Iron metabolism abnormalities in autoimmune hemolytic anemia and Jianpishengxue keli can ameliorate hemolysis and improve iron metabolism in AIHA mouse models.

OBJECTIVE: Autoimmune hemolytic anemia (AIHA) is rare heterogeneous disorder characterized by red blood cell (RBC) destruction via auto-antibodies, and after RBC is destroyed, proinflammatory danger-associated molecular patterns including extracellular hemoglobin, heme, and iron which causing cell injury. And oxidative stress represents one of the most significant effects of chronic hemolysis. Jianpishengxue keli can improve the symptoms of anemia patients with kidney disease and tumors and are beneficial in promoting recovery from chronic inflammation. Therefore, it is presumed that Jianpishengxue keli can improve the symptoms of AIHA. We aimed to investigate iron metabolism in AIHA and effects of Jianpishengxue keli on AIHA murine model. METHODS: Nineteen hemolytic episode AIHA patients, 10 remission patients and 10 healthy controls (HCs) were enrolled in this study. Serum hepcidin, ferritin and other related indicators of iron metabolism were measured. Mouse models of AIHA were established and received high, medium, or low doses of Jianpishengxue keli by gavage daily for 14 and 28 days respectively. The level of RBCs, Hb, bilirubin, LDH, hepcidin, and the expression level of hepcidin mRNA, and hepatic ferroportin 1(FPN1) protein were evaluated. RESULTS: Serum hepcidin in hemolytic episode AIHA patients and remission patients were significantly higher than that in HCs (p = 0.0083 and p = 0.0473, respectively). Serum ferritin in hemolytic AIHA patients was significantly higher than that in HCs (p = 0.008). Serum transferrin saturation levels are increased in patients with AIHA[ (57.21 ± 8.96) %]. EPO in hemolytic group was higher than that in healthy control (p＜0.05). In AIHA mouse models, IBIL decreased after 14 days of high dose drug intervention. After 28 days, TBIL and IBIL both significantly decreased in all dose groups and LDH significantly decreased in the medium-and high-dose groups. Body weight improved, and the level of RBCs, Hb and hepcidin in the high-dose group returned to normal. After 14 and 28 days of intervention, hepatic hepcidin mRNA in all dose group significantly decreased. Hepatic FPN1 protein which were significantly lower in the AIHA mouse models, increased in all dose groups after drug intervention for 28 days. CONCLUSION: Iron metabolism abnormalities exists in AIHA patients and Jianpishengxue keli can ameliorate hemolysis and improve iron metabolism in AIHA mouse models.KEY MESSAGESIron metabolism abnormalities exists in hemolytic episode AIHA patients. Hepcidin and ferritin levels significantly elevated and also correlated with the severity of AIHA patients. Jianpishengxue keli can ameliorate hemolysis and prompt the recovery of AIHA.

Atezolizumab-induced hemolytic anemia - A case report.

INTRODUCTION: Atezolizumab is currently the only immunotherapy used in conjunction with nab-paclitaxel for locally advanced or triple negative breast cancer. Limited data is available regarding hemolytic anemia as a side effect of atezolizumab. CASE REPORT: We describe a 59-year-old female with a history of triple negative breast cancer with bone metastases presenting for follow up on Cycle 1, Day 15 of atezolizumab and nab-paclitaxel (100 mg/m2). Patient's complete blood count (CBC) showed macrocytic anemia, with further workup significant for autoimmune hemolytic anemia (AIHA) attributed to atezolizumab.Management and outcome: Patient was started on a high dose prednisone taper starting at 80 mg daily for 16 days, folic acid 1 mg three times daily, iron sucrose, and darbepoetin alfa. Patient's counts recovered, and she was able to start Cycle 2 and continued through Cycle 10 without any additional pre-medications. DISCUSSION: Hemolytic anemia induced by atezolizumab is a rare side effect that was successfully treated in this patient with a prednisone taper.

Successful treatment of severe refractory autoimmune hemolytic anemia after hematopoietic stem cell transplant with abatacept.

BACKGROUND: After hematopoietic stem cell transplantation (HSCT) autoimmune hemolytic anemia (AIHA) is a known and fairly common complication. It is often refractory to conventional therapies including corticosteroids, intravenous immunoglobulin, splenectomy, and the more recently described use of monoclonal antibodies. The high morbidity associated with these severe persistent cases elucidates the gaps in alternative therapies available for treatment. STUDY DESIGN AND METHODS: We described the successful use of abatacept for severe refractory AIHA after HSCT in three patients. RESULTS: Three pediatric patients with refractory AIHA after allogeneic stem cell transplantation were observed to be unresponsive to multitude immunosuppressive therapies, resulting in persistent transfusion dependency. Treatment with abatacept, a fusion protein that inhibits T-cell activation by binding to CD80/CD86 on antigen-presenting cells (APCs), thus blocking the required CD28 interaction between APCs and T cells, resulted in the resolution of hemolysis. CONCLUSION: Abatacept may provide significant clinical benefit in the management of AIHA after HSCT.

