fibrin and Abortion--Habitual

Chronic inflammatory placental disorders are a group of rare but devastating gestational syndromes associated with adverse pregnancy outcome. This review focuses on three related conditions: villitis of unknown etiology (VUE), chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition (MPFD). The hallmark of these disorders is infiltration of the placental architecture by maternal immune cells and disruption of the intervillous space, where gas exchange between the mother and fetus occurs. Currently, they can only be detected through histopathological examination of the placenta after a pregnancy has ended. All three are associated with a significant risk of recurrence in subsequent pregnancies. Villitis of unknown etiology is characterised by a destructive infiltrate of maternal CD8+ T lymphocytes invading into the chorionic villi, combined with activation of fetal villous macrophages. The diagnosis can only be made when an infectious aetiology has been excluded. VUE becomes more common as pregnancy progresses and is frequently seen with normal pregnancy outcome. However, severe early-onset villitis is usually associated with fetal growth restriction and recurrent pregnancy loss. Chronic histiocytic intervillositis is characterised by excessive accumulation of maternal CD68+ histiocytes in the intervillous space. It is associated with a wide spectrum of adverse pregnancy outcomes including high rates of first-trimester miscarriage, severe fetal growth restriction and late intrauterine fetal death. Intervillous histiocytes can also accumulate due to infection, including SARS-CoV-2, although this infection-induced intervillositis does not appear to recur. As with VUE, the diagnosis of CHI requires exclusion of an infectious cause. Women with recurrent CHI and their families are predisposed to autoimmune diseases, suggesting CHI may have an alloimmune pathology. This observation has driven attempts to prevent CHI with a wide range of maternal immunosuppression. Massive perivillous fibrin deposition is diagnosed when >25% of the intervillous space is occupied by fibrin, and is associated with fetal growth restriction and late intrauterine fetal death. Although not an inflammatory disorder per se, MPFD is frequently seen in association with both VUE and CHI. This review summarises current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology and potential prophylaxis against recurrence in these

Topics: Abortion, Habitual; Chorioamnionitis; Chronic Disease; COVID-19; Female; Fetal Death; Fetal Growth Retardation; Fibrin; Humans; Placenta; Pregnancy; Pregnancy Outcome; SARS-CoV-2; Syndrome

A large body of evidence obtained during the past 6 years suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. While the majority of women with thrombophilia will have an uneventful gestation, case-control studies have demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss early onset preeclampsia, placental abruption, and severe intrauterine growth retardation (IUGR). Placental pathological findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition potentially to a greater degree than in normal pregnancy. Preliminary case-control studies suggest a benefit for prophylaxis with low molecular weight heparins (LMWH), and prospective randomized trials are in progress to define whether LMWH are effective in preventing pregnancy loss in women with thrombophilia and previous fetal wastage.

Topics: Abortion, Habitual; Factor V; Female; Fetal Death; Fibrin; Humans; Hyperhomocysteinemia; Mutation; Placenta; Pregnancy; Pregnancy Complications, Hematologic; Protein C; Prothrombin; Thrombophilia

To critically review the literature regarding inherited thrombophilia and recurrent fetal loss.. English-language literature review.. Women who experienced repeated pregnancy wastage.. Aspirin, glucocorticoids, heparin, and IV immunoglobulin for the prevention of miscarriage.. Live birth, miscarriage, preeclampsia, and pregnancy loss.. Recurrent fetal loss and other placental vascular pathologies of pregnancy have long been associated with antiphospholipid syndrome, an acquired autoimmune thrombophilic state. The number of known heritable thrombophilic disorders has grown rapidly in recent years with the identification of activated protein C resistance, factor V Leiden mutation, and hyperhomocysteinemia as major causes of thrombosis. Data accumulated over the past 2 years suggest that heritable thrombophilia is associated with an increased risk of fetal loss and preeclampsia. The present review discusses potential pathogenetic mechanisms for this association and evaluates reported therapeutic regimens for the prevention of fetal loss in women with thrombophilia.. Placental thrombosis may be the final common pathophysiologic pathway in most women with habitual abortions and repeated pregnancy wastage. Prophylactic antithrombotic therapy is indicated in women with heritable thrombophilia and antiphospholipid syndrome and probably is more effective than the previously used modalities of prednisone, aspirin, and IV immunoglobulin.

