Clinical Analysis of Cardiac Involvement in 53 Patients With Multiple Myeloma Coexistent With Light Chain Amyloidosis.
Yu Yuanyuan,Huang Zhongxia,Hu Wanli,Li Xin,Shen Man,Zhang Jiajia,Tang Ran,Chen Shilun,Chen Wenming
Clinical lymphoma, myeloma & leukemia
BACKGROUND:We identified 53 patients with multiple myeloma (MM) who had biopsy evidence of light chain amyloidosis (AL), and studied their cardiac involvement and outcomes. PATIENTS AND METHODS:Our cohort consisted of 53 patients in whom MM and AL were initially diagnosed from July 1, 2006 to June 30, 2016.The diagnosis of MM required > 10% of clonal plasma cells in bone marrow and 1 of the CRAB symptoms, meanwhile, the diagnosis of AL must meet pathologic diagnostic criteria and monoclonal immunoglobulin light chain. Echocardiograms and cardiac biomarker such as N terminal pro B-type natriuretic peptide was used for evaluation of cardiac damage on the baseline and before every cycle of the regimen. RESULTS:There were 36 men and 17 women with a median age of 59 years; their main organ involvement was kidney (72%) and heart (62%). Of these, 22 patients were treated with a bortezomib-based regimen, and the response rate was more effective than the other 21 patients who received non-bortezomib-based regimens (64% vs. 29%). The median overall survival (OS) for the total cohort was 12 months (P < .05). The median OS of the MM cohort with International Staging System stage I and II together was 34 months, which was longer than that of patients with stage III of 8 months. The median OS in Mayo stages I, II, and III was 38, 8, and 1 months, respectively (P < .05). Cardiac involvement significantly adversely affected survival (6 vs. 40 months), as did systolic blood pressure (< 90 mmHg, 3 vs. 8.5 months). CONCLUSIONS:Patients coexistent with MM and AL is rare; AL has a negative impact on survival for the total cohort. Especially, cardiovascular dysfunction caused by AL maybe a major determinant of shortening survival.
Immunoproteasome in IgA Nephropathy: State-of-Art and Future Perspectives.
Gan Ting,Li Yang,Zhou Xu-Jie,Zhang Hong
International journal of biological sciences
IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and renal failure. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the immunoproteasome probably plays an important role in IgAN. The immunoproteasome is a proteasome variant that is expressed when cells are stressed or receive inflammatory signals. While immunoproteasome is suggested to be mainly involved in major histocompatibility complex-I (MHC-I) antigen presentation, recent studies indicate that it may assert broad functions in trafficking events that activate both innate and adaptive immunity. In this review, we first summarize new insights into its functions in immunity, and discuss how it underlies its associations with IgAN. We also highlight its potential as a therapeutic target for the future.
Nephrotic syndrome in a patient with IgM myeloma with associated neutrophilia.
Gnerre Paola,Ottonello Luciano,Montecucco Fabrizio,Boero Michela,Dallegri Franco
European journal of haematology
An unusual case having IgM monoclonal gammopathy with clinical and pathologic features of multiple myeloma (MM) in association with neutrophilia and nephrotic syndrome is reported. The patient showed lytic bone lesions, decreased IgG and IgA levels, Bence-Jones proteinuria, nephrotic proteinuria with edema, and histological plasma cell infiltration typical of MM. Moreover, mature neutrophilic leukocytosis, hepatomegaly, high leukocyte alkaline phosphatase score (LAP), absence of Philadelphia (Ph) chromosome and bcr gene rearrangement were also evidenced, all these features representing findings typical of the recently described plasma cell dyscrasia-associated neutrophilia. After the diagnosis, the patient was treated with melphalan and prednisone, with an excellent response to the treatment. Different from the 30 cases so far reported, this is the first case of plasma-cell dyscrasia with associated neutrophilia due to IgM-producing monoclonal gammopathy. At the same time, this is the first reported case of nephrotic syndrome secondary to IgM myeloma.
Laboratory Features of Newly Diagnosed Multiple Myeloma Patients.
Hussain Azhar,Almenfi Hana Farag,Almehdewi Abdelfattah M,Hamza Mohammed S,Bhat Malpe Surekha,Vijayashankar Narasimha Prasad
OBJECTIVES:Multiple myeloma (MM) is a malignant disorder characterized by proliferation of a single clone of plasma cells derived from β-cells in the bone marrow. It is the second most common adult hematological malignancy, and it is the most common cancer with skeletal components as its primary site. The purpose of the retrospective study was to assess the hematological profile, different biochemical parameters, and the serum electrophoresis patterns of patients consistent with clinical symptoms of multiple myeloma. MATERIALS AND METHODS:A retrospective study of 99 patients diagnosed with multiple myeloma (MM) was carried out at the Hematology Department of Benghazi Medical Center (BMC) in Benghazi, Libya from January 2010 to March 2017. Information on the laboratory features was obtained at presentation (before treatment) and analyzed. RESULTS:Of the 99 study detected cases of multiple myeloma at diagnosis, 14% were younger than 45 years and 35% were 70 years or older. The mean age was 61 years, of which 42 (42.4%) were males and 57 (57.6%) were females. Anemia was seen in roughly half of the diagnosed cases, most of which was normocytic normochromic anemia. High erythrocyte sedimentation rate (ESR) was seen in 65.3% of cases and increased neutrophil-to-lymphocyte ratio (NLR) was seen in 29.7%. Other abnormal serum levels with regard to the cases are as follows: hyperproteinemia in 30%, low albumin/globulin (A/G) ratio in 54.2%, hypercalcemia in 11.3%, serum creatinine level of >2.0 mg/dL in 27.2% cases, and increased β2-microglobulin in 67%. Serum protein electrophoresis revealed a localized band in 70.8% of patients. Monoclonal bands were seen in 44 cases (95.7%) and a bi-clonal pattern in two cases (4.3%), 78% of M-band showed migration to γ-region of electrophoretogram and 18% to β-region. Hypogammaglobulinemia was detected in 32.8% and hypergammaglobulinemia was detected in 49.2%. Of the hypergammaglobulinemia, 18.1% showed polyclonal gammaglobulinemia. Bence Jones protein was positive in 50% cases. IgG was the commonest type, followed by IgA then light chain. In 26.5% of cases, the only diagnosis was multiple myeloma. Light chain multiple myeloma patients had high α2 globulin concentration and normal A/G ratio. Apart from the diagnosis of multiple myeloma, a number of cases had varying diagnoses including the following: 4% non-secretory myeloma, 2% amyloidosis with nephrotic syndrome, 2% liver cirrhosis, and 18.2% renal failure. Most patients presented in stage III. CONCLUSIONS:The presence of anemia, high ESR, and low A/G ratio in elderly patients should alert the clinician to investigate along the lines of multiple myeloma. In this study, unfortunately, the laboratory investigations were insufficient for diagnosing this disease in most patients. Most patients were diagnosed at stage III. Absence of paraprotein in the blood does not exclude multiple myeloma. It was further observed that most of the patients presented with significant renal damage, which attributed to hyperuricemia, hypercalcemia, or high NLR. Multiple causes of renal failure occur in myeloma and are often present at the time of diagnosis.
Successful treatment of nephrotic syndrome induced by lambda light chain deposition disease using lenalidomide: A case report and review of the literature
Mima Akira,Nagahara Dai,Tansho Kosuke
BACKGROUND:Light chain deposition disease (LCDD) is a monoclonal immunoglobulin deposition disease (MIDD) that is characterized by the deposition of monoclonal light chains in multiple organs, including the kidney. It is a rare disorder caused by an underlying monoclonal plasma cell dyscrasia. LCDD with renal involvement causes proteinuria, which sometimes can lead to nephrotic syndrome. The monoclonal light chains are mostly in the κ form. Treatment of LCDD is the same as that for multiple myeloma (MM); however, some conventional anticancer drugs show substantial toxicity and therefore cannot be administered to older patients or those with renal impairment. CASE PRESENTATION:An 80-year-old woman was referred to our department with severe nephrotic syndrome (13.6 g/gCr) and anemia. A renal biopsy showed mesangial proliferation and mesangial matrix expansion, and immunohistochemistry showed positive staining for λ chains along the glomerular basement membrane, but was negative for κ chains or amyloid deposition. A bone marrow biopsy revealed 64% plasma cells. Immunoglobulin G (IgG)-λ type M protein was detected, and the levels of free λ chain was significantly increased. We concluded that her nephrotic syndrome was caused by LCDD, which resulted from IgG-λ MM. The induction of a BCD<bold> </bold>(bortezomib, cyclophosphamide, and dexamethasone) treatment regimen did not lead to a hematological response or decrease in proteinuria. The administration of combination therapy of lenalidomide and prednisolone led to the successful reduction of proteinuria and hematuria. CONCLUSIONS:We presented a very rare case report describing the successful treatment of LCDD (λ chain)-induced nephrotic syndrome with lenalidomide.
Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease.
Uderhardt Stefan,Ackermann Jochen A,Fillep Tobias,Hammond Victoria J,Willeit Johann,Santer Peter,Mayr Manuel,Biburger Markus,Miller Meike,Zellner Katie R,Stark Konstantin,Zarbock Alexander,Rossaint Jan,Schubert Irene,Mielenz Dirk,Dietel Barbara,Raaz-Schrauder Dorette,Ay Cihan,Gremmel Thomas,Thaler Johannes,Heim Christian,Herrmann Martin,Collins Peter W,Schabbauer Gernot,Mackman Nigel,Voehringer David,Nadler Jerry L,Lee James J,Massberg Steffen,Rauh Manfred,Kiechl Stefan,Schett Georg,O'Donnell Valerie B,Krönke Gerhard
The Journal of experimental medicine
Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease.
Eosinophils may be involved in thrombus growth in acute coronary syndrome.
Sakai Tetsuo,Inoue Shin,Matsuyama Taka-Aki,Takei Masatoshi,Ota Hidekazu,Katagiri Takashi,Koboyashi Youichi
International heart journal
Thrombus aspiration therapy allows for the examination of thrombus and atheroma fragments in acute coronary syndrome (ACS). Inflammatory cells and platelet activation play key roles in thrombus formation in ACS. However, histopathologic evaluation of thrombi in ACS has not been adequately addressed. We performed histologic analysis of tissue samples obtained by thrombus aspiration therapy. We studied 165 samples from patients with ACS. The area of each sample, percentage of red thrombus, and percentage of white thrombus were measured. Samples were stained immunohistochemically with antibodies against macrophages, activated platelets, and interleukin (IL)-5. Seventy-six samples included atheroma fragments. Macrophages, neutrophils, and activated platelets were observed in thrombi and in atheroma fragments. Eosinophil infiltration was also observed predominantly in the area between white thrombus and red thrombus in 106 samples. We categorized all samples into 3 groups according to the grade of eosinophil infiltration (eos-, eos+, eos++ group). Sample area in the eos++ group was greater than that in the eos- group (P < 0.0001). In addition, the percentage of the red thrombus areas in the eos++ group and the eos+ group was greater than that in the eos- group (P < 0.009, P < 0.02, respectively). However, there was no difference in the percentage of white thrombus area between the 3 groups. Staining for IL-5 was identified in inflammatory cells within thrombi. Eosinophils may play an important role in coronary occlusion by promoting thrombus growth.
Hypercoagulability and tissue factor gene upregulation in hematologic malignancies.
Falanga Anna,Barbui Tiziano,Rickles Frederick R
Seminars in thrombosis and hemostasis
Thrombotic complications in patients with hematologic malignancies are as frequent as in those with solid tumors and significantly affect morbidity and mortality. In acute leukemia, thrombosis and bleeding manifestations may occur concomitantly as a part of the same thrombo-hemorrhagic syndrome. In patients with Philadelphia chromosome-negative chronic myeloproliferative disorders (i.e., essential thrombocythemia [ET] and polycythemia vera [PV]), a thrombosis rate as high as 40% has been recorded. A hypercoagulable state is present in virtually all of these patients, even without clinical manifestations. In this review, we focus on the pathogenic mechanisms underlying the hypercoagulable state of these two hematologic malignancies. Although the pathogenesis of hypercoagulability is complex, a central role is played by the fundamental molecular changes of both the leukemic cells and of the progeny arising from the hematopoietic progenitor cells that have undergone clonal rearrangement. These cells overexpress procoagulant factors, as well as adhesion molecules and cytokines capable of inducing procoagulant changes in the vascular wall and stimulating increased cellular interactions. Recent molecular studies in experimental models of human tumors have demonstrated for the first time that oncogene- and repressor gene-mediated neoplastic transformation induces activation of blood coagulation. Similarly, in cells from patients with acute promyelocytic leukemia, the T15-17 translocation induces hyperexpression of tissue factor (TF) and renders the patient hypercoagulable. Furthermore, in blood cells from patients with PV or ET, the presence of the JAK2V617F mutation translates into activation of hemostasis, with increased expression of platelet-associated TF microparticles and the formation of increased platelet/neutrophil aggregates. Understanding the pathophysiology of hypercoagulability is critical to the design of appropriate measures for intervention in these hematologic disorders to prevent thromboembolic complications.
Thromboembolic and bleeding complications in acute leukemia.
Kwaan Hau C,Huyck Timothy
Expert review of hematology
The risk of both thromboembolic and bleeding complications is high in acute leukemia. This double hazard has a significant negative impact on the morbidity and mortality of patients with this disease. The clinical manifestations of both complications show special features specific to the form of acute leukemia. Recognition of these characteristics is important in the diagnosis and management of acute leukemia. In this article, several additional issues are addressed, including the features of bleeding and thrombosis in acute promyelocytic leukemia, the current understanding of the leukostasis syndrome and the iatrogenic complications including catheter-associated thrombosis, and the adverse effects of therapeutic agents used in acute leukemia. As regards the bleeding complications, thrombocytopenia is a major cause. Corrective measures, including recent guidelines on platelet transfusions, are provided.
Role of microparticles in the hemostatic dysfunction in acute promyelocytic leukemia.
Kwaan Hau C,Rego Eduardo Magalhães
Seminars in thrombosis and hemostasis
Serious bleeding and thrombotic complications are frequent in acute promyelocytic leukemia (APL) and are major causes of morbidity and mortality. Microparticles (MP) have been used to study the risk and pathogenesis of thrombosis in many malignant disorders. To date, from published articles, this approach had not been applied to APL. In this article, the hemostatic dysfunction in this disorder is briefly reviewed. A study design to address this problem using MP is described. MP bearing tissue factor, profibrinolytic factors (tissue plasminogen activator and annexin A2), and the antifibrinolytic factor plasminogen activator inhibitor type 1 were measured using flow cytometry. The cellular origin of the MP was identified by specific cell surface markers. Comparison of the various populations of MP was made between samples collected at the time of diagnosis with those collected at molecular remission. Preliminary data suggest that this approach is feasible.
Microparticle bearing tissue factor: a link between promyelocytic cells and hypercoagulable state.
Gheldof Damien,Mullier François,Bailly Nicolas,Devalet Bérangère,Dogné Jean-Michel,Chatelain Bernard,Chatelain Christian
Patients with hematological malignancies have a 28-fold increased risk of venous thromboembolism (VTE). Among patients with acute myelogenous leukemia (AML), the 2-year cumulative incidence of VTE is 5.2%. Several studies suggest that microvesicles (MVs) harboring TF may play a role in VTE and disseminated intravascular coagulation (DIC) in acute promyelocytic leukemia (APL). The aim of this study was to assess the capacity of untreated (APL) cells to shed procoagulant MVs. APL cells (NB4 and HL-60 cell lines) and MVs were separated by filtration (0.1-0.22-0.45-0.65 μm). The procoagulant activity (PCA) was assessed by thrombin generation assay (TGA). Alternatively, MVs were incubated with anti-Tissue Factor (TF) antibodies, with annexin V to assess the contribution of TF and phospholipids (PL) to the PCA, respectively. NB4 cells had a high PCA mainly triggered by MVs of size under 0.45 μm. The PCA of MVs was related to the expression of active TF and PL. HL-60 cells had a weaker PCA since TF is mostly present in its inactive form. Moreover, HL-60 do not produce MVs<0.65 μm associated with PCA. MVs could have a predicting value for VTE and DIC in patients with acute promyelocytic leukemia and could inform physicians about the optimal use of a thromboprophylaxis.
