Di Minno Research Articles

Comparison among three different bleeding scores and the thrombin generation assay to assess the different hemorrhagic phenotypes in patients with FVII deficiency

Defining the bleeding risk in patients with FVII-deficiency is not easy. Aim of this study is to define correlation and differences between three different scores and the thrombin generation assay (TGA) in correctly evaluating the hemorrhagic phenotype in a group of FVII-deficient patients. Fifty-seven patients patients with FVII-deficiency whose hemorrhagic phenotype was assessed by Mariani, ISTH/SSC- Bleeding Assessment Tool (BAT) and Di Minno scores, and by the TGA, were enrolled in this study. TGA parameters (LagTime, Peak, ttPeak, ETP - endogenous thrombin potential) highlighted how both LagTime and ttPeak can discriminate major bleeders from the others, while the same conclusion could not be reached by the ETP and Peak. However, no TGA parameter was found to be useful in separating the mild hemorrhagic phenotype from the moderate one. Scores and TGA were found to be able to only define the severe hemorrhagic phenotypes. None of the methods was able to exactly discriminate the other phenotypes. Given these results, there is therefore a risk of either underestimating or overestimating the potential bleeding risk in patients with non-severe FVII-deficiency.

Vascular mechanisms and manifestations of COVID-19

Vascular mechanisms and manifestations of COVID-19

THE MORPHOLOGICAL EVALUATION OF THE EXPERIMENTAL MODEL OF SYSTEMIC GENERALIZED THROMBOSIS

The only regulated model of disseminated intravascular coagulation syndrome or disseminated intravascular coagulation syndrome is the Di Minno model of generalized thrombosis. Due to the expansion of the role of tissue factor and thrombin in the initiation of DIC, the aim of this study is the histological assessment of the Di Minno model under conditions of DIC initiation by tissue factor or thrombin with comparison with the classical variant. The study was performed on 80 male mice. All laboratory animals were divided into three groups depending on the trigger of thrombosis: Group I - collagen + adrenaline solution (0.5 mg / kg + 0.06 mg / kg), Group II - 10 mg / kg thromboplastin, Group III - 10 mg / kg thrombin. Histological studies of animal’s preparations demonstrate a lower content of blood clots in the lungs of laboratory animals, which suggests that the main cause of death of animals is not acute thrombosis, but the development of delayed manifestations of DIC when using tissue factor. In the case of thrombin using, on the contrary, the death of animals is recorded on the first day of the experiment and the results of the histological study demonstrate the massiveness of thrombosis, which is not initially provided for by this model, calculated to assess the effectiveness of new antiplatelet drugs in an acute experiment. Thus, on the basis of morphological studies, the limitations of the use of tissue factor and thrombin in model thrombosis have been demonstrated and the expediency of using physiological inducers of aggregation has been substantiated.

COVID-19 Pneumonia Hospitalizations Followed by Re-Presentation for Presumed Thrombotic Event

COVID-19 Pneumonia Hospitalizations Followed by Re-Presentation for Presumed Thrombotic Event

Гемостаз у лиц с сахарным диабетом 2‑го типа и ожирением при острой и хронической цереброваскулярной патологии

