Intervillous Fibrin Research Articles

Fibrin-type Fibrinoid in Placentae from Pregnancies Associated with Maternal Smoking: Association with Villous Trophoblast and Impact on Intervillous Porosity

Smoking during pregnancy perturbs maternal haemostasis via activated coagulation which could include greater coagulation (fibrin-type fibrinoid deposition) in the placental intervillous space. This might affect intervillous haemodynamics and transport of oxygen and nutrients to the fetus. Fibrin deposits could influence the sizes and numbers of intervillous spaces (‘pores’) and perivillous fibrin could reflect changes in the nature or activity of trophoblast. Here, we test whether or not smoking is associated with differences in the composition of villous trophoblast, the amounts and patterns of fibrin and, hence, the dimensions and numbers of intervillous pores. Random samples of placentae were taken from pregnancies classified according to smoking status (non-smokers, light smokers, heavy smokers). Stereology was used to estimate volumes of intervillous space and fibrin, test for differences in trophoblast composition and patterns of fibrin deposition at the villous surface, and determine the impact of deposits on the mean volumes and theoretical numbers of intervillous pores. No group differences were found in total volumes or surfaces of trophoblast or total volume of intervillous fibrin. However, the total surfaces of syncytial knots declined in smokers and the surfaces of syncytial bridges increased. Particularly in heavy smokers, this was associated with reduced deposits of perivillous fibrin at syncytial knots. In all placentae, the greatest deposits occurred where there was trophoblast denudation. Little fibrin was seen on thin regions of syncytium. Regardless of smoking status, intervillous fibrin reduced intervillous pore size and increased pore number. However, heavy smokers had larger pores. Reductions in syncytial knots are consistent with reports that smoking reduces the incidence of trophoblast apoptosis whilst increases in syncytial bridges are consistent with enhanced branching angiogenesis. Results confirm that perivillous fibrin accumulates preferentially at denudation sites. They also suggest that smoking perturbs the normal pattern of fibrin deposition, that the impact is greater in heavy smokers and that the placental site is privileged or active in terms of fibrinolytic or anti-coagulatory activity. This activity seems to reside in thin regions of syncytium.

Preeclampsia Associated With Antiphospholipid and Anti-β2-Glycoprotein-I Antibodies and Postpartum Thrombocytopenia, Cardiac Dysfunction, and Blindness: A Case Report

We describe a patient with severe preeclampsia and postpartum complications in whom we investigated a panel of autoimmune reactions. Case Report: A 27-year-old primigravida was referred at 37 weeks' gestation because of severe preeclampsia. A cesarean section was performed. Postpartum the patient developed severe cardiac dysfunction, thrombocytopenia, eclamptic seizures, and blindness. Immunohistochemical studies of the placenta showed marked deposition of terminal C5b-9 complement complex in intervillous fibrin and in intravillous stroma. Conclusion: The generation of C5b-9 complement complex may be involved in the pathogenesis ofpreeclampsia-eclampsia.

Measles Virus Infection in the Placenta of Monozygotic Twins

We report a case of monozygotic twins whose mother was infected with measles at 19 weeks' gestation. One of the twins died in utero at 32 weeks' gestation. The placenta of the stillbirth showed massive fibrin deposition, and some residual trophoblasts contained many inclusion bodies positive for measles virus antigen. Fetal organs and cells other than a few splenic lymphocytes showed no evidence of measles virus infection. The placenta of the surviving infant showed focal intervillous fibrin deposits, and only a few syncytiotrophoblasts were positive for measles virus antigen. At present, 7 months after the delivery, the surviving infant has not developed any sign of measles virus infection. Postpartum course of the mother has been uneventful, although high titers of serum anti-measles virus IgM persisted for 6 months after delivery. This case is informative in the following respects: the villous trophoblasts had diagnostic inclusion bodies and ultrastructural evidence of measles virus infection, the degree of viral involvement within the monochorionic placenta was uneven, both of the twins were virtually free from measles virus infection despite the marked involvement of the placenta, and measles virus infection had persisted in the monochorionic placenta for approximately 13 weeks.