Acute Budd-Chiari syndrome as an initial presentation of acute promyelocytic leukemia.
Bandyopadhyay Sanjay,Bandyopadhyay Debottam
Journal of cancer research and therapeutics
Budd-Chiari syndrome (BCS) is the constellation of clinical signs and symptoms resulting from occlusion of two or more hepatic veins, often due to an underlying thrombophilic disorder. Acute myeloid leukemia has been rarely reported to be associated with hepatic vein thrombosis due to hyperleukocytosis, hyperfibrinolysis and disseminated intravascular coagulation. We report a case of acute promyelocytic leukemia where the clinical onset of the hematological disease was with acute BCS.
The unique hemostatic dysfunction in acute promyelocytic leukemia.
Kwaan Hau C
Seminars in thrombosis and hemostasis
The hemostatic abnormalities seen in acute promyelocytic leukemia (APL) are unique and account for much of the morbidity and mortality of this disorder. Almost all patients present at diagnosis with laboratory findings of intravascular coagulation along with increased fibrinolysis. This unusual combination is correlated to the clinical manifestations with high risk of both bleeding and thrombosis. Recent studies have revealed that the leukemic promyelocytes in APL express increased amounts of tissue factor as well as elements of the fibrinolytic system, including tissue plasminogen activator, annexin A2, and plasminogen activator inhibitor type 1. These changes are responsive to differentiation therapy with all-trans-retinoic acid (ATRA) or with arsenic trioxide (ATO). Despite a dramatic reduction in mortality seen since the introduction of differentiation therapy with ATRA or with ATO, a large number of deaths still occur before complete remission is achieved. The early deaths are mostly attributable to the presenting coagulopathy. The prevention and management of this hemostatic abnormality have thus far been unsuccessful and remain a challenge to bring about a higher cure rate for this disease.
Acute promyelocytic leukemia presenting as pulmonary thromboembolism: Not all APLs bleed.
Vaid Ashok K,Batra Sandeep,Karanth Suman S,Gupta Sachin
Avicenna journal of medicine
We present a rare case of acute promyelocytic leukemia (APL) presenting as pulmonary thromboembolism being misdiagnosed as community-acquired pneumonia. Thrombotic phenomenon in APL are poorly understood and grossly underreported. In our case, following no response to standard antibiotic treatment, the patient was further investigated and detected to have an acute pulmonary thromboembolism following right lower limb deep vein thrombosis (DVT). Though, complete blood picture revealed only mild hyperleukocytosis, bone marrow biopsy and aspiration revealed 60% blasts and a positive t (15,17)(q22,12) and PML retinoic acid receptor alpha (RARA) fusion protein on molecular cytogenetics. He was diagnosed as APL and received treatment with all-transretinoic acid (ATRA) and arsenic trioxide (ATO) and therapeutic anticoagulation.
Congestive heart failure during induction with anthracycline-based therapy in patients with acute promyelocytic leukemia.
Kota Vamsi,Clemmons Amber,Chand Arati,Simmons Josh,Mansour Joshua,Kolhe Ravindra,Jillella Anand
The Journal of community and supportive oncology
BACKGROUND:Acute promyelocytic leukemia (APL) is a highly curable malignancy. However, 30% of patients die during therapy induction from bleeding, differentiation syndrome (DS), and/or infection. Recommendations suggest that congestive heart failure (CHF) is a presenting feature of DS. OBJECTIVE:To assess the incidence of CHF during induction in patients with APL. METHODS:A retrospective chart review was performed of patients diagnosed with APL from December 2004 to July 2013 and managed at Georgia Regents University Cancer Center. Baseline and follow-up ejection fractions (EF) were recorded and patients with a drop in EF during the induction period were evaluated. RESULTS:Of the 40 evaluable patients, 37 received idarubicin-based chemotherapy. 16 of the 37 patients had a repeat ECHO for suspected cardiomyopathy, and 6 of the 16 patients (37.5%) demonstrated a decrease in EF (absolute drop, 10%-35%). The cardiac function recovered completely in 4 patients and partially in 1 patient. Gender, history of hypertension, and body mass index did not seem to correlate with incidence of CHF. LIMITATIONS:The patient population is very small given the rarity of the disease. Present practice patterns do not routinely address CHF in the differential diagnosis. CONCLUSIONS:Patients with APL are at risk for cardiac toxicity for a number of reasons, including cytokine storm and inflammatory state, use of anthracyclines, and DS. The clinical presentation of DS most commonly involves dyspnea and fluid retention, which are also symptoms of heart failure. Prompt cardiac evaluation should be undertaken to rule out CHF in APL patients who are going to receive an anthracycline-based therapy, because early intervention may result in an improved outcome.
Persistent eosinophilic infiltration of the myocardium in a child in complete remission of acute lymphoblastic leukemia and eosinophilia. Potential role in late cardiac disease?
Tsuji Atsutoshi,Sasaki Michiko,Ishii Toru,Sato Seiji,Kanki Hideaki,Suzuki Satoru,Takeuchi Shigeyuki,Fukuda Toyoki
The Keio journal of medicine
This report describes the long-term (23 years) follow-up of a pediatric patient with acute lymphoblastic leukemia and eosinophilia who underwent multiple valve replacements. An 8-year-old boy with this complex disease was admitted in January 1984 and treated with 6-week course of vincristine, L-asparaginase, and prednisolone, which induced complete remission. He developed atrioventricular valvular insufficiency and infectious endocarditis at 13.5 and 17.3 years of ages, respectively, with progressive development of congestive heart failure. At 18.6 years of age, he underwent prosthetic valve replacement of both atrioventricular valves; the mitral valve was replaced with a mechanical prosthetic valve and tricuspid valve with a bioprosthetic valve. Histopathological examination of the ventricular endomyocardium showed extensive fibrous degeneration and persistent infiltration of eosinophils and lymphocytes. The right-side prosthesis was replaced twice, at 22.4 and 29 years of ages, due to degeneration of bioleaflets and thrombosis of the mechanical valve, respectively. Although he tolerated all surgical procedures, he developed liver cancer at 31 years of age and died. Autopsy could not be performed. The present study indicates that a subset of patients in complete remission of acute lymphoblastic leukemia and eosinophilia can show persistent myocardial eosinophilic infiltration and are at risk of late cardiac disease.
Eosinophilia in acute myeloid leukemia: Overlooked and underexamined.
Naymagon Leonard,Marcellino Bridget,Mascarenhas John
The presence of eosinophilia in acute myeloid leukemia (AML) suggests an underlying core binding factor (CBF) lesion, a platelet derived growth factor (PDGFR) translocation, or another rare translocation (such as ETV6-ABL1). Each of these cytogenetic entities carries unique diagnostic, prognostic, and therapeutic implications. CBF AML is most common and as such, its treatment is more clearly established, consisting of intensive induction chemotherapy followed by cytarabine based consolidation. Due in large part to its intrinsic chemo-sensitivity, CBF AML is associated with relatively high rates of remission and survival. PDGFR mediated AML is comparatively rare, and as such, diagnostic and treatment paradigms are not as well defined. Early identification of PDGFR translocations is essential, as they confer profound imatinib sensitivity which may, in many instances, spare the need for chemotherapy. Prompt recognition of such lesions requires a strong index of suspicion, and as such these diagnoses are often initially overlooked. Unfortunately, many cases of PDGFR associated AML, particularly those with other concurrent cytogenetic abnormalities, demonstrate treatment emergent imatinib resistance. Such patients continue to present a challenge, even with the advent of novel tyrosine kinase inhibitors (TKIs). Patients with rare translocations such as ETV6-ABL1 are not well described however seem to follow an aggressive clinical course, with limited response to imatinib, and poor outcomes. This review examines the significance of eosinophilia in the context of AML, with respect to its presentation, pathology, and cytogenetics, and with special attention to appropriate evaluation and treatment.