Введение. В настоящее время цереброваскулярные заболевания (ЦВЗ) в России являются второй по частоте причиной смерти среди больных сахарным диабетом (СД). С гипергликемией и избыточной массой тела связывают протромботические и провоспалительные изменения, приводящие к неблагоприятным исходам инсульта и прогрессированию ЦВЗ. Цель исследования: оценить роль избыточной массы тела как дополнительного фактора риска развития нарушений гемостаза при острых и хронических формах цереброваскулярной патологии у пациентов с СД 2‑го типа (СД‑2). Материалы и методы. В исследование включено 305 пациентов с ишемическими ЦВЗ: группа 1 — 87 больных с ишемическим инсультом (ИИ) и СД‑2; группа 2 — 58 пациентов с ИИ без СД; группа 3 — 80 больных с хроническими ЦВЗ (ХЦВЗ) и СД‑2; группа 4 — 80 пациентов с ХЦВЗ без СД. Выполнены общесоматический и неврологический осмотр, магнитно-резонансная томография головного мозга, инструментальные исследования с расчетом индекса массы тела (ИМТ) и лабораторные исследования с определением гликемии и гликированного гемоглобина (HbA1c), АДФ-индуцированной (АДФ-АТ) и адреналин-индуцированной (Адр-АТ) агрегации тромбоцитов, коагулограммы, включающей содержание фибриногена и Д-димеров, международное нормализованное отношение, активированное частичное тромбопластиновое время, фибринолитическую активность (ФА), индекс фибринолиза, активность плазминогена и уровень тканевого активатора плазминогена (t-РА). Результаты. Наибольших значений глюкоза и HbA1c достигали у пациентов с ИИ и СД‑2. Во всех группах больных с цереброваскулярной патологией СД‑2 сопровождался ожирением и повышенным ИМТ. ЦВЗ (как ИИ, так и хроническая форма) в сочетании с СД‑2 протекали на фоне протромботического состояния крови, связанного с нарушением всех звеньев гемостаза, и проявлялись увеличением АДФ-АТ и Адр-АТ, повышением содержания фибриногена и Д-димеров при одновременном снижении ФА, индекса фибринолиза, активности плазминогена и уровня t-PA. Самые выраженные нарушения наблюдали у пациентов с ИИ и СД‑2, особенно со стороны фибринолиза. Выявлены значимые корреляции между ИМТ и агрегацией тромбоцитов, уровнями фибриногена и Д-димеров, ФА и t-PA. Заключение. У лиц с СД‑2 острые и хронические ЦВЗ сопровождаются ожирением и увеличенным ИМТ, который взаимосвязан с активацией тромбоцитарного и плазменного гемостаза и снижением фибринолиза. Наибольшие изменения отмечены у пациентов с острым инсультом и СД‑2, для которых характерно сочетание гиперфибриногенемии и значительное снижение фибринолиза. Повышение ИМТ у больных ЦВЗ ассоциировано с выраженностью протромботических изменений. Introduction. At present cerebrovascular diseases (CVD) in Russia is the second most common cause of death among patients with diabetes mellitus (DM). Prothrombotic and pro-inflammatory changes leading to adverse outcomes of stroke and progression of CVD are associated with hyperglycemia and obesity. Aim: to assess the role of obesity as an additional risk factor for the development of hemostasis disorders in acute and chronic forms of cerebrovascular pathology in patients with type 2 diabetes mellitus (DM‑2). Materials and methods. The study included 305 patients with ischemic CVD: group 1 — 87 patients with ischemic stroke (IS) and DM‑2; group 2 — 58 patients with IS without DM; group 3 — 80 patients with chronic CVD (CCVD) and DM‑2; group 4 — 80 patients with CCVD without DM. The following studies were completed: somatic and neurological examinations, magnetic resonance imaging of the brain, calculation of body mass index (BMI) and laboratory tests with the determination of glycemia and glycated hemoglobin (HbA1c), ADP-induced (ADP-AT) and adrenaline-induced (Adr-AT) platelet aggregation, coagulogram with fibrinogen and D-dimers content, international normalized ratio, activated partial thromboplastin time, fibrinolytic activity (FA), fibrinolysis index (FI), plasminogen activity and level of tissue plasminogen activator (t-PA). Results. The highest values of glucose and HbA1c were found in patients with IS and DM‑2. In all groups of patients with cerebrovascular pathology DM‑2 was accompanied with obesity and increased BMI. CVD (both IS and chronic form) in combination with DM‑2 were accompanied by prothrombotic blood state (associated with hemostasis disorders), and manifested by enhancement of ADP-AT and Adr-AT, increasing of fibrinogen and D-dimers content and decreasing of FA, FI, plasminogen activity and t-PA. Most expressed disturbances (especially in fibrinolysis) were observed in patients with IS and DM‑2. Significant correlations were found between BMI and platelet aggregation, levels of fibrinogen and D-dimers, FA and t-PA. Conclusion. In patients with DM‑2 acute and chronic CVD are accompanied by obesity and increased BMI and associated with activation of platelet and plasma hemostasis and decreased fibrinolysis. The largest changes were noted in patients with acute stroke and DM‑2 and characterized by a combination of hyperfibrinogenemia and a significantly decreased fibrinolysis. Increasing of BMI in patients with CVD was associated with the severity of prothrombotic changes.

Combined Point of Care Tools Are Able to Improve Treatment Adherence and Health-Related Quality of Life in Patients with Severe Hemophilia: An Observational Prospective Study

