Mirko Di Capua

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.

Prophylaxis in children with hemophilia: evidence-based achievements, old and new challenges.

Recurrent joint bleeding leading to progressive musculoskeletal damage (hemophilic arthropathy), in spite of on-demand replacement with deficient factor concentrates, is the clinical hallmark of severe hemophilia A and B (i.e., the congenital deficiencies of coagulation factors VIII and IX with circulating levels <1 IU/dL). Fifty years of clinical experience, which began in Northern Europe and then initiated in other European countries and in North America, up to the recent randomized clinical trials, have provided definitive evidence that preventing bleeding from an early age through long-term regular prophylactic concentrate infusions limits the adverse clinical consequences of arthropathy and its complications in the quality of life of hemophilic children. Primary prophylaxis started after the first joint bleed and/or before the age of 2 is now the evidence-based, first-choice treatment in severe hemophilia. Interestingly, recent data also suggest a role for early prophylaxis in preventing inhibitor development, the most serious complication of hemophilia therapy. Secondary prophylaxis is aimed to avoid (or delay) the progression of arthropathy. The earlier the treatment is started, the better the outcomes in joint status and quality of life. Although prophylaxis has radically transformed the natural history of severe hemophilia, relevant barriers to its implementation and diffusion remain. Beyond the obvious economic constraints and problems with venous access and long-term adherence, uncertainties regarding the optimal prophylaxis regimen require further evaluation in prospective studies to optimize approaches based on definite outcome measures and cost-effectiveness/cost-utility analyses. Scientific evidence, current clinical strategies, and open issues of prophylaxis in children with hemophilia will be addressed in this review.

Bleeding and thrombosis in multiple myeloma and related plasma cell disorders.

A variety of disease- and treatment-related factors affect the coagulation system and the risk of bleeding and thrombotic complications in patients with multiple myeloma (MM) and related plasma cell disorders (PCD). As commonly observed in other cancer settings, the malignant clone induces a cytokine environment responsible for a hypercoagulable state. The increase of blood viscosity and impairment of platelet and coagulation function due to circulating monoclonal proteins are considered key mechanisms in the hemostatic abnormalities frequently detected in patients with PCD. However, clinically significant bleeding is relatively rare and poorly correlated with these abnormalities. Management is often challenging because of the multifactorial pathogenesis and underestimation or misdiagnosis of acquired bleeding disorders, particularly acquired von Willebrand syndrome. In recent years, growing interest in thromboembolic risk has emerged after the introduction of novel and more effective antimyeloma agents (thalidomide and lenalidomide), which was associated with increased risk of venous thromboembolism, particularly when associated with dexamethasone and multiagent chemotherapy in newly diagnosed patients. The clinical impact of bleeding and thrombotic complications in patients with PCD, with emphasis on MM, will be discussed in this review, reporting the current knowledge about pathophysiologic mechanisms and implications for management.

Mesoglycan: Clinical Evidences for Use in Vascular Diseases

Vascular glycosaminoglycans (GAG) are essential components of the endothelium and vessel wall and have been shown to be involved in several biologic functions. Mesoglycan, a natural GAG preparation, is a polysaccharide complex rich in sulphur radicals with strong negative electric charge. It is extracted from porcine intestinal mucosa and is composed of heparan sulfate, dermatan sulfate, electrophoretically slow-moving heparin, and variable and minimal quantities of chondroitin sulfate. Data on antithrombotic and profibrinolytic activities of the drug show that mesoglycan, although not indicated in the treatment of acute arterial or venous thrombosis because of the low antithrombotic effect, may be useful in the management of vascular diseases, when combined with antithrombotics in the case of disease of cerebral vasculature, and with antithrombotics and vasodilator drugs in the case of chronic peripheral arterial disease. The protective effect of mesoglycan in patients with venous thrombosis and the absence of side effects, support the use of GAG in patients with chronic venous insufficiency and persistent venous ulcers, in association with compression therapy (zinc bandages, multiple layer bandages, etc.), elastic compression stockings, and local care, and in the prevention of recurrences in patients with previous DVT following the standard course of oral anticoagulation treatment.

