Application of a diagnostic algorithm for inherited thrombocytopenias to 46 consecutive patients.
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BACKGROUND AND OBJECTIVES: The Italian Gruppo di Studio delle Piastrine recently developed a diagnostic algorithm to assist clinicians in the diagnosis of inherited thrombocytopenias. This algorithm is based on the simplest possible diagnostic investigations and can also be used in centers that are not highly specialized. The aim of the present study was to validate this diagnostic algorithm by applying it to a case series of genetic thrombocytopenias. DESIGN AND METHODS: The diagnostic algorithm was applied retrospectively to 46 consecutive patients observed during the last five years at a single institution. Twenty-eight were affected by defined illnesses or their variants, while 18 had a disorder that did not fit the criteria for any known genetic thrombocytopenia. The study was based on the evaluation of clinical records and laboratory tests. RESULTS: The diagnostic algorithm recognized: 4 homozygous and 4 heterozygous Bernard-Soulier syndromes, 11 MYH9-related diseases, one von WillebrandOs disease type 2B, one gray platelet syndrome and one X-linked thrombocytopenia with thalassemia. Moreover, it identified 4 patients with the clinical and laboratory features of heterozygous Bernard-Soulier syndrome not caused by mutations in the coding region of the GPIbalpha, GPIbbeta, GPIX or GPV genes, and two patients with the clinical phenotype of MYH9-related disease but without MYH9 mutations. Since the diagnostic flow chart did not allow prompt recognition of two subjects with MYH9-related disease, we introduced a small change to the previously proposed flow chart to obviate this defect. INTERPRETATION AND CONCLUSIONS: The diagnostic algorithm correctly diagnosed 26 of 28 patients with known disorders or phenotypic variants of known disorders. By a simple modification of the investigation sequence, its sensitivity reached 100%. The algorithm also identified 18 patients with new, as yet uncharacterized forms of genetic thrombocytopenia. (+info)
Heart and mind: (1) relationship between cardiovascular and psychiatric conditions.
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The relationship of our emotions and psyche to heart disease is intriguing. In this article we have reviewed the evidence linking cardiovascular and neuropsychiatric disorders and the possible mechanisms and pathophysiology of this association. This review is derived from Medline searches (1966-2002) using the relevant search terms (psychiatric disease, cardiovascular disease, depression, anxiety, and pathophysiology). Finally, the possible role of using mood enhancing therapies (mainly antidepressants) and their safety in patients with cardiovascular disorders is briefly discussed. In a companion paper, the therapeutic aspects of these two conditions is highlighted. (+info)
Low Mpl receptor expression in a pedigree with familial platelet disorder with predisposition to acute myelogenous leukemia and a novel AML1 mutation.
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Germ-line heterozygous mutations in the hematopoietic transcription factor AML1 (RUNX1) have been identified in patients with familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML), which is characterized by thrombocytopenia, abnormal platelet function, and propensity to myeloid malignancies. We identified a novel mutation in the AML1 gene in an FPD/AML pedigree characterized by a single nucleotide deletion that generates a frameshift and premature chain termination (Pro218fs-Ter225). Both wild-type and mutant transcripts were expressed in affected individuals by allele-specific reverse transcriptase-polymerase chain reaction (RT-PCR). Thrombopoietin (TPO) binds to the Mpl receptor and is the major regulator of megakaryopoiesis. To explore the mechanisms underlying thrombocytopenia, we studied the TPO/Mpl pathway in this newly identified pedigree. TPO levels were mildly to moderately elevated. On flow cytometry and immunoblotting, Mpl receptor expression was decreased and TPO-induced signaling was impaired. While no mutations were identified in the MPL gene by sequence analysis, low MPL mRNA levels were found, suggesting decreased gene expression. Of particular interest, several AML1-binding motifs are present in the MPL promoter, suggesting MPL is an AML1 target. In conclusion, we identified a C-terminal AML1 mutation that leads to a decrease in Mpl receptor expression, providing a potential explanation for thrombocytopenia in this FPD/AML pedigree. (+info)
Platelet aggregation testing in platelet-rich plasma: description of procedures with the aim to develop standards in the field.
