Healthy subjects frequently report minor bleedings that are frequently ‘background noise’ of normality rather than a true disorder. Nevertheless, unexpected or unusual bleeding may be alarming. Thus, ...the distinction between normal and pathologic bleeding is critical. Understanding the underlying pathologic mechanism in patients with an excessive bleeding is essential for their counseling and treatment. Most of these patients with significant bleeding will result affected by non‐severe inherited bleeding disorders (BD), collectively denominated mild or moderate BD for their relatively benign course. Unfortunately, practical recommendations for the management of these disorders are still lacking due to the current state of fragmented knowledge of pathophysiology and lack of a systematic diagnostic approach. To address this gap, an International Working Group (IWG) was established by the European Hematology Association (EHA) to develop consensus‐based guidelines on these disorders. The IWG agreed that grouping these disorders by their clinical phenotype under the single category of mild‐to‐moderate bleeding disorders (MBD) reflects current clinical practice and will facilitate a systematic diagnostic approach. Based on standardized and harmonized definitions a conceptual unified framework is proposed to distinguish normal subjects from affected patients. The IWG proposes a provisional comprehensive patient‐centered initial diagnostic approach that will result in classification of MBD into distinct clinical‐pathological entities under the overarching principle of clinical utility for the individual patient. While we will present here a general overview of the global management of patients with MBD, this conceptual framework will be adopted and validated in the evidence‐based, disease‐specific guidelines under development by the IWG.
Bernard-Soulier syndrome is a severe bleeding disease due to a defect of GPIb/IX/V, a platelet complex that binds the von Willebrand factor. Due to the rarity of the disease, there are reports only ...on a few cases compromising any attempt to establish correlations between genotype and phenotype. In order to identify any associations, we describe the largest case series ever reported, which was evaluated systematically at the same center.
Thirteen patients with the disease and seven obligate carriers were enrolled. We collected clinical aspects and determined platelet features, including number and size, expression of membrane glycoproteins, and ristocetin induced platelet aggregation. Mutations were identified by direct sequencing of the GP1BA, GP1BB, and GP9 genes and their effect was shown by molecular modeling analyses.
Patients all had a moderate thrombocytopenia with giant platelets and a bleeding tendency whose severity varied among individuals. Consistent with expression levels of GPIbα always lower than 10% of control values, platelet aggregation was absent or severely reduced. Homozygous mutations were identified in the GP1BA, GP1BB and GP9 genes; six were novel alterations expected to destabilize the conformation of the respective protein. Except for obligate carriers of a GP9 mutation with a reduced GPIb/IX/V expression and defective aggregation, all the other carriers had no obvious anomalies.
Regardless of mutations identified, the patients' bleeding diathesis did not correlate with thrombocytopenia, which was always moderate, and platelet GPIbα expression, which was always severely impaired. Obligate carriers had features similar to controls though their GPIb/IX/V expression showed discrepancies. Aware of the limitations of our cohort, we cannot define any correlations. However, further investigations should be encouraged to better understand the causes of this rare and underestimated disease.
Bernard-Soulier syndrome is a very rare form of inherited thrombocytopenia that derives from mutations in GPIbα, GPIbβ, or GPIX and is typically inherited as a recessive disease. However, some years ...ago it was shown that the monoallelic c.515C>T transition in the GPIBA gene (Bolzano mutation) was responsible for macrothrombocytopenia in a few Italian patients.
Over the past 10 years, we have searched for the Bolzano mutation in all subjects referred to our institutions because of an autosomal, dominant form of thrombocytopenia of unknown origin.
We identified 42 new Italian families (103 cases) with a thrombocytopenia induced by monoallelic Bolzano mutation. Analyses of the geographic origin of affected pedigrees and haplotypes indicated that this mutation originated in southern Italy. Although the clinical expression was variable, patients with this mutation typically had a mild form of Bernard-Soulier syndrome with mild thrombocytopenia and bleeding tendency. The most indicative laboratory findings were enlarged platelets and reduced GPIb/IX/V platelet expression; in vitro platelet aggregation was normal in nearly all of the cases.
Our study indicates that monoallelic Bolzano mutation is the most frequent cause of inherited thrombocytopenia in Italy, affecting 20% of patients recruited at our institutions during the last 10 years. Because many people from southern Italy have emigrated during the last century, this mutation may have spread to other countries.
Major surgery is associated with an increased risk of venous thromboembolism (VTE), thus the application of mechanical or pharmacologic prophylaxis is recommended. The incidence of VTE in patients ...with inherited platelet disorders (IPD) undergoing surgical procedures is unknown and no information on the current use and safety of thromboprophylaxis, particularly of low-molecular-weight-heparin in these patients is available. Here we explored the approach to thromboprophylaxis and thrombotic outcomes in IPD patients undergoing surgery at VTE-risk participating in the multicenter SPATA study. We evaluated 210 surgical procedures carried out in 155 patients with well-defined forms of IPD (VTE-risk: 31% high, 28.6% intermediate, 25.2% low, 15.2% very low). The use of thromboprophylaxis was low (23.3% of procedures), with higher prevalence in orthopedic and gynecological surgeries, and was related to VTE-risk. The most frequently employed thromboprophylaxis was mechanical and appeared to be effective, as no patients developed thrombosis, including patients belonging to the highest VTE-risk classes. Low-molecular-weight-heparin use was low (10.5%) and it did not influence the incidence of post-surgical bleeding or of antihemorrhagic prohemostatic interventions use. Two thromboembolic events were registered, both occurring after high VTE-risk procedures in patients who did not receive thromboprophylaxis (4.7%). Our findings suggest that VTE incidence is low in patients with IPD undergoing surgery at VTE-risk and that it is predicted by the Caprini score. Mechanical thromboprophylaxis may be of benefit in patients with IPD undergoing invasive procedures at VTE-risk and low-molecular-weight-heparin should be considered for major surgery.
