by thick layers of perivillous fibrinoid, without the typical changes of villous ischemia. The presence of villi choked by perivillous fibrinoid is compatible with sequelae of syncytiotrophoblastic damage, and/or alterations of or imbalances among factors that maintain the normal, fluid state of the blood in the intervillous space. Syncytiotrophoblast damage is the first detectable villous change, but it is unclear if it is the initiating or merely an early event in the cascade of MPVFD. Perivillous fibrinoid deposition is greatest in the basal zone, with variable penetration of the midchorionic and subchorionic zones. Accordingly, the authors support use of semiquantitative criteria for diagnosis of MPVFD,7 to promote diagnostic uniformity among pathologists and particularly to help distinguish it from other lesions with fibrinoid, such as massive chronic (histiocytic noninfectious) intervillositis (MCI), until the underlying causes of these lesions are better elucidated. The authors propose that the placental pathology report should specify one of the following patterns: 1. Classic—basal villous encasement by fibrinoid along entire maternal floor and of 3 mm or greater thickness on at least one slide 2. Borderline MPVFD—involvement of 25%–50% of villi on at least one slide in transmural or nearly transmural distribution 3. Transmural MPVFD—transmural perivillous fibrinoid extension, with encasement of 50% or greater of villi on at least one slide MPVFD may include foci of villitis and intervillositis, lymphoplasmacytic deciduitis in the extraplacental membranes or decidua basalis, and areas of ischemic change to frank infarction.The diagnosis of MPVFD, however, should be made on its predominance as the histopathologic feature (see Key Points and Differential Diagnosis). Estimates of the percentages of co-occurrence of villitis, intervillositis, and/or ischemic damage may be included in the report, especially if they are more than occasional findings, because their presence may influence treatment and frequency of clinical evaluations in subsequent pregnancies. Finally, a comment should be included indicating that MPVFD is associated with high risks for adverse perinatal outcomes and recurrence (discussed later). DIFFERENTIAL DIAGNOSIS The differential diagnosis includes 1. Normal perivillous fibrinoid deposition 2. Chorionic villous ischemia and infarction 3. Fetal thrombotic vasculopathy (FTV)12–16 and other pathologies likely representing maternal alloimmune graft-versus-host disorders17–24 4. Diffuse chronic villitis of unknown etiology (VUE) and chronic villitis with obliterative vasculopathy/vasculitis (CVOV)16,21 5. MCI25–28 Some perivillous fibrinoid deposition is a normal feature of mature placentas5 and likely reflects wear and tear damage to the syncytiotrophoblast. Injured trophoblast presumably releases tissue factors and/or other mediators that activate intervillous coagulation,1 and fibrinoid plugs seal the syncytiotrophoblast defects.5 Perivillous fibrinoid deposition, but not obliteration of the intervillous space, increases with advancing gestation. In term placentas, term stem villous surfaces show linear, thin fibrinoid profiles and patchy aggregates of perivillous deposition of laminated type of fibrin/ fibrinoid (Fig. 10) that progress throughout gestation in the subchorionic, basal, and marginal zones (ie, normal regions of relatively sluggish flow and/or hypoxia, within the maternal space).5 The main differential diagnosis for MPVFD is chorionic villous ischemic injury (including villous infarction secondary to placental bed underperfusion)29 because perivillous fibrinoid frequently surrounds areas with loss villous viability (Fig. 11). In chorionic villous ischemia/infarction, however, increased perivillous fibrinoid deposition is concentrated around stem villi and in zones of primary, relative ischemia (discussed previously). With infarction, there is collapse of the intervillous space and syncytial knot formation and stromal loss of nuclear detail precedes syncytiotrophoblast necrosis (Fig. 12). In MPVFD, intervillous spacing is preserved and syncytiotrophoblast injury is the initial feature of villous damage.1 Decidual arteriopathy of maternal hypertensive disorders (ie, thick-walled arterioles, atherosis, and fibrinoid necrosis) is typically absent in MPVFD.1,9 FTV (clusters or large areas of avascular, involuted-appearing distal terminal villi) is due to intermittent or sudden obstruction of blood flow within the villous tree. In most cases, FTV does not show perivillous fibrinoid deposition around sclerosed villi, but long-standing lesions of FTV may have foci of avascular villi with fibrinoid encasement (Fig. 13). MPVFD does not, however, display propagating thrombi or fields of chorionic villous