Maternal Diabetes Mellitus is Associated with Altered Deposition of Fibrin-type Fibrinoid at the Villous Surface in Term Placentae

doi:10.1053/plac.2002.0953

Placenta

Volume 24, Issue 5, May 2003, Pages 524-531

https://doi.org/10.1053/plac.2002.0953 Get rights and content

Abstract

Placentae from control and diabetic patients were used to test three null hypotheses: (1) there are no significant group differences in the volumes of villous syncytiotrophoblast compartments or intervillous fibrin-type fibrinoid, (2) perivillous fibrin-type fibrinoid is deposited randomly at the surface of trophoblast, and (3) amounts and deposition patterns of perivillous fibrin-type fibrinoid do not vary between groups. Term placentae were collected from non-diabetic subjects and five groups of diabetic women classified according to duration, severity and insulin dependence. Tissue specimens and sections were obtained by uniform random sampling. Volumes and surface areas of fibrin-type fibrinoid and trophoblast compartments (thin, syncytial knot, syncytial bridge and denuded regions) were estimated stereologically and compared using variance, chi-squared and contingency table analyses. As to null hypothesis (1), no group differences in volumes of trophoblast compartments were found but volumes of intervillous fibrin-type fibrinoid were greater in the non-insulin-dependent diabetic group. As to null hypothesis (2), regardless of group, fibrin-type fibrinoid was deposited preferentially at sites of denudation in every placenta examined. As to null hypothesis (3), villous surface areas occupied by perivillous fibrin-type fibrinoid were greater in type 1 (insulin-dependent) diabetics with complications (diabetic nephropathy or retinopathy). The surfaces of trophoblast occupied by fibrin-type fibrinoid were also notably larger in non-insulin-dependent diabetics and type 1 diabetics with complications. Except for the surface of denudation sites (which also increased in diabetes), there were no differences in the surfaces of trophoblast regions. These results confirm that the haemostatic steady state is perturbed in the diabetic placenta, that perivillous fibrin-type fibrinoid is deposited preferentially at sites of epithelial loss/damage, and that some diabetic groups are affected differentially.