Introduction: Ultrasound (US) assessment of joints is an evolving point of care tool for the detection of early joint arthropathy (Napolitano M, Kessler CM. Hemophilia A and B. Consultative Hemostasis and Thrombosis, Kitchens, 4th edition); population pharmacokinetic (pop-PK) studies are adopted as a useful instrument to set the prophylaxis regimen for patients with hemophilia, they may improve adherence (Nagao A.et al. Thromb Res. 2019 Jan; 173:79-84) and reduce the annual bleeding rate (ABR). Adherence to continuous intravenous administrations of factor VIII or Factor IX products is challenging, thus patients may experience breakthrough bleedings while on prophylaxis. Repeated US examinations of joint status have recently been advocated to attempt to remedy sub-optimal medication adherence (Di Minno A et al., Blood Rev. 2019 Jan;33:106-116). Aim of the current prospective analysis was to evaluate the impact of combined US assessment and pop-PK study on adherence to treatment and health related quality of life in patients with severe hemophilia A(HA) and B (HB) under regular prophylaxis. Material and methods: This prospective observational study was performed at a single tertiary center from January 2017 to June 2019. Research was conducted following the Helsinki Declaration. All patients included in the study provided a written informed consent for study participation. Patients with severe HA and HB routinely underwent, as part of regular 12-months follow-up visits, the following: US joints evaluation of elbows, knees and ankles using the HEAD-US protocol, treatment adherence evaluation by VERITAS-Pro questionnaire, health -related quality of life assessment by the standardized EQ-5D,EQ-VAS and pop-PK study (WAPPS-Hemo, McMaster University) as needed (i.e.in case of changes in life style, planned treatment switch); each patient visualised US and his estimated PK profile during medial encounters. Compliance to the prescribed treatment was also determined by analysis of patient diaries with infusion logs. Statistical analysis was performed using the SPSS software version 25.0 (SPSS Chicago, IL). Statistical tests were 2-sided, with a significance threshold of 0.05. Results: Twenty consecutive males with severe haemophilia were included in the current analysis, 13 with severe HA, 2 with HA with previous inhibitors and 5 HB, with a median age of 30 (range 14- 56) years and a median ABR of 5 (range:0-12). Nine patients were under primary prophylaxis, 8 under secondary prophylaxis and 3 under tertiary prophylaxis, they all self-infused at home. Four patients had one target joint and 3 patients had multiple target joints. For each enrolled subject, HEAD-US score, VERITAS-pro, EQ5D and EQ-VAS score were assessed at enrolment (T0) and at 12 (T12) and 24 (T24) months follow-up visits, respectively. Pop-PK was assessed in 11 patients: in 7 (5 HA,2 HB) it was assessed twice, before and after treatment switch to extended half-life (EHL) products, in 4 it was assessed once to modify prophylaxis treatment schedules for a more active life-style (N=2) or weight changes (N=2). Median ABR was 4 at T12 and 3.8 at T24. Reported breakthrough bleeds at T12 were 14, mainly trauma-related (N= 8) or affecting target joints (N=4), they were not reported at T24 in patients with PK-driven modified schedules (N=4) and in 4 patients under EHL treatments. Mean HEAD-US score at T0 resulted 8 (range:0-16), at T24 it was 6 (range:0-16). Mean Veritas-Pro score values were 42.7 at TO, 40.1 at T12 and 38.7 at T24. At T0, EQ-5D mean utility score was 0.82 (range: 0.68-1), at T24, the mean was 0.87 (range:0.72-1). In detail, at 24 months follow-up, there was a statistically significant (p<0.05) improvement in adherence to treatment with particular reference to the dimensions of communication and skipped doses. A tendency toward improved HEAD-US score, higher adherence and better quality of life scores, was observed in particular in patients switched to EHL products at T24, at a mean of 10 months after switching (range: 6-22 months). Conclusion: Several combined measures of haemophilia treatment monitoring, allowing visual assessment of joints status and PK profile estimates by patients have here shown to improve treatment adherence and quality of life in patients with HA and HB, this may be not only related to new available treatments but also to an increased awareness and education of patients. Disclosures Napolitano: BIOFVIIIx: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Shire: Other: Expert Testimony, Speakers Bureau; Kedrion: Other: Expert Testimony, Speakers Bureau; Octapharma: Speakers Bureau; Bayer: Consultancy, Other: Expert Testimony. Di Minno:Novo Nordisk: Speakers Bureau; CSL: Speakers Bureau; Sanofi: Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Kedrion: Speakers Bureau; Pfizer: Speakers Bureau.

Efficacy and Safety of BAY 94-9027 (Damoctocog Alfa Pegol) Prophylaxis in Patients with Severe Hemophilia a and Comorbidities: A Post Hoc Analysis of PROTECT VIII Data

Efficacy and Safety of BAY 94-9027 (Damoctocog Alfa Pegol) Prophylaxis in Patients with Severe Hemophilia a and Comorbidities: A Post Hoc Analysis of PROTECT VIII Data

The American College of Chest Physician score to assess the risk of bleeding during anticoagulation in patients with venous thromboembolism: reply

Essentials The risk of bleeding influences the duration of anticoagulation (AC) after venous thromboembolism. We assessed the ACCP bleeding risk score in an inception-cohort of patients receiving AC. 53% were categorized at high-risk, but their bleeding rate was low during long-term AC. ACCP score had low predictive value for bleeding. Summary Background The American College of Chest Physicians (ACCP) guideline proposes a score to decide on extended anticoagulation after an unprovoked venous thromboembolism (VTE). Methods We investigated the ACCP score to predict bleeding risk in an inception cohort of 2263 patients on long-term anticoagulation (1522 treated with vitamin K antagonists [VKAs] and the remaining with direct oral anticoagulants [DOACs]) belonging to the Italian START2 Register. Results More than half the patients were categorized as high risk; nevertheless, a higher proportion received anticoagulation for > 1 year compared with those in the low-risk category. For 3130 years (median 12 [interquartile range 6, 24] months), 48 bleeding outcomes occurred (1.53%/year) in the cohort (1.7%/year and 0.95%/year in high- and low-risk categories, respectively). The c-statistic of the ACCP score was 0.55 (0.48-0.63), 0.50 (0.42-0.58) and 0.56 (0.48-0.64) in low-, moderate- and high-risk categories, respectively. The bleeding incidence was higher during the first 90 days of treatment (3.0%/year) than afterwards (1.2%/year; relative risk (RR), 2.5 [1.3-4.7]), and similar among the three categories. The bleeding rate was not different during the initial 3 months of treatment in patients receiving VKAs or DOACs; it was, however, lower in the latter patients in the subsequent period (0.5%/year vs. 1.4%/year, respectively). Conclusion The bleeding rate during extended treatment was rather low in our patients. ACCP score had insufficiently predictive value for bleeding and cannot be used to guide decisions on extended treatment. New prediction tools for bleeding risk during anticoagulant treatments (including DOACs) are required.

