Complement activation and blockade in massive post-partum haemorrhage, thrombotic microangiopathy and acute kidney injury: a case report.

BACKGROUND: Thrombotic microangiopathy (TMA)-mediated acute kidney injury (AKI) following massive haemorrhage is a rare but severe complication of the post-partum period. It is associated with a poor renal prognosis and a high risk of end-stage kidney disease. Complement activation may occur in this picture. However, whether complement activation, and thus complement blockade, may be critically relevant in this setting is unknown. CASE PRESENTATION: A 50 year-old woman presented with massive delayed post-partum haemorrhage (PPH). Despite bleeding control and normalization of coagulation parameters, she rapidly developed AKI stage 3 associated with dysmorphic microhematuria and proteinuria up to 2 g/day with the need of renal replacement therapy. Blood tests showed signs of TMA associated with markedly increased sC5b-9 and factor Bb plasma levels, respectively markers of terminal and alternative complement pathway over-activation. This clinical picture prompted us to initiate anti-C5 therapy. sC5b-9 normalized within 12 h after the first dose of eculizumab, factor Bb and C3 after seven days, platelet count after nine days and haptoglobin after 3 weeks. The clinical picture improved rapidly with blood pressure control within 48 h. Diuresis resumed after three days, kidney function rapidly improved and haemodialysis could be discontinued after the sixth and last dose. Serum creatinine returned to normal two years after presentation. CONCLUSIONS: We suggest that massive PPH induced major activation of complement pathways, which ultimately lead to TMA-induced AKI. Various causes, such as oocyte-donation, the potential retention of placental material and the use of tranexamic acid may have contributed to complement activation due to PPH. The prompt administration of anti-C5 therapy may have rapidly restored kidney microcirculation patency, thus reversing signs of TMA and AKI. We propose that complement activation may represent a major pathophysiological player of this complication and may provide a novel therapeutic avenue to improve renal prognosis in TMA-induced AKI following massive PPH.

Immunological Role of the Maternal Uterine Microbiota in Postpartum Hemorrhage.

Recent metagenomics and microbiology studies have identified microorganisms that are typical of the fetoplacental unit. Considering this emerging evidence, the placenta, uterus, and the amniotic cavity are not sterile and not immune privileged. However, there is evidence for a beneficial interaction between active maternal immune system and the presence of commensal pathogens, which lead to an immune-tolerant state, thereby preventing fetal rejection. Multiple conditions associated with the loss of the normal flora are described (dysbiosis), which could result in perinatal and puerperal adverse events, including, directly or indirectly, postpartum hemorrhage. Altered flora when associated with a severe proinflammatory state and combined with patient's genetic and environmental factors confers a high-risk adverse outcome. Better understanding of the adverse role of dysbiosis in pregnancy outcome will improve maternal outcome.

Acute inflammation in the uterine isthmus coincides with postpartum acute myometritis in the uterine body involving refractory postpartum hemorrhage of unknown etiology after cesarean delivery.

Uterine atony is a major cause of postpartum hemorrhage. We recently proposed the new histological concept of postpartum acute myometritis (PAM) for the pathophysiology of refractory uterine atony of unknown etiology, which is characterized by the diffuse activation of mast cells and the complement system as well as the massive infiltration of macrophages and neutrophils into the uterine body. We herein focused on the uterine isthmus just adjacent to the body. The isthmus becomes significantly elongated throughout pregnancy. It is composed of myocytes and fibroblasts with an extracellular matrix that forms a passive lower segment during labor. The aim of this study was to histologically examine the uterine isthmus in cases of PAM in the uterine body. Under the amniotic fluid embolism-registry program in Japan, we selected PAM cases from uterine samples obtained by cesarean hysterectomy and delivered to us for analyses between 2011 and 2017. Control tissues were collected during elective cesarean section. We investigated the isthmus tissues of these cases and performed immunohistochemistry for inflammatory cell markers, i.e. neutrophil elastase, mast cell tryptase, CD68, CD3, and C5a receptor (C5aR). The numbers of tryptase-positive degranulating mast cells, elastase-positive neutrophils, CD68-positive macrophages, and C5aR-positive cells in the isthmus were significantly higher in uteri with PAM in the body than in controls without PAM. CD3 was negative in both groups. In conclusion, inflammation and an anaphylactoid reaction were histologically detected not only in the uterine body, but in the isthmus among cases of refractory PPH of unknown etiology after cesarean section.

The association between ABO blood group and obstetric hemorrhage.

