Ernesto Cimino

Longer‐acting factor VIII to overcome limitations in haemophilia management: the PEGylated liposomes formulation issue

Summary.  Injected factor VIII (FVIII), the current treatment for haemophilia A, leads to major improvements in the quality of life and life expectancy of individuals with this disorder. However, because injected FVIII has a short half‐life in vivo, this strategy has major limitations for highly demanding regimens (e.g. prophylaxis, immune tolerance induction, surgery). Newer formulations of longer‐acting FVIII are presently under investigation. The use of low molecular weight polyethylene glycol (PEG)‐containing liposomes as carriers for recombinant FVIII (rFVIII) results in the prolongation of haemostatic efficacy. Data from preclinical experiments in mice, early clinical evaluations, and pharmacokinetics and pharmacodynamics results indicate that an rFVIII pegylated liposomal formulation may provide potential clinical benefit to patients with severe haemophilia A by prolonging the protection from bleeding. In light of this potential clinical benefit, a multicentre, randomized, active‐controlled, non‐inferiority phase II trial with two parallel treatment arms and equal randomization after stratification for the presence or absence of target joints in patients and for ages ≥18 years vs. <18 years is currently being conducted. The study will test the hypothesis that rFVIII‐Lip once‐weekly prophylaxis is not inferior to rFVIII‐water for injection thrice‐weekly prophylaxis. A total of 250 patients will be enrolled with severe haemophilia A (<1% FVIII) on on‐demand or secondary prophylaxis treatment and with documented bleeds or injections during the 6 months before study entry. Sixty‐four centres in 14 different countries are involved in the study; recruitment is underway. In Italy, six centres have already included 15 patients (no screening failure). Eight of these patients have completed the run‐in phase and have begun the home treatment. No unexpected serious adverse events have been reported thus far. Data emerging from this phase II study will help collect relevant data to overcome current limitations in haemophilia management by employing treatment with longer‐acting rFVIII.

Acquired Haemophilia A in the Elderly: Case Reports

Acquired hemophilia A (AHA) is a very rare disease, caused by the development of autoantibodies, directed against circulating factor VIII of coagulation. Age distribution is bimodal, with a first peak occurring among young women in the postpartum period, and a second major peak of incidence among elderly patients in whom it is frequently associated with malignancy and drugs. This disease often represents a life-threatening bleeding condition, especially in the elderly, thus requiring a prompt therapeutic intervention, including control of acute bleeding and eradication of the inhibitor by immunosuppressive therapy. The diagnosis of AHA should be considered in any elderly patient who presents with bleeding and prolonged activated Partial Thromboplastin Time. Moreover, the coexistence of a series of underlying diseases associated with AHA should be always searched for. An early recognition and an adequate treatment of this coagulation disorder and of the possible associated diseases play a significant role for a favourable outcome, but concomitant morbidities in the elderly may limit aggressive therapy and may complicate the clinical scenario. We report 3 consecutive elderly patients successfully treated with recombinant activated factor VII and standard immunosuppressive regimens, with remission of the disease.

Diabetes Mellitus and Cardiovascular Prevention: The Role and the Limitations of Currently Available Antiplatelet Drugs

Diabetes mellitus (DM) is associated with macrovascular and microvascular complications. Platelets have a “key role” in atherogenesis and its thrombotic complications in subjects with DM. Moreover, the concomitant presence of multiple “classical” cardiovascular risk factors in diabetic subjects contributes to enhanced atherothrombotic risk. Antiplatelet agents are effective in primary and secondary prevention of arterial thrombosis (cardiovascular events, ischaemic stroke, and peripheral arterial occlusive disease). The role of chronic administration of antiplatelet drugs in primary prevention of arterial vascular events is known to be less clear than in secondary prevention, and, also in diabetic patients, the decision to give primary prophylaxis should be taken on an individual-patient basis, after a careful evaluation of the balance between the expected benefits and the risk of major bleedings. Although, currently, treatment has proven useful in reducing vascular events, diabetic patients continue to have a higher risk of adverse cardiovascular events compared with those in nondiabetic patients. This paper reviews the role of currently available antiplatelet drugs in primary and secondary prevention of vascular events in diabetic patients and the limitations of these drugs, and it discusses the role of novel and more potent antiplatelets and of new agents currently under clinical development.

Acute coronary syndrome and severe haemophilia: An unusual association with challenging treatment

Acute coronary syndrome and severe haemophilia: An unusual association with challenging treatment -

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.