Managing Haemophilia for Life: 5th Haemophilia Global Summit.

The 5th Haemophilia Global Summit was held in Barcelona, Spain, in September 2014. The programme was designed by an independent Scientific Steering Committee of haemophilia experts and explored issues relevant to the practical management of haemophilia, as well as key opportunities and challenges for care in the future. The topics outlined in this supplement were selected by the Scientific Steering Committee for their relevance to improving haemophilia care globally. In this supplement from the meeting, Gerry Dolan explores pharmacokinetics and dynamics in haemophilia, and Gerry Dolan and Ian Jennings jointly address the role of the laboratory in haemophilia care. The potential benefits of low-dose prophylaxis regimens for people with haemophilia in the developing world are reviewed by Jerzy Windyga, and the question of whether 'Future haemophilia research should be undertaken in the developing world' is debated by Jerzy Windyga and Cedric Hermans. Management strategies for ankle arthropathy are discussed by Sébastien Lobet and E. Carlos Rodríguez-Merchán, and the use of ultrasound for the early detection of haemophilic arthropathy is addressed by Matteo Nicola Dario Di Minno and Víctor Jiménez-Yuste. Finally, the role of patients in the future of haemophilia care is reviewed by Brian O'Mahony.

Antithrombotic activity of new 1‐ethylxanthine cyclohexylammonium salt (1054.5)

The previous findings in vitro show high antiaggregation activity of newly synthesized cyclohexilammonium salt of 2‐[1‐ethil‐3‐methyl‐7‐(dioxotiethanyl‐3)xantinyl‐8‐thio]acetic acid. The current findings are received in vivo on the model of collagen‐adrenaline thrombosis according to G.S. Di Minno subject to the FASEB Statement of Principles for the use of animals in research and education. Efficacy endpoint is the number of survived animals in comparison with the test group and comparator agents since the injection into the tail vein suspended matter of collagen and adrenalin upto the moment of death or during 14 days of monitoring. The survival analysis was carried out with the help of Kaplan‐Meier method. The difference in survival between the groups was assessed with the help of Wilkonson criterion.Intraperinoneal injection of the new secondary 1‐ethylxantin reduced mortality in lab mice by 1,3 times (P1<0,01) in comparison with the camparator agents. Thus, cyclohexilammonium salt of 2‐[1‐ethil‐3‐methyl‐7‐(dioxotiethanyl‐3)xantinyl‐8‐thio]acetic acid is a potential antithrombotic agent.

Human genome, environment and medical practice

After reading the interesting and thoughtful paper by Giovanni Di Minno and Giovanni De Gaetano [1], my first consideration is that the authors should be praised for their comprehensive view of genetic factors in health and disease, seen not only in their substantial steadiness, but also in their long-term gradual shifting, at least partly induced by man-provoked influences of multiple nature. I think that many factors capable of inducing changes in the genome, as polymorphisms, have undergone an unprecedented acceleration during the last two centuries, and especially in the last 20 years. The impact of exogenous and endogenous environmental aggressions has exponentially increased, and their damaging potential is now magnified through new conditions such as globalization, omni-pervasive information and connection, absolute increase and ageing of the world population, migrations and urbanization. These rapid changes are reflected in recently published data on the global burden of disease evaluated in 2010 versus 1990 [2]. For instance ischemic heart disease remains the first cause of death, but ranks now first also for disability, suggesting that younger people more often undergo a heart attack. A totally different disease, AIDS, ranks now as the fifth cause of disability though it was only 33rd in 1990, reflecting effective but ultimately non-successful therapy. Similarly, chronic pulmonary obstructive disease is only the fifth cause of death, but ranks second as a cause of durable disability. In the same time interval, some major risk factors for disability greatly increased: hypertension is now no 1 (4th in 1990); obesity, high glucose, and some unfavourable dietary changes have increased by more than 30 %; while the disabling effect of other factors such as malnourishment in childhood and defective breast-feeding sharply declined. How fast can our genome react and produce protective polymorphisms versus these extremely rapid changes? We hope that a defense will be provided at some time, but likely not within a few generations, and this increases the feeling of frailty, and the need for security that has become the main value of our times. Would the authors agree that the slow adaptation of our genome will not be able to cope with our fate as individuals, but only with our survival as species? A second observation concerns the thrombophilic polymorphisms, mainly Factor V Leiden and mutant Factor II. In this case, I would like to call attention to the complexity of all natural phenomena (or perhaps to the complexity that our human mind attributes to natural phenomena?).