Noninvasive assessment of liver fibrosis in patients with chronic hepatitis C (and congenital bleeding disorders): where do we stand?

The assessment and monitoring of liver fibrosis (LF) is a key issue in the management and definition of prognosis of patients with chronic hepatitis C (CHC). In this respect, despite recognized limitations (invasive nature, sampling errors, interobserver variability, nondynamic evaluation of LF), liver biopsy is traditionally considered the reference standard. These limitations stimulated the search for noninvasive approaches for the assessment of LF, particularly attractive in patients with hemophilia and other congenital bleeding disorders (CBD). In patients with congenital bleeding disorders (CBD), who often suffer from CHC because of the past use of nonvirally inactivated plasma-derived products, the risk of bleeding hamper to routinely obtain histological data for LF staging. A variety of methods have been proposed and, in some cases, validated in patients with CHC and other liver diseases, including biomarkers directly or indirectly associated with LF, often combined in scores or algorithms, and the more recently developed physical approaches, evaluating the properties of the liver parenchyma with instrumental techniques studying the propagation of specific signals, that is, transient elastography (TE), acoustic radiation force impulse imaging elastography, and magnetic resonance elastography. This review will describe the available strategies for noninvasive assessment of LF, with more details on the latter promising instrumental approaches. Moreover, although lacking of validation against liver biopsy, recent studies extending the use of noninvasive methods (particularly TE) in the setting of patients with CBD will be discussed.

Management of bleeding in acquired haemophilia A with recombinant activated factor VII: does one size fit all? A report of four cases.

Acquired haemophilia A (AHA) is a rare but clinically relevant bleeding disorder due to autoantibodies (inhibitors) against coagulation factor VIII (FVIII)1–3. AHA is usually triggered by infections, malignancies, autoimmune diseases, or pregnancy. Some cases associated with drug intake have also been described, but about half of cases remain unexplained and are classified as “idiopathic”. According to a 2-year prospective surveillance study from the UK, the incidence is approximately 1.5 cases per million persons per year1; the condition is most frequent in the elderly and the reported median age of affected individuals is above 70 years1,4,5. This acquired bleeding disorder should be suspected in subjects without a personal or family history of bleeding who have unexplained haemorrhages, prolonged activated partial thromboplastin time (APTT) and a normal prothrombin time. A mixing test which does not correct the APTT, in the absence of lupus anticoagulant and heparin administration, together with low FVIII levels and circulating FVIII inhibitor, confirm the diagnosis3. In the majority of cases bleeding is spontaneous and can range from mild to life-threatening1,3–5. Bleeding sites in patients with AHA differ from those associated with congenital haemophilia, traumatic muscle bleeds and haemarthroses being uncommon. Indeed, most events are spontaneous subcutaneous, deep muscle and retroperitoneal bleeds, although mucosal (gastrointestinal, lung, urogenital) and intracranial bleeds also occur. Bleeding is the main cause of death in the early phase of AHA and its severity does not correlate strictly with FVIII levels or inhibitor titre. The management of AHA is directed at controlling the bleeding, eradicating inhibitors in order to prevent subsequent haemorrhagic complications, and treating any underlying associated disease2,3. Early treatment of bleeds is recommended. Available haemostatic agents do not have predictable efficacy; therefore, clinical review by physicians experienced in the management of inhibitors, supported by appropriate imaging and laboratory studies, is important6–8. Among the different approaches to control haemorrhages in AHA patients, the use of desmopressin and antifibrinolytics is mostly anecdotal and reserved only for minor bleeding. In selected cases FVIII concentrates, either recombinant or plasma-derived, could be appropriate9. According to international recommendations, bypassing agents, i.e. recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC), are considered the first-line approach for the treatment of bleeding episodes6,7. The dosages and regimens of rFVIIa (Novoseven®) that have been reportedly used in AHA are widely heterogeneous3,10–13, but current recommendations suggest bolus administrations of 90 μg/kg every 2–3 hours, until haemostasis is achieved6–7, similar to the treatment in patients with congenital haemophilia and inhibitors. The largest available collection of treatment records, the European Acquired Haemophilia (EACH2) registry, showed consistent concordance among physicians (rFVIIa dosage range 84.7–102.9 μg/kg every 2–6 hours)13. Unfortunately, due to the rarity of AHA, no methodologically rigorous study has been conducted to determine the most effective and safest dosage in this setting. Bypassing agents are generally well tolerated in AHA patients, although severe thrombotic complications may occur, such as myocardial infarction, disseminated intravascular coagulation, arterial and venous thrombosis, pulmonary embolism and stroke11,13. Although a causal relationship between bypassing agents and such thrombotic complications cannot be established in most cases, caution is required, in particular taking into account that the elderly age and frequent comorbidities of patients treated with these agents increase the risk of thromboembolism3,9,14. Here we describe four patients with AHA whose bleeds were treated with lower dosages and/or longer intervals of bolus administrations of rFVIIa than those recommended. These regimens were chosen because of the high risk of thrombotic complications, given the patients’ risk profile, concomitant with the need to treat severe, even life-threatening, haemorrhagic events.

