Aplastic Pancytopenia Research Articles

Bone marrow failure may be caused by chromosome anomalies exerting effects on RUNX1T1 gene

BackgroundThe majority of the cases of bone marrow failure syndromes/aplastic anaemias (BMFS/AA) are non-hereditary and considered idiopathic (80–85%). The peripheral blood picture is variable, with anaemia, neutropenia and/or thrombocytopenia, and the patients with idiopathic BMFS/AA may have a risk of transformation into a myelodysplastic syndrome (MDS) and/or an acute myeloid leukaemia (AML), as ascertained for all inherited BMFS. We already reported four patients with different forms of BMFS/AA with chromosome anomalies as primary etiologic event: the chromosome changes exerted an effect on specific genes, namely RUNX1, MPL, and FLI1, leading to the disease.ResultsWe report two further patients with non-hereditary BM failure, with diagnosis of severe aplastic anaemia and pancytopenia caused by two different constitutional structural anomalies involving chromosome 8, and possibly leading to the disorder due to effects on the RUNX1T1 gene, which was hypo-expressed and hyper-expressed, respectively, in the two patients. The chromosome change was unbalanced in one patient, and balanced in the other one.ConclusionsWe analyzed the sequence of events in the pathogenesis of the disease in the two patients, including a number of non-haematological signs present in the one with the unbalanced anomaly. We demonstrated that in these two patients the primary event causing BMFS/AA was the constitutional chromosome anomaly. If we take into account the cohort of 219 patients with a similar diagnosis in whom we made cytogenetic studies in the years 2003–2017, we conclude that cytogenetic investigations were instrumental to reach a diagnosis in 52 of them. We postulate that a chromosome change is the primary cause of BMFS/AA in a not negligible proportion of cases, as it was ascertained in 6 of these patients.

Canine Monocytic Ehrlichiosis: An Update on Diagnosis and Treatment

Abstract Canine monocytic ehrlichiosis (CME) is a tick-borne disease of worldwide distribution. The major causative agent is Ehrlichia canis, a gram-negative, obligate intracellular, pleomorphic bacterium of the genus Ehrlichia, which infects monocytes, macrophages and lymphocytes, forming intracytoplasmic, membrane-bound bacterial aggregates, called morulae. After an incubation period of 8-20 days, the course of E. canis infection, can be sequentially divided into acute, subclinical and chronic phases, although these phases can hardly be distinguished in the clinical setting. Clinical recovery is the typical outcome of acutely infected dogs, entering the subclinical phase, during which they show no or minimal clinical signs and/or mild hematological abnormalities. Immunocompetent dogs may eliminate the infection during the acute or subclinical phases, but an unpredictable proportion of dogs will eventually develop the chronic phase, characterized by aplastic pancytopenia and high mortality, due to septicemia and/or severe bleeding. This article outlines briefly the pathogenesis of CME due to E. canis, and more thoroughly reviews the recent scientific literature pertaining to the diagnosis and treatment of this devastating disease.

The Impact of Eltrombopag Administration on the Clinical Course of Severe Refractory Fatal Acquired Aplastic Anemia

The Impact of Eltrombopag Administration on the Clinical Course of Severe Refractory Fatal Acquired Aplastic Anemia

Eosinophilic fasciitis with paroxysmal nocturnal hemoglobinuria

Eosinophilic fasciitis is a rare connective tissue disorder, which can be associated with hematological complications in 10% of cases, such as aplastic anemia or acquired amegakaryocytic thrombocytopenia. Paroxysmal nocturnal hemoglobinuria had never been described in a patient suffering from eosinophilic fasciitis. We report an original case of a 59-year-old patient who developed a moderate aplastic pancytopenia while he was treated for a biopsy-proven eosinophilic fasciitis. A complete set of investigations was carried out and was found to be negative, including a first research of paroxysmal nocturnal hemoglobinuria. Two years after disease onset, while pancytopenia remained stable, occurrence of morning dark urine led to found a paroxysmal nocturnal hemoglobinuria clone. We discuss a potential link between the two conditions and hypothesize that paroxysmal nocturnal hemoglobinuria blood cells may pre-exist for a long time and take a survival advantage in the setting of marrow injury, as observed in eosinophilic fasciitis with hematological complications. We finally suggest that paroxysmal nocturnal hemoglobinuria should be included as a hematological complication of eosinophilic fasciitis.