OP0162 Obesity and the prediction of the minimal disease activity. A prospective study in psoriatic arthritis patients

BackgroundClinical studies show an increased prevalence of obesity in PsA patients. By leading to an abnormal expression of “adipokines” (TNF-α, IL-6, leptin, adiponectin), obesity determines a pro-inflammatory status. Thus, an...

OP0163 Weight loss and induction of minimal disease activity in psoriatic arthritis patients starting TNF-α blockers treatment

BackgroundPsA patients exhibit an increased prevalence of obesity. By leading to an abnormal expression of “adipokines” (TNF-α, IL-6, leptin, adiponectin), obesity determines a pro-inflammatory status. Thus, an interaction between obesity-related...

Laboratory tests during direct oral anticoagulant treatment? No

The anticoagulant effect of Dabigatran etexilate, Rivaroxaban, and Apixaban is dose-predictable, steady, and little influenced by diet and drugs [1]. Thus, similar to lowmolecular weight heparin, laboratory tests have been unnecessary to evaluate such direct oral anticoagulant drugs (DOACs) in trials on thromboprophylaxis (Table 1). Nor such testing was needed in patients with atrial fibrillation (AF) receiving Dabigatran etexilate (RE-LY trial), Rivaroxaban (ROCKET AF trial) or Apixaban (ARISTOTLE trial). In the AF setting, vis-a-vis an at least as effective prevention of stroke and systemic embolism, the risk of intracranial hemorrhage was lower with DOACs than with INR-adjusted warfarin. Patients at high risk of bleeding are little represented in studies with DOACs [2, 3]. However, from October 2010 to December 2011, vis-avis 3.5 gastrointestinal bleedings and 2.4 intracranial hemorrhages/100,000 days at risk in new users of warfarin, 1.6 gastrointestinal bleedings and 0.8 intracranial hemorrhages/100,000 days at risk occurred among new users of Dabigatran in the every day practice in the USA [4]. At variance with the large majority of cases, there are special conditions and clinical settings (Table 2) in which the anticoagulant effect of DOACs should be measured [5]. However, peak concentrations of Rivaroxaban (&200 ng mL) are determined by HPLC methods that are not suitable for routine practice [6]. On the other hand, in healthy volunteers, a 20 % prolongation of the aPTT has been observed for single Apixaban doses ranging from 25 to 50 mg [7]. Moreover, depending on the reagent employed, the concentrations of Rivaroxaban that double the aPTT range from 389 to 617 ng mL [8]. Thus, the aPTT does not accurately assess the anticoagulant effect of Rivaroxaban or of Apixaban. A concentration-dependent prolongation of the aPTT occurs by spiking Dabigatran in human plasma [9]. However, such prolongation is linear only at Dabigatran concentrations [200 ng mL (expected drug exposure being 50–300 ng mL), and the effects on the aPTT vary up to 26 % between the most and least sensitive reagent [10]. Thus, the aPTT is not suitable for an accurate measurement of the anticoagulant effect of (high) Dabigatran concentrations. At variance with Apixaban, Rivaroxaban prolongs the PT in a dose-dependent manner. However, at approved dose regimens (10–20 mg), the changes observed are small, and the results depend on the reagents employed. Accordingly, rather than quantitative, this accessible clotting method provides qualitative estimates of the anticoagulant effect of Rivaroxaban [11]. Likewise, significant effects in the PT-INR (i.e., INR [1.2) are only found in response to concentrations of Dabigatran [200 ng mL [9]. Moreover, depending on the thromboplastin reagent used, major differences are observed in the results of the assays [10]. Thus, in its current form, the prothrombin time (PT), standardized as the International Normalized Ratio (INR), is not suitable for assessing the anticoagulant effect of Dabigatran. Nor is standardization between reagents and laboratories available for the very sensitive thrombin time (TT). [12] As a whole, while the PT and the aPTT provide little help distinguishing between treatment failure and non-adherence of patients, these routinely available clotting methods may be useful to establish whether the anticoagulant effect of a DOAC is higher than expected [an aPTT value twice the highest normal limit (i.e., [80 s) 12 h after the last administration of Dabigatran argues for G. Di Minno (&) E. Ricciardi A. Scalera Dipartimento di Medicina Clinica e Chirurgia, Clinica Medica, Universita degli Studi di Napoli ‘‘Federico II’’ Napoli, Via S. Pansini 5, 80131 Naples, Italy e-mail: diminno@unina.it

Upper tract urothelial cell carcinoma presenting as fever of unknown origin and acid-sterile pyuria

