Major Orthopaedic Surgery in Persons with Haemophilia A with and without Inhibitors Treated by Emicizumab: A Mid-Term, Large, and Successful Series at a Single Center.

Introduction: Patients with Haemophilia (PWH) need orthopaedic treatments and often they undergo surgery. Classically, PWH with inhibitors have to face such procedures earlier than other patients. Major orthopaedic surgery is not easy and complications are frequent. Emicizumab is the first monoclonal antibody introduced for haematological prophylaxis for PWH with inhibitors, achieving an efficacious haemostasis also in patients with severe haemophilia A with inhibitors, later demonstrated for PWH without inhibitors. A few years ago, emicizumab was also proposed for PWH undergoing surgery, as it supports excellent bleeding control. The literature on orthopaedic surgery using an emicizumab protocol is scarce: only isolated case reports with short-term follow-ups are available. Aim: The purpose of this study is the assessment of the mid-term outcomes of major orthopaedic surgery performed in a population of patients with and without inhibitors and an emicizumab regimen. Methods: We reviewed the records of 13 PWH (eight with high-titre inhibitors, five without) with a mean age of 54.6 years, undergoing 15 orthopaedic surgical procedures between 2017 and 2022: primary knee and hip arthroplasty, revision, pseudotumor excision, or amputation. Their prophylaxis consisted of the combination of emicizumab and boluses of rFVIIa (PWH with inhibitors) or rFVIII (PWH without inhibitors). The clinical parameters of evaluation were: VAS, Haemophilic Joint Health Score (HJHS), and standard radiologic studies. Follow-up was conducted at 1, 3, 6 months, and then yearly. The survival rate of all implants was also assessed. Results: The mean follow-up was 38.8 months (range: 12-65). All patients were successfully treated without complications during surgery. During the postoperative period, a patient affected by a septic complication two months after his pseudotumor excision underwent an above-the-knee amputation. All patients were regularly discharged to the rehabilitative ward, reporting satisfaction for pain reduction and improved joint and global function at the VAS and HJHS scores. No revisions or implant failures were recorded. Conclusions: A prophylaxis regimen with emicizumab and factor replacement in PWH with or without inhibitors undergoing major orthopaedic surgery ensures effective bleeding control and good postoperative clinical outcomes at mid-term follow-up, and may be routinely adopted in dedicated high-volume hospitals. This series is the most consistent to date reported at a single Haemophilia centre.

Thrombosis in Autoimmune Diseases: A Role for Immunosuppressive Treatments?

Autoimmune diseases are not infrequently associated with arterial or venous thrombotic events. Chronic inflammation and immune system impairment are considered the main pathogenetic mechanisms. Some of the drugs used in the treatment of such diseases have been associated with an increased risk of thrombosis. On the contrary, their anti-inflammatory and immune modulator activity could correct some mechanisms leading to thrombosis. In this review, recent evidence available on this topic is examined. There is a lack of adequate studies, but available evidence suggests that glucocorticoids and high-dose immunoglobulins are associated with an increased incidence of venous thromboembolism. Although available data do not allow drawing definite conclusions and more data are needed from future studies and registries, physicians should be aware of these associations.

Cardiovascular oncology: a new discipline inside internal medicine?

Cardiovascular disease and cancer incidence and prevalence have risen over the past few decades to become the leading causes of death. On the one hand, cancer patients will be treated with cardiotoxic chemotherapies; on the other, cardiovascular patients will receive a new diagnosis of cancer and will have to face treatments that may worsen their disease. Moreover, venous thromboembolism can commonly complicate the natural course of patients with cancer in an apparently spontaneous manner or can be triggered by a clinical event such as surgery, invasive procedures, a course of chemotherapy or radiotherapy and is known to be the second cause of death in these patients who also may need to be treated for pre-existing medical conditions or comorbidities. Thus, we introduce the concept of cardiovascular oncology (in the place of cardiooncology) to underline that the problems in this field are not limited to cardiotoxicity of chemotherapies and to the interaction between cardiologists and oncologists, and we focus on the role of the Internist, the only health care giver able to face the multiple problems that cancer patients may undergo.

The risk stratification in atrial fibrillation.