Topics: Abortion, Habitual; Antiphospholipid Syndrome; Antithrombin III Deficiency; Female; Fibrin; Humans; Hyperhomocysteinemia; Pregnancy; Protein C; Prothrombin; Thrombophilia

Topics: Abortion, Habitual; Animals; Autoantibodies; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Factor IX; Factor V; Factor VIII; Female; Fibrin; Humans; Immunoglobulins; Isoantibodies; Lupus Coagulation Inhibitor; Lupus Erythematosus, Systemic; Pregnancy; Prothrombin; Thrombosis; von Willebrand Factor

Topics: Abortion, Habitual; Animals; Antibodies; Antigen-Antibody Complex; Antigens; Blood Vessels; Choriocarcinoma; Complement System Proteins; Female; Fetus; Fibrin; Fibrinogen; Histocompatibility; Histocytochemistry; HLA Antigens; Humans; Immunoglobulins; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy in Diabetics; Uterine Neoplasms; Uterus

Massive perivillous fibrin deposition (MPFD) is frequently associated with detrimental pregnancy outcomes, and extensive perivillous fibrin deposition results in severe placental dysfunction and loss of maternofetal interface. Unfortunately, the fundamental pathogenesis of MPFD remains unknown, and systematic analyses of MPFD in miscarriage is lacking. We analyzed the frequency and clinicopathological characteristics of MPFD in first trimester miscarriages.. We analyzed a consecutive series of miscarriages (n = 582) gathered between March 2012 and June 2016. MPFD was classified as fibrin-type (f-MPFD) and matrix-type (m-MPFD) by immunostaining for fibrin and collagen type IV. The control group consisted of miscarriage cases (MC, n = 18) that were matched to f-MPFD with normal chromosome (f-MPFD-nc) for number of previous miscarriages and placental chromosomal status.. MPFD was identified in 2.7% of miscarriages. f-MPFD was associated with recurrent abortions. Compared with miscarriages without fibrin deposition, MPFD cases had higher proportion of those with normal placental chromosome (69.2% vs. 27.4%, P < 0.005) and higher frequency of villous syncytiotrophoblast C4d deposition (73.3% vs. 33.9%, P < 0.005). All C4d(+) f-MPFD patients had more than three recurrent miscarriages, whereas C4d(-) f-MPFD patients had no history of recurrent miscarriage (P < 0.05). Patients with f-MPFD-nc had significantly higher HLA PRA immunopositivity rate than did MC patients (P = 0.005).. MPFD was more common in miscarriages than in preterm and term pregnancies. Placental massive fibrin-type fibrinoid deposition and villous C4d immunoreactivity were associated with recurrent miscarriage.

Topics: Abortion, Habitual; Adult; Cohort Studies; Female; Fibrin; Humans; Placenta; Pregnancy; Pregnancy Trimester, First

Massive perivillous fibrin deposition (MPVFD) and chronic intervillositis (CI) are related rare pathological correlates of severe intrauterine growth restriction (IUGR) and fetal loss with high recurrence rates. No standard management has been established.. A patient underwent termination of pregnancy at 21 weeks for severe early onset IUGR. Placental histology showed mixed CI with MPVFD. Several months later, the patient became pregnant and was managed with prednisone and aspirin (ASA) but miscarried at 16 weeks. Placental pathology showed MPVFD and focal CI. For two subsequent pregnancies, she was treated with intravenous immunoglobulin (IVIG), heparin, and ASA. Both pregnancies resulted in healthy near-term deliveries with normal placentas.. IVIG, heparin, and ASA can be an option in patients with recurrent pregnancy loss due to MPVFD and CI.

