Postpartum acute myometritis suppresses expression of contraction-associated proteins in the gravid uterus.

Uterine atony is a major contributor to postpartum hemorrhage. We previously proposed the novel histological concept of postpartum acute myometritis (PAM) to elucidate the pathophysiology of uterine atony. This concept involves the infiltration of macrophages and neutrophils, as well as mast cell and complement activation in the myometrium. However, the pathological mechanism underlying uterine atony in the context of PAM remains unclear. Herein, we focused on uterine contraction-associated proteins (CAPs) including connexin 43 (Cx43), oxytocin receptors (OXR), prostaglandin receptors EP1, EP3, FP, and protease-activated receptor (PAR)-1. This follow-up study aimed to compare CAP expression between PAM and control groups. We selected 38 PAM subjects from the cases enrolled in our amniotic fluid embolism registry between 2011 and 2018. Control tissues from 10 parturients were collected during cesarean section. We stained the myometrial tissues with the following CAP markers, inflammatory cell markers, and other markers: Cx43, OXR, EP1, EP3, FP, PAR-1, C5a receptor, tryptase, neutrophil elastase, CD68, ß-actin, and Na+/K+-ATPase. The immunostaining-positive areas of Cx43, OXR, EP1, EP3, and FP standardized by ß-actin in the PAM tissue were significantly smaller than in the control group, whereas those of PAR-1 and Na+/K+-ATPase increased significantly in the PAM group. The Cx43- and OXR-positive areas correlated negatively with the immunostaining-positive cell numbers of CD68 and tryptase with halo, respectively. PAM may impair individual and synchronized myocyte contraction, leading to uterine atony refractory to uterotonics. Further cell-based studies are needed to elucidate the molecular mechanism by which inflammatory cells suppress CAP expression.

Comparative analysis of hyperfibrinolysis with activated coagulation between amniotic fluid embolism and severe placental abruption.

Amniotic fluid embolism (AFE) and placental abruption (PA) are typical obstetric diseases associated with disseminated intravascular coagulation (DIC). AFE is more likely to be complicated with enhanced fibrinolysis than PA. AFE may have an additional mechanism activating fibrinolytic cascade. We aimed to compare the coagulation/fibrinolysis factors among AFE, PA, and peripartum controls. We assessed AFE cases registered in the Japanese AFE Registry, and PA cases complicated with DIC (severe PA) and peripartum controls recruited at our hospital. The following factors in plasma were compared: prothrombin fragment 1 + 2 (PF1 + 2), plasmin α2-plasmin inhibitor complex (PIC), tissue factor (TF), tissue plasminogen activator (tPA), annexin A2 (AnnA2), total thrombin activatable fibrinolysis inhibitor (TAFI) including its activated form (TAFIa), and plasminogen activator inhibitor-type 1 (PAI-1). PF1 + 2 and PIC were markedly increased in both AFE (n = 27) and severe PA (n = 12) compared to controls (n = 23), without significant difference between those disease groups; however, PIC in AFE showed a tendency to elevate relative to PF1 + 2, compared with severe PA. AFE had significantly increased tPA and decreased total TAFI levels compared with severe PA and controls, which might be associated with further plasmin production in AFE and underlie its specific fibrinolytic activation pathway.

Massive platelet-rich thrombus formation in small pulmonary vessels in amniotic fluid embolism: An autopsy study.

OBJECTIVE: To identify pulmonary/uterine thrombus formation in amniotic fluid embolism (AFE). DESIGN: Retrospective, observational. SETTING: Nationwide. POPULATION: Eleven autopsy cases of AFE and control cases. METHODS: We assessed pulmonary and uterine thrombus formation and thrombus area in AFE and pulmonary thromboembolism (PTE) as a control. The area of platelet glycoprotein IIb/IIIa, fibrin, neutrophil elastase, citrullinated histone H3 (a neutrophil extracellular trap marker) and mast cell chymase immunopositivity was measured in 90 pulmonary emboli, 15 uterine thrombi and 14 PTE. MAIN OUTCOME MEASURES: Pathological evidence of thrombus formation and its components in AFE. RESULTS: Amniotic fluid embolism lung showed massive thrombus formation, with or without amniotic emboli in small pulmonary arteries and capillaries. The median pulmonary thrombus size in AFE (median, 0.012 mm2 ; P < 0.0001) was significantly smaller than that of uterine thrombus in AFE (0.61 mm2 ) or PTE (29 mm2 ). The median area of glycoprotein IIb/IIIa immunopositivity in pulmonary thrombi in AFE (39%; P < 0.01) was significantly larger than that of uterine thrombi in AFE (23%) and PTE (15%). The median area of fibrin (0%; P < 0.001) and citrullinated histone H3 (0%; P < 0.01) immunopositivity in pulmonary thrombi in AFE was significantly smaller than in uterine thrombi (fibrin: 26%; citrullinated histone H3: 1.1%) and PTE (fibrin: 42%; citrullinated histone H3: 0.4%). No mast cells were identified in pulmonary thrombi. CONCLUSIONS: Amniotic fluid may induce distinct thrombus formation in the uterus and lung. Pulmonary and uterine thrombi formation may contribute to cardiorespiratory collapse and/or consumptive coagulopathy in AFE.

Consumptive Coagulopathy Involving Amniotic Fluid Embolism: The Importance of Earlier Assessments for Interventions in Critical Care.

OBJECTIVES: Amniotic fluid embolism is a rare disease that induces fatal coagulopathy; however, due to its rarity, it has not yet been examined in detail. The strict diagnostic criteria by Clark for amniotic fluid embolism include severe coagulopathy complicated by cardiopulmonary insufficiency, whereas the Japanese criteria also include postpartum hemorrhage or Disseminated Intravascular Coagulation in clinical practice. Amniotic fluid embolism cases with preceding consumptive coagulopathy may exist and are potential clinical targets for earlier assessments and interventions among amniotic fluid embolism cases fulfilling the Japanese, but not Clark criteria. The present study was performed to compare coagulopathy in the earlier stage between the amniotic fluid embolism patients diagnosed by Clark criteria (Clark group, n = 6), those by the Japanese criteria (Non-Clark group, n = 10), and peripartum controls and identify optimal clinical markers for earlier assessments of amniotic fluid embolism-related consumptive coagulopathy. DESIGN: Retrospective case-control study. SETTING: A single university-based center. Our amniotic fluid embolism registry program has accumulated clinical information and blood samples since 2003. PATIENTS: Amniotic fluid embolism patients in the Clark and Non-Clark groups between 2009 and 2017 and peripartum controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical information was collected on hemoglobin levels, platelet counts, and coagulation- and fibrinolysis-related variables. Fibrinolytic parameters were also measured and compared among the three groups before blood transfusion. Fibrinogen levels in all patients in the Clark group and most in the Non-Clark group decreased earlier than hemoglobin levels, which was consistent with the high hemoglobin/fibrinogen ratio and, thus, is a promising clinical marker for the earlier assessment of amniotic fluid embolism-related consumptive coagulopathy. CONCLUSIONS: Earlier evaluations of consumptive coagulopathy and hyperfibrinolysis using the hemoglobin/fibrinogen ratio following preemptive treatment may reduce the occurrence or prevent the aggravation of severe coagulopathy in amniotic fluid embolism patients.