Case reports Case 1 A 79-year old male presented with recent-onset haematuria, easy bruising and ... more Case reports Case 1 A 79-year old male presented with recent-onset haematuria, easy bruising and muscle hematomas of the lower limbs. He had a history of moderate renal All rights reserved-For personal use only No other use without premission
Background: The prevalence of thrombophilic abnormalities in patients with cerebral vein thrombos... more Background: The prevalence of thrombophilic abnormalities in patients with cerebral vein thrombosis has been reported to be similar to that in patients with deep vein thrombosis of the lower limb. The role of gender-specific risk factors (pregnancy, oral contraceptives) is well established, whereas that of other acquired risk conditions is debated. Materials and methods: We screened 56 patients with cerebral vein thrombosis and 184 age- and sex-matched apparently healthy controls for prothrombin (factor II, FII) G20210A and factor V Leiden polymorphisms; protein S, protein C, and antithrombin deficiency; anticardiolipin antibodies; hyperhomocysteinaemia and other putative risk factors. Results: The G20210A polymorphism was found in 29.1% of patients and in 5.7% of controls (odds ratio [OR] 7.1; P<0.0001; adjusted OR 12.67, P<0.0001). Frequencies of factor V Leiden and hyperhomocysteinaemia were not significantly different in patients and controls, nor were the other thrombophilic tests and some established cardiovascular risk factors, such as smoking, obesity or overweight and arterial hypertension. Conversely, 53.7% of the women who developed cerebral vein thrombosis did so while assuming oral contraceptives (OR 6.12; P<0.0001), with a further increase of risk in FII G20210A carriers (OR 48.533). Some associated diseases (onco-haematological disorders and infections) also had a significant role. Over a median 7-year follow-up, irrespective of the duration of antithrombotic treatment, 9/56 (16%) patients had further episodes of venous/arterial thrombosis. No significant risk factor for recurrent thrombosis was identified. Discussion: In spite of the limitations of the sample size, our data confirm the role of FII G20210A mutation in this setting and its interactions with acquired risk factors such as oral contraceptives, also highlighting the risk of recurrent thrombosis in cerebral vein thrombosis patients.
Starting from the clinical observations that moderate haemophiliacs experienced only few bleeding... more Starting from the clinical observations that moderate haemophiliacs experienced only few bleeding episodes and rarely developed significant joint deterioration (haemophilic arthropathy), and the pioneer experience in Sweden, prophylaxis (i.e. the regular and long-term administration of clotting factor concentrate in order to prevent bleeding) has been practiced for more than forty years in severe haemophilia and is currently recommended as the first choice of treatment by the World Health Organisation and World Federation of Hemophilia and by many national medical/scientific organizations. Observational studies clearly established the superiority of prophylaxis over on-demand treatment in reducing the risk of arthropathy, also showing that starting prophylaxis earlier in life and after very few joint bleeds was associated with better joint outcomes, and led to the current definitions of primary (started before the age of 2 yrs and after no more than one joint bleed) and secondary prophylaxis. More recently, evidences from randomized trials, which were previously lacking in this setting, were also provided. This review summarizes available data from which current clinical practice of primary (and early secondary) prophylaxis in children with severe haemophilia was drawn. Open issues concerning optimal regimens and barriers to the implementation of prophylaxis are also discussed.
Seminars in Thrombosis and Hemostasis, Nov 1, 2011
A variety of disease- and treatment-related factors affect the coagulation system and the risk of... more 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.
Severe acute respiratory syndromerelated coronavirus 2 (SARS-CoV-2) infection has spread worldwid... more Severe acute respiratory syndromerelated coronavirus 2 (SARS-CoV-2) infection has spread worldwide. The most of patients presents fever, dyspnea and cough as a typical viral infection, others show peculiar clinical and laboratory signs, such as anosmia, ageusia and thrombocytopenia. We here describe a severe coronavirus disease 2019 patient (76-year old, male) that developed an immune thrombocytopenia and acquired pseudo-thrombocytopenia that were refractory to immunomodulators even after resolution of respiratory failure. The patient developed thrombocytopenia (platelets 88,000/mm 3) that got worse the following day (14,000/mm 3). We started 1 mg/kg of methylprednisolone i.v. daily. Platelet count increased up to 209,000/mm 3 , in sodium citrate, but remained about 14,000/mm 3 in EDTA 10 days after the beginning of methylprednisolone. The patient showed great improvement in respiratory parameters and radiological finding. About one week after he developed a thrombocytopenia up to 70,000/mm 3. We did not modify the steroids dosage. Platelet count slowly began to increase and in about 10 days returned to normal values.