Synthesis of eosinophil-associated enzymes in HL-60 promyelocytic leukemia cells.
Fischkoff S A,Brown G E,Pollak A
Eosinophils derived from HL-60 cells share many of the abnormalities of granule histochemistry and morphology frequently seen in eosinophils of patients with certain malignancies, especially those seen in acute myelomonocytic leukemia with abnormal eosinophils (FAB class M4eo). In order to understand the pathogenesis of these abnormalities, four enzymes, characteristic of the eosinophil, were studied in HL-60 promyelocytic leukemia cells at various stages of eosinophilic differentiation. Using biochemical and ultrahistochemical techniques, the following differences from normal eosinophil development were demonstrated. First, both myeloperoxidase and eosinophil peroxidase coexisted in the population of maturing HL-60 eosinophils. Second, the granules formed from the condensation of material in vacuoles which were derived from dilated segments of the endoplasmic reticulum; the role of the Golgi apparatus in processing of peroxidase appeared minimal. Third, low levels of lysophospholipase and arylsulfatase were present in the cells compared to normal eosinophils. Finally, crystallizations resembling precursor structures of Auer rods appeared in the granules of about 5% of the cells. These findings suggest that several disorders of the control of protein synthesis and processing exist in HL-60 eosinophils which may be responsible for the abnormal granule morphology and histochemistry.
All-Trans Retinoic Acid Impairs Platelet Function and Thrombus Formation and Inhibits Protein Kinase CßI/δ Phosphorylation.
Luo Qi,Wei Guangyu,Wang Xiamin,Xu Xiaoqi,Ju Wen,Li Zhenyu,Gardiner Elizabeth E,Andrews Robert K,Zeng Lingyu,Xu Kailin,Qiao Jianlin
Thrombosis and haemostasis
All-trans retinoic acid (ATRA) is widely used for induction of complete remission in patients with acute promyelocytic leukemia (APL). ATRA also regulates protein kinase C (PKC) activity. Therapeutic use of ATRA reportedly interferes with hemostatic function in APL patients, including effects on coagulation or other vascular cells, although effects of ATRA on platelets remain unclear. This study aims to investigate the effect of therapeutic-relevant doses of ATRA on platelet function. Human platelets were preincubated with ATRA (0-20 μM) for 1 hour at 37°C, followed by analysis of aggregation, granule secretion, receptor expression by flow cytometry, platelet spreading, or clot retraction. Additionally, ATRA (10 mg/kg) was injected intraperitoneally into mice and tail bleeding time and arterial thrombus formation were evaluated. ATRA inhibited platelet aggregation and adenosine triphosphate release induced by collagen (5 μg/mL) or thrombin (0.05 U/mL) in a dose-dependent manner without affecting P-selectin expression or surface levels of glycoprotein (GP) Ibα, GPVI, or αβ. ATRA-treated platelets demonstrated reduced spreading on immobilized fibrinogen or collagen and reduced thrombin-induced clot retraction together with reduced phosphorylation of Syk and PLCγ2. In addition, ATRA-treated mice displayed significantly impaired hemostasis and arterial thrombus formation in vivo. Further, in platelets stimulated with either collagen-related peptide or thrombin, ATRA selectively inhibited phosphorylation of PKCßI (Ser661) and PKCδ (Thr505), but not PKCα or PKCßII phosphorylation (Thr638/641). In conclusion, ATRA inhibits platelet function and thrombus formation, possibly involving direct or indirect inhibition of PKCßI/δ, indicating that ATRA might be beneficial for the treatment of thrombotic or cardiovascular diseases.
The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia.
Breen Karen A,Grimwade David,Hunt Beverley J
British journal of haematology
Coagulopathy occurs in most patients with (APML) and is life-threatening; therefore prompt diagnosis and recognition of any coagulation defect is imperative. Unfortunately haemorrhage remains a major cause of early death, preventing some from reaching treatment. The coagulopathy is caused directly or indirectly by the leukaemic cells through expression of activators of coagulation and fibrinolysis, proteases and cytokine generation, compounded by failure of platelet production due to marrow invasion. At presentation the predominant feature is usually hyperfibrinolysis. Since the introduction of all-trans retinoic acid (ATRA), patient outcome has dramatically improved; yet, haemorrhagic complications remain the most frequent cause of mortality. Thrombotic complications occur but are less well recognized and potentially underreported. Supportive measures and prompt initiation of ATRA currently represent the mainstay of treatment of the coagulopathy in patients with suspected APML, but unanswered questions remain as to the optimal approach to further decrease the associated haemorrhagic and thrombotic risks. In particular, it is unclear how to best predict and monitor the coagulopathy; whether there is a role for the early use of antifibrinolytics; the most appropriate trigger for giving fibrinogen replacement and the value of low-dose anticoagulation to suppress coagulation activation once fibrinolysis has been suppressed.
The double hazard of thrombophilia and bleeding in acute promyelocytic leukemia.
Tallman Martin S,Abutalib Syed A,Altman Jessica K
Seminars in thrombosis and hemostasis
Acute promyelocytic leukemia (APL), once highly fatal, has emerged as the most curable subtype of acute myeloid leukemia in adults. Cure is now expected in approximately 70 to 90% of patients when treatment includes all- TRANS retinoic acid (ATRA) combined with anthracycline-based chemotherapy. Early mortality most often is due to a severe and often catastrophic bleeding, often intracerebral in location, and remains a major cause of treatment failure. Thrombosis, either at diagnosis or during the course of treatment, may be unrecognized and reflects the complexity of the coagulopathy. The dual phenomenon of bleeding and thrombosis is attributable to at least three processes: disseminated intravascular coagulation; fibrinolysis (generated in part by expression of annexin-II on the APL cell surface); and direct proteolysis of several proteins including fibrinogen and von Willebrand factor. Both ATRA and arsenic trioxide are associated with rapid resolution of the coagulopathy. The use of heparin, once a mainstay of therapy for patients with APL, has been all but abandoned. Preliminary studies suggest no role for the routine use of antifibrinolytic agents. The most important therapeutic strategy is early institution of ATRA at the first suspicion of the diagnosis (without waiting for genetic confirmation) and aggressive blood product support during induction.
A combined immunostimulatory and immunoinhibitory short interference RNA reduces hypercoagulability in a rat model of acute promyelocytic leukaemia.
Iversen Per Ole,Sørensen Dag Reidar,Sioud Mouldy
Thrombosis and haemostasis
Acute promyelocytic leukaemia (APL) confers an increased risk of thrombosis and bleeding. Current treatments are insufficient to inhibit these complications. We recently showed that a combined immunoinhibitory and immunostimulatory short interference (si) RNA effectively inhibited leukaemic growth and metastasis in rats with APL. We now asked if the reported anti-leukaemic effects of siRNA treatment could be explained by inhibition of hypercoagulability. We measured markers of coagulation and fibrinolysis in plasma collected from APL rats with overt leukaemia using conventional assays. Coagulopathy developed in untreated leukaemic rats evidenced by increase in several haemostatic markers. Treatment of leukaemic rats with the siRNA reduced (p < 0.05) the concentration of thrombin-anti-thrombin complex (a marker of coagulation) by 40% compared with rats treated with an inactive, control siRNA. Substantial reductions (p < 0.05) were also obtained for two markers of fibrinolysis: D-dimer (72%) and plasminogen activator inhibitor type 1 (51%). The activity of tissue factor, the main initiator of coagulation, was not increased (p > 0.05) in untreated leukaemic rats compared with healthy rats, and did not change (p > 0.05) upon treatment with the siRNA. The bifunctional siRNA reduces the hypercoagulable state in APL in addition to its direct anti-leukaemic properties, supporting testing of this small molecule in human APL.
Thrombosis of the cerebral veins and sinuses in acute promyelocytic leukemia after all-trans retinoic acid treatment: a case report.