Urothelial carcinomas are the fourth most common tumors. They can be divided in carcinomas of the lower urinary tract, if located in the bladder or urethra, or upper urinary tract carcinomas if located in the pyelocaliceal cavities and ureter. Bladder tumors represent the most common malignancy of the urinary tract, and account for the 90–95 % of urothelial carcinomas. On the other hand, upper tract urothelial carcinomas are uncommon, and account only for 5–10 % of urothelial tumors [1, 2]. We report a case of a 63-year-old woman referred to our department in February 2011 for a fever of unknown origin (FUO). She had suffered 30 months prior from mammary ductal carcinoma (staged pT1bN0), treated with quadrantectomy and tamoxifen, switched to exemestane after 2 years (of therapy); moreover, she was affected from HCV-related chronic hepatitis (viraemia: 1.22 9 10 IU/ mL, genotype 1b; naive) discovered in 1997. She complained of fevers up to 39 C mostly ‘‘nocturnal’’ sometimes accompanied by diarrhea, malaise, loss of appetite, weight loss and profuse sweating begun 4 months before. The patient was previously admitted in a different department of internal medicine for the same clinical status. During the hospitalization an abdomen computed tomography (CT scan) was performed that revealed only a reduced enhancement of contrast media in the upper pole of the left kidney. The patient was therefore discharged with a diagnosis of ‘‘fever in remission and renal ischemia’’. 1 month later, the temperature was still elevated, and the patient was admitted to our department. The physical examination revealed an emaciated facies, a body temperature of 37.8 C, a blood pressure of 160/80 mm Hg, and a murmur 2/6 Levine of the mitral valve; the remainder of the physical examination was normal. A complete blood count (CBC) showed a neutrophil leucocytosis (WBC: 11,200/mm, Ne 79.3 %) and a microcytic hypochromic anemia (related to a b-thalassemia trait). Other laboratory tests: GOT, GPT and c-GT were mildly elevated (1.25 ULN), C-reactive protein (CRP) was 1.77 mg/dL (normal value \0.5 mg/dL); electrolytes, erythrocyte sedimentation rate (ESR), blood culture, chest X-ray and urine culture were negative. At echocardiography, performed to exclude a subacute infective endocarditis, the patient presented only a mild mitral regurgitation with left atrial enlargement; there was no sign of valvular vegetations. At urine analysis the patient presented acid-sterile pyuria. Since the most common cause of sterile pyuria is renal tuberculosis, we proceeded with PPD skin test and Koch bacillus research in the urine; both were negative. As the patient was still febrile, an abdomen-CT scan with contrast media infusion was repeated, and revealed again an impairment of perfusion of the left kidney upper pole (reported as renal ischemia), but this time revealed also many lymphoadenopathies near the left renal vein and in the para-aortic region; the biggest one was 1.3 cm in the lumbar para-aortic region. Therefore, we decided to proceed with a total body F-fluorodeoxyglucose (FDG) positron emission tomography combined with computed tomography (PET/CT) to better evaluate the abdominal lymphoadenopathies, and to indentify a possible focus responsible of the fever. The only site with high FDG uptake was the lymph node in the lumbar region (max-standardized uptake value 8.7). About 20 days after admission the patient still presented M. Di Capua (&) P. Ierano E. Marrone A. M. Cerbone G. Di Minno Department of Clinical and Experimental Medicine, Regional Reference Centre for Coagulation Disorders, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy e-mail: mirdica@hotmail.com