Topics: Abortion, Habitual; Abortion, Spontaneous; Adult; Anticoagulants; Aspirin; Chorionic Villi; Dalteparin; Female; Fetal Growth Retardation; Fibrin; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Placenta; Placenta Diseases; Platelet Aggregation Inhibitors; Pregnancy

Massive perivillous fibrin deposition (MPFD) is associated with serious complications of pregnancy including recurrent spontaneous abortion, fetal growth restriction, and fetal demise. The aim of this study was to determine whether maternal plasma concentrations of angiogenic/antiangiogenic factors in MPFD differ from those of uncomplicated pregnancies.. This retrospective longitudinal case-control study included MPFD cases (n = 10) and control patients (n = 175) with uncomplicated pregnancies who were enrolled in a longitudinal study and delivered at term. Serial plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor (sVEGFR)-1 and -2 were determined by an enzyme-linked immunosorbent assay (cases, n = 28 samples; controls, n = 723 samples). Individual analyte concentrations were averaged across gestational age at specimen collection intervals. Linear mixed models were used to test for differences in log-transformed mean analyte concentrations both overall and as a function of time.. The following results were found: (1) patients with MPFD had a lower mean plasma PlGF concentration (P = .03) and higher mean plasma concentrations of sVEGFR-1 and sEng (both P < .01) than controls, adjusted for potential confounders; (2) the mean plasma concentration of PlGF differed further among cases and controls as a function of gestational age interval (P < .0001); however, mean sVEGFR-1 and sEng group differences as a function of gestational age interval approached but did not reach significance (P = .09 and P = .11, respectively); (3) patients with MPFD had lower mean plasma concentrations of PlGF/sVEGFR-1 (P < .0001) and PlGF/sEng (P < .001): both of these relationships differed further as a function of gestational age interval (both P < .0001); and (4) differences in mean sVEGFR-1, sEng, and the ratios of PlGF to sVEGFR-1 and PlGF to sEng were observed before 20 weeks of gestation.. An imbalance of angiogenic/antiangiogenic factors is present in patients with MPFD prior to the diagnosis. We propose that these changes participate in the mechanisms responsible for adverse pregnancy outcomes in patients with MPFD.

Topics: Abortion, Habitual; Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Case-Control Studies; Female; Fetal Death; Fibrin; Humans; Longitudinal Studies; Placenta Diseases; Pregnancy; Young Adult

The present work was intended to study the process of fibrin formation and lysis and plasmin generation in a group of patients with recurrent miscarriage (RM), due to the presence of antiphospholipid antibodies (N = 10); as well as in women with RM without the antiphospholipid syndrome (APS) (N = 6), compared with those of a group of healthy women (N= 8). In the group of patients with APS, nine were positive for antibodies against cardiolipin (aCL), five for anti-beta2-glycoprotein I (anti-beta2GPI), four for both antibodies, and one for antibodies against prothrombin (aPT) and lupus anticoagulant (LA). Fibrin formation and lysis was followed by turbidity and plasmin generation using chromogenic substrate S2251. The polymerization curves from RM patients without APS and the LA patient showed an increased slope and maximum turbidity compared to those of the control group. The speed of lysis was higher in the LA patient (21 +/- 0) 10(-4) deltaOD/seg and the RM patients without APS (19.6 +/- 5.7) 10(-4) deltaDO/seg, compared to that of the control group (14.5 +/- 2.8) 10(-4) deltaDO/seg. Plasmin generation increased only in RM patients without APS (85 +/- 24%) against the control group (52 +/- 3%), p = 0.005. The changes observed in the fibrin polymerization and lysis process of women with RM without APS and LA seem to be related to their higher fibrinogen levels, while the increased plasmin generation was related to the patients' morbidity.