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Lipopolysaccharide (LPS) can traverse the intestinal barrier and enter bloodstream, causing endotoxemia and triggering inflammation. Increased circulating LPS was reported in arterial thromboembolism. We investigated whether increased LPS levels occur in acute pulmonary embolism (PE) and if it is associated with a prothrombotic state.
We studied 120 normotensive PE patients (aged 59 [48–68] years) on admission, after 5–7 days, and after a 3-month anticoagulation. Serum LPS levels, along with zonulin, a marker of gut permeability, endogenous thrombin potential (ETP), fibrin clot permeability (K_s), clot lysis time (CLT), fibrinolysis proteins, and platelet markers were assessed.
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Low-grade endotoxemia is detectable in patients with acute PE and may contribute to increased thrombin generation and PAI-1-mediated hypofibrinolysis.
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These relative volumes were indexed in the variable names (e.g. as posSTROrel). Absolute volumes were estimated by multiplying these volume fractions with the volume of the placenta, which was derived from PW by assuming the tissue density to be 1.05 g/ml [15]. These absolute volumes [ml] were indexed in the variable names (e.g. as posSTROabs).
The classification of histologically stained villous cross sections in villous types (terminal, intermediate and stem villi) by stromal peculiarities is known to be observer predicated. Therefore, quantitative histology of villous trees has not become a routine endpoint of studies on the role of the placenta in prenatal programming, as opposed to the gross placental parameters weight and thickness. The classification of villous cross sections in central (stem) and peripheral (terminal) parts based on the presence or absence, respectively, of immunohistochemical detection of myofibroblasts in perivascular position is less observer dependent. We hypothesized that it will, possibly, identify microscopic correlates of placental weight and thickness within the villous tree.
50 placentas from clinically normal pregnancies were processed for the present study. Thin villous cross sections, obtained in a systematic random manner, were stained immunohistochemically to detect γ-smooth muscle (sm) actin and to classify them subsequently as part of central or peripheral villous tree. The volume fractions of histological structures visible in villous cross sections (stroma, lumen, endothelium and syncytium) were estimated by design-based stereology.
The present study reveals a significant correlation of placental weight and thickness with the volume estimate of stroma that have myofibroblasts in perivascular position.
The positive linear correlation between the volume of central parts of villous trees and the placental weight and thickness is new. Surprisingly, the volume of more peripheral parts of villous trees, which is the main site of materno-fetal exchange does not correlate with placental weight and thickness.
Stereology of the placenta in type 1 and type 2 diabetes
2011, Placenta
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Following delivery, the cord was clamped within 30 s and placental dimensions measured. Following trimming of the placental membranes and cord, each placenta was weighed on the same scales and then the volume of the fresh placenta was measured from calculation of the weight, assuming a tissue density of 1.05 g/ml [16–20]. In the lab, the placenta was placed flat and a perspex grid placed over it.
To assess by stereology the placental structure in type 1 (T1DM) and type 2 (T2DM) diabetic pregnancies compared to normal non-diabetic (ND) controls.
Prospective case control study. Placentae were sampled in a systematic random fashion. Stereological analysis was performed using a computerised stereology programme (Image Pro 6.2, Media Cybernetics, Inc, Silver Spring MD, USA). Participants were matched for gender of infant and mode of delivery.
Volume, length and surface area of placental components; clinical outcome.
Ten ND, eight T2DM and ten T1DM women consented to the study. There was no difference between the groups regarding maternal age, neonatal birth weight, or placental weight. On stereological examination, terminal villous volume was significantly increased in both diabetic groups compared to ND controls. Capillary volume and length was increased in T1DM pregnancies compared to ND and T2DM. Capillary length was increased in both diabetic groups compared to ND. When all diabetic groups were compared based on severity of glycaemia those with poor glycaemic control (HbA1c>7%) had higher placental capillary volume than those with good glycaemic control.
This study demonstrates an association between maternal diabetes and increased terminal villous volume. Additionally capillary volume and length is increased in the placentae of normally grown infants of T1DM diabetic mothers compared to non-diabetic controls. Maternal glycaemia appears to influence capillary, but not stromal, development. This suggests that factors other than glycaemia have a role in placental development in pre-gestational diabetes.
Variation in composition of the intervillous space lining in term placentas of mothers with pre-eclampsia
2010, Placenta
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Increased deposition of fibrin within the basal plate, particularly on the intervillous space lining will lead to an increased area of fibrin barrier, impairment of anchoring villus development and remodelling of spiral arteries by extravillous trophoblast cells emanating from anchoring villi. Resulting poor placentation may be fundamental to progression to systemic pre-eclampsia [43–47]. Massive perivillous fibrin deposition in placentas of diabetic women causes poor fetal outcomes and is associated with miscarriage and intra uterine growth retardation in failed antigcoagulant treatment of antiphophospholipid antibody syndrome [48–50].
To define composition of chorionic plate and test effects of pre-eclampsia on basal plate composition.
Retrospective cohort study where distinct area fractions were measured in: healthy term chorionic plate (CP: n = 11), healthy placental basal plate (n = 11), mild pre-eclamptic basal plate (n = 10) and severe pre-eclamptic basal plate (n = 11).
CP lining is partly endothelial. Mean anchoring villus (AV)/acellular (NS) basal plate area ratio decreased in pre-eclampsia (p = 0.048). There was a decreasing trend with increasing disease severity. Basal plate endothelial cell proportion was not significantly lower in severe pre-eclampsia than in healthy or mild pre-eclamptics.
An inverse relationship between the proportions of fibrin and anchoring villi indicates that increased basal plate fibrin deposition and reduced basal plate materno-fetal anchoring area are part of pre-eclamptic disease progression. Endothelium lining intervillous surfaces may originate from circulating maternal endothelial progenitor cells.
Villous histomorphometry and placental bed biopsy investigation in type I diabetic pregnancies
2006, Placenta
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In diabetic pregnancies complicated by fetal growth retardation syncytial knots are found more frequently, the percentage of vasculo-syncytial membranes tends to be lower, and the trophoblastic basement membrane is significantly thicker [6]. Villous surface areas occupied by perivillous fibrin-type fibrinoid are greater in Type I diabetics with complications (diabetic nephropathy or retinopathy) confirming that the haemostatic steady state is perturbed in the diabetic placenta [33]. The presence of an attenuated vascular response to vasoconstrictor and vasodilator agents in diabetic and preeclamptic pregnancies indicates that the placenta may not be able to respond adequately to demands for altered blood flow in situations where this is necessary, thus leading to further fetal compromise [1].
Insulin-dependent diabetes mellitus (Type I) is associated with disregulation of the glucose and oxygen metabolic pathways during pregnancy, both of which affect placental villous development. Term complete placentas and placental bed biopsies, between 37 and 40 weeks, from 12 singleton pregnancies complicated by Type I diabetes were collected following delivery by elective Caesarean section. The controls consisted of 10 term placentas from uncomplicated pregnancies delivered by elective Caesarean section. Villous morphology was investigated using unbiased histomorphometric techniques, in relation to the degree of transformation of the spiral arteries and the presence of fetal macrosomia. A significant increase in fetal and placental weights, placental volume, volumes of the intervillous space and the trophoblast was found in the diabetic group compared to the controls. A significant reduction in the villous membrane specific diffusing capacity was observed between the diabetic and control groups (1.32 vs 1.72 cm³ min⁻¹ mmHg⁻¹ kg⁻¹, P = 0.032). A significant increase in the volume of the intermediate and terminal villi, the surface area of the villi and of the fetal capillaries, and the harmonic thickness of the villous membrane was found in the macrosomic subgroup compared to the controls. There were no differences between the hypertensive subgroup with histological evidence of partial transformation of the spiral arteries and the controls. These data indicate that placental development in insulin-dependent diabetic pregnancies is affected differentially when pregnancies complicated by fetal macrosomia are separated from those complicated by maternal hypertensive disorders with partial transformation of the spiral arteries. The reduction in the specific diffusing capacity of the villous membrane may contribute to the fetal hypoxia and increased fetal and neonatal morbidity associated with diabetes.
Fibrin enhances differentiation, but not apoptosis, and limits hypoxic injury of cultured term human trophoblasts
2005, Placenta
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Apoptosis could thereby create denudations in the trophoblast layer. Extensive morphometric analyses [3,20–24] have clarified that fibrin-type fibrinoid is preferentially located at sites of de-epithelialization and demonstrate that fibrin-type fibrinoid deposition is more prevalent in some complicated pregnancies [23,25]. However, other pregnancies complicated by placental dysfunction exhibit less villous fibrin in the placenta [18].
We hypothesized that fibrin enhances apoptosis and modulates differentiation of trophoblast in vitro. Cytotrophoblasts isolated from normal term human placentas were cultured ≤72 h in DMEM–10%-FBS on a fibrin matrix in standard or hypoxic conditions. Trophoblasts were cultured on plastic (control), type I collagen (matrix control), or dishes with fibrinogen, fibrin degradation products (FDP), thrombin, plasma fibronectin or cellular fibronectin. Apoptosis was determined by western analysis of the cleavage products of poly-ADP-ribose polymerase and cytokeratin 18 and caspase 3 activity. Cell cycle regulation was quantified by expression of proliferating cell nuclear antigen (PCNA) and p27 protein. Differentiation was determined by media level of hCG and hPL. Compared to the two controls, fibrin matrix had no effect on trophoblast apoptosis or total cell death in standard conditions. Neither fibrin nor collagen altered expression of PCNA or p27. In contrast, fibrin significantly increased the secretion of both hCG and hPL. Fibrin, but not FDP, thrombin or fibronectins, promoted hormonal differentiation. Fibrin limited the impact of a ≤8 h of hypoxia on trophoblast hormone release but did not avert the effects of 24 h of low oxygen and did not alter apoptosis in hypoxic trophoblast. We conclude that fibrin provides an environment conducive for trophoblast re-epithelialization of the surface of villi, where injury is marked by fibrin deposition.