Association of histologic features and cytogenetic abnormalities in ectopic pregnancies

Objective: To evaluate the association between specific histologic features and cytogenetic abnormalities in ectopic pregnancies. Design: Blinded histologic analysis. Setting: University hospital. Patient(s): Fifty-four patients with ectopic pregnancy for whom successful karyotypes and sufficient histologic material were available. Intervention(s): Histologic evaluation of chorionic villi from ectopic pregnancies was done by two pathologists who were unaware of the cytogenetic outcome. Seventeen histologic features were evaluated: villus size, villus contour, ghost villi, hydropic villi, trophoblastic hyperplasia, trophoblastic hypoplasia, syncytial knots, Hofbauer cells, blood vessels, trophoblastic lacunae, trophoblastic inclusions or cisterns, degeneration, fibrohyalinization, microcalcifications, and perivillous and intervillous fibrin deposits. Main Outcome Measure(s): The association between histopathologic features and cytogenetic outcome. Result(s): The presence of ghost villi and intervillous or perivillous fibrin was found to be associated with cytogenetic abnormalities. These features are associated with previous fetal cell death. Conclusion(s): This study does not support an association between specific histologic features of chorionic villi and cytogenetic abnormalities in ectopic pregnancies. The only histologic features that were associated with cytogenetic abnormalities (i.e., ghost villi and intervillous and perivillous fibrin) are merely a result of previous fetal cell death.

Histologie Distribution and Biochemical Properties of α1‐Microglobulin in Human Placenta

The embryo is protected from immunologic rejection by the mother, possibly accomplished by immunosuppressive molecules located in the placenta. We investigated the distribution and biochemical properties in placenta of the immunosuppressive plasma protein alpha 1-microglobulin. Placental alpha 1-microglobulin was investigated by immunohistochemistry and, after extraction, by electrophoresis, immunoblotting and radioimmunoassay. alpha 1-Microglobulin staining was observed in the intervillous fibrin and in syncytiotrophoblasts, especially at sites with syncytial injury. Strongly stained single cells in the intervillous spaces and variably stained intravillous histiocytes were noted. Solubilization of the placenta-matrix fraction and placenta membrane fraction released predominantly the free form of alpha 1-microglobulin, but, additionally, an apparently truncated form from the placenta-membrane fraction. The soluble fraction of placenta contained two novel alpha 1-microglobulin complexes. The biochemical analysis indicates the presence in placenta of alpha 1-microglobulin forms not found in blood. The histochemical analysis supports the possibility that alpha 1-microglobulin may function as a local immunoregulator in the placenta.

Immunological studies of the placenta in maternal connective tissue disease.

Maternal connective tissue disease is an important cause of second-trimester fetal loss. In order to assess the pathological changes in the placenta in maternal connective tissue disease, we reviewed the clinical histories and performed histologic and immunofluorescence studies on nine placentas: five from mothers with systemic lupus erythematosus (SLE), two from mothers with mixed connective tissue disease (MCTD), one from a mother with rheumatoid arthritis (RA), and one from a mother without prior known connective tissue disease. Excessive intervillous fibrin deposition and infarction were noted in all cases. Immunofluorescent and immunoperoxidase studies showed deposits of fibrinogen, IgG, IgM, IgA, and complement 3 (C3) localized to the trophoblast basement membrane (TBM). Electron microscopy documented thickening of the trophoblast basal lamina in three SLE placentas examined. The use of immunofluorescence may be enhanced further if antitrophoblast antibodies can be linked to placental compromise.

Effect of a calcium ionophore (A23187) on 86Rb(K) efflux from human placental trophoblast cells in culture

The placentae of 11 chimpanzees and five orang-utans were collected from Japanese zoos immediately after delivery and were examined according to the methods routinely used for the human placenta. Plancenta extrachorialis (circumvallate and circummarginate placenta) occurred in 80 per cent of the specimens collected from each species. In both groups, the placental vessels were distributed predominantly in the magistral pattern, and the umbilical cord was eccentrically inserted.Subchorionic fibrin, sometimes marked, was seen in all 16 placentae, and there was a high incidence of small intervillous thrombi and deposits of intervillous fibrin. These observations, together with the histological and ultrastructural findings, confirm the previously reported similarity between the placentae of the great apes and the human placenta.

Clinical Significance and Treatment of Massive Intervillous Fibrin Deposition Associated with Recurrent Fetal Growth Retardation

Retrospective examinations of 8,139 placentae were performed to clarify the relationship between placental disorders with massive intervillous fibrin deposition (MIFD) and intrauterine growth retardation (IUGR). Although the incidence of MIFD was low (0.4%), the small-for-date (SFD) birth rate in the MIFD group was significantly higher than that in the control group (62.9 vs. 8.3%; p < 0.001). Seventeen of 35 patients in the MIFD group had no clinical complications. MIFD itself was thought to be the main cause of IUGR in these patients. 78.4% of multiparae in the MIFD group have unsuccessful obstetrical histories such as intrauterine fetal death and fetal growth retardation. Four of 6 patients with a history of MIFD and SFD delivery in a previous pregnancy repeated the same episode. These data indicate that the MIFD recurrence rate in subsequent pregnancies must be high. Patients with a history of both SFD delivery and MIFD in previous pregnancies were defined as high-risk patients and they were given orally 30 mg of aspirin and 150 mg of dipyridamole daily and/or daily intravenous injection of 10,000 IU heparin during pregnancy. As a result, MIFD did not recur in all cases of the treated group and 87.5% (7/8) of the treated group could deliver approximate-for-date infants compared with 33.3% (2/6) of the untreated group (p < 0.05). These results indicate that anticoagulant and antiplatelet therapies are extremely effective for prevention of MIFD and IUGR due to MIFD.