Can serum TGF-beta 1 be used to evaluate the response to antiviral therapy of haemophilic patients with HCV-related chronic hepatitis?

Congenital coagulation disorders limit the use of liver biopsy, especially when repeated assessment is needed. TGF-beta 1 plays a pivotal role in inducing fibrosis and has been proposed as its surrogate marker. Aiming at validating the clinical utility of this cytokine, fifteen haemophilic patients suffering from HCV-related chronic hepatitis were treated with Peg-IFN alpha2β plus Ribavirin. Serum TGF-beta 1, viral load and liver enzymes were analyzed at baseline and at six, twelve, and eighteen months. As expected, patients initially showed significantly higher TGF-beta 1 levels than age-matched controls (43.8 ng/mL, 28.7–46.4 vs. 26.9 ng/mL, 23.0–34.0, median and 95% CI; p=0.004). The end of therapy response rate was 67%. The main finding was a significant drop in TGF-beta 1 at six months compared to baseline values; this drop de facto predicted the levels reached in the following six months, which were fixed at lower concentrations (37.0 ng/mL, 21.9–43.8 and 27.0 ng/mL, 24.1–44.0 respectively; p<0.009), independently of treatment outcome (three patients were breakthrough, twelve were sustained virological responders (SVRs). During the treatment period none had clinical or biochemical signs of inflammation in other areas. Treatment was followed by a six-month follow-up, at the end of which TGF-beta 1 was increased compared to the previous values, reaching the initial levels in ten SVRs (45 ng/mL, 24.5–52.9). Interestingly, at a longer follow-up, two out of ten SVRs, who displayed the highest values of TGF-beta 1, relapsed. Serum TGF-beta 1 could be used to assess therapeutic outcome and short-term prognosis of HCV-related chronic hepatitis.

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.

Safety of Switching Factor VIII Products in the Era of Evolving Concentrates: Myths and Facts

Recent advances in the development of factor VIII (FVIII) concentrates offer patients with hemophilia the opportunity to switch to products considered safer or with improved properties. In some cases, product switch occurs due to side effects, convenience issues, or economic reasons affecting clinical choices. Reluctance to change FVIII concentrates is shown by patients and also by their physicians, because of concerns in particular about the risk of inhibitor development. A literature review was performed to retrieve the best evidence regarding safety issues of switching FVIII concentrate in patients with severe hemophilia A. Product switch was not associated with an increased inhibitor risk in four studies in patients during the first 50 to 75 exposure days, or in three studies reporting national switches in Canada and United Kingdom. The latter, the only available study comparing switcher and nonswitcher patients, showed an inhibitor incidence similar to that historically reported in the United Kingdom. In 16 phase III clinical trials and 6 postmarketing studies of FVIII concentrates, few de novo inhibitors were detected in previously treated patients, mostly transient and low-titer, with some additional recurrent inhibitors in patients with previous positive testing. On the whole, although rigorous controlled studies are lacking, literature data do not support increased risk of inhibitor development or other safety issues related to product switch. Therefore, in the presence of clinical needs, the advantages of switching FVIII products should not be missed because of perceived more than evidence-based challenges, in particular in this era of products with improved properties recently introduced or available in few years. Caution, however, is suggested in patients with high inhibitor risk, including in those in concomitance with surgery or intensive treatment. A careful inhibitor testing prior to and after product switch is always needed, to identify real de novo inhibitors and to gather further information in the current evolving scenario, in particular comparing switch and nonswitch patients.

Successful and Safe Long-Term Standard Antiviral Therapy in a Patient with "Explosive" Immune Response in Course of HCV-Related Liver Cirrhosis