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^f1: To whom correspondence should be addressed at: Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, E Floor, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. Tel.: +115-970-9414; Fax: +115-970-9259; E-mail: [email protected]

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Regular ArticlesMaternal Diabetes Mellitus is Associated with Altered Deposition of Fibrin-type Fibrinoid at the Villous Surface in Term Placentae

Abstract

Eur J Obstet Gynecol Reprod Biol

Early Human Dev

Am J Obstet Gynecol

Placenta

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Annals Anat

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Am J Cardiol

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Am J Obstet Gynecol

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J Autoimmun

Am J Obstet Gynecol

Prog Cardiovasc Dis

Metabolism

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Am J Obstet Gynecol

Am J Med

Quantitative aspects of placental structure

J Pathol Bacteriol

Histological changes in placental syncytiotrophoblasts of poorly controlled gestational diabetic patients

Endocrinol J

Inhibitors of fibrinolysis in diabetic children, mothers, and their newborn

Am J Hematol

Is there a physiological intravascular coagulation in obstetrical cases?

Acta Obstet Gynecol Scand

Coagulation and fibrinolysis parameters in normal pregnancy and in gestational diabetes

Am J Perinatol

Denudations as paracellular routes for alphafetoprotein and creatinine across the human syncytiotrophoblast

Am J Physiol, Regul Integr Comp Physiol

Nonenzymatic glycosylation reduced the susceptibility of fibrin to degradation by plasmin

Diabetes

Outcomes of pregnancy in insulin dependent diabetic women: results of a five year population cohort study

Br Med J

Coagulation activation in diabetes mellitus: the role of hyperglycaemia and therapeutic prospects

Diabetologia

Fibrinogen and diabetes mellitus: is it time for intervention trials?

Diabetologia

Plasma cofactors of platelet function: correlation with diabetic retinopathy and haemoglobin A1a-c. Studies in diabetic patients and normal persons

Ann Intern Med

Free radical activity and hemostatic factors in NIDDM patients with and without microalbuminuria

Diabetes

Regular Articles
Maternal Diabetes Mellitus is Associated with Altered Deposition of Fibrin-type Fibrinoid at the Villous Surface in Term Placentae