The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (α)-granules in platelets. The genetic defect responsible for gray ...platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and α-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the α-granule content by immunofluorescence analysis for α-granule secretory proteins. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet α-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the α-granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the α-granule deficiency than individuals with two NBEAL2 mutated alleles. Our data extend the spectrum of mutations responsible for gray platelet syndrome and demonstrate that macrothrombocytopenia with α-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the α-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype.
MYH9 -related disease ( MYH9 -RD) is an autosomal dominant thrombocytopenia with giant platelets variably associated with young-adult onset of progressive sensorineural hearing loss, presenile ...cataract, and renal damage. MYH9 -RD is caused by mutations of MYH9 , the gene encoding for non-muscle heavy-chain myosin-9. Wild-type and mutant myosin-9 aggregate as cytoplasmic inclusions in patients’ leukocytes, the identification of which by immunofluorescence has been proposed as a suitable tool for the diagnosis of MYH9 -RD. Since the predictive value of this assay, in terms of sensitivity and specificity, is unknown, we investigated 118 consecutive unrelated patients with a clinical presentation strongly consistent with MYH9 -RD. All patients prospectively underwent both the immunofluorescence assay for myosin-9 aggregate detection and molecular genetic analysis of the MYH9 gene. Myosin-9 aggregates were identified in 82 patients, 80 of which (98%) had also a MYH9 mutation. In the remaining 36 patients neither myosin-9 aggregates nor MYH9 mutations were found. Sensitivity and specificity of the immunofluorescence assay was evaluated to be 100% and 95%, respectively. Except for the presence of aggregates, we did not find any other significant difference between patients with or without aggregates, demonstrating that the myosin-9 inclusions in neutrophils are a pathognomonic sign of the disease. However, the identification of the specific MYH9 mutation is still of importance for prognostic aspects of MYH9 -RD.
Therapeutic plasma exchange (PE) is the accepted therapy for thrombotic thrombocytopenic purpura (TTP). Because not all patients achieve remission, other treatment modalities have been used in ...addition to PE, but no randomized clinical trial evaluated their efficacy. The aim of this multicentric study was to compare the effectiveness of standard- versus high-dose methylprednisolone as an adjunctive treatment to PE in the acute phase of TTP. Sixty patients with idiopathic TTP were randomized to receive methylprednisolone 1 mg/kg/die intravenous or 10 mg/kg/die for 3 days, thereafter, 2.5 mg/kg/die in addition to PE. Both dosages of steroids were well tolerated. At the end of induction therapy (day 23), the percentage of patients failing to achieve complete remission was significantly higher in the standard dose (16 of 30) than in the high-dose group (seven of 30). Also, the number of cases without a good response at day 9 and the number of deaths were higher in the standard-dose arm, but the differences did not reach the statistical significance. Results of present study indicate that the association of PE with high-dose instead of standard-dose steroids reduces the percentage of TTP patients that fail to achieve complete remission.
MYH9-related disease (MYH9-RD) is a rare autosomal dominant genetic syndrome characterized by congenital thrombocytopenia associated with the risk of developing progressive nephropathy, sensorineural ...deafness, and presenile cataract. During the collection of a large case-series of patients with MYH9-RD we noticed several cases with unexplained elevation of liver enzymes. Our aim was to evaluate if the alteration of liver tests is a feature of the MYH9-RD and to define its clinical significance.
Data concerning liver tests, prospectively recorded in the Italian Registry for MYH9-RD, were collected and compared with those of three control populations: patients with autoimmune thrombocytopenia, patients with inherited thrombocytopenias other than MYH9-RD, and the participants to a large epidemiologic survey in an Italian geographic isolate. Thirty-eight of 75 evaluable MYH9-RD patients (50.7%) showed an elevation of ALT and/or AST, and 17 of 63 (27.0%) an increase of GGT. The increases ranged from 1.9 ± 0.7 to 2.7 ± 1.6 fold the upper normal limit. The prevalence of liver test alterations was significantly higher in MYH9-RD patients than in each of the control populations, with odds ratios ranging from 8.2 (95% CIs 2.2-44.8) to 24.7 (14.8-40.8). Clinical follow-up and more detailed liver studies of a subset of patients, including ultrasound liver scan, liver elastography and liver biopsy in one case, did not show any significant structural damage or evolution towards liver insufficiency.
Elevation of liver enzymes is a frequent and previously unrecognized feature of the MYH9-RD syndrome; however, this defect does not appear to have poor prognostic value.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glanzmann’s thrombasthenia is a bleeding disorder caused by mutations of the ITGA2B or ITGB3 genes. This paper describes two Italian families with moderate thrombocytopenia with large platelets, ...defective platelet function and moderate/severe mucocutaneous bleeding, transmitted as an autosomal dominant trait and associated with a novel mutation in the ITGB3 gene, encoding the integrin β chain β3. This report adds to previous studies of mutant alleles which illustrate the importance of signaling via this integrin for platelet function as well as for platelet formation.
PDF
