Francesco Frattini

Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels

BACKGROUND Anaphylaxis after Hymenoptera stings has been reported in subjects with mastocytosis, but few data exist regarding disease prevalence in populations allergic to these insects. OBJECTIVE The incidence of clonal mast cell (MC) disorders in subjects with both systemic reactions to Hymenoptera stings and increased serum baseline tryptase (sBT) levels was assessed by using bone marrow (BM) aspirates and biopsy specimens. METHODS Subjects with a history of a systemic reaction caused by a Hymenoptera sting underwent the standard diagnostic work-up for Hymenoptera allergy, and sBT levels were measured. Subjects with an increased sBT level had BM evaluation that included histology/cytology, flow cytometry, and detection of KIT mutations. RESULTS Forty-four (11.6%) of 379 subjects with systemic reactions had increased sBT levels (>11.4 ng/mL), and 31 (70.5%) of these had a history of anaphylaxis. Thirty-four subjects with increased sBT levels underwent a BM analysis. Histology detected diagnostic or subdiagnostic MC infiltrates in 22 (65%) of 34 patients. Abnormal MCs were identified by means of flow cytometry and cytology in 26 (78.8%) of 33 and 20 (58.8%) of 34 subjects, respectively. A KIT mutation was detected in 17 (54.8%) of 31 subjects. The diagnosis was indolent systemic mastocytosis in 21 (61.7%) of 34 subjects and monoclonal MC activation syndrome in 9 (26.5%) of 34 subjects. All subjects with anaphylaxis had one of those 2 disorders. CONCLUSION The concomitant presence of systemic reactions (especially anaphylaxis) after Hymenoptera stings and increased sBT levels strongly suggests that a BM examination is indicated for the diagnosis of clonal MC disease.

Non-O blood type is the commonest genetic risk factor for VTE: results from a meta-analysis of the literature.

It is well known that the ABO blood group exerts a major influence on hemostasis, as O blood group individuals have lower von Willebrand factor and factor VIII levels than non-O blood group subjects. To evaluate the possible clinical implication of the different ABO blood groups on the risk of developing venous thromboembolism (VTE), we conducted a meta-analysis of the existing literature. After an electronic search strategy using Medline and Embase and a manual review of abstract books of the International Society on Thrombosis and Haemostasis and of reference lists of all retrieved articles, we included in the systematic review 38 studies with 10,305 VTE cases. The prevalence of non-O blood group was significantly higher in VTE patients compared with controls with a resulting pooled odds ratio (OR) of 2.09 (95% confidence interval [CI], 1.83, 2.38; p < 0.00001). Similar findings were obtained when the genotypes A1O/BO/A2B (OR 1.73, 95% CI, 1.47, 2.05; p < 0.00001) and A1B/A1A1/BB (OR 1.87, 95% CI, 1.84, 2.44; p < 0.00001) were analyzed. The maximum VTE risk was observed in non-O-factor V Leiden patients (OR 7.60, 95% CI, 3.21, 17.99), while for G20210A prothrombin mutation it was not possible to perform a pooled analysis due to a paucity of published studies. Finally, the association between non-O blood group and VTE was weaker when provoked VTE cases were considered (OR 1.33, 95% CI, 1.18, 1.50), while it was substantially unchanged when unprovoked VTE cases were analyzed (OR 1.88, 95% CI, 1.42, 2.50). In conclusion, considering its prevalence, non-O blood group is a candidate to be one of the most important genetic risk factors for venous thrombosis.

von Willebrand factor and cancer: A renewed interest

Von Willebrand factor (VWF), the largest human plasma protein, is an adhesive multimeric glycoprotein that mediates platelet adhesion to both the subendothelial matrix and endothelial surfaces and acts as a carrier for coagulation factor VIII in the circulation. Besides its essential role in hemostasis, there is growing evidence from the literature that VWF has an additional antitumor effect, mainly by exerting negative modulation on angiogenesis and apoptosis. Current knowledge on the link between VWF and cancer is summarized in this review, based on an analysis of the most important experimental and clinical studies.

Relationship between ABO blood group and hemorrhage: a systematic literature review and meta-analysis.

Several studies have suggested that patients with non-O blood group have an increased risk of both venous and arterial thromboembolic events. On the contrary, the role of ABO blood group on the risk of bleeding complications remains unclear. Thus, we performed a meta-analysis of the literature with the aim of assessing this potential association. MEDLINE and Embase databases were searched from 1946 to March 2012. Studies comparing the prevalence of different ABO blood groups in bleeding patients as well as in controls without bleeding complications were potentially includible. Two reviewers independently selected studies and extracted study characteristics, quality, and outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial and pooled using a random-effects model. Twenty-two studies totalling 9,468 bleeding patients and more than 450,000 controls were included. The prevalence of O blood group was significantly higher in bleeding patients than in controls, with a resulting pooled OR of 1.33 (95% CI = 1.25 to 1.42; p < 0.001). The result of this meta-analysis of a very large sample of bleeding patients and controls suggests that O blood group is a potentially important genetic risk factor for bleeding. High-quality prospective studies are warranted to confirm these preliminary findings.

