Microangiopathic hemolytic anemia associated with gastric cancer

A case of advanced gastric cancer associated with metastatic carcinomatosis of the bone marrow, microangiopathic hemolytic anemia (MAHA) and disseminated intravascular coagulation (DIC) was reported. A 71-year-old woman complained of lumbago and general fatigue. At the time of admission, besides anemia, jaundice and a tendency to bleeding, the laboratory data showed, hyperbilirubinemia, elevated FDP and hemolytic anemia with fragmented red cells. The bone marrow was infiltrated by carcinoma, and an upper GI series examination showed Borrmann II type gastric cancer on the greater curvature of the antrum. After remission of both MAHA and DIC by mitomycin C, neothramycin and FOY, the patient successfully underwent subtotal gastrectomy. However, she died of cerebral hemorrhage on the 96th postoperative day.     

隐匿性弥漫性癌肿相关微血管病性溶血性贫血4例并文献分析

目的探讨隐匿性弥漫性癌肿相关微血管病性溶血性贫血（MAHA）患者的临床特点,有利于癌肿的早期诊断和治疗。方法报道4例隐匿性弥漫性癌肿相关MAHA病例,并综合国内相关文献进行分析。结果近30年间国内报道19例隐匿性弥漫性癌肿相关MAHA患者,包括现在报道4例共23例患者,中位年龄45岁（16～86岁）,男8例,女15例,突出的临床表现包括MAHA相关症状、发热、多处骨痛、神经精神异常、皮肤黏膜出血以及上腹痛伴呕血或黑便,发生率分别为78%、48%、48%、35%、35%和26%。实验室检查：Hb中位数52（26～89）g/L,血小板中位数35（5～98）×109/L;12例患者凝血功能检查7例有PT延长等异常,其中4例并发DIC;11例患者骨髓涂片和病理活检发现转移癌细胞。经病理诊断的21例患者中腺癌17例,其中胃癌11例。结论隐匿性弥漫性癌肿继发MAHA患者多为腺癌,骨痛、骨髓涂片和活检以及动态凝血纤溶检查,有助于与血栓性微血管病性溶血性贫血（TTP）的早期鉴别诊断,及时发现转移癌的证据,进一步胃镜等检查有利于尽快确定原发癌的部位。     

Systemic malignancies as a cause of unexpected microangiopathic hemolytic anemia and thrombocytopenia

Tumor cells from malignancies of any type-carcinoma, sarcoma, lymphoma, leukemia-may cause systemic arteriolar and capillary obstructions. The high shear rates of blood passing through these obstructions result in fragmentation of the red cells and can cause severe anemia, described as microangiopathic hemolytic anemia (MAHA).The thrombi caused by these obstructions consume platelets and can lead to severe thrombocytopenia. MAHA (defined by fragmented red cells on the peripheral blood smear and evidence of hemolysis) and thrombocytopenia are the clinical features of syndromes described as thrombotic microangiopathies (TMAs). If a malignancy is not recognized as the cause of TMA, the diagnosis of thrombotic thrombocytopenic purpura (TTP) may be considered and plasma exchange, the essential treatment for TTP, may be initiated-a critical decision because this treatment carries a high risk of serious complications. This review describes the clinical features that should suggest a search for systemic malignancy as the cause of unexpected MAHA and thrombocytopenia. Recognition of a systemic malignancy is critical to the initiation of appropriate chemotherapy and avoidance of inappropriate use of plasma exchange treatment.     

Mitomycin--C-induced thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: cumulative toxicity of an old drug in a new era

Mitomycin-C (MMC) is a first-line therapy for anal squamous cell carcinoma (ASCC), and it continues to be used for several other indications. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are serious complications of MMC therapy. Herein, we describe a 73-year-old woman with recurrent ASCC treated with MMC who developed chronic microangiopathic hemolytic anemia (MAHA) and thrombocytopenia after receiving a cumulative dose of 50 mg/m(2). These hematologic adverse events persisted for 9 months and resolved after discontinuation of chemotherapy followed by multiple courses of oral corticosteroids. This report describes an atypically chronic and mild form of secondary TTP/HUS and discusses the possible role of corticosteroids in its management.     