Topics: Abortion, Habitual; Adult; Antibodies, Anticardiolipin; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Autoantigens; beta 2-Glycoprotein I; Biopolymers; Blood Coagulation; Enzyme Activation; Female; Fibrin; Fibrinolysin; Fibrinolysis; Humans; Lupus Coagulation Inhibitor; Nephelometry and Turbidimetry; Plasminogen; Pregnancy; Streptokinase; Thrombin; Thrombophilia; Young Adult

We have studied some biophysical properties of the fibrin network during the normal state of pregnancy and in patients with recurrent miscarriage (RM), in the first trimester of pregnancy. The fibrin polymerization process, followed by turbidity, showed that the rate of fibrin monomer assembly and the final turbidity was increased in the pregnant group (normal and with history of RM) compared to non-pregnant women (normal and RM), which is consistent with the increased fibrinogen concentration during pregnancy. No changes were observed in the Darcy constant (Ks) of RM clots, pregnant or not; however, in pregnant control subjects the Ks increased (p = 0.03). The fibrin lysis rate was increased in pregnant women compared to non-pregnant, being faster in women with RM. The rheological properties of the fibrin network in the non-pregnant group (control and RM patients) were similar; in the pregnant state, the fibrin network of the control group was 1.3 times stiffer compared to the control non-pregnant women, and almost unchanged in RM patients. In this study we have found changes in the clot structure that seem to be related to normal pregnancy and an increased rate of the fibrin lysis process in the RM patients, which may have clinical relevance.

Topics: Abortion, Habitual; Blood Coagulation Tests; Female; Fibrin; Fibrinolysis; Hemostasis; Humans; Microscopy, Electron, Scanning; Nephelometry and Turbidimetry; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Trimester, First; Thrombelastography; Time Factors; Venezuela

Inherited thrombophilias are associated with an increased risk of maternal thromboembolism and certain adverse pregnancy outcomes, including second- and third-trimester fetal loss, placental abruption, severe intrauterine growth restriction, and early-onset, severe preeclampsia. Pregnant patients with severe thrombophilias, especially antithrombinopathies are at very high risk for both thromboembolism and adverse pregnancy outcomes. A case of a patient with antithrombin deficiency is reported, who had two successful pregnancies after eight miscarriages. Our case shows that a combined treatment with antithrombin substitution and a prophylactic, body-weight-adjusted dose of low-molecular-weight heparin may be successful in preventing pregnancy loss and thromboembolism in antithrombin deficiency during pregnancy, although other complications, such as preeclampsia and intrauterine growth restriction cannot always be prevented.

Topics: Abortion, Habitual; Adult; Anticoagulants; Female; Fibrin; Heparin; Humans; Infertility, Female; Pregnancy; Pregnancy Complications, Hematologic; Thromboembolism; Thrombophilia; Treatment Outcome

To establish the incidence, recurrence rate and consequences of massive perivillous fibrinoid.. Retrospective analysis of the histology of all placentas with a diagnosis of massive perivillous fibrinoid between 1991 and 1998, together with the maternal case records.. The histopathology department of the Rotunda Hospital, Dublin, Ireland.. A relatively homogeneous group of pregnant women in the northern part of Dublin City, which is the catchment area for the Rotunda Hospital, delivered between 1991 and 1998.. Retrospective review of archival placental pathology and maternal charts.. The incidence of massive perivillous fibrinoid, perinatal outcome and recurrence rate.. The incidence of massive perivillous fibrinoid was 0.028%, with a recurrence rate of approximately 18%. All the infants suffered intrauterine growth restriction; there was a 31% fetal loss rate and a 33% preterm delivery rate.. Massive perivillous fibrinoid is associated with intrauterine death, intrauterine growth restriction and preterm delivery. It has a significant recurrence rate and both the clinical findings of intrauterine growth restriction and the postmortem findings imply a syndrome of chronic placental insufficiency.