Acquired FXIII inhibitors: a systematic review.

Coagulation factor XIII (FXIII) is a protein that promotes fibrin stabilization by forming multiple covalent cross-links between fibrin monomers. Beside congenital FXIII deficiency, due to FXIII gene mutations, severe acquired FXIII deficiency has been described in association with autoantibodies against coagulation FXIII. These inhibitors, which occurs very rarely but may cause life-threatening bleeding complications, may arise spontaneously or in association with autoimmune and lymphoproliferative disorders or medications. The management of patients with acquired FXIII inhibitors is very demanding and treatment regimens must be focused on eradication of the inhibitor and to increase the plasma FXIII levels. In this systematic review, we analyse all the published case-reports on anti-FXIII autoantibodies focusing on the clinical features and treatment modalities of this acquired hemorrhagic condition.

Novel treatments for epistaxis in hereditary hemorrhagic telangiectasia: a systematic review of the clinical experience with thalidomide

Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant bleeding disorder that affects one in 5,000–8,000 individuals [1, 2]. It is characterized by mucocutaneous telangiectasia and arteriovenous malformations in the pulmonary, cerebral and hepatic circulations [3]. The disorder is primarily caused by mutations in genes involved in vascular development and repair, e.g. the endoglin gene (ENG) located on chromosome 9 and the gene encoding activin receptor-like kinase-1 (ALK-1) located on chromosome 12 [4]. Recurrent and severe epistaxis is the most common presentation of HHT, frequently leading to severe anemia requiring blood transfusions [3]. Several approaches have been tried for the management of nosebleeds in HHT, including compression techniques, bilateral embolization, surgical arterial ligature and other techniques such as laser therapy, sclerosing agents, electrocautery and septodermoplasty [5]. Adjuvant medical treatments include estrogens, progestogens and antifibrinolytic agents such as tranexamic acid [6, 7]. However, most of these therapeutic measures are only palliative and largely unsatisfactory, creating therapeutic challenges and worsening the quality of life of HHT patients, especially those with severe bleeding who experience important impediments to daily activities. Recently, angiogenesis has been implicated in the pathogenesis of HHT [3]. Circulating concentrations of both transforming growth factor-b and vascular endothelial growth factor are significantly increased and anti-angiogenic drugs such as bevacizumab and thalidomide have, therefore, been tried in the treatment of vascular malformations in this disease [8–12]. The clinical experience on the role of thalidomide, a potent immunosuppressive and anti-angiogenic agent, for the pharmacological management of HHTassociated epistaxis is systematically reviewed in this paper. We performed an extensive literature search through MEDLINE, EMBASE, OVID, and SCOPUS using ‘‘Hereditary hemorrhagic telangiectasia’’, ‘‘HHT’’, ‘‘Osler-WeberRendu syndrome’’, ‘‘vascular malformation’’, ‘‘epistaxis’’, ‘‘nosebleeds’’, ‘‘thalidomide’’ and ‘‘antiangiogenic agents’’ as search terms. Further references not initially identified in the search but referenced within these articles were also reviewed. Unpublished works were identified by searching the abstract books of the most important conferences on hematological diseases. Overall, 29 cases from seven studies on the use of thalidomide for epistaxis in HHT patients refractory to standard medical and local surgical treatments were collected [13–19] (Table 1). After the first report by Kurtin [13] of improvement of nosebleed in a patient with epithelioid leiomyosarcoma and concomitant HHT, a few investigators have assessed the potential role of this anti-angiogenic drug in this clinical setting. The largest case series available in the literature is that including the results of an interim analysis of an ongoing prospective trial conducted by Balduini and colleagues and recently published in an abstract format [19]. Thalidomide was administered to eight patients at a starting dose of 50 mg/day and increased by 50 mg/day every 4 weeks until response to a maximum of 200 mg/day. A complete or partial response, defined as cessation or reduction in the severity of epistaxis, was observed in all patients but one, with significant decreases of transfusion requirements and improvement of quality of life. Six of the seven patients who had a clinical response to this drug responded within 1 month of starting treatment. Interestingly, an experimental study conducted by Lebrin and colleagues [17] showed that thalidomide M. Franchini (&) F. Frattini S. Crestani C. Bonfanti Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantua, Italy e-mail: massimo.franchini@aopoma.it

Haemophilia B: current pharmacotherapy and future directions

Introduction: Hemophilia B is a rare hereditary hemorrhagic disorder characterized by deficiency of the clotting factor IX (FIX). Hemophilia B patients experience mild to severe bleeding complications according to the degree of FIX defect. Nowadays, the most challenging complication of individuals with hemophilia B is the development of alloantibodies, which render the standard replacement therapy with FIX concentrates ineffective, exposing them to a significantly increased morbidity and mortality. Areas covered: This review summarizes the most important events leading to the development of the current FIX products available for the treatment of hemophilia B patients. In addition, it focuses on the more recent advances in the production of new FIX molecules aimed at improving the clinical management of such patients. Expert opinion: Although the availability of plasma-derived FIX concentrates has greatly improved the clinical management of hemophilia B patients, the introduction of FIX products using recombinant DNA technology has represented the most significant therapeutic progress in hemophilia B therapy, ensuring an advanced level of safety. The development of rFIX products with extended half lives will further improve the therapeutic armamentarium for hemophilia B patients.

