Assessing joint health in haemophilia patients: The combined value of physical examination and ultrasound imaging.

INTRODUCTION: Early diagnosis of joint damage is pivotal in haemophilia to prevent the occurrence and progression of haemophilic arthropathy thus providing optimal personalised management. The haemophilia joint health score version 2.1 (HJHS) is based on a physical examination of the mainly affected joints. Musculoskeletal ultrasound has demonstrated the capability to detect early changes in terms of synovitis and osteochondral damage. The haemophilia early detection with ultrasound (HEAD-US) score has been proposed as a simple and reliable evaluation tool. AIM: This study aims to investigate the correlation between the HJHS and the HEAD-US scores performed by two independent operators (physical therapist and musculoskeletal ultrasound expert) for the evaluation of the joint health status of patients with haemophilia. METHODS: Consecutive adult patients independent of the severity degree were included. Elbows, knees and ankles were evaluated by a physical therapist by HJHS and by a musculoskeletal ultrasound expert following the HEAD-US protocol. RESULTS: We observed a good positive correlation between HJHS and HEAD-US (Spearman's rho 0.72). The main discrepancy in conceptually similar domains was found between the HJHS swelling and the HEAD-US synovitis (rho 0.17), as ultrasound was able to detect even mild synovitis when HJHS swelling was scored 0 in up to 40% of cases. CONCLUSIONS: The HJHS and HEAD-US correlate well even when performed by two independent operators. Musculoskeletal ultrasound is particularly useful for the early detection of synovitis. The routine assessment of both scores helps clinicians define the stage and extension of joint involvement and set up a personalised treatment.

Predictive parameters for spontaneous joint bleeding during emicizumab prophylaxis.

ABSTRACT: Emicizumab is approved for prophylaxis of patients with hemophilia A (HA). Despite its efficacy in reducing bleeding, some patients on emicizumab still experience hemarthrosis, but no tool is yet available to identify those at a higher risk of spontaneous joint bleeding. This study aimed to evaluate whether laboratory measurements (global coagulation assays and emicizumab concentration) and/or arthropathy scores can distinguish patients at higher risk of spontaneous joint bleeding while on emicizumab prophylaxis. A thrombin generation assay was performed upon the addition of tissue factor and synthetic phospholipids. Nonactivated thromboelastography was performed on citrated whole blood. Emicizumab concentrations were measured using a modified 1-stage factor VIII assay. The degree of hemophilic arthropathy was assessed using the Hemophilia Joint Health Score and Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score. A Cox proportional hazards model was used to evaluate the association between variables and bleeding. The predictive power of these variables was investigated using receiver operating characteristic (ROC) analysis. Forty patients with severe HA, with or without inhibitors, on emicizumab prophylaxis were enrolled in an observational cohort study. Ten of 40 developed spontaneous joint bleeding. None of the laboratory parameters were able to distinguish patients with a higher risk of spontaneous joint bleeding. ROC analysis showed that during emicizumab prophylaxis, only the presence of synovitis and a higher HEAD-US score were associated with spontaneous joint bleeding (area under the curve, 0.84). A greater degree of arthropathy and the presence of synovitis could help predict the risk of spontaneous joint bleeding in patients with HA on emicizumab prophylaxis.

Safety and efficacy of combined dual antiplatelet therapy and factor VIII prophylaxis in patients with haemophilia A after acute coronary syndrome.

INTRODUCTION: The increased life expectancy of patients with haemophilia A (HA) has led to a growing prevalence of cardiovascular risk factors and events. There is still scarce evidence on the safety and appropriate duration of dual antiplatelet therapy (DAPT) after acute coronary syndrome (ACS) in HA patients. AIM: We describe our experience on the clinical management of Italian HA patients after ACS. METHODS: Nine patients with congenital HA treated with DAPT after a revascularization procedure performed for ACS have been enrolled and followed at the Angelo Bianchi Bonomi Haemophilia and Thrombosis Center in Milan between 2005 and September 2022. The safety and efficacy of DAPT with or without FVIII prophylaxis were assessed. RESULTS: Ten ACS events occurred in the nine HA patients (four mild and five severe). All events were treated with percutaneous transluminal coronary angioplasty with deployment of 1 to 3 drug-eluting stents followed by DAPT for 1-12 months. All patients except one were treated with FVIII prophylaxis during DAPT aimed at achieving FVIII trough levels ≥20-30 IU/dL. DAPT was effective in all cases in preventing early ACS recurrence, with only a late recurrence. We observed two clinically relevant non-major bleeds (one in a patient without FVIII prophylaxis) and three minor bleeds. No venous thrombosis occurred. CONCLUSION: The long-term secondary antithrombotic prevention consisting of DAPT and FVIII prophylaxis achieving a trough level of 20-30 IU/dL can be effective and safe in HA patients.

Characterization of Immunogenicity and Safety of COVID-19 mRNA-1273 in HIV-Positive Italian Patients with Hemophilia: A Prospective Single-Center Cohort Study.

To characterize the immunogenicity of mRNA-1273 (Moderna, Cambridge, MA, USA) vaccine in HIV-positive hemophilic patients during the third COVID-19 wave in Italy and to investigate biomarkers of coagulation and endothelial perturbation before and after complete vaccination schedule, twenty-three consecutive adult HIV-positive patients with hemophilia were included. Blood was collected before and two weeks after vaccination. We measured anti-SARS-CoV-2 spike protein antibodies to assess immunogenicity; circulating biomarkers of coagulation (protein C and D-dimer), endothelial perturbation (von Willebrand factor (VWF)) and anti-Platelet Factor 4 (PF4) antibodies were analyzed. Flow-based analysis of thrombus formation was performed in nine patients using a flow-chamber device. Two weeks after completing the vaccination schedule, all patients had anti-spike antibodies values consistent with an effective immunization. Mean (±standard deviation) basal values of protein C and VWF (106 ± 21% and 171 ± 45%, respectively) were not significantly different from data obtained two weeks after the second dose (103 ± 20%, 162 ± 43%, respectively). D-dimer median values (interquartile range) were not significantly different at baseline (442 (603-142) ng/mL) and after the second dose (477 (654-262) ng/mL). Anti-PF4 antibodies were detected in three patients with no associated clinical manifestations. No significant differences were found in flow-based analysis of thrombus formation. Our data demonstrate that in HIV-positive patients with hemophilia, SARS-CoV-2 vaccination is effective and safe, with no effects on coagulation and endothelial perturbation.

