Toshihiko Asahina

Congenital blood coagulation factor XIII deficiency and successful deliveries: a review of the literature.

Congenital deficiency of blood coagulation factor XIII is an uncommon, inherited disorder characterized by hemorrhagic diathesis, habitual abortions and defective wound healing. We analyzed 8 reported successful pregnancies in women with a congenital deficiency of A-subunit of factor XIII (XIIIA), in which the plasma level of maternal factor XIIIA and/or the precise replacement therapies are described. Because decidual bleeding usually begins from 5 to 6 weeks’ gestation and, without replacement therapy, spontaneous abortion always occurs, we herein offer the following prenatal and peripartum management guidelines and observations: i) the level of plasma A-subunit of factor XIII antigen (XIIIA-Ag) or factor XIII activity (XIII-act) must be at least 2%–3%, and, if possible, higher than 10% to prevent decidual bleeding and miscarriage during the pregnancy; ii) factor XIIIA concentrate is better than fresh frozen plasma or cryoprecipitate for replacement therapy; iii) the administration of 250 international units (IU) every 7 days is sufficient to maintain the level of plasma XIIIA-Ag or XIII-act more than 10% in the early period of gestation (through 22 weeks’ gestation); however, 500 IU every 7 days is indicated in the later period (from 23 weeks’ gestation) to maintain that level; iv) during labor, the desired level of plasma XIIIA-Ag or XIII-act should be higher than 20%, and, if possible, higher than 30% in order to make ready for any risk of severe obstetrical hemorrhagic complications; thus a booster dose of 1000 IU is indicated before labor; v) no replacement therapy is necessary in the puerperium because it is usually uneventful without it. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to recall that congenital deficiency of factor XIII is a rare inherited disorder that has adverse pregnancy outcomes if not recognized and treated and explain that replacement treatment with factor XIIIA during early pregnancy improves the pregnancy outcome, however the replacement therapy must be increased to maintain the recommended level of plasma XIII activity during pregnancy and labor.

Studies on the Role of Adhesive Proteins in Maintaining Pregnancy

It is well known that maternal fibrinogen (Fg) and factor X III are essential for maintaining early pregnancy. We studied their role by analysis of clinical reports and immunohistochemical investigation. Methods: (1) We analyzed the pregnancy cases of congenital afibrinogenemia and congenital factor X III deficiency. (2) Immunohistochemical staining of Fg, subunit A of factor X III (X IIIA) and fibronectin (Fn) were performed in the human implantation site, placenta, and endometrial cells cultured in serum-free medium. Results: (1) Afibrinogenemia needed to be administrated Fg from 4 weeks’ gestation (4 wG), and factor X III deficiency needed factor X III concentrate from 5 wG, in order to prevent abortion. (2) Implantation tissues: Fg, cellular X IIIA and Fn were present at the decidual stroma around invasive cytotrophoblasts at 5 wG. X IIIA-positive cells coincided with LN-5-positive macrophages. Placenta: Fg, cellular X IIIA and Fn were present in the decidual layer. Endometrial culture cells: Fn was secreted by spindle-like shaped cells. X IIIA was secreted by round-shaped cells. Conclusion: Maternal Fg and factor X III are essential just after 4∼5 wG, and in that period they and Fn are present abundantly in decidual stroma around invasive cytotrophoblasts. It is concluded that when cytotrophoblasts invade endometrium maternal Fg, factor X III and Fn are concerned with cytotrophoblasts’ anchoring as adhesive proteins.