The challenge of diagnosing pulmonary embolism in children, pregnant women, and elderly patients: a descriptive review of the literature.

The prompt and accurate diagnosis of pulmonary embolism (PE) greatly influences patient outcomes. However, diagnosing PE is one of the most difficult challenges confronting physicians, even more so when the clinical suspicion is addressed in children, during pregnancy, or in elderly patients. In these patient groups, symptoms and signs from concomitant conditions or diseases may mimic PE and make difficult defining clinical probability categories for PE as usually applied to general adult patients. Moreover, the diagnostic techniques show wider, specific limitations in these settings. PE is considered rare in children. The diagnostic management of a child with suspected PE is largely extrapolated from the knowledge achieved in adult patients. An increased risk of venous thromboembolism is reported in all trimesters of pregnancy and in the puerperium. An accurate diagnosis of PE in pregnancy has important implications, including the need for prolonged anticoagulation, delivery planning, and prophylaxis during future pregnancies, as well as concerns about future oral contraceptive use and estrogen therapy. Although incidence, morbidity, and mortality increase steadily with age, PE remains an underdiagnosed disease in elderly patients. About 40% of PE found at necropsy were not suspected antemortem. In the present article, challenges in diagnosing PE in children, during pregnancy, and in the elderly will be discussed, reviewing the available clinical, laboratory, and instrumental diagnostic strategies.

Acquired Hemophilia: An Overview on Diagnosis and Treatment

Acquired hemophilia (AH) is a rare but severe bleeding diathesis characterized by autoantibodies against a clot- ting factor, in most cases Factor VIII (FVIII). This bleeding disorder occurs more frequently in the elderly and may be as- sociated with several conditions, such as malignancies, autoimmune diseases, postpartum or drugs; however, about half of cases remain idiopathic. At variance with congenital hemophilia, in which hemarthroses are the most common bleeding manifestations, in patients with AH hemorrhages involving soft tissues (muscle, skin) are more frequently reported. AH is diagnosed in patients without previous personal or family bleeding history in which prolonged activated partial throm- boplastin time is not corrected after mixing and incubating for 2-4 hours at 37°C equal volumes of patient and normal plasma, FVIII:C levels are reduced and a specific FVIII inhibiting activity is detected and measured by the Bethesda assay or its Nijmegen modification. A prompt recognition of this life-threatening bleeding disorder and an early and aggressive treatment are mandatory, as diagnostic delays or inadequate treatments are associated with high mortality rates (up to 44% in literature). Therapeutic approach of AH is devoted to stop acute bleeds and to eradicate the FVIII autoantibody. Bleed- ing episodes can be treated with FVIII concentrates or desmopressin in patients with low titer inhibitors, but FVIII bypass- ing agents (activated prothrombin complex concentrates and recombinant activated FVIIa) are required for those with high-titer inhibitors or more severe bleeds. Steroids alone or in combination with cyclophosphamide are effective for eradicating autoantibodies in most cases. More recently, increasing evidence suggests a role for rituximab in this setting, in particular as a second-line approach.

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