Diffuse bone metastasis with hematologic disorders from gastric cancer: clinicopathological features and prognosis

Bone metastases diffusely invading the bone marrow from gastric cancer often manifest a rapid clinical course and the prognosis is very poor due to hematologic disorders such as DIC (disseminated intravascular coagulation) and/or MAHA (microangiopathic hemolytic anemia). The objective of this study was to clarify the clinicopathological features and prognosis of patients with gastric cancer in whom diffuse bone metastasis associated with hematologic disorders were evident. Thirty-eight patients with bone metastasis from a primary gastric cancer were thus selected and placed into 2 groups consisting of 15 with diffuse bone metastasis with DIC and/or MAHA, and 23 patients who had bone metastasis without hematological disorders. We compared the clinicopathological features and prognosis between the two groups. The clinicopathological features in patients with diffuse bone metastasis accompanied by hematologic disorders were significantly related to undifferentiated adenocarcinoma, a relatively younger age, elevated levels of serum ALP-BI and LDH, and a lower frequency of extraosseous metastasis. The median survival time after manifestation was 2 and 11 months for the patients with or without hematologic disorders, respectively. The prognosis was significantly worse in cases of DIC with the median survival being only one month. Since, prognosis of diffuse bone metastasis from gastric cancer is significantly poor, close attention should be directed to the specific clinicopathologic features related to diffuse bone metastasis plus hematologic disorders. Regarding high risk patients, a regular follow-up of the serum chemistry levels and a bone scan will aid in the early detection of the disease.     

Anemia hemolítica microangiopática y metástasis cardíaca por carcinoma de cabeza y cuello

Microangiopathic haemolytic anemia (MAHA) complicates occasionally clinical evolution of disseminated tumors, usually adenocarcinoma-type, but is association with a squamous cell cancer of head and neck origin is rare. Additionally, head and neck cancer is an unusual origin of cardiac metastases. We present a patient with head and neck squamous cell cancer who developed intravascular haemolysis with thrombopenia. Postmortem study showed tumor cells into the heart and tumor emboli in pulmonary arterioles, the later often described in the cases of MAHA. We discuss the physiopathology of MAHA and its association with cancer. We briefly discuss epidemiology and pathogeny of cardiac metastases.     

Malignant Pheochromocytoma Accompanied by Microangiopathic Hemolytic Anemia: A Case Report

A 63-year-old woman was in hsopital for persistent backache.Four months prior to admission she had been pointed out as havinghypertension for the first time. On admission, she had anemia(hemoglobin 7.0 g/dl) with reticulocytosis, and a blood smearshowed fragmented erythrocytes. A bone marrow aspirate disclosederythroid hyperplasia and invasion of cancer cells. The chestroentgenogram showed a coin-lesion of the right lung and leftpleural effusion. A diagnosis of microangiopathic hemolyticanemia (MAHA) associated with carcinomatosis was made, but theprimary site of the cancer was unknown. Respiratory failuredeveloped and the patient died a month later. Surprisingly,the autopsy revealed a malignant pheochromocytoma arising fromthe right adrenal gland with massive metastases to the lungs,liver, lymph nodes and systemic bones, and also disseminatedintravascular coagulation (DIC). The DIC would probably accountfor the MAHA in this case. To our knowledge, this is the firstreported case of malignant pheochromocytoma accompanied by MAHA.     

Pure red cell aplasia associated with non-Hodgkin's lymphoma and hemolytic anemia.

Pure red cell aplasia (PRCA) rarely occurs in non-thymic lymphoproliferative disorders. The present article describes a patient with non-Hodgkin's lymphoma (follicular, mixed type), who concurrently developed PRCA and warm type autoimmune hemolytic anemia during the clinical course. The PRCA and hemolytic anemia were successfully treated with prednisolone (60 mg/day). The patient died two years later, however, from advanced lymphoma without any recurrence of the PRCA or hemolytic anemia. To our knowledge, only 20 cases of PRCA associated with malignant lymphoma have been reported. The pathogeneses of the PRCA and hemolytic anemia in our patient are discussed.     

A phase I pharmacodynamic trial of sequential sunitinib with bevacizumab in patients with renal cell carcinoma and other advanced solid malignancies

Background

Sunitinib treatment results in a compensatory increase in plasma VEGF levels. Acute withdrawal of sunitinib results in a proliferative withdrawal flare, primarily due to elevated VEGF levels. Concurrent sunitinib plus bevacizumab is poorly tolerated with high (37 %) incidence of microangiopathic hemolytic anemia (MAHA). We evaluated a sequential design administering bevacizumab during the sunitinib treatment break to suppress the sunitinib withdrawal flare.

Methods

Patients with no prior VEGF treatment were enrolled in this study. All patients had target lesions amenable to serial FLT PET/CT imaging. Sunitinib 37.5 mg was given on days 1–28 every 6 weeks with bevacizumab 5 mg/kg on day 29. If safe and tolerable, sunitinib increased to 50 mg. FLT PET/CT scans would be obtained at baseline (D1), week 4, and week 6 to evaluate pharmacodynamics of the sequential combination. Sunitinib pharmacokinetics and total, free, and bound VEGF levels were obtained on each cycle at D1, pre-bevacizumab (D29), 4 h post-bevacizumab (D29H4), and day 42 (D42).