The value of histomorphological features of chorionic villi in early spontaneous abortion for the prediction of karyotype.

This study was conducted to evaluate the value of histomorphological features of chorionic villi, such as size, shape, vascularity, trophoblast proliferation and trophoblastic pseudo-inclusions, for the prediction of chromosomal abnormality. Slides of 83 early spontaneous abortions were assessed by three observers. Assessments and karyotype were compared and likelihood ratios computed. Likelihood ratios of < or = 0.40 or > or = 2.50 were not obtained by all three observers for any of the features. One or two observers obtained likelihood ratios of > or = 2.50 for lacunar stromal hydrops, presence of trophoblastic hyperplasia, moderate to abundant trophoblastic hyperplasia, presence of trophoblastic lacunae, few intervillous fibrin deposits and few intervillous trophoblastic buds. Likelihood ratios of < or = 0.40 were found for small chorionic villi and presence of basophilic staining. Lacunar stromal hydrops and trophoblastic lacunae were predictive of triploid karyotype, but not specific for any other type of chromosomal abnormality. After application of data previously obtained on Cohen kappas, lacunar stromal hydrops, moderate to abundant trophoblastic hyperplasia and presence of trophoblastic lacunae remained as possibly useful features, again mainly for identifying triploidy. Most of the items claimed to be related to abnormal karyotype, however, were not predictive at all.

Some Placental Considerations Related to Neurodevelopmental and Other Disorders

Many newborns who appear normal at birth later manifest substantial neurologic and other disease. Pathologists are able to explain some of that sad enigma. Placental pathology frequently reveals the pathogenesis of cerebral palsy, mental retardation, and other neurodevelopmental disorders. This requires recognition of gross placental abnormalities and insightful light microscopic examination. Chorioamnionitis is now proven to be the major cause of premature onset of labor and prematurity. There is important need for investigation of pathogenetic processes associated with ascending intrauterine infection. Major complications therein include bacterially mediated fetal hypoperfusion resulting from placental and umbilical vasocontraction. Placentas of 10% of newborns have villitis of unknown etiology. The importance of villitis is incompletely known. The fetus may discharge meconium on more than one occasion, particularly so when the fetus is postmature. Clinicians may not recognize that fetal discharge has occurred if the event occurred 4 days or more prior to delivery. Intra-amniotic meconium associated with oligohydramnios probably causes placental and umbilical vasocontraction. Meconium probably thus contributes to the pathogenesis of pulmonary vasoconstriction, persistent fetal circulation, necrotizing enterocolitis, and damage of the fetal brain, liver, and kidneys. Fetal hypoxia and asphyxia may be acutely or chronically acquired. Major placental lesions associated with neonatal asphyxia include chronic ischemic change, nucleated red blood cells, intravillous hemorrhages, intimal vascular fibrin cushions, meconium staining, and intervillous fibrin.

Doppler velocimetry and small for gestational age pregnancies in sickle cell disease associated with abnormal placental pathology

SummaryPlacentas from singleton deliveries of 108 prospectively followed pregnant women, 18 with sickle cell disease (16 SS, 2 SC) 36 with AS and 54 with AA haemoglobin were examined and findings correlated with antepartum Doppler results and neonatal outcome. Systolic/diastolic ratios ⩾3 were designated as abnormal. Gross and microscopical examinations of placentas were done by a pathologist blinded to the Doppler results and pregnancy outcome.Results of our study show moderate to severe villous sclerosis as well as intervillous fibrin deposits in 31 per cent (5/16) of SS placentas examined but these were absent in the placentas of SC, AS and AA patients. The same patients with sickle cell (SS) disease demonstrated both abnormal uterine and umbilical systolic/diastolic ratios. Four of these five pregnancies resulted in the births of small for dates babies. In contrast, the nine SS women with normal Doppler studies and the two patients with only an abnormal uterine Doppler had normal or minimal placental ...

