Serum levels of thrombopoietin, IL-11, and IL-6 in pediatric thrombocytopenias

 We measured serum levels of thrombopoietin (TPO), interleukin (IL)-11, and IL-6 in 90 different samples from 67 pediatric patients with thrombocytopenia (TP). The cytokine levels were determined by enzyme-linked immunosorbent assays (ELISA), and the biological activity of TPO was measured using a cell line transfected with human c-mpl. In patients with impaired megakaryocytopoiesis, as found in diseases such as aplastic anemia, amegakaryocytic TP, or TP with absent radii, we found TPO levels which were highly elevated compared with normal values (mean=261 AU/ml, n=52, vs. 22 AU/ml in healthy controls). In contrast, patients suffering from idiopathic thrombocytopenic purpura (mean=16 AU/ml, n=31) or platelet function defects (mean=23 AU/ml, n=7) demonstrated normal TPO levels. The biological activity tested in the bioassay correlated well with the ELISA data. However, sera of some patients with amegakaryocytic TP demonstrated a remarkably higher biological activity of TPO than expected from the ELISA data. Within the different groups there was no correlation between platelet counts and TPO levels. Only 27% of all samples had elevated levels of IL-11 (mean=450 pg/ml, n=20). Elevated IL-6 serum levels were detected in only 13% of all samples analyzed (mean=42 pg/ml, n=12). We conclude that megakaryocytopoiesis is regulated mainly by TPO, that it is dependent on the platelet and the megakaryocytic mass, and that IL-11 plays an additional role in supporting the platelet production. IL-6 does not appear to be up-regulated in children with thrombocytopenia. Received: November 19, 1998 / Accepted: April 9, 1999     

Thrombopoietin in thrombocytopenias of childhood.

This review summarizes the biology of thrombopoietin (TPO) in childhood. Studies on TPO and its receptor (c-mpl) have improved the understanding of inherited and acquired thrombocytopenias in childhood. Data are presented in this review regarding the molecular biology of TPO, differences in cellular effects on megakaryopoiesis, the regulation of TPO production, and TPO concentrations in health and disease. For neonatal thrombocytopenia, the focus is on early-onset thrombocytopenia associated with maternal diabetes, pregnancy-induced hypertension, intrauterine growth retardation, hypoxia, and sepsis. Fetal alloimmune thrombocytopenia allows insight into the biology of TPO when fetal megakaryopoiesis is chronically stimulated. In the thrombocytopenia absent radii syndrome and congenital amegakaryocytic thrombocytopenia, thrombocytopenia is caused by a disorder in the signal transduction at the c-mpl level and respectively directly on c-mpl. TPO concentrations in other inherited thrombocytopenias such as Fanconi anemia, Shwachman syndrome, Wiskott-Aldrich syndrome, and Bernard-Soulier syndrome are discussed. For acquired thrombocytopenias, data on TPO in aplastic anemia, immune thrombocytopenia, human immunodeficiency virus infection, and liver disease are given. Possible indications for a treatment with recombinant TPO in childhood are discussed, but the criteria to identify patients who would benefit need detailed evaluation.     

Inherited thrombocytopenias: an approach to diagnosis and management

Inherited thrombocytopenias vary in their presentation, associated features, and molecular etiologies. An accurate diagnosis is important to provide appropriate therapy as well as counseling for the individual and their family members. As the genetic basis of more disorders is understood, it will be possible to diagnose a greater fraction of patients as well as learn more about the process of megakaryopoiesis and platelet production.     

Usefulness of a new indicator test for the diagnosis of peripheral and autonomic neuropathy in patients with diabetes mellitus.

AIMS: The aim of the present study was to assess the performance of a new indicator test (NIT), based on the measurement of sweat production after exposure to dermal foot perspiration, in the diagnosis of both peripheral sensorimotor polyneuropathy (PSN) and autonomic neuropathy in patients with diabetes. METHODS: One hundred and seventeen diabetic patients were examined. PSN was assessed using the neuropathy symptoms score, the neuropathy disability score and the vibration perception threshold. Cardiac autonomic neuropathy (CAN) was assessed using the battery of the four classical standardized tests proposed by Ewing et al., Diabetes Care 1985; 8: 491-498. Sudomotor dysfunction was assessed using the NIT. Results: Fifty patients (42.7%) had PSN and 44 patients (37.6%) had CAN. Of the 50 patients with PSN, 43 had a positive NIT (sensitivity 86%) and, out of the 67 patients without PSN, a negative NIT was obtained in 45 patients (specificity 67%). The positive and the negative predictive value of the NIT in detecting PSN were 66.2 and 86.5%, respectively. The sensitivity and specificity of NIT in detecting CAN was 59.1 and 46.5%, respectively. In the case of severe CAN, the sensitivity was increased to 80.9% and the specificity to 50%. CONCLUSIONS: The NIT has good sensitivity and negative predictive value for diagnosis of PSN and can be used as a screening method for detection of this complication in patients with diabetes. In addition, the test has a low sensitivity for detection of autonomic neuropathy in patients with milder forms of CAN.     

