Altered release of thrombomodulin and HMGB1 in the placenta complicated with preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a severe pregnancy complication due to placental dysfunction. Thrombomodulin (TM), a glycoprotein expressed on the trophoblast cell membrane, plays an organ-protective role in the placenta by regulating coagulation and inflammation. TM-mediated regulation of High Mobility Group Box1(HMGB1) is an essential mechanism that contributes to placental homeostasis and prevents pregnancy complications in mice. Here, we aimed to clarify the role of placental TM and HMGB1 in the pathophysiology of human PE. METHODS AND RESULTS: In this study, maternal blood serum and placental tissue were obtained from 72 PE patients and 110 normal controls. Soluble TM(sTM) and HMGB1 levels in the maternal serum were assessed. The placental TM and HMGB1 expression levels were evaluated using immunohistochemistry and qPCR. Serum sTM and HMGB1 levels gradually increased with gestational age in normal pregnancies; however, both circulating sTM and HMGB1 levels were significantly higher in the PE group. Serum HMGB1/sTM ratio was elevated in PE patients compared to that in normal controls, which correlated positively with the clinical severity of PE. The immunohistochemistry analysis revealed the loss of TM and the increase in extranuclear HMGB1. TM mRNA expression was diminished in PE placentas, which negatively correlated with soluble fms-like tyrosine kinase-1 (sFlt-1) expression. DISCUSSION: The increase in circulating sTM and HMGB1 could be attributed to the enhanced placental TM shedding in PE patients. The molecular events mediated by the imbalance in the placental TM and HMGB1 levels could be an underlying feature of PE; maternal serum HMGB1/sTM ratio could reflect this status.

Thrombomodulin and pregnancy in the limelight: Insights into the therapeutic aspect of thrombomodulin in pregnancy complications.

BACKGROUND: Thrombomodulin (TM) is a transmembrane glycoprotein expressed on the endothelial cell functioning as a cofactor in the anticoagulation system. However, aside from anticoagulation, recent studies have revealed its multiple organ protective roles such as anti-inflammation, angiogenesis, and cell proliferation, which may redefine the function of TM. Although TM is predominantly expressed on placental trophoblasts, the physiological role of TM during pregnancy remains unclear. Because the understanding of TM function has drastically progressed, these new discoveries shed light on the unknown activities of placental TM. Moreover, the clinical application of recombinant TM (rTM) has opened the possibility of TM as a therapeutic target for pregnancy complications. OBJECTIVES: Here, we comprehensively review the studies elucidating the role of TM during pregnancy from both classic and newly discovered perspectives, and seek for its potential as a therapeutic target for pregnancy complications. METHODS: Basic research using trophoblast cells and transgenic mice, as well as cohort studies of inherited TM deficiency and clinical trials of rTM were summarized, which led us to further discuss the clinical application of rTM as a novel therapeutic for pregnancy complications. RESULTS AND CONCLUSION: Accumulating evidence suggest the relevance of placental TM deficiency in pregnancy complications such as miscarriage, fetal growth restriction, and preeclampsia. Most importantly, promising results in animal studies and clinical trials further assure the possibility of rTM as an optimal therapeutic for such conditions. The therapeutic potential of TM raised throughout this review could drastically change the clinical approach to pregnancy complication and improve maternal outcomes.

Group A Streptococcal Toxic Shock Syndrome after a Routine Gynecological Procedure.

Streptococcal toxic shock syndrome (STSS) is a life-threatening illness mainly caused by invasive group A Streptococcus (GAS) infection. Herein, we report a case of a postmenopausal woman who developed STSS from an ascending vaginal GAS infection after cytocervical sampling. The patient complained of vaginal discharge, for which she underwent gynecological examination with vaginal sampling. The following day, there was onset of diarrhea and vomiting. After 7 days, she was admitted to our hospital with septic shock. Necrotizing enterocolitis was suspected and surgical intervention was performed; however, the patient was diagnosed with primary peritonitis and antibiotics were initiated. On day 2, GAS was suspected by blood cultures, and antibiotics were changed in consideration of STSS. On day 4, GAS was confirmed in blood, ascitic fluid, and vaginal swab specimens, and STSS caused by an ascending vaginal GAS infection was diagnosed. This case report indicates that STSS could occur following cytocervical sampling for vaginal discharge. If a woman has unexplained septic shock, especially with gastroenteritis symptoms, STSS should be considered as a differential diagnosis.