Ciccone Maria,Rigolin Gian Matteo,Viglione Giulia Marta,Borrelli Massimo,Serino Maria Luisa,Cuneo Antonio
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis
Thrombosis of the cerebral veins or sinuses is a rare cerebrovascular disorder, which seldom represents a complication of acute promyelocytic leukemia. To the best of our knowledge, it never occurred during treatment with all-trans retinoic acid. We report a case of a 35-year-old woman affected by acute promyelocytic leukemia, who developed massive thrombosis of the cerebral sinuses and veins when she was in complete morphological and molecular remission after all-trans retinoic acid and idarubicin treatment. Anticoagulant therapy contributed to progressive dissolution of the thrombosis as documented by magnetic resonance imaging with complete disappearance of neurological signs without sequelae.
Occurrence of thrombotic events in acute promyelocytic leukemia correlates with consistent immunophenotypic and molecular features.
Breccia M,Avvisati G,Latagliata R,Carmosino I,Guarini A,De Propris M S,Gentilini F,Petti M C,Cimino G,Mandelli F,Lo-Coco F
Although the occurrence of thrombosis in acute promyelocytic leukemia (APL) has been reported during retinoic acid treatment, no studies carried out in large clinical cohorts have specifically addressed this issue. We analyzed 124 APL patients treated with the all-trans retinoic acid and idarubicin protocol and compared clinico-biologic characteristics of 11 patients who developed thrombosis with those of 113 patients who had no thrombosis. In seven patients, the events were recorded during induction, whereas in four patients deep vein thrombosis occurred in the post-induction phase. Comparison of clinico-biological characteristics of patients with and without thrombosis revealed in the former group higher median white blood cell (WBC) count (17 x 10(9)/l, range 1.2-56, P=0.002), prevalence of the bcr3 transcript type (72 vs 48%, P=0.01), of FLT3-ITD (64 vs 28%, P=0.02), CD2 (P=0.0001) and CD15 (P=0.01) expression. No correlation was found with sex, age, French-American-British subtype, all-trans-retinoic acid syndrome or with thrombophilic state that was investigated in 5/11 patients. Our findings suggest that, in APL patients consistent biologic features of leukemia cells may predict increased risk of developing thrombosis.
Acute myocardial/cerebral infarction as first/relapse manifestation in one acute promyelocytic leukemia patient.
Li Ying,Suo Shanshan,Mao Liping,Wang Lei,Yang Chunmei,Xu Weilai,Lou Yinjun,Mai Wenyuan
International journal of clinical and experimental medicine
In the clinical setting, bleeding is a common manifestation of acute promyelocytic leukemia (APL), whereas thrombosis is relatively rare, especially as an initial symptom. Here, we report an unusual case of APL with acute myocardial infarction as the first manifestation and cerebral infarction as the relapse manifestation in a healthy young woman. This unique case emphasizes that a thrombotic event could be the first manifestation of an underlying hematological disorder such as APL and could also be a sign of relapse. Rapid detection of the underlying disorder and the timely use of anticoagulation therapy and ATRA are crucial for preventing further deterioration of the disease and saving the patient's life.
Thrombo-hemorrhagic deaths in acute promyelocytic leukemia.
Breccia Massimo,Lo Coco Francesco
Acute promyelocytic leukemia (APL) has become the most curable form of acute myeloid leukemia after the advent of all-trans retinoic acid (ATRA). However, early deaths (ED) mostly due to the disease-associated coagulopathy remain the major cause of treatment failure. In particular, hemorrhagic events account for 40-65% of ED and several prognostic factors have been identified for such hemorrhagic deaths, including poor performance status, high white blood cell (WBC) count and coagulopathy. Occurrence of thrombosis during treatment with ATRA may be associated with differentiation syndrome (DS) or represent an isolated event. Some prognostic factors have been reported to be associated with thrombosis, including increased WBC or aberrant immunophenotype of leukemic promyelocytes. Aim of this review is to report the incidence, severity, possible pathogenesis and clinical manifestations of thrombo-haemorrhagic deaths in APL.
Thrombosis in acute promyelocytic leukemia.
Rashidi Armin,Silverberg Marc L,Conkling Paul R,Fisher Stephen I
INTRODUCTION:Compared to bleeding, major thromboses are a less commonly encountered problem in acute promyelocytic leukemia (APL), and our knowledge about the epidemiology of major thromboses in APL stems mainly from individual case reports. The purpose of this study was to provide a better understanding of the epidemiology of APL-related thrombosis as a first step towards developing preventive strategies. MATERIALS AND METHODS:We report a rare case of catastrophic acute myocardial infarction in a patient with APL while she developed the all-trans retinoic acid (ATRA) syndrome. We describe the pathogenesis of APL-related thrombosis and review all previously reported cases of major thromboses in APL. RESULTS:We found 94 cases of major thromboses in patients with APL. Both genders were almost equally affected. More than 80% of events occurred before or during induction therapy with deep vein thrombosis/pulmonary embolism (DVT/PE), cardiac events, and cerebrovascular accidents (CVA) constituting more than 75% of all cases. Arterial events were slightly more common than venous events. Only 2 arterial events occurred after completion of induction therapy. Thrombosis was associated with life-threatening hemorrhage in about 15%, significant coagulative defects in about 50%, and ATRA syndrome in about 13% of cases. Cardiac thrombotic events, DVT/PE, and CVA were associated with ATRA syndrome in 24%, 4.5%, and 5% of cases, respectively (p=0.09). None of the observed trends and associations reached statistical significance. CONCLUSIONS:This review advances our understanding of the epidemiology of major thromboses in APL. With accumulation of more cases in the literature, some of our results may become statistically significant.
Risk Markers for Significant Bleeding and Thrombosis in Pediatric Acute Promyelocytic Leukemia; Report From the Children's Oncology Group Study AAML0631.
Rajpurkar Madhvi,Alonzo Todd A,Wang Yi-Cheng,Gerbing Robert B,Gamis Alan S,Feusner James H,Gregory John,Kutny Matthew A
Journal of pediatric hematology/oncology
Acute promyelocytic leukemia (APL) is characterized by a heightened risk of coagulopathy with significant morbidity and mortality. Here we report our evaluation of presenting white blood cell (WBC) and the International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) scoring system as markers for early death and nonlethal coagulopathy in pediatric APL. We evaluated 79 pediatric patients treated on a Children's Oncology Group phase III clinical trial. There were 4 early deaths and 13 nonlethal, clinically significant (grade III to IV) coagulopathy events during induction. Elevated presenting WBC was significantly associated with early death but not with both lethal and nonlethal coagulopathy events. An ISTH DIC score of ≥5 (the original ISTH criteria for overt DIC) was not associated with either early deaths or coagulopathy events. An ISTH DIC score threshold of 6, however, was significantly associated with early death (12% score ≥6 vs. 0% score <6) and with both lethal and nonlethal coagulopathy events (35% score ≥6 vs. 11% score <6). In pediatric APL patients, the presenting WBC is a marker for risk of early death. Although the ISTH score using a cutoff of ≥6 showed improved correlation with adverse coagulation events during induction, the sensitivity was only 70.6% (95% confidence interval, 44.0%-89.7%) and the specificity was 64.5% (95% confidence interval, 51.3%-76.3%). Thus, there is a strong need to identify other biomarkers that can predict APL-associated coagulopathy.
Acute promyelocytic leukemia cell adhesion to vascular endothelium is reduced by heparins.
Vignoli Alfonso,Marchetti Marina,Falanga Anna
Annals of hematology
Adhesion of acute promyelocytic leukemia (APL) cells to endothelial cells (EC) is among the mechanisms of the APL-associated coagulopathy, responsible for early hemorrhagic deaths in affected patients. We compared the effects of dalteparin and enoxaparin, two low-molecular-weight heparins (LMWH), and unfractionated heparin (UFH), on APL NB4 adhesion to micro- (HMEC-1) and macro-vascular EC (HUVEC), in resting and interleukin-1β (IL-1β)-stimulated conditions. The heparin effect on EC adhesion molecule (ICAM-1, VCAM-1, E-selectin) expression was also assessed. In HMEC-1, dalteparin inhibited IL1β-induced NB4 adhesion by 80%, enoxaparin by 52%, and UFH by 44%. Similar results were obtained in HUVEC. This was associated with a significant decrease of VCAM-1 and ICAM-1 expression. In conclusion, we show that LMWH significantly counteract APL cell adhesion to the vessel wall, by modulating EC adhesion molecule expression. This property of heparins may represent one approach for hampering excess clotting activation and microthrombi deposition in APL.
