Summary
The transcription factor GATA-1, together with its cofactor FOG-1, regulates erythropoiesis and megakaryocytopoiesis. Mutations in the DNA or FOG-1 binding sites of its N-terminal zinc finger ...result in different illnesses. Alterations of the FOG-1 face are responsible for dyserythropoietic anemia with thrombocytopenia while R216Q, the only mutation identified in the DNA face, induces X-linked thrombocytopenia with thalassemia (XLTT). The former disorder has been studied in detail whereas little is known about the latter since only one family has been investigated. We studied a second family with an R216Q, showing that XLTT and dyserythropoietic anemia with thrombocytopenia, even if different clinical entities, are closely related disorders. In both cases, patients present mild dyserythropoiesis, red cell hemolysis, severely defective maturation of megakaryocytes, macrothrombocytopenia with α-granule deficiency, and abnormalities of the cytoplasmic membrane system. However, a thalassemia minor phenotype has only been described in patients with XLTT whereas severe anemia and thrombocytopenia with evident defects of platelet composition and function may be observed only in dyserythropoietic anemia with thrombocytopenia.
A few studies in patients with reactive thrombocytosis identified levels of the hormone higher than expected, and suggested that TPO behaves as an acute-phase protein and was responsible for ...increased platelet count. At the opposite, other studies did not find any significant rise of the hormone in patients who similarly developed reactive thrombocytosis. To gain further information on this topic, we compared TPO levels and platelet counts in two series of patients hospitalized for acute illnesses: one with strong elevation of both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and the other with normal values. Within the group of subjects with high ESR and CRP, 38 had normal platelet counts, while 15 had thrombocytosis. No thrombocytosis was observed in control patients. Patients with high acute phase indexes had significantly higher TPO levels and platelet counts than control patients. We identified significant positive correlations between ESR and CRP, and between TPO and CRP. Interestingly, no significant relationship between platelet counts and TPO levels was find. When we grouped patients with acute-phase reaction according to absence or presence of thrombocytosis, we found similar TPO values. Conversely, positive correlations between platelet count and IL-6 and between TPO and IL-6 have been identified. All together our results confirm that TPO acts as an acute phase protein but exclude the possibility that it is uniquely responsible for thrombocytosis of inflammatory disorders, which might recognize in IL-6 a credible candidate as a cooperating factor.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
We have recently studieda case series of 46 unrelated patients with inherited thrombocytopenias and identified 18 cases that did not fit any known platelet disorder. In two unrelated ...families, a mild thrombocytopenia with normal platelet size was transmitted in an autosomal dominant fashion. Bleeding time was prolonged in 5 investigated patients. In all of them, flow cytometry and SDS-PAGE of platelet glycoproteins (GP) showed a reduced content of GPIa, a subunit of the GPIa-IIa complex (also known as integrin α2β1) that is a major collagen receptor on platelets.All other membrane GPs were within the normal range. GPIa deficiency was associated with severely reduced
in vitro
platelet adhesion to molecules known to interact selectively with GPIa.
In vitro
platelet aggregation was normal in all subjects, except for a suboptimal platelet response to fibrillar collagen in two patients.A mild defect of α-granules was observed in all affected subjects. No mutation was identified in the genes encoding for GPIa or GPIIa. Since no other similar cases have been reported in the literature, we suggest that an autosomal dominant thrombocytopenia associated with GPIa deficiency and α-granule defect represents a new form of inherited thrombocytopenia.
Department of Internal Medicine, IRCCS Policlinico San Matteo-University of Pavia, Italy.
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.
TPO, the primary regulator of megakaryopoiesis, is produced at a constant rate and is removed from the circulation by adsorption to specific receptors on platelet and megakaryocyte surfaces. An ...inverse relationship between platelet count and TPO therefore exists in healthy subjects. However, a few studies in patients with reactive thrombocytosis identified levels of the hormone higher than expected, and suggested that TPO behaves as an acute-phase protein and was responsible for increased platelet count. At the opposite, other studies did not find any significant rise of the hormone in patients who similarly developed reactive thrombocytosis.
