Carlo Bonfanti

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.

Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism. A multicentre retrospective cohort study.

Bleeding is a common and feared complication of oral anticoagulant therapy. Several prediction models have been recently developed, but there is a lack of evidence in patients with venous thromboembolism (VTE). The aim of this study was to validate currently available bleeding risk scores during long-term oral anticoagulation for VTE. We retrospectively included adult patients on vitamin K antagonists for VTE secondary prevention, followed by five Italian Anticoagulation Clinics (Cuneo, Livorno, Mantova, Napoli, Varese), between January 2010 and August 2012. All bleeding events were classified as major bleeding (MB) or clinically-relevant-non-major-bleeding (CRNMB). A total of 681 patients were included (median age 63 years; 52.0% female). During a mean follow-up of 8.82 (± 3.59) months, 50 bleeding events occurred (13 MB and 37 CRNMB), for an overall bleeding incidence of 9.99/100 patient-years. The rate of bleeding was higher in the first three months of treatment (15.86/100 patient-years) than afterwards (7.13/100 patient-years). The HAS-BLED showed the best predictive value for bleeding complications during the first three months of treatment (area under the curve [AUC] 0.68, 95% confidence interval [CI] 0.59-0.78), while only the ACCP score showed a modest predictive value after the initial three months (AUC 0.61, 95%CI 0.51-0.72). These two scores had also the highest sensitivity and the highest negative predictive value. None of the scores predicted MB better than chance. Currently available bleeding risk scores had only a modest predictive value for patients with VTE. Future studies should aim at the creation of a new prediction rule, in order to better define the risk of bleeding of VTE patients.

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.

Cancer-associated thrombosis: investigating the role of new oral anticoagulants

Venous thromboembolism (VTE) is a common complication of cancer and has a significant impact on morbidity and mortality in patients with malignancies. Low molecular weight heparins (LMWHs) currently represent the drug of choice for both initial and long-term treatment of cancer-associated thrombosis. In recent years, however, a new class of novel oral anticoagulants (NOACs) inhibiting directly thrombin or activated factor X have been proposed as an alternative therapeutic option on the basis the results of subgroup analyses of phase III randomized controlled trials, including few cases of patients with cancer. After analysis of the available literature data, we conclude that although potentially interesting, future research specifically conducted in cancer patients is needed to clarify the role of these newer anticoagulant agents in prevention and treatment of cancer-related VTE.

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.

Association between particulate air pollution and venous thromboembolism: A systematic literature review

Air pollution is a leading global problem for public health. A number of ambient pollutants have been involved, including carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3) and particulate matter (PM). Although exposure to PM has been linked to a wide array of cardiovascular and respiratory disorders, its effect on venous thrombotic disorders is still uncertain. To elucidate this issue, we have performed a systematic review on the existing literature on the association between PM and venous thromboembolism (VTE), using MEDLINE, EMBASE and Cochrane electronic databases. Of the 158 reviewed studies, 11 of them (3 case-crossover studies, 2 time-series studies, 2 case-control studies, 2 prospective cohort studies, 2 retrospective studies) involving more than 500,000 events fulfilled the inclusion criteria and results are presented here. Because there was substantial heterogeneity in study design, duration of follow-up, statistical measure of effects, clinical outcomes and threshold, we refrained to perform a quantitative analysis of the available data and carried out only a systematic review. Overall, the literature data suggest a link between PM and VTE, but further trials on larger populations of patients with homogeneous study designs and outcomes are warranted.