Thrombomodulin promotes placental function by up-regulating placental growth factor via inhibition of high-mobility-group box 1 and hypoxia-inducible factor 1α.

INTRODUCTION: Pregnancy is a state of maternal systemic stress due to inflammation and hypoxic reactions originating from the utero-placental unit. Maternal tolerance to these stresses is a key for successful outcomes. Thrombomodulin (TM), a glycoprotein expressed on cell surface, regulates local inflammatory pathways by inhibiting proinflammatory factor, High-mobility-group box1(HMGB1). Although TM is highly expressed on placental trophoblast cells, biological activities of TM during pregnancy remains unclear. Here, we hypothesized that TM may contribute to the maternal stress coping mechanisms. METHODS: By administering recombinant-TM (rTM) to the pregnant mice, we investigated the influence of TM functions on the placenta and fetal growth. We further examined its effect on trophoblast cells, focusing on HMGB1-regulated inflammatory signalings and hypoxia-inducible factor 1α (HIF1α)-dependent regulation of placental angiogenic factors. RESULTS: Administration of rTM increased fetal weight and fetal/placental-weight ratios, which implies the improvement of placental function. These features were accompanied by maternal serum HMGB1 reduction and suppressed placental proinflammatory cytokine, IL-6 and TNF-α, expressions. In addition, rTM reduced HIF1α protein accumulation and enhanced placental growth factor (PlGF) expression in the placenta, that explains the improvement of maternal features. DISCUSSION: Our study revealed the supportive effect of TM on the placental function in mice. By inhibiting HMGB1, rTM suppresses proinflammatory cytokines, downregulates HIF1α and induces PlFG expression in the placental tissue. Our results have elucidated the novel aspects of TM; the regulation of placental inflammatory cytokines and angiogenic factors, during pregnancy. These findings may reveal potential therapeutic opportunities for the management of maternal complications.

Recombinant Thrombomodulin Attenuates Preeclamptic Symptoms by Inhibiting High-Mobility Group Box 1 in Mice.

Preeclampsia (PE) is a common gestational complication that involves systemic endothelial dysfunction and inflammatory responses primarily due to placental damage. Recombinant thrombomodulin (rTM), a novel anticoagulant clinically used for disseminated intravascular coagulation, is reported to have a unique anti-inflammatory endothelial repair function by inhibiting proinflammatory mediator high-mobility group box 1 (HMGB1). Despite the severe patient outcomes, there are currently no effective therapeutic options to treat PE. Here, we verified the efficacy of rTM as a novel therapeutic agent for PE using a murine model and human trophoblast cells. We revealed the therapeutic potential of rTM in an angiotensin II(Ang II)-induced PE mouse model. Injection of rTM significantly attenuated clinical features of PE, such as hypertension, proteinuria, fetal growth restriction, and impaired placental vasculature. Elevation of maternal soluble fms-like tyrosine kinase-1 (sFlt-1), a well-accepted causal factor of PE that induces systemic endothelial dysfunction, was suppressed in response to rTM treatment. Supporting these findings, our in vitro experiments revealed that rTM reduces Ang II-triggered overproduction of sFlt-1 in human trophoblast cells. Moreover, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), well-known key inflammatory mediators in PE pathogenesis, were diminished by rTM. SiRNA knockdown experiments further determined that these processes were directly mediated by HMGB1. Our studies demonstrate that rTM exerts its clinical effect as HMBG1 inhibitor and ameliorates placental dysfunction, which is central to PE pathogenesis. Our findings suggest that rTM could be a promising therapeutic that significantly improve the outcomes of PE patients.

Uterine Torsion in an Elderly Woman Associated with Leiomyoma and Continuously Elevating Muscle Enzymes: A Case Study and Review of Literature.