Eosinophils are a major intravascular location for tissue factor storage and exposure.
Moosbauer Christine,Morgenstern Eberhard,Cuvelier Susan L,Manukyan Davit,Bidzhekov Kiril,Albrecht Sybille,Lohse Peter,Patel Kamala D,Engelmann Bernd
Blood cell progenitors were scanned for the presence of the coagulation starter protein tissue factor (TF) by immunoelectron microscopy. Thereby, substantial TF expression was observed in the precursor cells of eosinophils. TF levels were lower in basophil precursors and barely detectable in neutrophil progenitors. In peripheral blood immediately processed to avoid activation of the TF gene, mature eosinophils were found to considerably express TF, unique among the granulocyte and monocyte fractions. TF was preferentially located in the specific granules in resting eosinophils. Platelet-activating factor (PAF), and more pronounced, granulocyte-macrophage colony-stimulating factor (GM-CSF) plus PAF, caused translocation of preformed TF to the eosinophil cell membrane. GM-CSF/PAF also increased the TF transcript levels. The activated eosinophils exhibited procoagulant activity that was abrogated by TF inhibition. Targeting the extracellular domain of TF with specific antibodies markedly suppressed the initial phase of the eosinophil passage across the IL-4-activated endothelium. Eosinophil rolling and firm adhesion remained unaffected. This suggests that TF specifically facilitates the early transendothelial migration of the eosinophils. In summary, eosinophils maintain a high TF expression during maturation, providing a main source of preformed TF in blood, which might be relevant for the thrombogenesis promoted by hypereosinophilic conditions.
[Hypereosinophilic syndrome with DIC treated successfully with a combination of high-dose methylprednisolone and cyclosporin A].
Fukuta A,Hara T,Tsurumi H,Moriwaki H
[Rinsho ketsueki] The Japanese journal of clinical hematology
A 47-year-old man was admitted to our hospital with subcutaneous nodules on the bilateral lower legs and disseminated intravascular coagulation (DIC). Peripheral blood examination revealed leukocytosis with an increase of mature eosinophils, thrombocytopenia and abnormal coagulation. Bone marrow aspiration revealed an increased eosinophil count, and a diagnosis of hypereosinophilic syndrome (HES) was made. Prednisolone (PSL) therapy was not effective. Subsequent methylPSL pulse therapy followed by PSL brought about a transient improvement of the HES and DIC, but after reduction of the PSL, the HES worsened. After addition of cyclosporin A to the PSL, however, the HES improved and did not worsen.
Significance of eosinophil accumulation in the thrombus and decrease in peripheral blood in patients with acute coronary syndrome.
Jiang Ping,Wang De-zhao,Ren Ya-li,Cai Jian-ping,Chen Bu-xing
Coronary artery disease
BACKGROUND AND AIMS:It is well known that the interaction between platelets (PLTs), endothelial cells, and leukocytes contributes to thrombosis in patients with acute coronary syndrome. The aim of this study was to investigate the significance of PLTs and eosinophils (EOS) in coronary arterial thrombi. METHODS:PLT count, mean PLT volume, PLT mass, EOS count, EOS percentage, and troponin I level in peripheral blood were determined in 81 patients with angina pectoris (AP) and 49 patients with acute myocardial infarction (AMI). A total of 12 thrombus specimens from AMI patients were submitted for histopathological analysis. EOS presence in thrombectomy specimens were checked by hematoxylin-eosin staining and confirmed by Luna staining. RESULTS:Results showed that EOS were present in all 12 samples (100%). Cell count and percentage of EOS in peripheral blood of patients with AMI were lower than those in patients with AP (both P<0.00001). A higher PLT count was observed in AMI patients (243±70), especially among female patients or those who were older than 60 years, when compared with AP patients (216±60; all P<0.05). According to the troponin I level, we divided AMI patients into groups I (≥20 ng/ml) and II (<20 ng/ml). Group I had a lower EOS percentage compared with group II (P=0.0496). PLT count was also lower in group I with no statistical difference found (P=0.1202). Moreover, there was an inverse correlation between the EOS percentage and the troponin I level (r=-0.434). CONCLUSION:In conclusion, patients with AMI presented with a decreased EOS percentage and an increased PLT count. The decreased EOS percentage suggested serious myocardial damage. The study indicated that EOS play an important role in thrombosis in patients with acute coronary syndrome.
Enhanced tissue factor expression by blood eosinophils from patients with hypereosinophilia: a possible link with thrombosis.
Cugno Massimo,Marzano Angelo V,Lorini Maurizio,Carbonelli Vincenzo,Tedeschi Alberto
Thrombotic risk is increased in eosinophil-mediated disorders, and several hypotheses have been proposed to link eosinophilia and thrombosis. In particular, eosinophils have been described as source of tissue factor (TF), the main initiator of blood coagulation; however, this aspect is still controversial. This study was aimed to evaluate whether TF expression varies in eosinophils isolated from normal subjects and patients with different hypereosinophilic conditions. Eosinophils were immunologically purified from peripheral blood samples of 9 patients with different hypereosinophilic conditions and 9 normal subjects. Western blot analysis and real-time polymerase chain reaction (RT-PCR) were performed to test eosinophil TF expression. For comparison, TF expression was evaluated in monocytes from blood donors and in human endothelial (ECV304) and fibroblast (IMR90) cell lines. Western blot analysis revealed a major band of 47,000 corresponding to native TF in homogenates of purified eosinophils with a higher intensity in the 9 patients than in the 9 controls (p<0.0001). According to RT-PCR cycle threshold (Ct), TF gene expression was higher in eosinophils from patients than in those from controls, median (range) 35.10 (19.45-36.50) vs 37.17 (35.33-37.87) (p = 0.002), and was particularly abundant in one patient with idiopathic hypereosinophilic syndrome and ischemic heart attacks (Ct: 19.45). TF gene expression was moderate in monocytes, Ct: 31.32 (29.82-33.49) and abundant in endothelial cells, Ct: 28.70 (27.79-29.57) and fibroblasts, Ct: 22.77 (19.22-25.05). Our results indicate that human blood eosinophils contain variable amounts of TF. The higher TF expression in patients with hypereosinophilic disorders may contribute to increase the thrombotic risk.
Extracellular traps derived from macrophages, mast cells, eosinophils and neutrophils are generated in a time-dependent manner during atherothrombosis.
Pertiwi Kartika R,de Boer Onno J,Mackaaij Claire,Pabittei Dara R,de Winter Robbert J,Li Xiaofei,van der Wal Allard C
The Journal of pathology
Extracellular traps generated by neutrophils contribute to thrombus progression in coronary atherosclerotic plaques. It is not known whether other inflammatory cell types in coronary atherosclerotic plaque or thrombus also release extracellular traps. We investigated their formation by macrophages, mast cells, and eosinophils in human coronary atherosclerosis, and in relation to the age of thrombus of myocardial infarction patients. Coronary arteries with thrombosed or intact plaques were retrieved from patients who died from myocardial infarction. In addition, thrombectomy specimens from patients with myocardial infarction were classified histologically as fresh, lytic or organised. Neutrophil and macrophage extracellular traps were identified using sequential triple immunostaining of CD68, myeloperoxidase, and citrullinated histone H3. Eosinophil and mast cell extracellular traps were visualised using double immunostaining for eosinophil major basic protein or tryptase, respectively, and citrullinated histone H3. Single- and double-stained immunopositive cells in the plaque, adjacent adventitia, and thrombus were counted. All types of leucocyte-derived extracellular traps were present in all thrombosed plaques, and in all types of the in vivo-derived thrombi, but only to a much lower extent in intact plaques. Neutrophil traps, followed by macrophage traps, were the most prominent types in the autopsy series of atherothrombotic plaques, including the adventitia adjacent to thrombosed plaques. In contrast, macrophage traps were more numerous than neutrophil traps in intact plaques (lipid cores) and organised thrombi. Mast cell and eosinophil extracellular traps were also present, but sparse in all instances. In conclusion, not only neutrophils but also macrophages, eosinophils, and mast cells are sources of etosis involved in evolving coronary thrombosis. Neutrophil traps dominate numerically in early thrombosis and macrophage traps in late (organising) thrombosis, implying that together they span all the stages of thrombus progression and maturation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Eosinophil-platelet interactions promote atherosclerosis and stabilize thrombosis with eosinophil extracellular traps.