Invasive procedures and minor surgery in factor VII deficiency

HaemophiliaVolume 18, Issue 3 p. e63-e65 LETTER TO THE EDITORS Invasive procedures and minor surgery in factor VII deficiency G. MARIANI, G. MARIANI University of L’Aquila, Dipartimento di Medicina Interna e Sanità, L’Aquila, ItalySearch for more papers by this authorA. DOLCE, A. DOLCE National Institute of Statistics, Palermo, ItalySearch for more papers by this authorM. NAPOLITANO, M. NAPOLITANO University of L’Aquila, Dipartimento di Medicina Interna e Sanità, L’Aquila, ItalySearch for more papers by this authorJ. INGERSLEV, J. INGERSLEV University Hospital Skejby, Centre for Haemophilia and Thrombosis, Aarhus, DenmarkSearch for more papers by this authorM. GIANSILY-BLAIZOT, M. GIANSILY-BLAIZOT Laboratory of Haematology, University Hospital, Montpellier, FranceSearch for more papers by this authorM. D. DI MINNO, M. D. DI MINNO Dipartimento di Medicina Clinica e Sperimentale, Centro di Coordinamento regionale per le Emocoagulopatie, Università di Napoli ‘Federico II’ Naples, ItalySearch for more papers by this authorG. AUERSWALD, G. AUERSWALD Children’s Hospital Organisation, Klinikum Bremen-Mitte, Bremen, GermanySearch for more papers by this authorA. R. DE SAEZ, A. R. DE SAEZ National Haemophilia Centre, Banco Metropolitano de Sangre DC, Caracas, VenezuelaSearch for more papers by this authorA. TAGLIAFERRI, A. TAGLIAFERRI Centro Emofilia e Trombosi, Ospedale Regionale di Parma, ItalySearch for more papers by this authorA. BATOROVA, A. BATOROVA The National Haemophilia Centre, Institute of Haematology and Blood Transfusion, University Hospital, Bratislava, SlovakiaSearch for more papers by this authorON BEHALF OF THE STER (SEVEN TREATMENT EVALUATION REGISTRY); OTHER AUTHORS ARE LISTED AT THE END OF THE MANUSCRIPT, ON BEHALF OF THE STER (SEVEN TREATMENT EVALUATION REGISTRY); OTHER AUTHORS ARE LISTED AT THE END OF THE MANUSCRIPTSearch for more papers by this author G. MARIANI, G. MARIANI University of L’Aquila, Dipartimento di Medicina Interna e Sanità, L’Aquila, ItalySearch for more papers by this authorA. DOLCE, A. DOLCE National Institute of Statistics, Palermo, ItalySearch for more papers by this authorM. NAPOLITANO, M. NAPOLITANO University of L’Aquila, Dipartimento di Medicina Interna e Sanità, L’Aquila, ItalySearch for more papers by this authorJ. INGERSLEV, J. INGERSLEV University Hospital Skejby, Centre for Haemophilia and Thrombosis, Aarhus, DenmarkSearch for more papers by this authorM. GIANSILY-BLAIZOT, M. GIANSILY-BLAIZOT Laboratory of Haematology, University Hospital, Montpellier, FranceSearch for more papers by this authorM. D. DI MINNO, M. D. DI MINNO Dipartimento di Medicina Clinica e Sperimentale, Centro di Coordinamento regionale per le Emocoagulopatie, Università di Napoli ‘Federico II’ Naples, ItalySearch for more papers by this authorG. AUERSWALD, G. AUERSWALD Children’s Hospital Organisation, Klinikum Bremen-Mitte, Bremen, GermanySearch for more papers by this authorA. R. DE SAEZ, A. R. DE SAEZ National Haemophilia Centre, Banco Metropolitano de Sangre DC, Caracas, VenezuelaSearch for more papers by this authorA. TAGLIAFERRI, A. TAGLIAFERRI Centro Emofilia e Trombosi, Ospedale Regionale di Parma, ItalySearch for more papers by this authorA. BATOROVA, A. BATOROVA The National Haemophilia Centre, Institute of Haematology and Blood Transfusion, University Hospital, Bratislava, SlovakiaSearch for more papers by this authorON BEHALF OF THE STER (SEVEN TREATMENT EVALUATION REGISTRY); OTHER AUTHORS ARE LISTED AT THE END OF THE MANUSCRIPT, ON BEHALF OF THE STER (SEVEN TREATMENT EVALUATION REGISTRY); OTHER AUTHORS ARE LISTED AT THE END OF THE MANUSCRIPTSearch for more papers by this author First published: 22 February 2012 https://doi.org/10.1111/j.1365-2516.2012.02751.xCitations: 21 Guglielmo Mariani, Hematology, Department of Internal Medicine and Public Health, University of L’Aquila, Piazzale Tommasi 1, 67100 L’Aquila, Italy. Tel.: +39 0862 368294; fax: +39 0862 368208; e-mail: guglielmo.mariani@univaq.it Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume18, Issue3May 2012Pages e63-e65 RelatedInformation

Guilty by Association: Platelet Reactivity and Inflammation in Psoriatic Arthritis

Patients with rheumatoid arthritis (RA) die prematurely from cardiovascular disease (CVD)1. The risk of adverse cardiovascular events and subsequent mortality in patients with RA is comparable to that associated with type 2 diabetes mellitus2. There is an emerging body of evidence that patients with other forms of inflammatory arthritis (IA), in particular psoriatic arthritis (PsA), are at a similarly elevated risk of CVD3. Platelets play a key role in the complex chain of events leading to the thrombotic occlusion of a coronary artery4. Antiplatelet therapy with aspirin and/or a variety of other agents is effective at reducing the mortality associated with incident CVD5 and is recommended for the primary prevention of same in patients at high risk of atherothrombotic events4. Despite the greatly increased risk of heart disease and strokes, there are currently no antiplatelet guidelines for the primary prevention of CVD in patients with IA3, and platelet function remains largely uninvestigated in this patient population. It is within this context that the recent work of Di Minno and colleagues, reported in this issue … Address correspondence to Dr. MacMullan; E-mail: pmacmullan{at}hotmail.com

Treatment of hemophilia: a review of current advances and ongoing issues

Replacement of the congenitally deficient factor VIII or IX through plasma-derived or recombinant concentrates is the mainstay of treatment for hemophilia. Concentrate infusions when hemorrhages occur typically in joint and muscles (on-demand treatment) is able to resolve bleeding, but does not prevent the progressive joint deterioration leading to crippling hemophilic arthropathy. Therefore, primary prophylaxis, ie, regular infusion of concentrates started after the first joint bleed and/or before the age of two years, is now recognized as first-line treatment in children with severe hemophilia. Secondary prophylaxis, whenever started, aims to avoid (or delay) the progression of arthropathy and improve patient quality of life. Interestingly, recent data suggest a role for early prophylaxis also in preventing development of inhibitors, the most serious complication of treatment in hemophilia, in which multiple genetic and environmental factors may be involved. Treatment of bleeds in patients with inhibitors requires bypassing agents (activated prothrombin complex concentrates, recombinant factor VIIa). However, eradication of inhibitors by induction of immune tolerance should be the first choice for patients with recent onset inhibitors. The wide availability of safe factor concentrates and programs for comprehensive care has now resulted in highly satisfactory treatment of hemophilia patients in developed countries. Unfortunately, this is not true for more than two-thirds of persons with hemophilia, who live in developing countries.