To gain further information on this topic, we compared TPO levels and platelet counts in two series of hospitalized patients: one (53 patients aged 73 ± 17 years) with strong elevation of both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and the other (28 age-matched control patients) with normal values. All subjects had been admitted to hospital for acute illnesses: infections, cancer, heart failure or ischemia, stroke, deep vein thrombosis or pancreatitis. Within the group of subjects with high ESR and CRP, 38 had normal platelet counts, while 15 had thrombocytosis at the admittance (n=9) or developed it during their stay (n=6). No thrombocytosis was observed in control patients. Patients with high acute phase indexes had significantly higher TPO levels (R&D Systems, Minneapolis, USA) and platelet counts than control patients (TPO 189.55pg/ml ± 139 vs 62.04pg/ml ± 83, p<0.0001; platelets 310×109/L ± 98 vs 242×109/L ± 67, p=0.0016). Since similar TPO and platelet values were found in patients grouped according to their disorders, we assumed that the acute phase, but not the basic illness, was responsible for the increase of TPO and platelets. We identified strong, positive correlations between ESRc (ESR corrected for Hct) and CRP (r=0.809, p<0.0001), but only weak correlations between TPO and CRP (r=0.584, p<0.0001). Interestingly, no significant relationship between platelet counts and TPO levels (r=0.180, p=NS) was find. When we grouped patients with acute-phase reaction according to absence (platelets 280×109/L ± 61) or presence (platelets 516×109/L ± 105) of thrombocytosis, we found similar TPO values (184pg/ml ± 146 vs 203.4pg/ml ± 126, p=NS). By measuring plasma glycocalicin (GC, Takara Bio Inc. Shiga, Japan) and estimating the glycocalicin index (GCI, by normalizing GC levels for the individual platelet count), which reflects platelet turnover, we excluded that shortened platelet survival masked increased platelet production in subjects with inflammatory conditions and normal platelet count. In fact, identical values of GCI were found in patients with normal platelet count or thrombocytosis (2.434 ± 1.4 vs 2.496 ± 2.5). Finally, no correlation was detected between TPO and GCI (r=0.003, p=NS). Conversely, a strong positive correlation between IL-6 (R&D Systems) and CRP (r=0.692, p<0.0001), and a trend towards correlation between platelet count and IL-6 (r=0.493, p<0.0001) and between TPO and IL-6 (r=0.484, p<0.0001) have been identified. All together our results confirm that TPO acts as an acute phase protein but exclude the possibility that it is uniquely responsible for thrombocytosis of inflammatory disorders, which might recognize in IL-6 a credible candidate as a cooperating factor.
Department of Internal Medicine, IRCCS S. Matteo Universit di Pavia, Italy.
BACKGROUND AND OBJECTIVES: May-Hegglin anomaly (MHA) and Sebastian syndrome (SBS) are inherited macrothrombocytopenias with ...D hle-like bodies in leukocytes. MHA-SBS are due to mutations of the gene (MYH9) for the heavy chain of non-muscle myosin IIA (NMMHC-IIA), the only myosin II expressed in platelets. The bleeding tendency is often more severe than expected on the basis of platelet count, but no abnormality of platelet function has been identified. To characterize platelet abnormalities deriving from MYH9 mutations better, we studied surface glycoproteins (GPs) in platelets from MHA-SBS patients. DESIGN AND METHODS: Eight patients from 4 unrelated families were studied. Platelet surface GPs were studied by flow cytometry in both the whole platelet population and subpopulations of platelets identified according to their size. RESULTS: Flow cytometry identified a defect of the GPIb/IX/V complex in the whole platelet population in 7 of 8 patients. Moreover, in all patients the subpopulation of large platelets had defective expression of this complex. INTERPRETATION AND CONCLUSIONS: These findings indicate that MYH9 mutations may be responsible for reduced surface expression of GPIb/IX/V. This defect could contribute to the bleeding tendency of these patients. The identification of a GPIb/IX/V defect in MHA-SBS platelets raises the question of the differential diagnosis from heterozygous Bernard-Soulier syndrome.
The sudden increase in the number of critically ill patients following a disaster can be overwhelming.
The main objective of this study was to assess the real number of available and readily freeable ...beds ("bed surge capacity") and the availability of emergency operating rooms (OR) in a maximum emergency using a theoretical simulation.
The proportion of dismissible patients in four areas (Medical Area, Surgical Area, Sub-intensive Care Units, Intensive Care Units) and three emergency OR was assessed at 2 and 24 hours after a simulated maximum emergency. Four scenarios were modeled. Hospitalization and surgical capacities were assessed on weekdays and holidays. The creation of new beds was presumed by the possibility of moving patients to a lower level of care than that provided at the time of detection, of dislocation of patients to a discharge room, with care transferred to lower-intensity hospitals, rehabilitation, or discharge facilities. The Phase 1 table-top simulations were conducted during the weekday morning hours. In particular, the 24-hour table-top simulations of a hypothetical event lasted about 150 minutes compared to those conducted at 2 hours, which were found to be longer (about 195 minutes). Phase 2 was conducted on two public holidays and a quick response time was observed within the first 40 minutes of the start of the test (about 45% of departments).
The availability of simulated beds was greater than that indicated in the maximum emergency plans (which was based solely on the census of beds). Patients admitted to Intensive Care and The Sub-Intensive Area may be more difficult to move than those in low-intensity care. The availability of emergency OR was not problematic. Age influenced the possibility of remitting/transferring patients.
Simulation in advance of a maximum emergency is helpful in designing an efficient response plan.
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