Marx Charlotte,Novotny Julia,Salbeck Danby,Zellner Katie R,Nicolai Leo,Pekayvaz Kami,Kilani Badr,Stockhausen Sven,Bürgener Niklas,Kupka Danny,Stocker Thomas J,Weckbach Ludwig T,Pircher Joachim,Moser Markus,Joner Michael,Desmet Walter,Adriaenssens Tom,Neumann Franz-Josef,Gerschlick Anthony H,Ten Berg Jurrien M,Lorenz Michael,Stark Konstantin
Clinical observations implicate a role of eosinophils in cardiovascular diseases because markers of eosinophil activation are elevated in atherosclerosis and thrombosis. However, their contribution to atherosclerotic plaque formation and arterial thrombosis remains unclear. In these settings, we investigated how eosinophils are recruited and activated through an interplay with platelets. Here, we provide evidence for a central importance of eosinophil-platelet interactions in atherosclerosis and thrombosis. We show that eosinophils support atherosclerotic plaque formation involving enhanced von Willebrand factor exposure on endothelial cells and augmented platelet adhesion. During arterial thrombosis, eosinophils are quickly recruited in an integrin-dependent manner and engage in interactions with platelets leading to eosinophil activation as we show by intravital calcium imaging. These direct interactions induce the formation of eosinophil extracellular traps (EETs), which are present in human thrombi and constitute a substantial part of extracellular traps in murine thrombi. EETs are decorated with the granule protein major basic protein, which causes platelet activation by eosinophils. Consequently, targeting of EETs diminished thrombus formation in vivo, which identifies this approach as a novel antithrombotic concept. Finally, in our clinical analysis of coronary artery thrombi, we identified female patients with stent thrombosis as the population that might derive the greatest benefit from an eosinophil-inhibiting strategy. In summary, eosinophils contribute to atherosclerotic plaque formation and thrombosis through an interplay with platelets, resulting in mutual activation. Therefore, eosinophils are a promising new target in the prevention and therapy of atherosclerosis and thrombosis.
All-trans-retinoic acid enhances apoptosis induction by tyrosine kinase inhibitors in the eosinophilic leukemia-derived EoL-1 cell line.
Robert Carine,Apàti Agota,Chomienne Christine,Papp Béla
Imatinib and retinoids induce apoptosis in FIP1L1/PDGFRalpha-positive EoL-1 leukemia cells. Although imatinib induces complete remission in most FIP1L1/PDGFRalpha-positive patients, response to imatinib is sometimes suboptimal. In order to enhance the potency of the molecularly targeted therapy of eosinophilic leukemia, we investigated the effect of retinoids combined with tyrosine kinase inhibitors on EoL-1 cells. We demonstrate that retinoids combined with tyrosine kinase inhibitors lead to enhanced apoptosis induction in EoL-1 cells. Our results suggest that tyrosine kinase inhibitors combined with retinoids may constitute a valuable therapeutic approach for sensitive neoplasias that may display enhanced anti-leukemic potency when compared to single drug treatments.
Apoptosis induction by retinoids in eosinophilic leukemia cells: implication of retinoic acid receptor-alpha signaling in all-trans-retinoic acid hypersensitivity.
Robert Carine,Delva Laurent,Balitrand Nicole,Nahajevszky Sarolta,Masszi Tamàs,Chomienne Christine,Papp Béla
Hypereosinophilic syndrome (HES) has recently been recognized as a clonal leukemic lesion, which is due to a specific oncogenic event that generates hyperactive platelet-derived growth factor receptor-alpha-derived tyrosine kinase fusion proteins. In the present work, the effect of retinoids on the leukemic hypereosinophilia-derived EoL-1 cell line and on primary HES-derived cells has been investigated. We show that all-trans-retinoic acid (ATRA) inhibits eosinophil colony formation of HES-derived bone marrow cells and is a powerful inducer of apoptosis of the EoL-1 cell line. Apoptosis was shown in the nanomolar concentration range by phosphatidylserine externalization, proapoptotic shift of the Bcl-2/Bak ratio, drop in mitochondrial membrane potential, activation of caspases, and cellular morphology. Unlike in other ATRA-sensitive myeloid leukemia models, apoptosis was rapid and was not preceded by terminal cell differentiation. Use of isoform-selective synthetic retinoids indicated that retinoic acid receptor-alpha-dependent signaling is sufficient to induce apoptosis of EoL-1 cells. Our work shows that the scope of ATRA-induced apoptosis of malignancies may be wider within the myeloid lineage than thought previously, that the EoL-1 cell line constitutes a new and unique model for the study of ATRA-induced cell death, and that ATRA may have potential for the management of clonal HES.
The Effects of All-Trans Retinoic Acid on the Induction of Oral Tolerance in a Murine Model of Bronchial Asthma.
Sakamoto Hirotaka,Koya Toshiyuki,Tsukioka Keisuke,Shima Kenjiro,Watanabe Satoshi,Kagamu Hiroshi,Kimura Yosuke,Sakagami Takuro,Hasegawa Takashi,Suzuki Eiichi,Narita Ichiei
International archives of allergy and immunology
BACKGROUND:Active suppression induced by regulatory T (Treg) cells is reported to be one of the mechanisms involved in oral tolerance. All-trans retinoic acid (ATRA) has been reported to affect Treg cell differentiation. The present study examined the effects of ATRA on the induction of oral tolerance in a murine model of bronchial asthma. METHODS:BALB/c mice were sensitized to and challenged with ovalbumin (OVA) through feeding followed by OVA challenges. In some study groups ATRA was orally administered concomitantly with OVA feeding either in the presence or absence of the retinoic acid receptor antagonist LE135. Lung CD4+ T cells were isolated from mice exposed to ATRA and/or OVA, and transferred to control mice. Airway hyperresponsiveness (AHR), cell counts and cytokine levels in bronchoalveolar lavage (BAL) fluid, and lung histology were assessed. RESULTS:Concomitant administration of ATRA with OVA ameliorated AHR, airway eosinophilia, elevation of cytokines in BAL fluid and goblet cell metaplasia. The proportion of Treg cells in the lungs was increased in mice treated with OVA and ATRA, as compared to those treated with OVA only. Transfer of lung CD4+ T cells from mice treated with OVA and ATRA induced suppression of AHR and airway inflammation. LE135 completely reversed the effects of ATRA on AHR, airway allergic inflammation and the number of Treg cells in the lungs. CONCLUSION:These data suggested that oral administration of ATRA with OVA had the potential to enhance oral tolerance in this murine model of bronchial asthma. These effects were mediated, at least in part, by Treg cell expansion.
Time course of arsenic species in red blood cells of acute promyelocytic leukemia (APL) patients treated with single agent arsenic trioxide.
Guo Meihua,Wang Bin,Liu Shuchuan,Wang Wenjing,Gao Chunlu,Hu Shuang,Fan Shengjin,Hai Xin,Zhou Jin
Expert review of clinical pharmacology
BACKGROUND:Arsenic trioxide (ATO) is widely applied to treat acute promyelocytic leukemia (APL). To elucidate metabolism and toxicity of arsenic, we analyzed time course of arsenic species in red blood cells (RBCs) of APL patients. METHODS:Nine APL patients received ATO (0.16 mg/kg/day) through 18-h infusion. Blood was collected before daily administration (days 2 to 9), and at different time points on day 8. Inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were detected by HPLC-ICP-MS. RESULTS:Arsenic species reached C at 18 h on day 8. Arsenicals gradually accumulated during days 2 to 9, whereas their percentages remained almost constant. The general trend in red blood cells (RBCs) was iAs > MMA > DMA. MMA was consistently the predominant methylated arsenic metabolite in RBCs. iAs, MMA, and tAs (tAs = iAs + DMA + MMA) concentrations (P < 0.0001), MMA/DMA ratios (P = 0.0016) and iAs% (P = 0.0013) were higher in RBCs than in plasma. CONCLUSIONS:Time course of arsenic species reveal kinetic characteristic of ATO metabolites in RBCs. Arsenic species accumulated with administration frequency. Arsenic species in RBCs were remarkably different from those in plasma. Time course of arsenic species in RBCs is important in ATO clinical application.