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Platelet function testing consisting of platelet aggregation and secretion often is requested in the clinical evaluation of patients with bleeding problems. At present, there are no uniform clinical laboratory standards for the performance or interpretation of these studies. The present report describes one laboratory's methods and interpretations of platelet aggregation and secretion studies of platelet-rich plasma using each of the common platelet agonists. Diagnostic categories for the evaluation of the platelet function testing are presented. The diagnostic categories then are applied to the evaluation of 61 patients referred to our medical center for these studies. The aims of this report are to present clinical platelet aggregation and secretion studies and to provide a working schema to evaluate these results. Our intent is to stimulate interest in the development of professional guidelines for platelet function testing in the clinical laboratory. (+info)
Platelet dysfunction-eosinophilia syndrome in parasitized Venezuelan children.
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Platelet dysfunction was detected in six children with purpura and eosinophilia. We conducted clinical evaluations, hematologic and platelet function tests, clotting studies (bleeding time, prothrombin time, partial thromboplastin time, thrombin time, factor XIII, factor VIII, and von Willebrand factor), assays for IgG and IgM antibodies to platelets, and a search for stool parasites. Mild bleeding phenomena (ecchymoses, petechiae, epistaxis, and gingival) were transient. All children showed intestinal parasites and marked eosinophilia (mean count = 2,615.2 cells/muL, 95% confidence interval = 1,259.6-5,429.8). Main abnormalities included prolonged bleeding times (50%) and defective aggregation with collagen (100%) adrenaline (66%), or ADP (66%). Antibodies to platelets were not detected. Anti-parasite therapy reversed the hemorrhagic manifestations and normalized eosinophil counts and platelet alterations. No relationship could be established between excess eosinophils, intensity of bleeding, or type and degree of platelet abnormalities. Thrombocytopathic features mimicked the intrinsic defect of storage pool disease. The possible pathogenic roles of eosinophilia and parasitism are reviewed. This is the first report of this pathologic combination in Latin American children. (+info)
Inherited platelet disorders.
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The inherited platelet disorders are a heterogeneous collection of rare diseases that are infrequently encountered in clinical practice. They are, however, fascinating abnormalities, which have taught us a great deal about normal platelet biochemistry and physiology. In this section of the presentation we will review disorders of the platelet membrane, platelet granule packaging disorders, the hereditary macrothrombocytopenias, platelet signaling disorders and disorders of platelet coagulant function. The molecular basis of the disorders, the cardinal features of their clinical presentation and best methods to make their diagnosis and the latest information regarding therapy will be presented. (+info)
Acquired disorders of platelet function.
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A qualitative abnormality of platelet function should be considered in patients with mucocutaneous bleeding in the absence of thrombocytopenia or von Willebrand disease. Antiplatelet drugs are the most common cause of acquired platelet disorders leading to bleeding. Uremia, hepatic cirrhosis, myeloma and related disorders, polycythemia vera, essential thrombocythemia, and cardiopulmonary bypass have long been recognized as clinical situations in which platelet dysfunction may contribute to bleeding. When an acquired platelet disorder is suspected, it is useful to examine platelet function by measuring the bleeding time, examining platelet-dependent closure time in a platelet function analyzer and performing platelet aggregometry. When a specific acquired platelet disorder is diagnosed, many treatment options are available including controlling the underlying disease, giving platelet transfusions and administering a hemostatic drug. (+info)
Diagnosis and management of mild bleeding disorders.
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Mild bleeding disorders are a common reason for a referral to a hematologist and these conditions can be challenging to evaluate. Recent research has highlighted that some bleeding symptoms are quite common in the general population and that there is clinical variability in symptom expression among individuals with defined bleeding problems. Moreover, bleeding risks for many bleeding disorders are unknown. This article reviews symptoms and problems that can be considered suspicious of a mild form of bleeding disorder and the diagnostic investigations useful to evaluate these problems. A stepwise approach is presented for the diagnostic evaluation, to allow detection of common and rare coagulation and fibrinolytic defects, and adequate assessments of potential von Willebrand factor and platelet problems. Some common problems in the diagnosis and management of mild bleeding problems are reviewed, including the common failure to establish a diagnosis with testing. An approach is proposed for translation of knowledge to patients who are challenged by mild bleeding problems. (+info)