Evaluation of the safety and tolerability of rivaroxaban in dogs with presumed primary immune-mediated hemolytic anemia.

OBJECTIVE: To evaluate the safety and tolerability of rivaroxaban (RIV), an oral direct factor Xa inhibitory drug, in dogs with presumed primary immune-mediated hemolytic anemia (pIMHA). DESIGN: Prospective, multicenter, positive-controlled, unblinded clinical trial. Client-owned dogs were enrolled between October 2012 and March 2014. SETTING: Private referral centers. ANIMALS: Twenty-four client-owned dogs with pIMHA. Enrolled dogs were randomized in 2 treatment groups to receive by mouth RIV or clopidogrel (CL) and low-dose aspirin (LDA). All dogs were monitored for 90 days from the enrollment in the study. INTERVENTIONS: Enrolled dogs were given a standardized immunosuppressive protocol and RIV or CL and LDA. MEASUREMENTS AND MAIN RESULTS: There was no identifiable adverse drug reaction, evidence of hemorrhage, significant prolongation of prothrombin time or activated partial thromboplastin time, or increase in transfusion requirements associated with RIV therapy compared to CL and LDA in dogs with pIMHA. There was no significant difference between treatment groups with respect to thrombotic events, survival rates to discharge, at 1 month and 3 months from diagnosis. CONCLUSIONS: This study suggests that RIV at a median dose of 0.89 mg/kg by mouth once daily was safe and well tolerated in a small group of dogs with presumed pIMHA able to tolerate oral medications and treated with a standardized immunosuppressive treatment protocol. Conclusions regarding the relative efficacy of RIV as compared to CL and LDA cannot be made due to the small size of the treatment groups and because pharmacodynamic effects were not assessed.

Rituximab is an effective and safe therapeutic alternative in adults with refractory and severe autoimmune hemolytic anemia.

Rituximab-induced B-cell depletion has been proven to be a useful therapy for autoimmune hemolytic anemia (AIHA). The aim of this retrospective study was to evaluate the effectiveness of rituximab in the treatment of 36 patients with AIHA refractory to several treatments. These patients had received a median of four (one to eight) previous treatments, and 13 patients had undergone splenectomy. Rituximab was administered by intravenous infusion at a dose of 375 mg/m(2) once weekly for four doses in 29 patients, and 7 patients received one to six doses. Overall, 28 (77%) of 36 patients achieved response. Twenty-two patients (61%) reached a complete response (CR), and 6 patients (16%) obtained a partial response. All patients that reached CR (61%) were able to maintain the response during more than 6 months, with a median follow-up of 14 months (1-86 months). Sixteen patients maintained response for more than 1 year. The predictors of maintained response were achievement of CR and negative Coombs test result. Splenectomized patients showed a better response rate than those nonsplenectomized. Rituximab was well tolerated, and only one patient presented a transitory rash during infusion. Rituximab induced clinical responses in multitreated severe refractory both warm and cold AIHA patients with little toxicity, and consequently, this therapy should be considered as an early therapeutic option in this setting.

[High-dose intravenous immunoglobulin therapy and neonatal jaundice due to red blood cell alloimmunization]. / Immunoglobulines polyvalentes intraveineuses et ictère néonatal par allo-immunisation érythrocytaire.

Neonatal jaundice resulting from immunological hemolysis is not uncommon. While it is possible to prevent a large number of Rh-isoimmune hemolytic diseases by administration of specific anti-D immunoglobulins to the mother, the prevention of incompatibility in the ABO groups is not feasible. In spite of advances made in the use of phototherapy, and in order to avoid kernicterus, the treatment of these jaundices can require one or several exchange transfusions (ET), a therapy which is not devoid of risk. For some time now, the data concerning the efficiency of high-dose intravenous immunoglobulin therapy (HDIIT) in the treatment of these jaundices have been increasing. A review of the literature shows that, if used as soon as possible in newborn infants over 32 weeks of gestation age, afflicted with Rh or ABO hemolytic disease, the HDIIT brings about, with no undesirable side effects, a significant decrease in the ET number as well as a significant reduction in the length of phototherapy and hospitalization. The data suggesting that HDIIT could increase the risk of late transfusion is open to controversy.