Factors affecting thrombohemorrhagic early death in patients with acute promyelocytic leukemia treated with arsenic trioxide alone.
Hou Wenyi,Zhang Yingmei,Jin Bo,Cao Weifan,Lu Ming,Yan Liru,Yang Huiyuan,Tian Xuanyu,Hou Jinxiao,Fu Jinyue,Zhao Hongli,Li Haitao,Zhou Jin
Blood cells, molecules & diseases
Acute promyelocytic leukemia (APL) is often accompanied by a potentially devastating coagulopathy. Predictors of thrombohemorrhagic early death (TH-ED)/early bleeding death are not well characterized. In this retrospective study, eleven baseline clinical variables that can be assessed easily and promptly were chosen for evaluation in a cohort of 364 patients with APL who were administered arsenic trioxide (ATO) alone as remission induction therapy. TH-ED was defined as death from bleeding or thrombosis within 30 days after hospital admission. Cox proportional hazards regression model was used for both the univariate and multivariate analyses. Totally, 53 patients died from severe bleeding (51 cases) or thrombosis (2 cases), and at 30 days the cumulative incidences of TH-ED were 14.6%. Six independent risk factors for TH-ED were identified, including relapse, male, white blood cell (WBC) count above 10 × 10/L, fibrinogen level below 1 g/L, D-dimer level above 4 mg/L and increased creatinine level. Increased creatinine level was the most powerful risk factor, followed by WBC count > 10 × 10/L. This study identified risk factors for TH-ED in a large cohort of patients with APL, which enriched clinical information on identifying patients at high risk of TH-ED.
Comparative analysis of causes and predictors of early death in elderly and young patients with acute promyelocytic leukemia treated with arsenic trioxide.
Jin Bo,Zhang Yingmei,Hou Wenyi,Cao Fenglin,Lu Ming,Yang Huiyuan,Tian Xuanyu,Wang Yuan,Hou Jinxiao,Fu Jinyue,Li Haitao,Zhou Jin
Journal of cancer research and clinical oncology
PURPOSE:Early death (ED) is the main cause of acute promyelocytic leukemia (APL) treatment failure, and the ED rate is higher for elderly patients than that for young ones. To date, no studies have been found focusing on ED in elderly patients with APL. METHODS:This study retrospectively analyzed the clinical data of 409 consecutive patients with APL (139 patients ≥ 50 years old, 270 patients < 50 years old). All patients received arsenic trioxide alone as induction therapy. The baseline clinical characteristics and ED occurrence and predictors between elderly and young patients with APL were compared and analyzed. RESULTS:The clinical features of elderly patients at admission were not significantly different from those of young ones. The ED rate of elderly patients was significantly greater than that of young patients (23.74% vs 11.85%, P = 0.0018). Hemorrhage is the main cause of ED in elderly patients, followed by infection and differentiation syndrome. From the 15th to 30th days of treatment, elderly patients had a higher mortality rate than that of young patients (7.83% vs 2.06%, P = 0.009). Male, white blood cell (WBC) count > 10 × 10/L, fibrinogen < 1.0 g/L and low albumin levels were independent risk factors for ED in elderly patients, while ED was only correlated with WBC count, fibrinogen and creatinine levels in young patients. CONCLUSION:The results of this study may help design more rational treatment plans for elderly patients with APL based on early mortality risk to reduce the ED rate.
Induction of apoptosis in human eosinophilic leukemic cell line (EOL-1).
Noda H,Sakagami H,Kokubu F,Kurokawa M,Tokunaga H,Takeda M,Adachi M
International archives of allergy and immunology
Exposure of human eosinophilic leukemic EOL-1 cells to H2O2, ascorbic acid derivatives, actinomycin D, low-molecular-weight polyphenols, UV irradiation, or hyperthermia resulted in nuclear fragmentation, but failed to induce internucleosomal DNA cleavage. The findings suggest that internucleosomal DNA fragmentation is not a universal biochemical hallmark of apoptosis. Removal of Ca2+ ions from the culture medium significantly reduced the cytotoxic activity of sodium ascorbate, but not that of H2O2. H2O2 significantly elevated the intracellular Ca2+ concentration, with or without Ca2+ in the culture medium. This suggests that sodium ascorbate and H2O2 initiate cell death by different mechanisms. Induction of apoptosis in in vitro systems might be useful in studying the pathogenesis of allergy or asthma.
Arsenic trioxide alleviates airway hyperresponsiveness and eosinophilia in a murine model of asthma.
Chu Kuan-Hua,Lee Chen-Chen,Hsin Shao-Chi,Cai Bao-Chang,Wang Jin-Hong,Chiang Bor-Luen
Cellular & molecular immunology
Asthma is one of the most common chronic airway inflammatory diseases. The clinical hallmarks of asthma include elevated serum levels of immunoglobulin E (IgE), eosinophilic inflammation and airway hyper-responsiveness (AHR). Arsenic trioxide (As2O3) is considered a carcinogen; however, it has also been used to treat diseases, such as syphilis, in traditional Chinese and Western medicine. Today, As2O3 is used as one of the standard therapies for acute promyelocytic leukemia (APL). Previous studies have indicated that As2O3 can induce apoptosis in eosinophils. However, the effect of As2O3 on asthma has not been investigated. We used ovalbumin (OVA)-immunized mice as a model for asthma and treated mice with As2O3 at doses of 2.5 and 5 mg/kg. The mice were then monitored for OVA-specific IgE production, airway inflammatory cell infiltration and AHR. We found that administration of As2O3 in OVA-immunized mice abrogated airway eosinophil recruitment by downregulating eotaxin expression but did not alter serum IgE or IL-5 levels in bronchoalveolar lavage fluid (BALF). Furthermore, the development of AHR and cellular infiltration into the airway were reduced by treating mice with As2O3. In vitro data suggested that low concentrations of As2O3 could induce only a small degree of apoptosis in primary pulmonary cells but could significantly inhibit the secretion of eotaxin by these cells. These results indicate that the administration of As2O3 to OVA-immunized mice can suppress lung allergic inflammatory responses. As2O3 might therefore have therapeutic potential in treating allergic airway inflammatory diseases.
Novel t(5;11)(q32;q13.4) with NUMA1-PDGFRB fusion in a myeloid neoplasm with eosinophilia with response to imatinib mesylate.
Zou Ying S,Hoppman Nicole L,Singh Zeba N,Sawhney Sameer,Kotiah Sandy D,Baer Maria R
We report a NUMA1-PDGFRB fusion in a myeloproliferative neoplasm with eosinophilia in a 61-year old man, with response to imatinib mesylate therapy. A t(5;11) chromosome translocation involving bands 5q32 and 11q13.4 was identified by metaphase chromosome analysis, and rearrangement of the platelet-derived growth factor receptor beta (PDGFRB) gene on 5q32 was demonstrated by FISH using a PDGFRB break-apart probe set. Bacterial artificial chromosome (BAC) FISH mapping of the PDGFRB fusion partner gene narrowed the breakpoint at 11q13.4 to a 150 kb genomic region containing three genes, including NUMA1. Mate pair sequencing analysis demonstrated NUMA1-PDGFRB fusion. The fusion protein includes coiled-coil domains of nuclear mitotic apparatus protein 1 (NuMA1, involved in protein homodimerization and heteroassociation) and tyrosine kinase domains of PDGFRB. Diverse rearrangements involving the PDGFRB gene have been identified in myeloid and lymphoid neoplasms with eosinophilia, but rearrangement of the nuclear mitotic apparatus protein 1 (NUMA1) gene has previously been reported in a human malignancy in only one instance, a NUMA1-RARA fusion caused by a t(11;17) translocation in a patient with acute promyelocytic leukemia. The NUMA1-PDGFRB fusion is the second instance of rearrangement of NUMA1, encoding an element of the mitotic apparatus, in human cancer.