Atrial fibrillation (AF) is the most common rhythm disorder and represents a major public health problem because it carries an increased risk of arterial thromboembolism and ischemic stroke. Because the absolute benefit of antithrombotic therapy depends on the underlying risk of stroke, an accurate stratification of patients' risk is needed to choose the appropriate antithrombotic strategy. Over the years, several stroke risk stratification models (RSMs) were developed based on the 'classic' risk factors for stroke such as increasing age, hypertension, diabetes mellitus, and left ventricular dysfunction. Among all RSMs, the CHADS(2) score is the most popular and used one thanks to its simplicity and endorsement in several widely promulgated practice guidelines. Despite its validation in large datasets and specific population of AF patients, it has many limitations, especially due to the non-inclusion of several proven risk factors for stroke and to the classification of a large number of patients in the intermediate risk category, so creating ambiguity over the most appropriate antithrombotic therapy. Thus, the CHA(2)DS(2)-VASc score was introduced and was demonstrated to perform better than the CHADS(2), even in a "real world" population of elderly AF patients. Recently, in view of the availability of new oral anticoagulant drugs, that can overcome the limitations of warfarin and allow a more personalized therapy, many efforts are being made to identify other possibilities to assess the thromboembolic risk in AF patients. It has been demonstrated that an increase in C-reactive protein and interleukin-6 and the presence of G20210A factor II gene polymorphism and hyper-homocysteinemia are independent risk factors for ischemic complications in AF patients. Even the presence of chronic renal disease and the daily AF burden, registered with implantable monitors, are associated with an increase risk of stroke. Finally, the assessment of thromboembolic risk should go hand in hand with the consideration of the risk of bleeding. For this purpose, it has been recently developed a practical bleeding risk score, the HAS-BLED, which was included in the last ESC guidelines for the risk stratification of AF patients before starting anticoagulant therapy.

Molecular mimicry between Helicobacter pylori antigens and H+, K+ --adenosine triphosphatase in human gastric autoimmunity.

Autoimmune gastritis and Helicobacter pylori-associated gastric atrophy develop through similar mechanisms involving the proton pump H+,K+-adenosine triphosphatase as autoantigen. Here, we report that H. pylori-infected patients with gastric autoimmunity harbor in vivo-activated gastric CD4+ T cells that recognize both H+, K+-adenosine triphosphatase and H. pylori antigens. We characterized the submolecular specificity of such gastric T cells and identified cross-reactive epitopes from nine H. pylori proteins. Cross-reactive H. pylori peptides induced T cell proliferation and expression of T helper type 1 functions. We suggest that in genetically susceptible individuals, H. pylori infection can activate cross-reactive gastric T cells leading to gastric autoimmunity via molecular mimicry.

T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions.

Atherosclerotic lesions are infiltrated by macrophages and T lymphocytes, potentially reactive to pathogens. We studied in vivo activated T lymphocytes that infiltrate atherosclerotic plaques of Helicobacter pylori-infected patients with or without anti-Chlamydia pneumoniae antibodies. In all atherosclerotic lesions, T helper type 1 (Th1) cells were predominant. C. pneumoniae-specific T cells were detected only in the plaques of anti-C. pneumoniae seropositive patients, whereas H. pylori-specific T cells were found in the gastric mucosa but not in the plaques of the same patients. Plaque-derived Th1 cells expressed cytotoxicity, proapoptotic activity, and help for monocyte tissue factor production. Although multifactorial, atherosclerosis can be regarded as a Th1-driven immunopathological condition.

Characterization of H+,K+-ATPase T cell epitopes in human autoimmune gastritis.

Human autoimmune gastritis (AIG) is an organ-specific inflammatory disorder leading to gastric atrophy and pernicious anemia. Gastric H+,K(+)-ATPase was identified as the autoantigen in both human disease and experimental murine AIG (EAIG). Studies of EAIG significantly contributed to current knowledge of human AIG, but to what extent EAIG mimics AIG is still debated, and the autoantigenic epitopes in AIG are yet unknown. This study aimed to identify the H+,K(+)-ATPase epitopes recognized by gastric T cell clones from AIG patients, to define their TCR Vbeta usage and epitope-induced cytokine response. Sixteen H+,K(+)-ATPase-reactive CD4+ gastric T cell clones of four AIG patients were tested for proliferation to overlapping 15-mer peptides spanning the a and beta chains of H+,K(+)-ATPase. We identified 6 epitopes in the a chain and 5 in the beta chain; TCR Vbeta usage was not restricted. Four (36%) of the 11 H+,K(+)-ATPase epitopes recognized in AIG were found to overlap with epitopes that are relevant in EAIG, including a previously described gastritogenic epitope. Gastric T cell recognition of the peptide epitopes resulted in secretion of Th1 cytokines. Our data suggest a striking similarity between human AIG and EAIG, at the epitope level, with regard to cytokine secretion and likely also with regard to pathogenic mechanisms.