Editorial

The articles in this supplement report the lectures given at the Bayer Schering Pharma Conference entitled ‘Haemophilia: new challenges and winning directions’ held in Milan on 30 January, 2009. The focus of this meeting was to discuss some hot topics in the field of haemophilia, such as the safety issue and venous access management, and to establish a vision for the future development of haemophilia treatment. The opening lecture was given by Prof. Di Minno on the strategies adopted to achieve longer-acting FVIII molecules that may potentially facilitate enhanced treatment compliance because of the need for less frequent infusions. Preclinical and phase I clinical studies have shown that the most promising formulation is the recombinant FVIII molecule conjugated with pegylated liposomes (BAY 79-4980) and the results of the ongoing phase II multicentre double-blind randomized trial are awaited with great anticipation. The first session of this conference was focused on the issue of viral safety. Professor Zanetti assessed the issue of emerging infections, from severe acute respiratory syndrome (SARS) to influenza pandemics and vector-borne (i.e., West Nile and Chikungunya viruses) viruses. These pathogens, along with prions, may represent a new challenge for haemophilia treatment centres. Consequently, the manufacturing process of recombinant FVIII products has further evolved during the last few years to minimize the risk of blood-borne infections by improving the techniques for purification of the protein, by implementing further viral inactivation steps and by avoiding the use of human or animal proteins at any stage of the production process. In the second session, Dr Coppola analysed the literature data on the genetic and non-genetic risk factors for inhibitor development in haemophilia A patients. The presence of null mutations (large deletions, nonsense mutations and inversions) in the FVIII gene, a positive family history of inhibitors and intensive treatment have been identified as the most relevant risk factors for inhibitor development; on the other hand, several studies have recently outlined the potential protective effect of regular early prophylaxis on inhibitor formation. The second session was dedicated to the management of venous access in haemophilia patients. Dr Santagostino discussed the choice and management of venous access in haemophilic children. Although peripheral veins are the preferred option, central venous access devices (CVADs) are often necessary in children especially in the home setting when frequent infusions for prolonged periods (i.e. prophylaxis or immune tolerance induction regimens) are required. Fully implantable devices have a lower incidence of infections than external CVADs, although they carry the inconvenience of needle sticks. Arteriovenous fistula (AVF) has been recently introduced in haemophilic children as a suitable alternative to central catheters. This latter option was discussed by Professor Berardinelli. Based on the published literature data and on her personal experience, the author concluded that AVF is a suitable venous access for haemophilia children because it is easy to use, is well accepted by children and their parents and has a lower rate of complication compared with CVADs. Professor Izzi reviewed the current literature on the use of CVADs in haemophilia patients. Finally, he presented his personal experience on the use of external tunnelled central venous catheter (CVC) Broviac in haemophilic children documenting the usefulness and safety of this device. M.F. has received fees for the manuscript. E.S. has no conflicts of interest.

Inflammatory biomarkers in coronary artery disease

Current evidence supports that inflammation is a major driving force underlying the initiation of coronary plaques, their unstable progression, and eventual disruption; patients with a more pronounced vascular inflammatory response have a poorer outcome. Biomarkers are generally considered to be proteins or enzymes - measured in serum, plasma, or blood - that provide independent diagnostic and prognostic value by reflecting an underlying disease state. In the case of coronary artery disease (CAD), inflammatory biomarkers, have been extensively investigated; more evidence exists for C-reactive protein (CRP). Using high sensitivity (hs) assays, epidemiologic data demonstrate an association between hs-CRP and risk for future cardiovascular morbidity and mortality among those at high risk or with documented CAD. Moreover, a series of prospective studies provide consistent data documenting that mild elevation of baseline levels of hs-CRP among apparently healthy individuals is associated with higher long-term risk for cardiovascular events. Yet, the predictive value of hs-CRP is found to be independent of traditional cardiovascular risk factors. Recent studies suggest that, besides CRP, other inflammatory biomarkers such as cytokines [interleukin (IL)-1, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1)], soluble CD40 ligand, serum amyloid A (SAA), selectins (E-selectin, P-selectin), myeloperoxidase (MPO), matrix metalloproteinases (MMPs), cellular adhesion molecules [intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1)], placental growth factor (PlGF) and A(2) phospholipases may have a potential role for the prediction of risk for developing CAD and may correlate with severity of CAD. Finally, indications suggest that the increased risk associated with inflammation may be modified with certain preventive therapies and biomarkers may help to identify the individuals who would benefit most from these interventions.