Magnesium supplement in pregnancy‐induced hypertension

The placenta and the umbilical cord obtained from 18 women with pregnancy-induced hypertension were investigated by light microscopy. The umbilical artery was studied by electron microscopy. 10 placentae and umbilical cords from normal pregnancies served as controls. The study was performed as a double-blind randomized controlled study in which 11 women were allocated to magnesium and 7 to placebo treatment. The treatment comprised a 48-hour intravenous magnesium/placebo infusion followed by daily oral magnesium/placebo intake until one day after delivery. Magnesium supplement increased birth weight and placental weight significantly. Light microscopic study of the placentae and the umbilical cord arteries showed no difference between the three groups concerning the occurrence of infarctions, cytotrophoblastic hyperplasia, vasculo-syncytial membranes, basement membrane thickening, stromal fibrosis or intervillous fibrin. Ultrastructurally, the endothelial cells of the umbilical arteries from women with pregnancy-induced hypertension showed a significant increase in the amount of dilated endoplasmic reticulum and basal laminae thickness when all 18 cases were compared with the controls. There was no significant difference when the magnesium group, the placebo group and the control group were compared separately. The present study suggests that magnesium supplement has a beneficial effect on fetal growth in pregnancy-induced hypertension. With regard to the light and electron microscopic changes we were unable to demonstrate any significant difference between the magnesium, placebo and control groups.

“Placental Polyp”

A case of the chronic type of placental polyp, occurring in a 37-year-oldwoman approximately 9 years after abortion of her last known pregnancy, is reported. The placental polyp was predominantly composed of necrotic and hyalinized chorionic villi without identifiable lining trophoblast; however, some villi showed a thin rim of apparently viable syncytiotrophoblast that exhibited focal strong positivity for human chorionic gonadotropin by immunohistochemical studies. Intermediate trophoblast, especially abundant within the intervillous fibrin, appeared most viable and showed strong positivity for human placental lactogen (hPL); syncytiotrophoblast also showed focal positivity for hPL. The basal aspect of the polyp was composed of abundant decidua that contained dilated and ectatic blood vessels. This study demonstrates the presence of cytoplasmic markers for pregnancy in a chronic type of placental polyp, apparently of 9 years' duration, and draws attention to an entity that may be encountered more frequently due to the current prevalence of induced abortions.

Clinical and pathologic aspects of recurrent placental villitis

In a retrospective survey, recurrent villitis was identified in ten of 59 patients in whom placental villitis had been diagnosed. The ten patients had a total of 41 pregnancies, with a reproductive loss of 60 per cent. In addition to enhanced fetal losses in all trimesters of gestation and postnatally, the incidences of fetal growth retardation and premature delivery were increased. There was no evidence of recent TORCH (toxoplasma, rubella, cytomegalovirus, herpes) infection, but all patients tested had rubella immunity. In six patients genital cultures were positive for gonorrhea and assorted microorganisms. Uterine abnormalities, including two septate uteri, one incompetent cervix, one submucosal leiomyoma, and one retroflexion, were common, and vaginal bleeding had occurred in five patients. Other factors included obesity (five patients) and clinical and laboratory evidence of autoimmunity (four of the five patients tested). In a control group of 20 patients with nonrecurrent villitis, the perinatal loss rate (37 per cent) was lower, and the incidences of positive cultures, uterine structural anomalies, obesity, and autoimmunity were also lower. Placental histologic findings included decidual plasma cell and intervillous fibrin and histiocytic infiltration, in addition to villous inflammation. These lesions, although consistent for a given patient, defined two clinically relevant groups of patients. The results of this study suggest that recurrent villitis is more frequent than previously reported, that it is associated with high perinatal mortality, and that immunologic and structural abnormalities in the host may play a role in its pathogenesis.

The effects of dietary supplementation during pregnancy on placental morphology, pathology, and histomorphometry

We related the macroscopic and microscopic morphology and the histomorphometry of the placenta to prenatal nutrutional supplementation. In the Prenatal Project, a controlled clinical trial, three dietary treatments (supplement, a high-protein beverage; complement, a balanced protein-calorie beverage, or routine vitamin and mineral tablets) were randomly allocated to poor Black pregnant women, and the outcome was assessed. Herein we report the effects on placental morphology and histomorphometry. There were significantly fewer preterm deliveries in the complement group, and this was reflected by an increase in the size of decidual cells, an index associated with placental aging. Several other characteristics of the placentas of the complement group may have been more directly associated with improved perinatal outcome: decreased intervillous fibrin, lower incidence of gross surface infarct, and smaller (and presumably less edematous) cells of the villous stroma, may have mediated increased placental perfusion. There was no evidence of any placental change associated with the increase in very preterm delivery and the highly significant depressed birth weight among preterm deliveries in the supplement group. The significantly lower incidence of meconium staining of Wharton’s jelly among controls seems likely to have been a chance finding. While there were several other indices that reflected placental aging, the significantly increased chorioamnionitis, acute funisitis, and acute decidual inflammation among placentas of those who delivered prematurely [the former two associated with very early delivery (<35 wk gestation)] were likely to have been involved as causes of premature delivery.