stromal-vascular karyorrhexis with preservation of syncytiotrophoblast.5,12,15 Diffuse VUE and CVOV represent high-grade, destructive lymphohistiocytic villitides affecting greater than 5% of the terminal villi of midtrimester to late third-trimester placentas (32 weeks or 107 108 Faye-Petersen & Ernst Fig. 10. Pattern of normal perivillous fibrin deposition. (A) Subchorionic zone with fair amount of perivillous fibrinoid deposition beneath the chorionic plate and surrounding the most proximal stem villi. (B) Midzonal region with small nodules of perivillous fibrinoid, which appear most prominent around stem villi. (C) Basal zone appears similar to midzonal region with small nodules of perivillous fibrinoid, especially around stem villi. Only a small amount of perivillous fibrinoid is noted directly adjacent to the basal plate (hematoxylin-eosin, original magnifications [A] 20, [B] 40, and [C] 20). greater of gestation) with perivillous fibrinoid deposition around individual and clusters of chorionic villi (see Fig. 13). CVOV also affects distal stem villi and includes villous lymphohistiocytic vasculitis and thrombosis. Both show variable presence of lymphoplasmacytic deciduitis and chronic chorioamnionitis and may include a prominent component of perivillous fibrinoid deposition.15,16,21,30 MPVFD displays scant foci of chronic villitis and no chorionic villous stem vessel vasculitis or thrombosis. MCI is characterized by diffuse mononuclear infiltrates (lymphocytes, monocytes, and histiocytes) in the intervillous space, the essential absence of villitis, and may show mild villous and intervillous fibrinoid deposition.8 Literature on this lesion is inconsistent, however. In a recent study, Parant and colleagues28 defined the severe Fig. 11. Gross comparison of infarction and MPVFD. (A) Gross image of a villous infarction secondary to ischemia. Note the wedge-shaped lesion with a tan homogeneous, firm cut surface and well- defined borders. Compare with gross image of MPVFD (B), which shows more diffuse involvement of the parenchyma with linear and small nodular accumulations of fibrinoid but no formation of a well-defined lesion. Massive Perivillous Fibrin Deposition Fig. 12. Differential diagnosis of MPVFD-comparison of MPVFD and infarction. (A) MPVFD, (B) subacute infarction, and (C) remote infarction. Note that in MPVFD the intervillous space is filled with fibrinoid, but the spacing between the villi is preserved, and in infarction there is collapse of the intervillous space. Note also the presence of coagulative necrosis of villi in infarct compared with the more fibrotic but not necrotic villi of MPVFD (hematoxylin-eosin, original magnifications [A] 100, [B] 200, and [C] 200). category of pathology of chronic intervillositis of unknown etiology (with greater than 50% of the intervillous space on the slide showing infiltrate) as also including “massive and confluent perivillous fibrinoid with mild mononuclear infiltrate.” Thus, the authors propose that the diagnosis of MPVFD and other lesions be based on the predominant, histopathologic feature and that any secondary feature be included as a modifier and semiquantitated. Fig. 13. Differential diagnosis of MPVFD—comparison of MPVFD with FTV/avascular villi and chronic villitis/VUE. (A) MPVFD, (B) FTV/avascular villi, and (C) chronic villitis/VUE. In FTV, avascular villi (B) are characterized by sclerotic-appearing villi with preservation of the intervillous space; however, the villi can become encircled in small amounts of perivillous fibrinoid. Stem villous or chorionic thrombi, which can accompany avascular villi, are typically not seen in MPVFD. In chronic villitis/VUE (C), there is perivillous fibrinoid deposition associated with villous agglutination and chronic inflammation. MPVFD does not typically show agglutination of villi or significant chronic inflammation of villous parenchyma (hematoxylin-eosin, original magnifications [A–C] 100). 109 110 Differential Diagnosis OF MPVFD MPVFD Differential Entity 1. Distal chorionic villous tree branches are diffusely choked and normally to widely spaced by thick layers of fibrinoid Normal-term perivillous fibrinoid 1. Deposition is around scattered stem villi, in thin profiles. 2. Perivillous fibrinoid is a thin layer in relatively ischemic zone of basal and subchorionic villi; terminal villi show occasional aggregates as intervillous bridges. Chronic chorionic villous ischemia/infarction 1. Grossly, a permeative network of fibrinous 1. Grossly, infarctions are triangular shaped or material is seen based at maternal surface rounded. and branching upwards toward chorionic plate. 