UNLABELLED: Whether intra- and early post-partum hemorrhage is influenced by ABO blood groups remains unknown. Therefore, we compared women with O to non-O blood groups with regard to maternal post-partum hemorrhage and transfusion need. This retrospective study was conducted in a single tertiary center between 2005 and 2014. For the purpose of the study, parturients were categorized as O and non-O blood groups. Data included all deliveries but excluded patients with missing blood grouping or hemoglobin values, and/or stillbirth. Drop in hemoglobin was defined as hemoglobin concentration at admission for delivery minus lowest hemoglobin concentration post-delivery. Study outcomes were postpartum hemorrhage, hemoglobin drop >2-7 g/dL inclusive, and packed red blood cells transfusion. STATISTICS: descriptive, χ(2) (p < 0.05 significant) and multivariable regression models [odds ratio (OR), 95 % confidence interval (CI), p value]. 125,768 deliveries were included. After multivariable analysis, women with O blood type relative to women with non-O blood type had significantly higher odds of postpartum hemorrhage (OR 1.14; 95 % CI 1.05-1.23, p < 0.001), higher odds of statistically significant hemoglobin decreases of >2, 3, or 4 g/dL (OR 1.07; 95 % CI 1.04-1.11, p < 0.001, OR 1.08; 95 % CI 1.03-1.14, p = 0.002, OR 1.14; 95 % CI 1.05-1.23, p = 0.001; respectively), and higher odds, albeit not statistically significant of 5, 6, or 7 g/dL decreases in hemoglobin (OR 1.13; 95 % CI 1.00-1.29, p = 0.055, OR 1.05; 95 % CI 0.84-1.32, p = 0.66, OR 1.15; 95 % CI 0.79-1.68, p = 0.46; respectively), but no difference in blood products transfusion (OR 1.03; 95 % CI 0.92-1.16, p = 0.58). In conclusion, women with blood type O may be at greater risk of obstetrical hemorrhage.

Histological characteristics of the myometrium in the postpartum hemorrhage of unknown etiology: a possible involvement of local immune reactions.

The aim of this study was to evaluate the histological characteristics of the myometrium obtained in postpartum hemorrhage (PPH) of unknown etiology secondary to uterine atony. These characteristics were selected from among registered cases of clinically suspected amniotic fluid embolism (AFE) and classified as PPH of unknown etiology because of no obvious cause of PPH at Hamamatsu University School of Medicine, a registration center for clinical AFE in Japan. Immunohistochemical studies were performed on myometrium using anti-mast cell tryptase, anti-neutrophil elastase, anti-CD68, anti-CD88, anti-CD3, and anti-ZnCP-1 antibodies. Massive infiltrations of inflammatory cells with mast cell degranulation within the myometrium secondary to complement activation were observed in PPH of unknown etiology (n=34), but not in control pregnant women (n=15) or after delivery in women without PPH (n=18). The concomitant immunohistochemical detection of meconium in myometrium suggests that amniotic fluids or fetal materials are one of the candidates for inducing maternal local immune activation in the PPH of unknown etiology. Postpartum acute myometritis in the absence of an infective etiology may be a histological characteristic of PPH of unknown etiology.

Case of acquired hemophilia with factor VIII inhibitor in a mother and newborn.

We report a mother and newborn in the puerperium with hemorrhage secondary to factor VIII inhibitor. A 31-year-old gravida 1 para 1 delivered at a local clinic with a massive postpartum hemorrhage. The activated partial thromboplastin time was prolonged and factor VIII inhibitor was detected. The persistent hemorrhage improved following treatment, including transfusion, steroid therapy, and bypass therapy with factor VII formulations. After hysteroscopic removal of the retained placenta, the hemorrhage decreased. The newborn developed significant swelling of the hands after routine blood sampling and factor VIII inhibitor was detected. The inhibitor disappeared without any special treatment in the 5th month postpartum in the mother and the 4th month postpartum in the newborn. Factor VIII inhibitor may be transferred via the placenta from the mother to the fetus. Therefore, the newborn should also be carefully observed in a case of massive hemorrhage after delivery.

Postpartum acquired factor VIII inhibitors.

The development of factor VIII autoantibodies is a rare but severe complication of pregnancy. Although the natural history of postpartum acquired hemophilia A is usually benign, with a high percentage of spontaneous remissions and a low mortality, its quick recognition is important to control bleeding episodes. Based on an analysis of the literature, this review presents the current knowledge on the pathogenesis, diagnosis, epidemiology, natural history, clinical manifestations, and therapeutic management of postpartum acquired hemophilia A.

Case report: massive postpartum transfusion of Jr(a+) red cells in the presence of anti-Jra.

Jr(a) is a high-prevalence antigen. The rare Jr(a-) individuals can form anti-Jr(a) after exposure to the Jr(a) antigen through transfusion or pregnancy. The clinical significance of anti-Jr(a) is not well established. This study reports a case of a 31-year-old woman with a previously identified anti-Jr(a) who required massive transfusion of RBCs after developing life-threatening postpartum disseminated intravascular coagulopathy. Despite the emergent transfusion of 15 units of Jr(a) untested RBCs, she did not develop laboratory or clinical evidence of acute hemolysis. The patient's anti-Jr(a) had a pretransfusion titer of 4 and a monocyte monolayer assay (MMA) reactivity of 68.5% (reactivity > 5% is considered capable of shortening the survival of incompatible RBCs). The titer increased fourfold to 64 and the MMA reactivity was 72.5% on Day 10 posttransfusion. Review of laboratory data showed evidence of a mild delayed hemolytic transfusion reaction by Day 10 posttransfusion. Despite rare reports of hemolytic transfusion reactions due to anti-Jr(a) in the literature, most cases, including this one, report that this antibody is clinically insignificant or causes only mild delayed hemolysis. Clinicians should be advised to balance the risks of withholding transfusion with the small chance of significant hemolysis after transfusion of Jr(a+) RBCs in the presence of anti-Jr(a).