Usefulness of endoscopic ultrasonography in the preoperative diagnosis of submucosal digestive tumours.

INTRODUCTION: The preoperative diagnosis of submucosal lesions in the gut may be complicated. Conventional endoscopy does not allow to clearly establishing a diagnosis, and does not adequately assess lesion size. Furthermore, endoscopic biopsy is usually not diagnostic. Cytology as performed by means of fine-needle puncture does not have enough sensitivity and specificity to be considered the gold standard in the diagnosis of these lesions. We will now assess the usefulness of endoscopic ultrasonography in the study of submucosal digestive tumors. MATERIALS AND METHODS: We have prospectively collected ultrasonographic studies from all the patients with submucosal tumors who were treated surgically. We assessed the sensitivity and specificity of this technique in the diagnosis of malignancy in said lesions, alongside factors that predict malignant behavior with the highest reliability. We also valued the reliability of ultrasound endoscopy in the assessment of lesion size and the wall layer where lesions are located. The results of histological studies were considered the gold standard. RESULTS: The average size of lesions as measured by ultrasound endoscopy was 37.42 mm, with no significant differences in surgical piece: 38.98 (p = 0.143). However, conventional endoscopy underestimates the size of lesions. Endoscopic ultrasonography was able to adequately establish the origin layer of lesions in all cases. Sensitivity, specificity, positive predictive value, and negative predictive value of ultrasound endoscopy in the diagnosis of malignancy were 89.5, 90.9, 89.5, and 90.9%, respectively. In the univariate analysis, the ultrasonographic characteristics associated with a diagnosis of malignancy included presence of ulceration (p = 0.043), size above 4 cm (p = 0.049), irregular edges of lesion (p = 0.0001), a heterogeneous ultrasonographic pattern (p = 0.002), and the presence of cystic areas above 2 mm (p = 0.012). In the multivariate analysis, the last three factors were considered independent predictive factors for malignancy. CONCLUSIONS: Endoscopic ultrasonography has a great sensitivity and specificity in the diagnosis of malignancy regarding submucosal lesions. The irregularity of lesion borders, a heterogeneous ultrasonographic pattern, and the presence of cystic areas above 2 mm in size were considered independent predictive factors for malignancy.     

Usefulness of contrast-enhanced EUS in the diagnosis of upper GI tract diseases.

BACKGROUND: We evaluated the usefulness of contrast-enhanced endoscopic ultrasonography (EUS) in the diagnosis of upper gastrointestinal (GI) tract diseases. METHODS: The subjects were 42 patients with upper GI tract diseases: 4 esophageal carcinomas, 30 gastric carcinomas, 5 gastric myogenic tumors, and 3 gastric ulcers. After the lesion was observed by EUS, air-filled albumin (0.22 mL/kg) was intravenously injected at a rate of 1 mL/sec into the right cubital median vein, and observation was continued for 10 minutes. RESULTS: Enhancement of the third and fifth layers was observed in all normal esophageal and gastric walls. No esophageal carcinomas were enhanced. Enhancement was observed in 5 gastric carcinomas that had abundant, enlarged, and winding vascular beds. In all esophageal and the other 25 gastric carcinomas, although the tumors per se were not enhanced, enhancement of the third and fifth layers around the lesions clearly demarcated the tumor boundaries. As a result, accuracy for detection of the depth of gastric carcinoma improved from 76.7% for EUS to 90% for contrast-enhanced EUS. All gastric myogenic tumors were enhanced, and irregularly shaped sonolucent areas within these tumors became clear, but we could not distinguish between leiomyoma and leiomyosarcoma. CONCLUSIONS: Contrast-enhanced EUS is a noninvasive, useful diagnostic method for assessment of the depth of invasion of esophageal and gastric carcinomas.     