Bone marrow depletion with haemorrhagic diathesis in calves in Germany: characterization of the disease and preliminary investigations on its aetiology.

Since 2007 a new fatal haemorrhagic diathesis in calves has been observed in all areas of Germany. Analysis of 56 cases submitted for necropsy allowed its characterization. Calves fell ill within the first month of life independent of breed and sex. Only single or a few animals per herd were affected. Petechial and ecchymotic haemorrhages in many organs and tissues, particularly in skin, subcutis and gastrointestinal tract, were major findings in all animals. Microscopically a severe depletion of bone marrow cells was always observed. Lymphocytic depletion (43%) and inflammatory lesions (46%) were less frequently observed. Blood analysis of five animals indicated an aplastic pancytopenia. The resulting thrombocytopenia is regarded as major pathomechanism of this Haemorrhagic Disease Syndrome (HDS). Pedigree analysis gave no indication of hereditary disease. Tests for specific toxins such as S-(1,2-Dichlorovinyl)-L-cysteine (DCVC), furazolidone, or mycotoxins resulting in bone marrow depletion were negative. Bacterial infections, Bovine Viral Diarrhoea Virus, and Bluetongue Virus were ruled out as cause of the disease. HDS shares similarities with a circoviral infection in chickens (chicken infectious anaemia). A broad-spectrum PCR allowed detection of circoviral DNA in 5 of 25 HDS cases and in 1 of 8 non-HDS cases submitted for necropsy. Sequencing of the whole viral genome revealed a high similarity (up to 99%) with Porcine Circovirus type 2b. Single bone marrow cells stained weakly positive for PCV2 antigen by immunohistochemistry in 1 of 8 tested HDS animals. This is the first report of circovirus detection in cattle in Germany. The exact cause of HDS still remains unknown. A multifactorial aetiology involving infection, poisoning, immunopathy, or a genetic predisposition is conceivable. Additional research is necessary to clarify the pathogenesis and the potential role of PCV2 in HDS.

Absence of Myelofibrosis in Dogs with Myelosuppression Induced by Ehrlichia canis Infection

Bone marrow (BM) pathology was assessed in 10 dogs with Ehrlichia canis-induced aplastic pancytopenia. BM core biopsy sections were stained with haematoxylin and eosin and with haematoxylin/van Gieson and Gordon and Sweets' reticulin stain for the detection of collagen and reticulin fibres, respectively. Iron stores were assessed by Perls' Prussian blue staining. There was no significant deposition of collagen or reticulin in any sample, but in seven dogs the BM was depleted of haemosiderin. These findings suggest that myelofibrosis does not play a significant role in the development of BM failure in canine monocytic ehrlichiosis and that iron deficiency may exacerbate the anaemia in the myelosuppressive phase of the disease.

Soluble Platelet Glycoprotein V in Distinct Disease States of Pathological Thrombopoiesis

Quantitative platelet disorders (i.e., thrombocytosis or thrombocytopenia) may also be associated with qualitative platelet alterations. Clonal thrombocythemia (CT), reactive thrombocytosis (RT), immune thrombocytopenic purpura (ITP), and thrombocytopenia of aplastic pancytopenia (AA) or infiltrative bone marrow disorders represent the major classes of pathological thrombopoiesis. Glycoprotein V may serve as an in vivo marker of platelet activation in thrombotic and hemorrhagic states. The aim of this study was to assess circulating plasma soluble platelet glycoprotein V (sGPV) concentrations in distinct disease states of pathological thrombopoiesis. The whole study group comprised 20 patients with thrombocytopenia, 32 patients with thrombocytosis and 14 healthy adults as the control group. sGPV was significantly increased in the group of thrombocytosis patients in comparison to the thrombocytopenic group and the healthy control groups. When sGPV levels were corrected according to platelet number (sGPV/tr), this ratio was very high in patients with thrombocytopenia compared to patients with thrombocytosis and the control group. Our results suggest that there is an ongoing platelet activation associated with thrombocytosis regardless of its origin is either CT or RT. Therefore, glycoprotein V system may serve to activate residual platelets in thrombocytopenia regardless of its origin is either ITP or AA.