Acquired factor VIII inhibitors as a cause of primary post-partum haemorrhage.

Acquired haemophilia was diagnosed following detailed investigation of a post-partum haemorrhage unresponsive to standard management. Circulating factor VIII inhibitors and low factor VIII levels were detected and intravenous DDAVP treatment lead to a resolution of symptoms. This case highlights the importance of haematological investigations in persisting post-partum haemorrhage.

Postpartum acquired haemophilia: clinical recognition and management.

Postpartum acquired haemophilia is a rare but serious complication of an otherwise normal pregnancy. Patients usually present with postpartum haemorrhage (PPH) or uncontrolled bleeding following surgical interventions, which fail to respond to conservative treatment. A high index of clinical suspicion along with early laboratory diagnosis and prompt institution of appropriate therapy is essential for the management of acute bleeding episodes. Our patient, a 32-year-old female, presented with severe PPH and shock. She had undergone dilation and curettage three times, with subsequent total abdominal hysterectomy and internal iliac artery ligation, before she was diagnosed with acquired haemophilia (factor VIII autoantibodies) and an inhibitor level of 8 Bethesda units (BU). The patient underwent an abdominal laparotomy for removal of the abdominal packing used in the previous operation, and blood and blood clots, and was given FEIBA(R) therapy. The patient responded to these measure and the factor VIII inhibitor level decreased to 2 BU at the time of discharge 10 weeks later.

[Acquired autoantibodies against human factor VIII: a new case]. / Auto-anticorps acquis anti-facteur VIII humain: une nouvelle observation.

The finding of a prolonged partial thromboplastin time and a normal prothrombin time localized the coagulation defect to the intrinsic or contact activation limb of the coagulation cascade. Because the situation is a source of hemorrhage, a rational and rapid approach is necessary with measure of factors of intrinsic limb of coagulation (especially factors VIII and IX, for the diagnosis of classic hemophilia), study of von Willebrand factor and search of coagulation factor inhibitors. We report the case of a 25-year old woman with high titer postpartum antibody against factor VIII for illustrating the diagnosis approach.

[Immune thrombocytopenic purpura and pregnancy: maternal risk factors]. / Immun thrombocytopeniás purpura és terhesség: az anya veszélyeztetettsége.

Authors analyse 75 pregnancies and 51 deliveries, respectively, of 45 mothers with chronic immune thrombocytopenia (ITP) from the point of view of maternal risks. Pregnancies that occurred in active disease were electively terminated. It was found that pregnancy contributed to the clinical manifestation of ITP, and antepartal bleeding took place in 18%, and preeclampsia emerged in 6%. The chronic ITP showed exacerbation during pregnancy in 27.3%, thus causing antepartal bleeding in 4.5% and postpartal bleeding in 15.9%. Postpartal bleeding presented in total 20%, not only in cases with severe ITP, but also in moderate ones. Postpartal blood transfusion was needed in 16%. The postpartal reduction of hemoglobin level determined 2-3 days following delivery was higher than in those ITP patients who had no postpartal haemorrhage than that in the general obstetrical population. This suggests an increased blood loss associated with delivery in patients with ITP. Maternal morbidity of patients with ITP in whom the disease first manifested during pregnancy was higher than that of those patients in whom pregnancy was associated with the remission of ITP. In order to decrease the maternal risks in ITP we advise that pregnancy should occur and be carried during remission.

Rh immunoglobulin use with placenta previa and abruptio placentae.

Patients with obstetric hemorrhage from placenta previa or abruptio placentae may be at increased risk of Rh sensitization because they fail to receive Rh immunoglobulin (RhIG) or are given an inadequate dose. To evaluate the use of RhIG in this clinical situation, we studied 498 patients with hemorrhage from placenta previa or abruptio placentae treated at a large municipal hospital from 1975 to 1979. All 25 RhIG candidates received the product before their discharge from the hospital. This rate of RhIG use was equal to that for patients whose infants were delivered without these complications and significantly higher than that for patients with spontaneous abortion and ectopic pregnancy at the same hospital (P less than .05). Prompt administration of an adequate dose of RhIG to candidates with bleeding from placenta previa or abruptio placentae can further reduce Rh hemolytic disease.

Pregnancy and antibody to factor VIII.

A patient who had developed a factor VIII antibody three weeks after the birth of her first baby became pregnant for the second time 10 weeks later. The pregnancy was normal apart from extensive spontaneous bruising during the first two months. This bleeding tendency disappeared in the third month of gestation and the antibody became undetectable during the eighth month. It has not reappeared seven months later. An unexplained long bleeding time and low platelet count were noted during the last trimester. The literature on postpartum coagulation inhibitors is reviewed.