Usefulness of echocardiography in the diagnosis of infectious endocarditis

Thirty-four patients with clinical diagnosis of infective endocarditis were studied with M mode and/or two-dimensional echocardiography. of them. Twenty-two were men; their ages ranged from 9 to 67 years. In 23 cases surgical or post mortem confirmation of the echocardiographic diagnosis was obtained. The clinical features as well as history of previous cardiopathy (94.1%) and its type (congenital 38.2%, rheumatic 29.4%, rheumatic with valvular prosthesis 23.5%) were analyzed. In the 23 patients with proven endocarditis, the echocardiographic diagnosis was positive in 19 (82%); vegetations were evident in 13. In 6 patients vegetations were not found. There were 3 false positive cases and one false negative, giving a sensitivity of 0.81 and a specificity of 0.85. The causes of false negative and false positive findings were analyzed. These were closely related to the duration of the disease and time which elapsed between the echocardiographic study and confirmation in surgery or necropsy as well as the size of the vegetations. The echocardiographic diagnosis was difficult when a valvular prosthesis was present. Echocardiography is a useful technique for diagnosis and follow up of patients with infective endocarditis.     

Role of the kidneys in thrombopoietin production.

Extracts of plasma from normal rats, rats injected with rabbit anti-rat platelet serum (RARPS), nephrectomized rats and nephrectomized rats injected with RARPS were tested in thrombocytotic mice for the presence of thrombopoietin. Only fractions of plasma from unoperated rats that had been made thrombocytopenic by injection of RARPS gave positive results for thrombopoietin. The results suggest that the kidneys play a role in thrombopoietin production.     

Usefulness of ultrasonography for diagnosis of malignant lymphoma of the thyroid.

Background: Recent developments in ultrasonography (US) and the prevalence of ultrasound-guided fine needle aspiration biopsy (US-FNAB) has enabled physicians to detect and diagnosis thyroid diseases, including thyroid malignant lymphoma, much more easily. Methods: We describe our diagnostic strategy for malignant lymphoma on US screening. We screened possible malignant lymphoma patients by US characteristics such as enhanced posterior echoes. Results: Among 170 patients suspected of malignant lymphoma between 2000 and 2004, 74 (43.5%) were also diagnosed as having or suspected of lymphoma by US-FNAB. Five patients dropped out, and 67 of 69 patients who underwent surgical examination were pathologically diagnosed as having lymphoma. Finally, 79 (47.9%) of 165 US-suspected patients were confirmed as having lymphoma. Only 21.5% of lymphoma patients complained of rapidly growing goiter. Conclusion: US screening for goiters contributes markedly to diagnosis of lymphoma at an early phase, facilitating early initiation of therapy.     

Usefulness of laboratory investigations for the diagnosis of acrodermatitis chronica atrophicans.

The authors report a clinical case of acrodermatitis chronica atrophicans in a 65 year old diabetic woman. The characteristic cutaneous lesion restricted to the dorsal aspect of the left hand has been evolved since two years, together with a progressive development of a typical Dupuytren disease. This yielded a contracture of the last 3 phalanges of the same left hand. Confirmatory techniques included the histology of the skin, the reactivity of specific-IgG antibodies showing high avidity and Western blot. Of this, the immunodominant antigens which were extracted from 3 genospecies of Borrelia sensu lato i.e. Bb sensu stricto, Bb garinii, Bb afzelii were compatible with past infection. Apart from the diabetic status which may have predisposed the patient to the development of Dupuytren disease, the authors question about the potential role of Borrelia burgdorferi in the occurrence of this associated disease.     

Controversies in the treatment of pediatric immune thrombocytopenias

Although pediatric immune thrombocytopenia (ITP) is common, there is no consensus on the optimal approach to therapy. Childhood ITP differs in its clinical course and trigger from adult immune thrombocytopenic purpura. There appear to be two clinical phenotypes among children with ITP: children with polyclonal autoantibody production triggered by an external exposure such as infection, and children with coexistent immune deficiency or dysregulation on a congenital or acquired basis. Treatment implications exist for each group. The first may be best managed by observation and conservative measures; for the latter, treatment could include normal intravenous gammaglobulin concentrate, anti-blood group D antigen (anti-Rh factor), or steroids. Early recognition of the thrombocytopenic child with immune dysfunction versus the normal child with a polyclonal response to a particular environmental antigen will result in better prognosis for both by selecting the appropriate therapy and minimizing long-term side effects.     

Treatment of inherited thrombocytopenias

The new techniques of genetic analysis have made it possible to identify many new forms of inherited thrombocytopenias (IT) and study large series of patients. In recent years, this has changed the view of IT, highlighting the fact that, in contrast to previous belief, most patients have a modest bleeding diathesis. On the other hand, it has become evident that some of the mutations responsible for platelet deficiency predispose the patient to serious, potentially life-threatening diseases. Today''s vision of IT is, therefore, very different from that of the past and the therapeutic approach must take these changes into account while also making use of the new therapies that have become available in the meantime. This review, the first devoted entirely to IT therapy, discusses how to prevent bleeding in those patients who are exposed to this risk, how to treat it if it occurs, and how to manage the serious illnesses to which patients with IT may be predisposed.