Utilización de eritropoyetina en un paciente con anemia hemolítica autoinmune con aloinmunización múltiple para la obtención de sangre autóloga prequirúrgica. Caso reportado en sangre, actualización / The use of recombinant erytropoietin in autologous blood donation in a patient with autoimmune hemolytic anemia and multiple red cells alloantibodies. Case report

Se presenta el caso de una mujer de 44 años con hipermenorrea por una hiperplasia uterina que no cede con tratamiento hormonal y que debe ser sometida, en primer lugar, a un legrado biópsico y luego a una histerectomía con diagnóstico de anemia hemolítica autoinmune y la presencia de 2 aloanticuerpos (anti c y anti Fya). Se le realizó tratamiento con corticoides a dosis inmunosupresoras y cuando se estabilizó su hematocrito se le realizó tratamiento con EPOrHu (6 dosis) con ferroterapia parenteral y se le extrajeron 2 unidades de sangre autólogas que fueron transfundidas durante la cirugía. La paciente logró un buen hematocrito prequirúrgico y postquirúrgico.

EOG as a monitor of desferrioxamine retinal toxicity.

Iron overload caused by blood transfusion-dependent anaemia usually results in lethal cardiac toxicity unless treated by iron-chelation therapy. Chelation therapy with desferrioxamine (DFO) is well established and widely used to remove excess iron. Unfortunately, visual disorders have been recorded after DFO infusion. In this investigation, a 61-year-old Caucasian female received DFO for her autoimmune haemolytic anaemia. Prior to starting with the DFO treatment, her baseline ophthalmic screening and electrooculogram (EOG) were completely normal. Two years later she noticed a grey scotoma in her right eye. Visual acuity in this eye was reduced from 6/5 to 6/9 and funduscopy revealed evidence of non-specific mottling of the retinal pigment epithelium of both retinae. The EOG was flat (106%) in the right eye and subnormal in the left (155%). The lower limit of our EOG Arden Ratio for normal subjects is 180%. After her DFO treatment was stopped, her right visual acuity returned to 6/5, her field tests showed progressive improvement bilaterally and the EOG went back to the normal range. While waiting for splenectomy, the patient was restarted on a lower dose of DFO and EOG measurements were carried out every two (or three) weeks to monitor for DFO toxicity. The EOG varied during this period indicating some deterioration of function in the retinal pigment epithelium. However, normalisation of the EOG values (right = 217%, left = 217%) occurred after splenectomy and cessation of DFO therapy. Her visual function was normal and her visual acuity 6/4 bilateral when she was discharged from our outpatient clinic. On reviewing her history it was apparent that the EOG was the most sensitive indicator of DFO toxicity.

Liposomal clodronate as a novel agent for treating autoimmune hemolytic anemia in a mouse model.

Autoimmune hemolytic anemia (AIHA) is a disease in which autoantibodies against red blood cells (RBCs) lead to their premature destruction. Most clinically significant autoantibodies are of the immunoglobulin G (IgG) type, which leads primarily to the uptake and destruction of RBCs by splenic and hepatic macrophages. Therapies such as corticosteroids and splenectomy are directed at interfering with this process. Liposomally encapsulated clodronate (dichloromethylene diphosphonate) has previously been found to be a potent antimacrophage agent. It selectively depletes animals of macrophages within 24 hours of administration by inducing apoptosis in these cells. Therefore, we hypothesized that liposomal clodronate would be a useful agent for treating AIHA. We tested this hypothesis in a mouse model of AIHA in which animals were given either anti-RBC antibodies or preopsonized RBCs. In either case, liposomal clodronate substantially decreased RBC destruction. This drug formulation was effective within hours by first blocking and then depleting phagocytic macrophages, and its action lasted for 1 to 2 weeks. Thus, in AIHA, liposomal clodronate therapy may act like a temporary, medicinal splenectomy. As such, it may prove useful in situations where rapid response to therapy is critical or other medical therapies are inadequate.

Successful resection of rectal carcinoma in an Evans' syndrome patient followed by predonisolone and high-dose immunoglobulin: report of a case.

A 69-year-old woman was admitted to our hospital because of anal bleeding and fatigue. The patient was previously diagnosed as having Evans' syndrome on the basis of hematological examination and had been treated with predonisolone for 8 years. On admission, severe anemia and thrombocytopenia were noted. Colonoscopy and Barium enema studies demonstrated an irregular tumor with hemorrhagic ulceration in the rectum, which was histopathologically confirmed as an adenocarcinoma. After red blood cells and platelets were transfused, and the patient was treated with high-dose gammaglobulin, predonisolone, and camostat mesylate, the platelet count gradually increased and hemolysis was well controlled. The patient then underwent Hartmann's operation and splenectomy without any postoperative complications. Predonisolone and high-dose immunoglobulin therapy in a rectal cancer burdened patient with Evans' syndrome is considered useful in combination with surgical treatment. This is the first case report of rectal carcinoma resection in a patient with Evans' syndrome.