Notes on the morphology of the chimpanzee and orang-utan placenta

The placentae of 11 chimpanzees and five orang-utans were collected from Japanese zoos immediately after delivery and were examined according to the methods routinely used for the human placenta. Placenta extrachorialis (circumvallate and circummarginate placenta) occurred in 80 per cent of the specimens collected from each species. In both groups, the placental vessels were distributed predominantly in the magistral pattern, and the umbilical cord was eccentrically inserted. Subchorionic fibrin, sometimes marked, was seen in all 16 placentae, and there was a high incidence of small intervillous thrombi and deposits of intervillous fibrin. These observations, together with the histological and ultrastructural findings, confirm the previously reported similarity between the placentae of the great apes and the human placentae.

PLACENTAL PATHOLOGY IN MIDTRIMESTER PREGNANCIES INTERRUPTED BY INTRA‐AMNIOTIC INJECTION OF HYPERTONIC UREA

The histological appearances of 52 placentae from patients who had a urea-induced second trimester abortion were studied. Extensive subchorionic intervillous fibrin deposition and swollen degenerated stromal cells (probably Hofbauer cells), were found both in the placenta and membranes. Between urea injection and abortion, serial vaginal smears showed signs of progesterone deficiency. The urea-induced placental and fetal damage was similar to that seen with hypertonic saline.

Blood coagulation and thrombosis. Problems in obstetrics and gynaecology.

2 of the 4 important causes of maternal death are hemorrhage and thrombosis. Factors in pregnancy which change the parameters of the hemostatic mechanism are related to hypercoagulability caused by the elevated level of circulating estrogens and the tendency towards intervillous fibrin deposition. In a normal pregnancy there may be a 25% increase in coagulation factors VII X VIII and IX. In addition there are changes in the fibrinolytic system. Increases in plasminogen and the amount of alpha-2 macroglobulin content have been noted. In users of oral contraceptives the probable causes of increase of thrombosis are changes similar to the changes of pregnancy increased level of fibrinogen factors VII and X and plasminogen which occur within 2 weeks of the start of the pill.

Placental changes after experimental abruptio placentae and fetal vessel ligation of rhesus monkey placenta

After vascular ligation of fetal vessels using rhesus monkey place11tas at 100 to 120 days' gestational age, syncytial trophoblasts and cytotrophoblasts were found to be still growing 40 to 50 da ys after treatment. The villi in the treated lesions were few, large, and fibrotic. There were neither intervillous fibrin deposits nor thrombi in the wide intervillous spaces. Because of the sparsity of villi. the syncytial trophoblast was seemingly increased in amount. The monkey fetuses appeared to tolerate the insult of fetal vascular ligation , but experimental abruptio placentae resulting in derangements of the maternal circulation caused fetal death in utero.

Intervillous fibrin deposition—the Rohr, Nitabuch, and Langhans striae: Evolution of the “additional” cytotrophoblast in the normal placenta in the second trimester of pregnancy

This study was carried out on 55 placentas collected at the time of cesarean section, after therapeutic termination of pregnancy by intra-amniotic injection of saline, by uterine curettage, and after spontaneous delivery at term following normal and hypertensive pregnancies. The findings showed that the so-called depositions of “fibrin” are the result of fibrinoid transformation of the cytotrophoblastic extravillous masses through the mechanism of an active cellular destruction. The striae of Rohr, Nitabuch, and Langhans appear to have the biologic sense of a peripheral fibrinoid barrier resulting in the effort to arrest the trophoblastic invasive proliferation by the same general process of cellular necrosis. This study was carried out on 55 placentas collected at the time of cesarean section, after therapeutic termination of pregnancy by intra-amniotic injection of saline, by uterine curettage, and after spontaneous delivery at term following normal and hypertensive pregnancies. The findings showed that the so-called depositions of “fibrin” are the result of fibrinoid transformation of the cytotrophoblastic extravillous masses through the mechanism of an active cellular destruction. The striae of Rohr, Nitabuch, and Langhans appear to have the biologic sense of a peripheral fibrinoid barrier resulting in the effort to arrest the trophoblastic invasive proliferation by the same general process of cellular necrosis.