Congenital Afibrinogenemia with Successful Delivery

We experienced a case of congenital afibrinogenemia and successfully performed cesarean section with administration of fibrinogen. The patient was administered fibrinogen every week to sustain a fibrinogen level above 60 mg/ dl according to our previously reported first case. Pregnancy course was uneventful, and fetal growth was normal, but unfortunately placental abruption occurred after the spontaneous onset of labor at 37 weeks gestation. The fibrinogen level before labor was 96 mg/dl, but decreased to 33 mg/dl when placental abruption was diagnosed. During and after the operation, it was increased to 147 and 199 mg/dl, respectively, through infusion of 10 g of fibrinogen, and massive bleeding was stopped. Two grams of fibrinogen were infused daily after cesarean section, and postpartum hemorrhage was normal. It is obvious that fibrinogen is an extremely important factor in maintaining pregnancy, and we conclude that fibrinogen level must be at least 60 mg/dl during pregnancy, 120 mg/dl during surgery and 150 mg/dl during labor, if possible as high as 200 mg/dl under the continuous infusion of fibrinogen to prevent placental abruption.

Congenital Blood Coagulation Factor XIII Deficiency and Perinatal Management

Transglutaminases are at least 9 enzymes which cross-link a number of proteins. This type of reaction not only enhances the original functions of substrate proteins, but also adds new functions to them. Factor XIII (FXIII) is a plasma transglutaminase circulating in blood as a heterotetramer and consisting of two catalytic A subunits and two non-catalytic B subunits. It is a proenzyme activated by thrombin in the blood coagulation cascade. It plays an important role(s) in hemostasis, wound healing, and maintenance of pregnancy. Accordingly, a lifelong bleeding tendency as well as abnormal wound healing and recurrent spontaneous miscarriage are common symptoms of FXIII deficiency. Genetic and molecular mechanisms of congenital deficiencies have been analyzed in vitro. The mechanisms of these defects have also been studied in detail by using FXIII gene knock-out mice in vivo. We analyzed eight successful outcomes of pregnancy in patients with congenital deficiency of FXIIIA, in which the plasmatic level of maternal FXIIIA and/or the precise substitute therapies were mentioned. Then we propose the following guidelines for the perinatal management: (i) decidual bleeding usually begins from 5 weeks of gestation and spontaneous abortion always occurs subsequently without substitute therapy; (ii) the plasma level of FXIIIA must be at least 2 approximately 3%, however, if possible, higher than 10% to prevent bleeding and miscarriage; (iii) the administration of 250 IU of FXIIIA concentrate each 7 days is enough to keep the level of plasma FXIIIA more than 10% in the early gestation, however 500 IU each 7 days is adequate in the later period to keep that level; (iv) during labor, the desired level is higher than 20%, if possible, higher than 30% to avoid any risk of strong obstetrical bleeding.

Zinc Coproporphyrin I Derived from Meconium Has an Antitumor Effect Associated with Singlet Oxygen Generation

Introduction: Zinc coproporphyrin I (ZnCP-I) is a photosensitive molecule and a major component of meconium. Here, we examined the effects of ZnCP-I as a potential photosensitizer in photodynamic therapy for tumors. Materials and Methods: (1) Aqueous ZnCP-I was irradiated with a pulsed YAG-SHG laser (wavelength: 532 nm)/YAG-SHG dye laser (wavelength: 566 nm). (2) HeLa cells were incubated in 200 mM ZnCP-I, and accumulation of ZnCP-I in HeLa cells was evaluated with ZnCP-I-specific fluorescence over 500 nm. (3) Aqueous ZnCP-I was administered intravenously to HeLa tumor-bearing mice at a dose of 10.2 mg/kg body weight. The tumors were irradiated with a filtered halogen lamp (wavelength: 580 nm) at 100 J/cm2 20 min after administration. Results: (1) An intense near-infrared emission spectrum was observed at around 1,270 nm after irradiation. The emission intensity was proportional to the laser power between 10 and 80 mW and was completely inhibited by addition of NaN3, a singlet oxygen scavenger. (2) ZnCP-I-specific fluorescence was detected in the HeLa cell cytoplasm. (3) Irradiated tumors treated with ZnCP-I were mostly necrotized. Conclusion: ZnCP-I accumulated in tumor cells, produced singlet oxygen upon irradiation, and necrotized the tumor cells. These results suggest that ZnCP-I may be an effective photosensitizer.