2. Chorionic villous ischemia is a minor finding 3. Distal chorionic villous tree branches are diffusely choked, and normally to widely spaced, by thick layers of fibrinoid 4. Atherosis/fibrinoid necrosis is not seen unless there is a complicating comorbidity of underlying maternal hypertension or thrombophilia 5. MPVFD shows no necrosis of decidua of extraplacental membranes unless there is a comorbid condition of hypertension or primary disorder with vasculopathy 1. Sampling artifact is much less of an issue, because basal distribution of fibrinoid is blanket-like grossly and 2. Distal chorionic villous tree branches are diffusely choked and normally to widely spaced by thick layers of fibrinoid 3. MPVFD does not show chorionic plate or stem villous and/or propagating thrombosis. 2. The Predominant feature is chorionic villous ischemia and infarction. 3. Villi show crowding with thin layers of intervening fibrinoid deposition. 4. Decidual arteriopathy is a feature in ischemiainduced pathology due to placental bed under perfusion. 5. Decidual laminar-like or leukocytoclastic necrosis in membranes is often present. FTV 1. Sampling affects detection of chorionic plate or stem villous thrombi and distal villous sclerosis in cases of FTV, and sampling artifact may lead to errors in interpretation of small perivillous fibrinoid depositions. 2. Characteristically, FTV shows scant to no perivillous fibrinoid deposition around sclerosed villi; the sclerosed villi remain isolated and free floating. 3. Occasionally, presumably long-standing clusters of sclerotic villi of FTV may show fibrinoid encasement. 1. MFPVD shows foci or patchy chronic villitis and intervillositis. 2. MPVFD does not show stem villous vasculitis/ thrombosis as a dominant feature. 3. The occasional focus of chronic villitis or intervillositis may reflect an overlap in aspects of pathologic mechanisms or pathways leading to DVUE, CVOV, and MPVFD. 1. MPVD can contain foci or patchy presence of chronic lymphocytic/monocytic intervillositis. 2. The occasional focus of chronic intervillositis may reflect an overlap in aspects of pathologic mechanisms or triggers of pathways leading to MCI and MPVFD, respectively. Diffuse chronic VUE and CVOV 1. The dominant histopathologic pattern is diffuse villitis and/or obliterative vasculitis/ vasculopathy. 2. CVOV has stem villous vasculitis or thrombosis as a dominant feature. MCI 1. MCI is diffusely present in all zones of the maternal space (subchorionic, middle, and basal). Massive Perivillous Fibrin Deposition IMPACT AND UPDATES IN PATHOGENESIS MPVFD is associated with high rates of adverse perinatal outcomes, such as prematurity (preterm delivery in 26%–60%), intrauterine growth restriction (24%–100%), spontaneous abortion, stillbirth (13%– 50%), neonatal death, and long-term neurologic impairment.3,4,31–34 Women delivering placentas with MPVFD more frequently have poor past reproductive histories (with or without documented placental examination).4,35 Studies have correspondingly revealed that MPVFD exhibits high recurrence risks (12%–78%),2–4,7,35–37 with earlier onset and more rapid progression by ultrasonographic examination.2,4,11,31 Prenatal, ultrasonographic findings of oligohydramnios; fetal intrauterine growth restriction (especially early onset); and a dense, hypoechogenic placenta have been noted as strongly suggestive of MPVFD,31 but Uxa and colleagues38 did not find these a consistent constellation of antenatal features. The classic triad, however, of these ultrasonographic findings may reflect the onset, extent, and rapidity of fibrinoid deposition, period of gestation, and compromise of fetal renal blood flow due to hypovolemia associated with decline in placental function. Taweevisit and Thorner39 linked MPVFD, fetal cystic renal dysplasia, and oligohydramnios and suggested that fetoplacental factors may also play a role in the pathogenesis of MPVFD, possibly through alterations in uterine hydrostatic pressure gradients. As discussed previously, the causes of the excessive accumulations of amorphous fibrinoid material encasing chorionic villi and features of loss of syncytiotrophoblast viability are incompletely understood. Elements of the maternal blood and trophoblast-generated procoagulant and anticoagulant molecules and matrix contribute to a normal villous surface and maintenance of a fluid intervillous space. The amorphous, perivillous material, normally present in the intervillous space, immunohistochemically and ultrastructurally appears to be a combination of serum fibrin of the maternal coagulation cascade (a laminated fibrin-type fibrinoid) and trophoblast-derived extracellular substance (matrix-predominant type fibrinoid).5–7,9,10,40 Abnormal amounts of fibrin or fibrinoid dominant deposition may partly reflect the relative numbers of proliferating or neighboring cytotrophoblasts and decidual cells.1 The microscopic features of MPVFD are