Seminars in Thrombosis and Hemostasis, Nov 1, 2011
The prompt and accurate diagnosis of pulmonary embolism (PE) greatly influences patient outcomes.... more 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.
Injected factor VIII (FVIII), the current treatment for haemophilia A, leads to major improvement... more 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.
In Western countries, the treatment of patients with inhibitors is presently the most challenging... more In Western countries, the treatment of patients with inhibitors is presently the most challenging and serious issue in haemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the healthcare of patients in this setting. Being designed to address questions of resource allocation and effectiveness, decision models are the golden standard to reliably assess the overall economic implications of haemophilia with inhibitors in terms of mortality, bleeding-related morbidity, and severity of arthropathy. However, presently, most data analyses stem from retrospective short-term evaluations, that only allow for the analysis of direct health costs. In the setting of chronic diseases, the cost-utility analysis, that takes into account the beneficial effects of a given treatment/healthcare intervention in terms of healthrelated quality of life, is likely to be the most appropriate approach. To calculate net benefits, the quality adjusted life year, that significantly reflects such health gain, has to be compared with specific economic impacts. Differences in data sources, in medical practice and/or in healthcare systems and costs, imply that most current pharmacoeconomic analyses are confined to a narrow healthcare payer perspective. Long-term/lifetime prospective or observational studies, devoted to a careful definition of when to start a treatment; of regimens (dose and type of product) to employ, and of inhibitor population (children/adults, low-responding/high responding inhibitors) to study, are thus urgently needed to allow for newer insights, based on reliable data sources into resource allocation, effectiveness and cost-utility analysis in the treatment of haemophiliacs with inhibitors.
Replacement of the congenitally deficient factor VIII or IX through plasma-derived or recombinant... more 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.
Vascular glycosaminoglycans (GAG) are essential components of the endothelium and vessel wall and... more 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.
Seminars in Thrombosis and Hemostasis, Feb 1, 2012
Recurrent joint bleeding leading to progressive musculoskeletal damage (hemophilic arthropathy), ... more 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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.
The Open atherosclerosis & thrombosis journal, Jun 25, 2009
Acquired hemophilia (AH) is a rare but severe bleeding diathesis characterized by autoantibodies ... more Acquired hemophilia (AH) is a rare but severe bleeding diathesis characterized by autoantibodies against a clotting factor, in most cases Factor VIII (FVIII). This bleeding disorder occurs more frequently in the elderly and may be associated 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 thromboplastin 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. Bleeding episodes can be treated with FVIII concentrates or desmopressin in patients with low titer inhibitors, but FVIII bypassing 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.
Acute bowel ischemia is a severe disease often with a poor outcome. Early diagnosis can improve o... more Acute bowel ischemia is a severe disease often with a poor outcome. Early diagnosis can improve outcome, but atypical clinical manifestations and nonspecific laboratory and instrumental diagnostic findings may delay computed tomographic angiography (CTA). Portomesenteric venous gas (PVG), indirect sign of pneumatosis intestinalis, is considered a late finding with poor prognosis. We report four cases where PVG, easily identified through point-of-care ultrasonography (POCUS), was an early sign of bowel ischemia leading to a precocious diagnosis confirmed at CTA. In acute non-traumatic abdominal pain, an evidence of PVG could be an early ultrasonographic finding of bowel ischemia in the emergency department.
Italy was the first Western country to face a massive SARS-CoV-2 outbreak. The limited informatio... more Italy was the first Western country to face a massive SARS-CoV-2 outbreak. The limited information initially available on the natural course of the disease required caution in the discharge of patients accessing health facilities. This resulted in overcrowded health facilities and emergency services. In this context, improvements of other forms of hospital care assistance were needed. This study shows the results of the first Italian remote monitoring program for COVID-19 patients. The program was implemented by the Azienda Socio Sanitaria (ASST) Lodi (Italy) by using the innovative Zcare software®. Data generated during patient recruitment, monitoring, and discharge were extracted from the Zcare software and statistically analysed. Data refer to a sample of 1196 patients enrolled in the remote monitoring program in 2020. Patients reported symptoms mainly during the first week. The most frequently reported symptoms were general fatigue, cough, and loss of taste and smell (dysosmia)....