Topics: Abortion, Habitual; Adult; Chorionic Villi; Female; Fetal Death; Fetal Growth Retardation; Fibrin; Gestational Age; Humans; Microscopy, Electron; Obstetric Labor, Premature; Placental Insufficiency; Pregnancy; Recurrence; Retrospective Studies

We present three pregnancies in which massive perivillous fibrous deposition (MPVFD) and maternal floor infarction (MFI) occurred in patients with primary antiphospholipid antibody syndrome (PAPS) attending a recurrent miscarriage clinic, and who were treated with low dose aspirin and heparin. We hypothesise that PAPS may be a predisposing factor to the development of this condition. The increased prevalence of late pregnancy complications in PAPS patients with a history of early miscarriage suggests that aspirin and heparin therapy does not eradicate the underlying pathological process but merely reduces the severity. Therefore, untreated early pregnancy losses may be converted into treated pregnancies with late antenatal complications. Some patients with PAPS may therefore be prone to suffer either the previously reported complications of the uteroplacental vasculature, such as pre-eclampsia, and/or specific complications related to the environment of the intervillus space, such as MPVFD/MFI.

Topics: Abortion, Habitual; Adult; Antiphospholipid Syndrome; Chorionic Villi; Female; Fibrin; Humans; Infarction; Placenta; Pregnancy

Factor XIII is a transglutaminase essential for normal hemostasis. We have studied the plasma FXIII levels and FXIII activity in 71 individuals and found these to be normally distributed. FXIII specific activity is also normally distributed. However, we show that FXIII activity is not directly dependent on FXIII levels, and individuals with low FXIII levels may have high FXIII activity and vice versa. We have determined the FXIIIA genotype in these individuals to assess whether the variation observed in FXIII specific activity is dependent on specific polymorphisms in the FXIIIA gene. Our data show that the Leu34 and Leu564 variants give rise to increased FXIII specific activity, while the Phe204 variant results in lower FXIII specific activity. We also report preliminary evidence that the Phe204 polymorphism may be associated with recurrent miscarriage. Overall, we have identified 23 unique FXIIIA genotypes. Certain specific FXIIIA genotypes consistently give rise to high, low, or median FXIII specific activity levels, while others appear to have little or no consistent influence on the FXIII phenotype. These genotype to phenotype relationships are discussed in light of the growing interest in the role of FXIII in clinical problems involving an increased thrombotic tendency.

Topics: Abortion, Habitual; Adolescent; Adult; Amino Acid Substitution; England; Enzyme-Linked Immunosorbent Assay; Factor XIII; Female; Fibrin; Gene Frequency; Genotype; Humans; Male; Middle Aged; Phenotype; Point Mutation; Polymorphism, Genetic; Pregnancy

Massive chronic intervillositis (MCI) is an unusual placental lesion associated with poor fetal growth and adverse pregnancy outcome; it has not previously been associated with spontaneous abortion or recurrent pregnancy loss. This article reports a patient who had 10 spontaneous abortions with repetitious massive chronic intervillositis documented in four of five gestations spanning all three trimesters. Characteristic placental histology induced massive infiltration of the maternal intervillous space by chronic inflammatory cells and fibrin, without associated chronic villitis; the cellular infiltrate was composed predominantly of LCA and CD68 immunoreactive cells with scattered CD45RO positivity, consistent with a monocyte/macrophage population with occasional T lymphocytes. Elevated maternal serum alpha-fetoprotein was documented in two pregnancies. These findings support the concept that this unusual placental lesion may have an immunologic basis, and suggest that MCI may be a histopathologically recognizable cause of recurrent spontaneous abortion.

Topics: Abortion, Habitual; Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Chorionic Villi; Chronic Disease; Female; Fibrin; Humans; Immunohistochemistry; Leukocyte Common Antigens; Macrophages; Male; Monocytes; Placenta Diseases; Pregnancy; Pregnancy Outcome; T-Lymphocytes

Topics: Abortion, Habitual; Abortion, Threatened; Animals; Basement Membrane; Colloids; Female; Fetal Death; Fetal Diseases; Fibrin; Glycosaminoglycans; Humans; Infant, Newborn; Infant, Premature; Iron; Mice; Necrosis; Placenta; Placenta Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Staining and Labeling; Trophoblasts