Results

Six patients enrolled in the safety cohort of sunitinib 37.5 mg plus bevacizumab (see Table). One patient experienced grade 1 MAHA, and after discussion with the Cancer Therapy Evaluation Program (CTEP), the trial was closed to further accrual. No imaging scans were obtained due to early closure.

Thymoma with Autoimmune Hemolytic Anemia

A 38-year-old Japanese male was referred to our hospital with abnormal chest X-ray results and severe Coombs-positive hemolytic anemia. He was diagnosed with a stage IV, WHO type A thymoma and was treated with oral prednisolone (1 mg/kg/day) and subsequent chemotherapy. After chemotherapy, the patient underwent surgical resection of the thymoma. Hemolysis rapidly disappeared and did not return after the discontinuation of oral corticosteroids. Corticosteroid therapy may be preferable to chemotherapy or thymoma surgical resection in the management of autoimmune hemolytic anemia with thymoma.Key words: Thymoma, Autoimmune hemolytic anemia, Chemotherapy, Corticosteroid therapy     

Evans' syndrome associated with microcystic adenoma of the pancreas

A case of autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura (Evans' syndrome), associated with a microcystic adenoma of the pancreas is reported. Early recognition of this rare entity is important, as corticosteroids and splenectomy are usually ineffective, whereas removal of the tumor may be a cure for this condition. Possible mechanisms of the hemolytic anemia and thrombocytopenia are also discussed.     

Disseminated Carcinoma Diagnosed by Bone Marrow Biopsy in Patients with Microangiopathic Hemolytic Anemia and Thrombocytopenia: A Report of Two Cases with Gastric Cancer and a Review of the Literature

Introduction

Malignancy is often associated with hematological disorders, but rarely is the diagnosis of malignancy secondary to the diagnosis of microangiopathic hemolytic anemia and thrombocytopenia.

Case reports

We report hereby two patients with metastatic gastric carcinoma presenting with microangiopathic hemolytic anemia and thrombocytopenia. Despite chemotherapy and repeated plasmapheresis in one patient, both patients succumbed shortly after the diagnosis of cancer was made.

Conclusion

A review of the literature regarding microangiopathic hemolytic anemia in cancer patients is discussed. In patients suffering from microangiopathic hemolytic anemia and thrombocytopenia, malignancy should be considered as a possible cause. Early diagnosis of malignancy may be critical for determining the patient’s prognosis and potentially avoiding unnecessary overtreatment.     

Friend lymphatic leukemia virus-induced autoimmune hemolytic anemia with glomerulonephritis in the rat

WKA/Mk rats injected with Friend lymphatic leukemia virus at birth developed a runt ing syndrome which was associated with a high incidence of hemolytic anemia. The anemia was characterized by the presence of incomplete anti-erythrocyte autoantibodies detected by the direct antiglobulin test and the indirect enzyme-augmented hemagglutination assay, and, in some cases, was followed by glomerulonephritis. This system in the rat may represent a new model of autoimmune hemolytic anemia in man.     

Coinfection of hepatitis A virus genotype IA and IIIA complicated with autoimmune hemolytic anemia, prolonged cholestasis, and false-positive immunoglobulin M anti-hepatitis E virus: a case report

A 37-year-old male presented with fever and jaundice was diagnosed as hepatitis A complicated with progressive cholestasis and severe autoimmune hemolytic anemia. He was treated with high-dose prednisolone (1.5 mg/kg), and eventually recovered. His initial serum contained genotype IA hepatitis A virus (HAV), which was subsequently replaced by genotype IIIA HAV. Moreover, at the time of development of hemolytic anemia, he became positive for immunoglobulin M (IgM) anti-hepatitis E virus (HEV). We detected HAV antigens in the liver biopsy specimen, while we detected neither HEV antigen in the liver nor HEV RNA in his serum. This is the first report of hepatitis A coinfected with two different genotypes manifesting with autoimmune hemolytic anemia, prolonged cholestasis, and false-positive IgM anti-HEV.     

Reversal of autoimmune hemolytic anemia associated with chronic lymphocytic leukemia following high-dose immunoglobulin

An 85-year-old man with chronic lymphocytic leukemia developed severe warm antibody-type autoimmune hemolytic anemia. Initial therapy with high-dose corticosteroids had no discernible effect on the hemolytic process. Following treatment with high-dose intravenous immunoglobulin (0.4 g/kg/d for 5 consecutive days) there was an immediate and sustained increase in hematocrit accompanied by a progressive decline in reticulocyte count. A review of the literature reveals that some patients with steroid-resistant immune hemolysis may benefit from high-dose immunoglobulin. This approach should be considered in elderly patients with severe anemia whose medical status precludes splenectomy.     