highly suggestive of either direct damage to the syncytiotrophoblast and/or disturbances in the balance of dually derived intervillous procoagulant/anticoagulant factors necessary to maintain the fluid state of the blood in the maternal space. To date, there is evidence that at least some MPVFD represents sequelae of a maternal autoimmune or alloimmune condition. In addition to its high risks of recurrence, 1. MPVFD is more common in women antiphospholipid (APL) antibody syndrome and other autoimmune disorders with or without thrombophilia.8,41–45 2. Women with a prior diagnosis of MPVFD and APL syndrome, treated with intravenous immunoglobulin, have had improved pregnancy outcomes.44 3. MPVFD may be discordant in dichorionic9 or monochorionic2 twin placentas. 4. MPVFD may coexist with chronic intervillositis.28,46 The syncytiotrophoblast may be the primary target of maternal antitrophoblast antibodies47 and release factors, such as tissue necrosis factor or Hageman factor, that activate coagulation. Somewhat challenging is the observation that MPVFD may be associated with maternal primary hypertension and preeclampsia.4,37,48 These associations, however, may represent overlap among maternal risk factors for MPVFD and hypertension, because hypertensive disorders and APL syndrome can co-occur. Alternatively, the sequelae of trophoblastic or villous hypoxic damage could result in confounding activation of abnormal coagulation in the intervillous space1,5 and potentiate an otherwise insignificant or low-grade trophoblastic abnormality or process of fibrinoid deposition. As a corollary to the above discussion, MPFVD has also been linked to primary maternal inherited coagulation factor deficiencies and abnormalities45,49–51 and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency52 with mutations in LCHAD gene.53 Thus, blood flow in the maternal space may become compromised by an intervillous process initiated by imbalances among the components and activities of the intervillous procoagulant/anticoagulant factors. Women, with or without an underlying autoimmune disease but with a history of a prior pregnancy complicated by a placental diagnosis of MPVFD, who were treated with low-dose heparin and aspirin during their subsequent pregnancies have had improved gestational outcomes.54 Anticoagulant therapy may prove to be protective against the recurrence or severity of MPVFD. In conclusion, the fibrinoid deposition of MPVFD likely represents the outcome of a final common pathway potentially triggered by a variety of conditions or pathologies that disturb the normal and inducible factors that maintain the integrity of the 111 112 Faye-Petersen & Ernst Pitfalls Massive perivillous fibrinoid deposition/MFI ! Most common misdiagnosis is chorionic villous ischemia/infarction.  Grossly placental bed ischemia due to maternal vascular disease creates triangular-shaped or rounded masses of infarcted villi whose broadest aspects lie along maternal surface; MPVFD has a diffuse pattern of distribution of fibrinoid along basal plate.  Chorionic villous ischemia shows thin layers of intervening fibrinoid deposition or small, nodular excrescences that bridge to other villi and predominantly involves stem villi and subchorionic regions. MPVFD isolates chorionic villi and obliterates intervillous space, from basal plate upward.  Infarction displays collapse of the intervillous space with fibrinoid depsosition and villous necrosis. MPVFD shows individuated villi surrounded by fibrin without coagulative necrosis.  MPVFD can result in abnormal channels of blood flow in maternal space and create zones of ischemia that compromise chorionic villi and result in foci of infarction. ! MPVD can contain foci of chronic villitis and MCI.  The occasional focus of chronic intervillositis may reflect an overlap in the portions of pathologic pathways between MCI and MPVFD. ! MPFVD may show rare focus of chorionic villous thrombosis. syncytiotrophoblast and the fluidity of blood in the maternal space. Ongoing damage and accelerating compromise of the blood flow within the intervillous space may obscure the inciting pathology or combine with elements of chronic villitis. The triggers, however, are likely potent and/or in high concentrations, because they seem to irreversibly commit the perivillous space to a process of marked fibrinoid deposition and accumulation. The rarity of MPVFD suggests that there are many sites of duplication within the normal villous protective and reparative systems, which guard against pathologic amounts of fibrinoid deposition.55–57 REFERENCES 1. Faye-Petersen O, Heller D, Joshi V. Handbook of placental pathology. 2nd edtion. Oxford (United Kingdom): Taylor & Francis; 2006. 53–110. 2. 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