Green tea polyphenol extract attenuates inflammation in interleukin-2-deficient mice, a model of autoimmunity.

Green tea polyphenols (GrTP) have been previously shown to decrease endotoxin-induced tumor necrosis factor-alpha production and lethality in mice. Our present studies demonstrate that GrTP inhibit inflammatory responses and may be useful in treating chronic inflammatory states, such as inflammatory bowel disease. In this preliminary study, we examined whether GrTP decrease disease activity in interleukin-2-deficient (IL-2(-/-) mice. Eight-week old IL-2(-/-) C57BL/6J mice who were fed nonpurified diet were randomly assigned to receive water with GrTP (5 g/L) or water alone (control) for up to 6 wk. After 1 wk, explant colon and lamina propria lymphocyte (LPL) cultures were established from a subgroup of mice and supernatants collected. Culture supernatants from GrTP-treated mice showed decreased spontaneous interferon-gamma and tumor necrosis factor-alpha secretion compared with that of controls. At 6 wk, the GrTP group had less severe colitis as demonstrated by lower histologic scores and wet colon weights. This was associated with lower plasma levels of serum amyloid A, increased weight gain and improved hematocrits. These results show that GrTP attenuated inflammation in IL-2(-/-) mice and suggest a role for GrTP in treating chronic inflammatory diseases such as inflammatory bowel disease.

[A case of Evans's syndrome in which thrombocytopenia and hemolysis was improved by Sairei-to].

A 51-year-old male diagnosed as having Evans's syndrome in 1991 was treated with 25 mg of prednisolone, but his anemia and thrombocytopenia progressed. Thus, in November 1993, treatment was begun with Sairei-to, a Chinese herbal medicine consisting of several water-soluble plant extracts. Following administration of 9.0 g/day of Sairei-to granules along with prednisolone, the platelet count increased from 6.1 x 10(4)/microliters to 12.3 x 10(4)/microliters after one week, while hemoglobin levels rose from 9.5 g/dl to 12.0 g/dl after three weeks. The patient maintained a good physical condition after the prednisolone dose was reduced, although Coomb's test and PAIgG levels remained positive. Sairei-to-seems to be a promising therapeutic agent for steroid-resistant ITP and AIHA, and seems to have no side effects.

Ulcerative colitis, autoimmune hemolytic anemia and rectovaginal fistula: report of a case.

A case of autoimmune hemolytic anemia associated with ulcerative colitis and rectovaginal fistula in a 27-year-old woman is reported. It appeared during the first episode of ulcerative colitis occurring in the immediate puerperium. Laboratory studies revealed a positive direct Coombs test with polyspecific sera and monospecific for IgG. Panagglutinins and cold agglutinins with titers under 1:50 were also demonstrated. Treatment with steroid therapy was sufficient for a swift and complete recovery of the patient, the direct Coombs test becoming negative six weeks after admission.

Ulcerative colitis complicated by autoimmune hemolytic anemia.

We have reported the rare association of severe autoimmune hemolytic anemia with active ulcerative colitis, and added to the sparse published recommendations concerning management. Although aggressive medical therapy resulted in only partial control of the inflammatory bowel disease and hemolysis, both disorders remitted rapidly after panproctocolectomy and splenectomy. Autologous red cells were safely transfused during surgery.

Water-insoluble paraproteins with anticoagulant properties.

A 78-year-old woman, who had received steroid therapy for four years, had strikingly prolonged prothrombin time (PT) and partial thromboplastin time (PTT). The presumptive diagnosis was chronic hemolytic anemia. Platelet count and functions, fibrinogen, and factor XIII assays were all normal, but other factors assayed abnormally low; Sia water-dilution test was positive. When water-insoluble protein was removed by centrifugation, coagulation factors became normal. Dissolution of this precipitate in normal plasma caused marked prolongation of PT and PTT and lower factor assays. Serum electrophoresis showed a homogeneous M spike and an anomalous IgM, lambda-antigenic type in the gamma-globulin zone at point of origin. Ultracentrifugation of serum and of the precipitate showed 10% S17 and almost 100% S17 components, respectively. Five other patients with water-insoluble paraproteins were tested; two were clot-inhibitory.