Activity of rituximab monotherapy in refractory splenic marginal zone lymphoma complicated with autoimmune hemolytic anemia

We describe the case of a 61-year-old patient with refractory splenic marginal zone lymphoma and secondary autoimmune hemolytic anemia, both successfully treated with rituximab. This case demonstrates that rituximab monotherapy might also be a valid therapeutic approach in marginal zone lymphoma and autoimmune hemolytic anemia after failure of first-line treatment. Maintenance therapy, although expensive, could be useful to improve event-free survival in patients with unfavorable clinical behavior.     

Monotherapy with rituximab induces rapid remission of recurrent cold agglutinin-mediated hemolytic anemia in a patient with indolent lympho-plasmacytic lymphoma

Cold agglutinin mediated immune hemolytic anemia secondary to lymphoproliferative disease (LPD), is primarily treated with measures directed to eliminate the malignant clone and as such, chemotherapy is usually given. The recent availability of monoclonal antibodies, has made it feasible to obtain both a clinical and molecular remission, as well as a remission on the functional level, such as elimination of secondary autoimmune phenomena. Recently we have administered a course of monotherapy with rituximab (4 weekly injections, x 375 mg/m2) to a patient with refractory and transfusion dependent cold agglutinin mediated hemolytic anemia secondary to indolent B-cell lymphoma. She achieved complete remission with a significant improvement in hemolysis and also became transfusion independent with a current follow-up of over one year. In individual cases, Rituximab has the potential of achieving not only a complete clinical remission (CR) but also a molecular CR, as well as a "functional" CR, by eliminating the clinical manifestations of autoimmunity; in this case, cold agglutinin mediated hemolytic anemia, secondary to NHL. Good results in autoimmunity secondary to lymphoma raises the possibility of future potential benefit of this agent in other primary autoimmune disorders.     

Immune hemolytic anemia associated with streptococcal preparation OK-432

In the course of administration of an immunopotentiator, streptococcal agent OK-432, a patient with lung cancer was found to have severe anemia and a strongly positive antiglobulin test. In the absence of the drug, eluates from the patient's erythrocytes reacted strongly by the indirect antiglobulin test with a panel of washed Group O erythrocyte samples. The eluated antibody was composed of monoclonal IgG1-lambda. Upon discontinuing the drug the patient's hemoglobin level increased slowly with concomitant normalization of the reticulocyte count. Although very rare, drug-induced immune hemolytic anemia should be included in the list of adverse effects of immunopotentiators. This is the first reported case of immune hemolytic anemia associated with OK-432.     

Microangiopathic hemolytic anemia associated with advanced gastric cancer

Progressive, severe anemia developed in a 66-year-old man with advanced gastric cancer. A total gastrectomy was performed, after a rapid blood transfusion, to stop possible bleeding from cancer. There was no blood accumulation in the resected stomach. Laboratory data showed remarkable hemolysis and disseminated intravascular coagulation after the operation. A peripheral blood smear showed leukoerythroblastosis, which is indicative of bone marrow metastasis. Intensive therapy failed to control hemolysis and disseminated intravascular coagulation. On the 17th postoperative day, the patient suffered sudden respiratory arrest and subsequently died, possibly of a cerebrovascular accident. This is a rare case of microangiopathic hemolytic anemia associated with metastasis of gastric cancer to the bone marrow. Operative procedures should not considered for the patient with microangiopathic hemolytic anemia caused by cancer metastasis, because they offer no advantages for the patient's prognosis. Evaluation of causes of anemia can be helpful in managing patients with cancer.     

Erythropoietin restores the antitumor effectiveness of photodynamic therapy in mice with chemotherapy-induced anemia.

PURPOSE: The study was designed to examine the impact of anemia on the antitumor efficacy of photodynamic therapy (PDT) in a murine colon-26 adenocarcinoma model syngeneic with BALB/c mice. EXPERIMENTAL DESIGN: Acute hemolytic anemia was induced by a single i.p. injection of phenylhydrazine hydrochloride (150 mg/kg). Anemia induced by i.p. administration of carboplatin (100 mg/kg) was corrected by s.c. treatment with recombinant human erythropoietin (1000 units/kg/day). The effectiveness of PDT (10 mg/kg Photofrin, 150 J/cm2 laser dose) was evaluated by measurements of the footpad edema and tumor volume. All of the RBC-related parameters were measured from the tail vein. RESULTS: Phenylhydrazine hydrochloride injection resulted in a blunted response of normal tissues to Photofrin-mediated PDT-induced edema formation. Similarly, the antitumor response in mice with hemolytic anemia was nearly completely abrogated. The antitumor effectiveness of PDT was also significantly diminished in a more realistic clinical situation when anemia was induced by administration of carboplatin. Importantly, administration of recombinant human erythropoietin completely restored the sensitivity of the tumor to PDT in carboplatin-treated mice. CONCLUSIONS: These results indicate that anemia can negatively influence the therapeutic effectiveness of PDT. For optimal antitumor response anemia should be corrected before PDT procedure.