Treatment of hemophilia B: focus on recombinant factor IX

Hemophilia B is a recessive X-linked bleeding disorder characterized by deficiency of the coagulation factor IX (FIX). In hemophilia B patients the severity of the bleeding phenotype is related to the degree of the FIX defect. Hemophilia B treatment has improved greatly in the last 20 years with the introduction first of plasma-derived and then of recombinant FIX concentrates. Replacement therapy may be administered through on-demand or prophylaxis regimens, but the latter treatment modality has been shown to be superior in prevention of hemophilic arthropathy and in improvement of patients’ quality of life. The purpose of this narrative review is to summarize the current knowledge on treatment strategies for hemophilia B, focusing on recombinant FIX products either clinically used or in development. There is only one rFIX product that is licensed to treat hemophilia B patients; from the analysis of the literature data presented in this review, the authors conclude that this rFIX product has demonstrated an excellent safety profile and excellent clinical efficacy for halting and preventing bleeds in hemophilia B patients. While prophylaxis has emerged as the best therapeutic strategy for such patients because of its ability to prevent hemophilic arthropathy and to improve patients’ quality of life, the pharmacokinetically tailored dosing of rFIX is another key point when planning hemophilia B treatment, as it allows optimization of the factor concentrate usage. Further clinical studies are needed to better assess the safety and efficacy (ie, the incidence of adverse reactions and inhibitor development) of newer rFIX products.

Bleeding complications in patients with hematologic malignancies.

Abnormalities of hemostasis are frequently encountered in patients with hematologic malignancies leading to both hemorrhagic and thrombotic adverse events. The prompt recognition and management of such complications, which have a negative impact on the morbidity and mortality of these patients, represents a major challenge for hematologists. This review describes the most important changes of hemostasis associated with hemorrhage in hematologic malignancies with particular emphasis on their contributory etiologic factors, complex pathogenic mechanisms, clinical manifestations, and therapeutic strategies. In particular, platelet and acquired coagulation abnormalities, bleeding complications in acute leukemia, and hematopoietic stem cell transplantation are discussed.

ABO blood group and risk of coronary artery disease

Given the influence of ABO blood group on hemostasis, particularly on von Willebrand factor and coagulation factor VIII plasma levels, a number of investigators have tried to analyze the possible clinical implications of this association [1]. However, while there are convincing data on the role of non-O blood group as a contributory risk factor for developing venous thromboembolism [2], data in the literature on an association between ABO blood group and arterial vascular disease are quite inconclusive, as outlined in a meta-analysis by Wu et al. [3]. In this regard, He et al. [4] recently conducted a metaanalysis of data from the Health Professionals Follow-up Study (HPFS), Nurses’ Health Study (NHS) and five other prospective cohort studies in which several thousands of participants were enrolled and concluded that individuals with non-O blood group had an 11 % increased risk of developing coronary heart disease (CHD) as compared with O blood group individuals. We would like to share with the readers of the Journal our experience in this clinical setting. Between January 2004 and September 2012, 1,879 consecutive cases of CHD were admitted to the Emergency Department of our city Hospital. The blood group distribution in these cases was compared to that in the healthy general population (4,272 consecutive blood donors from Mantova) (Table 1). The data were collected retrospectively in a case–control setting. A statistically significant difference of prevalence of O group was detected (40.9 % in CHD patients vs. 44.5 % in controls; P = 0.010 Pearson’s v test). Moreover, although the two populations differed considerable with regards to gender (females: 34.9 % in the CHD group vs. 46.7 % in the control group, P = 0.0001 Pearson’s v test) and age distribution (mean age: 77 years in the CHD group vs. 34 years in the control group, P = 0.0001 Pearson’s v test), O blood group maintained a significant protective effect (P = 0.022) in a logistic regression model including, besides blood group O/non-O, the abovementioned covariates, female gender and age, in order to adjust for possible confounding effects (Table 2). From this model, we can predict a protective effect from blood group O of 9 % in a male of 60 years and of 10 % in a female of the same age. Interestingly, the results of our study are almost identical to those of the meta-analysis by He et al. [4] and once again confirm that O blood group can be considered to protect against the risk of developing CHD. M. Franchini (&) C. Rossi F. Frattini S. Crestani C. Bonfanti Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantua, Italy e-mail: massimo.franchini@aopoma.it