Serial Analysis of Hematopoietic Progenitors in Mpl−/− Mice.

Thrombopoietin (TPO) is the pivotal regulator of megakaryocytopoiesis but also an important factor for early multipotent hematopoietic progenitors. Loss-of-function mutations in the human MPL gene coding for the TPO receptor are the cause of congenital amegakaryocytic thrombocytopenia (CAMT), a rare inherited bone marrow failure syndrome presenting as isolated thrombocytopenia at birth and progressing to aplastic pancytopenia during the first years of life. In contrast, Mpl−/− mice although exhibiting thrombocytopenia and severely reduced numbers of early hematopoietic progenitors do not develop any signs of pancytopenia or generalized bone marrow failure during lifetime. To identify parallels and differences in the impact of TPO on hematopoietic development between mice and men we serially analyzed subpopulations of hematopoietic cells from early progenitors to mature peripheral blood cells from Mpl−/− mice (kindly provided by Warren Alexander, WEHI, Melbourne, Australia) over a period of 24 months. We determined frequency, clonogenicity and proliferative potential of hematopoietic progenitors from different hematopoietic tissues. Compared to wild type mice we found a strong reduction of multipotent stem cells (HSC), of common myeloid progenitors (CMP), of megakaryocyte/erythrocyte lineage restricted progenitors (MEP) but also of common lymphoid progenitors (CLP) in Mpl−/− mice. We did not find any significant changes in the frequency of these cells over a period of 24 months. For the CMP and MEP subpopulations of myeloid progenitors we found not only a decreased frequency but also a reduced clonogenicity and proliferative capacity. Interestingly, these functional restrictions significantly increased significantly during aging, a finding that was similar to our results obtained with myeloid progenitors from CAMT patients. Impaired proliferation of myeloid progenitors rather than a reduced number could be the reason for development of pancytopenia in CAMT patients.

A retrospective study of aplastic pancytopenia in the dog: 9 cases (1996–2003)

Aplastic pancytopenia is defined by the presence of pancytopenia in blood and a hypocellular bone marrow with the hematopoietic space replaced by adipose tissue. Several causes of acquired aplastic pancytopenia are known; however, in some cases, an underlying cause is never determined. The objective of this retrospective study was to identify the incidence, potential causes, and outcome of aplastic pancytopenia in dogs. Bone marrow cytologic and core biopsy reports were reviewed to identify dogs diagnosed with aplastic pancytopenia between July 1, 1996 and June 30, 2003. Four-hundred eighty-six bone marrow reports that included aspirate and core biopsy evaluations were reviewed. Signalment, treatment given, previous and current disease conditions, clinical signs of disease, clinical laboratory data, therapy, response to therapy, and survival time were recorded. Nine dogs (1.85% of bone marrow samples reviewed) met the criteria for inclusion. Two dogs (22%) had associated diseases that included monocytic ehrlichiosis and Sertoli cell tumor. In 7 dogs (78%), the cause of aplastic pancytopenia could not be definitively determined, although an idiosyncratic drug reaction to griseofulvin was suspected in 1 of the dogs. The median age of dogs diagnosed with aplastic pancytopenia was 3.2 years, and apparent breed or sex predilection was not identified. Median HCT, total WBC count, and platelet count on the day of presentation were 21.8%, 1.0 x 10(3)/microL, and 2.0 x 10(3)/microL, respectively. Six of 9 dogs diagnosed with aplastic pancytopenia died or were euthanized within 21 days. Two dogs had complete hematologic recovery. One dog was living 3 years after diagnosis, but hematologic recovery was never documented. Aplastic pancytopenia is diagnosed infrequently and idiopathic aplastic pancytopenia may account for up to 67% or more of canine cases. Although the prognosis is guarded, some dogs with aplastic pancytopenia recover.