Case reports Case 1 A 79-year old male presented with recent-onset haematuria, easy bruising and ... more Case reports Case 1 A 79-year old male presented with recent-onset haematuria, easy bruising and muscle hematomas of the lower limbs. He had a history of moderate renal All rights reserved-For personal use only No other use without premission
Background: The prevalence of thrombophilic abnormalities in patients with cerebral vein thrombos... more Background: The prevalence of thrombophilic abnormalities in patients with cerebral vein thrombosis has been reported to be similar to that in patients with deep vein thrombosis of the lower limb. The role of gender-specific risk factors (pregnancy, oral contraceptives) is well established, whereas that of other acquired risk conditions is debated. Materials and methods: We screened 56 patients with cerebral vein thrombosis and 184 age- and sex-matched apparently healthy controls for prothrombin (factor II, FII) G20210A and factor V Leiden polymorphisms; protein S, protein C, and antithrombin deficiency; anticardiolipin antibodies; hyperhomocysteinaemia and other putative risk factors. Results: The G20210A polymorphism was found in 29.1% of patients and in 5.7% of controls (odds ratio [OR] 7.1; P<0.0001; adjusted OR 12.67, P<0.0001). Frequencies of factor V Leiden and hyperhomocysteinaemia were not significantly different in patients and controls, nor were the other thrombophilic tests and some established cardiovascular risk factors, such as smoking, obesity or overweight and arterial hypertension. Conversely, 53.7% of the women who developed cerebral vein thrombosis did so while assuming oral contraceptives (OR 6.12; P<0.0001), with a further increase of risk in FII G20210A carriers (OR 48.533). Some associated diseases (onco-haematological disorders and infections) also had a significant role. Over a median 7-year follow-up, irrespective of the duration of antithrombotic treatment, 9/56 (16%) patients had further episodes of venous/arterial thrombosis. No significant risk factor for recurrent thrombosis was identified. Discussion: In spite of the limitations of the sample size, our data confirm the role of FII G20210A mutation in this setting and its interactions with acquired risk factors such as oral contraceptives, also highlighting the risk of recurrent thrombosis in cerebral vein thrombosis patients.
Starting from the clinical observations that moderate haemophiliacs experienced only few bleeding... more Starting from the clinical observations that moderate haemophiliacs experienced only few bleeding episodes and rarely developed significant joint deterioration (haemophilic arthropathy), and the pioneer experience in Sweden, prophylaxis (i.e. the regular and long-term administration of clotting factor concentrate in order to prevent bleeding) has been practiced for more than forty years in severe haemophilia and is currently recommended as the first choice of treatment by the World Health Organisation and World Federation of Hemophilia and by many national medical/scientific organizations. Observational studies clearly established the superiority of prophylaxis over on-demand treatment in reducing the risk of arthropathy, also showing that starting prophylaxis earlier in life and after very few joint bleeds was associated with better joint outcomes, and led to the current definitions of primary (started before the age of 2 yrs and after no more than one joint bleed) and secondary prophylaxis. More recently, evidences from randomized trials, which were previously lacking in this setting, were also provided. This review summarizes available data from which current clinical practice of primary (and early secondary) prophylaxis in children with severe haemophilia was drawn. Open issues concerning optimal regimens and barriers to the implementation of prophylaxis are also discussed.
Seminars in Thrombosis and Hemostasis, Nov 1, 2011
A variety of disease- and treatment-related factors affect the coagulation system and the risk of... more 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.
Severe acute respiratory syndromerelated coronavirus 2 (SARS-CoV-2) infection has spread worldwid... more Severe acute respiratory syndromerelated coronavirus 2 (SARS-CoV-2) infection has spread worldwide. The most of patients presents fever, dyspnea and cough as a typical viral infection, others show peculiar clinical and laboratory signs, such as anosmia, ageusia and thrombocytopenia. We here describe a severe coronavirus disease 2019 patient (76-year old, male) that developed an immune thrombocytopenia and acquired pseudo-thrombocytopenia that were refractory to immunomodulators even after resolution of respiratory failure. The patient developed thrombocytopenia (platelets 88,000/mm 3) that got worse the following day (14,000/mm 3). We started 1 mg/kg of methylprednisolone i.v. daily. Platelet count increased up to 209,000/mm 3 , in sodium citrate, but remained about 14,000/mm 3 in EDTA 10 days after the beginning of methylprednisolone. The patient showed great improvement in respiratory parameters and radiological finding. About one week after he developed a thrombocytopenia up to 70,000/mm 3. We did not modify the steroids dosage. Platelet count slowly began to increase and in about 10 days returned to normal values.