Hepatitis C virus (HCV) has been recognized to be both a hepato- and lymphotropic virus. HCV lymphotropism represents an essential detail in the pathogenesis of virus-related autoimmune and lymphoproliferative disorders, ranging from clonal expansion of B-cells with organ and non-organ-specific autoantibody production up to overt non-Hodgkin’s lymphoma along a continuous step-by-step model of B-cell lymphomagenesis, where the intermediated mixed cryoglobulinemia could be considered as a stage of suppressible antigen-driven lymphoproliferation. The HCV long-lasting extrahepatic replicative state generates an abnormal systemic immunological response, including rheumatoid factor (RF) and cryo- and non-cryoprecipitable immune complexes, as well as clinical manifestations, comprising dermatitis, polyarthralgias and arthritis, pulmonary disease, aplastic anemia, glomerulonephritis and vasculitis. The mechanism of these extra-hepatic disorders is thought of as linked to immune complex disease, but their pathogenesis is poorly clarified. Immune-suppressive treatment could induce high-level hepatitis C viremia and impair hepatic disease. We report a female patient, whose chronic HCV-related liver cirrhosis with associated explosive, but oligosymptomatic lymphoproliferative immune response, i.e., RF beyond three thousand times the upper of normal range (unr), type II cryoglobulinemia with cryocrit 40% and monoclonal gammopathy IgM-k, has been successfully and safely treated by long-lasting (sixty-six months) combined antiviral therapy (pegylated interferon alfa and ribavirin), at moderate and tapering dose regimen, prolonged for nearly 24 months after the first viral suppression. At the last follow-up (fifty-one months), the patient was showing very-long term antiviral response, progressive decline of secondary immune activation and absence of significant side-effects. Further research is required to fully verify the real impact on therapeutic choice/regimen.

Budd-Chiari syndrome in a paroxysmal nocturnal hemoglobinuria patient with previous cerebral venous thrombosis

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal stem cell disorder characterized by intravascular hemolytic anemia that results from the clonal expansion of hematopoietic stem cells harboring somatic mutations in an X-linked gene, termed PIG-A (phosphatidylinositol glycan class A). PIG-A mutations block glycosylphosphatidylinositol (GPI) anchor biosynthesis, resulting in a deficiency or absence of all GPI-anchored proteins on the cell surface. CD55 and CD59 are GPI-anchored complement regulatory proteins. Their absence on PNH red cells is responsible for the complement-mediated intravascular hemolysis, leading to the release of free hemoglobin, which contributes to many of the clinical manifestations of PNH including fatigue, pain, esophageal spasm and possibly serious thrombotic episodes [1]. Allogeneic hematopoietic stem cell transplantation is the only curative therapy for PNH. The complement inhibitor eculizumab, a humanized monoclonal antibody against C5, that inhibits terminal complement activation, recently approved in the US, has been shown to reduce hemolysis, decrease the erythrocyte transfusion requirements and the risk for thrombosis, and to improve quality of life of PNH patients [2, 3]. Major morbidity and mortality with PNH are often ascribed to the development of venous thromboembolism (VTE) [1–6], and several patients have recurrent thromboses [7]. VTE in PNH patients occur mostly at unusual sites. Data from a recent review report hepatic vein thrombosis, leading to Budd-Chiari syndrome (BCS), as the most frequent (40.7%) thrombotic complication, accounting for the majority of deaths [8], followed by cerebral vein and sinus thromboses, superior sagittal sinus being the most frequently involved site [8]. Inherited thrombophilia may increase the risk of serious thromboembolic events in PNH patients [9]. In patients experiencing VTE, early anti-thrombotic therapy (heparin, thrombolysis) aimed to limit the extension of thrombosis, or to dissolve formed thrombi, should improve the prognosis of this severe complication. PNH patients suffering from VTE should be treated with anticoagulant drugs indefinitely [1]. Thrombocytopenia often complicates PNH, and this issue must be addressed when an anticoagulation management plan is formulated [1]. Recurrent, life-threatening thrombosis merits consideration for bone marrow transplantation (BMT) [1]. Over the past few years significant advances in other therapeutic approaches, such as transjugular intrahepatic portosystemic shunt (TIPS), have contributed to the improvement of survival in this setting [8]. We report the case of a 29-year-old woman, R. D. The family history was negative for VTE and cardiovascular disease. She was a non-smoker. And had been slightly overweight since childhood. When she was 19 years old, an isolated moderate thrombocytopaenia (50,000/mmc) was detected although in the absence of bleeding. As idiopathic thrombocytopaenia was diagnosed, she was treated with long-term steroids, with an improvement in the platelet count (120,000/mmc). At the age of 27, while on oral contraceptives for 3 months, she experienced a sudden occurrence of headache and visual loss, followed by seizures and coma. A computed tomography (CT scan) showed multiple cerebral venous thromboses. Screenings A. Tufano (&) N. Macarone Palmieri E. Cimino A. M. Cerbone Regional Reference Centre for Coagulation Disorders, Department of Clinical and Experimental Medicine, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy e-mail: atufano@unina.it