Anomalous plasma concentrations and impaired secretion of growth factors in Fanconi's anemia.

In Fanconi's anemia, which is known to be an autosomal recessive Mendelian trait with four complementary groups. In addition to stunning phenotypic variation at clinical and cellular levels, aplastic pancytopenia is a common feature. Since either an early block of differentiation in stem cells or their insufficient support by stromal functions could be an underlying factor, levels of stem cell factor (SCF) and cytokines have been measured in blood and in supernatants of monocytes after stimulation with granulocyte-macrophage colony stimulating factor (GM-CSF). In two of three FA patients, no GM-CSF was detectable, and simultaneously SCF was decreased to 8% and 15% of normal values. The combination of low SCF and GM-CSF may be implied in the pathogenesis of marrow aplasia, since comparison with W/Sl mice shows that impairment of the SCF/c-kit function alone has different effects. Also, this explains that treatment with GM-CSF in a recent study enhanced only leukogenesis and not all three lineages. In the third patient, both factors were normal, and here a different mechanism may act. In all three FA patients, interleukin 6 (IL-6) production in stimulated monocytes was decreased, which may hamper immune defense of infections in a nonspecific way.

Recovery from chronic idiopathic bone marrow aplasia of a young mother after intravenous injection of unprocessed cells from the liver (and yolk sac) of her 22 mm CR-length embryo. A preliminary report.

Although direct evidence for any take of injected cells is lacking, a gradually developing full clinical and subtotal haematological recovery occurred after the interruption of pregnancy in a 29‐year‐old patient suffering from chronic idiopathic aplastic pancytopenia for more than 15 months. She was treated with i.v. injection of 2.5 × 105 ‘yolk sac’ and 4.2 × 107 ‘liver’ cells from her own 22 mm crown‐rump length female embryo. Before this interruption her disease was transfusion‐dependent and did not improve during additional conventional therapy. Neither transfusion nor any other treatment was necessary during her recovery. She became free of complaints and now sustains remission, 19 months after our intervention.

A case of aplastic anemia and pancytopenia with tegretol therapy.

A CASE OF APLASTIC ANEMIA AND PANCYTOPENIA WITH TEGRETOL THERAPY WILLIAM R. FELLOW M.D.C.M., WILLIAM R. FELLOW M.D.C.M. Dearborn, MichSearch for more papers by this author WILLIAM R. FELLOW M.D.C.M., WILLIAM R. FELLOW M.D.C.M. Dearborn, MichSearch for more papers by this author First published: April 1969 https://doi.org/10.1111/j.1526-4610.1969.hed0901092.xCitations: 13AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume9, Issue1April 1969Pages 92-93 RelatedInformation

Agranulocytosis occurring during phethenylate ("thiantoin") sodium therapy.

Putnam and Merritt's method of testing the anticonvulsant activity of drugs in animals opened an era of intensive search for more effective drugs with which to control epilepsy. 1 Innumerable chemical substances were tested, and, beginning with diphenylhydantoin sodium, several were subsequently introduced into clinical practice. Whereas some of the new anticonvulsant drugs are now considered valuable additions to the therapeutic armamentarium for epilepsy, their toxic side-effects create a certain amount of hazard in the treatment of this disease. There have been reports of the occurrence of bone marrow depression, exfoliative dermatitis, nephrosis, and hepatitis, with recoveries and fatalities. Apparently depression of the blood elements is the commonest among these serious complications. In 1950, Abbott and Schwab noted that there had been 25 fatal reactions in the previous four years, which occurred during trimethadione, methylphenylethyl hydantoin, or phenacemide administration; 15 of the patients died with aplastic anemia or pancytopenia (6