Seminars in Thrombosis and Hemostasis, Nov 1, 2011
The prompt and accurate diagnosis of pulmonary embolism (PE) greatly influences patient outcomes.... more 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.
Injected factor VIII (FVIII), the current treatment for haemophilia A, leads to major improvement... more 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.
In Western countries, the treatment of patients with inhibitors is presently the most challenging... more In Western countries, the treatment of patients with inhibitors is presently the most challenging and serious issue in haemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the healthcare of patients in this setting. Being designed to address questions of resource allocation and effectiveness, decision models are the golden standard to reliably assess the overall economic implications of haemophilia with inhibitors in terms of mortality, bleeding-related morbidity, and severity of arthropathy. However, presently, most data analyses stem from retrospective short-term evaluations, that only allow for the analysis of direct health costs. In the setting of chronic diseases, the cost-utility analysis, that takes into account the beneficial effects of a given treatment/healthcare intervention in terms of healthrelated quality of life, is likely to be the most appropriate approach. To calculate net benefits, the quality adjusted life year, that significantly reflects such health gain, has to be compared with specific economic impacts. Differences in data sources, in medical practice and/or in healthcare systems and costs, imply that most current pharmacoeconomic analyses are confined to a narrow healthcare payer perspective. Long-term/lifetime prospective or observational studies, devoted to a careful definition of when to start a treatment; of regimens (dose and type of product) to employ, and of inhibitor population (children/adults, low-responding/high responding inhibitors) to study, are thus urgently needed to allow for newer insights, based on reliable data sources into resource allocation, effectiveness and cost-utility analysis in the treatment of haemophiliacs with inhibitors.
Replacement of the congenitally deficient factor VIII or IX through plasma-derived or recombinant... more 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.
Vascular glycosaminoglycans (GAG) are essential components of the endothelium and vessel wall and... more 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.
Seminars in Thrombosis and Hemostasis, Feb 1, 2012
Recurrent joint bleeding leading to progressive musculoskeletal damage (hemophilic arthropathy), ... more 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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.
The Open atherosclerosis & thrombosis journal, Jun 25, 2009
Acquired hemophilia (AH) is a rare but severe bleeding diathesis characterized by autoantibodies ... more Acquired hemophilia (AH) is a rare but severe bleeding diathesis characterized by autoantibodies against a clotting factor, in most cases Factor VIII (FVIII). This bleeding disorder occurs more frequently in the elderly and may be associated 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 thromboplastin 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. Bleeding episodes can be treated with FVIII concentrates or desmopressin in patients with low titer inhibitors, but FVIII bypassing 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.
Acute bowel ischemia is a severe disease often with a poor outcome. Early diagnosis can improve o... more Acute bowel ischemia is a severe disease often with a poor outcome. Early diagnosis can improve outcome, but atypical clinical manifestations and nonspecific laboratory and instrumental diagnostic findings may delay computed tomographic angiography (CTA). Portomesenteric venous gas (PVG), indirect sign of pneumatosis intestinalis, is considered a late finding with poor prognosis. We report four cases where PVG, easily identified through point-of-care ultrasonography (POCUS), was an early sign of bowel ischemia leading to a precocious diagnosis confirmed at CTA. In acute non-traumatic abdominal pain, an evidence of PVG could be an early ultrasonographic finding of bowel ischemia in the emergency department.
Italy was the first Western country to face a massive SARS-CoV-2 outbreak. The limited informatio... more Italy was the first Western country to face a massive SARS-CoV-2 outbreak. The limited information initially available on the natural course of the disease required caution in the discharge of patients accessing health facilities. This resulted in overcrowded health facilities and emergency services. In this context, improvements of other forms of hospital care assistance were needed. This study shows the results of the first Italian remote monitoring program for COVID-19 patients. The program was implemented by the Azienda Socio Sanitaria (ASST) Lodi (Italy) by using the innovative Zcare software®. Data generated during patient recruitment, monitoring, and discharge were extracted from the Zcare software and statistically analysed. Data refer to a sample of 1196 patients enrolled in the remote monitoring program in 2020. Patients reported symptoms mainly during the first week. The most frequently reported symptoms were general fatigue, cough, and loss of taste and smell (dysosmia)....
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Papers by Mirko Di Capua