Uterine torsion is extremely rare in postmenopausal women. Total ischemia of the uterus may cause life-threatening conditions; hence, accurate diagnosis and surgical intervention are crucial. However, preoperative diagnosis is often challenging due to nonspecific clinical features and laboratory findings. We report a case of uterine torsion in a 73-year-old woman who presented with mild but gradually worsening intermittent abdominal pain. During a 5-day observation, repeated blood exams showed elevating serum muscle enzyme levels, lactate dehydrogenase (LDH), and creatinine kinase (CPK), in addition to nonspecific signs of inflammation. Computed tomography (CT) scans were obtained before and after the worsening of symptoms, which revealed changes in size and position of the enlarged uterus with a large leiomyoma, even within a 5-day interval. Based on these findings, the preoperative diagnosis was uterine torsion. Emergency surgery revealed a 540-degree torsion of the uterus at the cervix and uterine body junction. Total hysterectomy and bilateral salpingo-oophorectomy were performed. Plasma muscle enzyme levels normalized after surgery, and the patient recovered without complications. In conclusion, uterine torsion should be considered during differential diagnosis in elderly women with large leiomyoma, even when symptoms are mild. Elevating plasma muscle enzymes may be an indication of uterine torsion; hence, repeated laboratory works and CT scanning should be performed when symptoms progress. Comparison of CT images, taken before and after the worsening of symptoms, may also be relevant for diagnosis. Since uterine torsion may cause rapid deterioration and become life-threatening, early diagnosis and surgical intervention are crucial to avoid serious complications.

Impact of Th1/Th2 cytokine polarity induced by invariant NKT cells on the incidence of pregnancy loss in mice.

OBJECTIVE: This study aimed to investigate the association of Th1/Th2 polarity induced by CD1d-restricted invariant natural killer T (iNKT) cells with pregnancy outcome. METHODS: Two types of iNKT cell stimulants with different cytokine induction properties, alpha-galactosylceramide (AGC; Th1-biased inducer), and a sphingosine-truncated derivative of AGC (OCH; Th2-biased inducer) were administered to pregnant mice on day 9.5 post-coitus (pc), and the incidence of pregnancy loss was evaluated. Serum Th1/Th2 cytokine levels after the iNKT cell stimulations were assessed. Cytokine production from cultured splenocytes following iNKT cell activation was analyzed. RESULTS: No fetal loss was observed after OCH administration, in clear contrast with the high frequency of pregnancy loss after AGC exposure. High serum levels of IL-4 and IL-10 were detected upon OCH administration, whereas a temporary surge of IFN-γ was observed after AGC administration. In splenocyte cultures, increases in IL-4 and IL-10 were noted after OCH administration, whereas IL-12 production was enhanced by AGC. Additionally, AGC-induced pregnancy loss was inhibited by IL-4 administration. CONCLUSION: The resistance of mouse pregnancy to iNKT cell stimulation by OCH and the prevention of AGC-induced fetal loss by IL-4 were demonstrated. In pregnancy, the regulation of Th1/Th2 polarity by iNKT cells is a key to healthy fetal growth.

Antepartum intracranial hemorrhage due to unrecognized unilateral moyamoya disease: a case report.

PURPOSE: Moyamoya (meaning a "hazy puff of smoke" in Japanese) disease is a rare cerebrovascular occlusive disease. Moyamoya disease may become symptomatic for the first time during pregnancy. We report a case of antepartum intracranial hemorrhage due to unrecognized unilateral moyamoya disease, which was subsequently diagnosed as HELLP syndrome during the postpartum period. STUDY DESIGN: A case report of a 29-year-old Japanese primigravida who was transported to our hospital at 39 weeks of gestation because of sudden loss of consciousness and left hemiplegia. On arrival, her blood pressure was 143/94 mmHg with 1+ proteinuria by dipstick. Brain computed tomography revealed a right putaminal hemorrhage with intraventricular hemorrhage. The patient delivered a neonate by emergency cesarean section, and an intracranial hematoma was subsequently evacuated. Approximately 3 h postoperatively, she was diagnosed with HELLP syndrome and the following were initiated: IV magnesium sulfate, antihypertensive agents, and transfusion of 10 units of platelets. Angiographic findings were consistent with unilateral moyamoya disease. CONCLUSIONS: Moyamoya disease is a rare entity that must be considered in the differential diagnosis of hemorrhagic stroke during pregnancy. It is important to perform careful monitoring and adequate management with cooperation between obstetricians and other specialists when serious complications arise.