Residual burden of liver disease after HCV clearance in hemophilia: a word of caution in the era of gene therapy.

Ruling out advanced fibrosis/cirrhosis is mandatory for persons with hemophilia (PWH) who are candidates for gene therapy. However, clinical evaluation and noninvasive tests (NITs) may be inaccurate after hepatitis C virus (HCV) clearance. We conducted a prospective hepatological screening to detect advanced fibrosis/cirrhosis in PWH after HCV clearance. Any risk factor of chronic liver damage was registered by using biochemical data, liver stiffness measurement (LSM), and ultrasound (US). A pre/post-HCV clearance analysis was conducted prospectively in a subgroup of patients who underwent LSM, US, and NITs for fibrosis. We evaluated 119 patients (median age, 53 years; range, 36-87 years) with a previous HCV infection (hemophilia A, n = 108; hemophilia B, n = 11). Ninety-six (81%) presented at least 1 potential risk factor of chronic liver damage. Metabolic risk factors were the most prevalent, with 51 patients (44%) having US steatosis. In 21 patients (18%), clinical, biochemical, liver morphology, and/or LSM were suggestive of advanced fibrosis/cirrhosis. Furthermore, 10 patients (8%) had esophageal varices and 3 (3%) had hepatocellular carcinoma. In 57 patients included in the prospective analysis, LSM and NITs were reduced after HCV clearance (P < .05), but US signs specific of cirrhosis remained unchanged. Overall, 23 of 80 patients (29%) with LSM <10 KPa had at least 1 US sign suggestive of advanced fibrosis/cirrhosis. A similar proportion (18%) was observed for LSM <8 KPa. Overall, risk factors of chronic liver damage are frequent after HCV clearance, but changes in LSM and NITs after clearance may be inaccurate to rule out advanced fibrosis/cirrhosis. A specific diagnostic workup is warranted to evaluate liver health in PWH in the era of gene therapy.

Updates on Novel Non-Replacement Drugs for Hemophilia.

Over the last decade, the world of hemophilia has experienced an unprecedented therapeutic advance, thanks to the progress in bioengineering technologies, leading to the introduction of drugs with novel mechanisms of action based on restoring thrombin generation or coagulation factor VIII mimicking. Apart from the bispecific monoclonal antibody emicizumab, already approved for patients with severe hemophilia A with and without inhibitors, novel non-replacement drugs designed to reduce the treatment burden of patients with hemophilia A or B with or without inhibitors are undergoing evaluation in clinical trials. Thanks to their innovative mechanism of action and subcutaneous administration, these drugs promise to provide effective bleeding protection together with improved adherence and improve health-related quality of life for patients with hemophilia. On the other hand, rare thromboembolic events have been reported with some of these drugs and warrant continuous post-marketing surveillance and investigation of predisposing factors, although the overall safety profile of most of these drugs is good. Finally, new challenges need to be faced in the clinical and laboratory monitoring of the hemostatic status in patients treated with these innovative therapies. In this review, we provide an update on the available data on novel non-replacement drugs currently undergoing evaluation in clinical trials for patients with hemophilia.

Plasma Exchange in a Patient with Immune Thrombocytopenia Associated with Antiphospholipid Syndrome Hospitalized for COVID-19.

Thrombocytopenia is a common feature of antiphospholipid syndrome (APS) and rarely requires treatment. Here we present the case of a 71-year-old man hospitalized for severe immune thrombocytopenia (ITP) secondary to APS and concomitant SARS-CoV-2 infection. The patient was successfully treated with systemic corticosteroids, intravenous immunoglobulins, and plasma exchange (PEX). Few data are published on the use of plasma exchange in the treatment of thrombocytopenia in non-catastrophic APS. In the setting of acute infection when immunosuppressive therapies might be contraindicated, plasma exchange may be considered an effective therapeutic option. SARS-CoV-2 infection may be a trigger for a relapse of immune thrombocytopenia.

Assessment of post-partum haemorrhage risk among women with moderate thrombocytopenia.

It is unknown whether moderate thrombocytopenia represents a risk factor for post-partum haemorrhage (PPH). We assessed PPH risk among women with a platelet count of between 100 and 50 × 109 /l and stratified the risk for O/non-O blood group. We included consecutive women undergoing vaginal delivery or caesarean section with moderate thrombocytopenia. Women with >150 × 109 /l platelets at delivery were selected as controls and matched for age, type of birth and ethnicity. Odds ratios (ORs) with their 95% confidence intervals (95% CIs) were calculated as risk estimates. A total of 94 thrombocytopenic women and 94 controls were included in the study. The rate of PPH was significantly higher in thrombocytopenic women than in controls (37% vs. 10%, p < 0.001); there was a higher risk of PPH in the thrombocytopenic group when compared to the control group (adjusted OR 4.7, 95% CI 2.1-10.8, p < 0.01) and this association was stronger in blood group O carriers (adjusted OR 11.0, 95% CI 2.4-49.6, p < 0.01). In conclusion, our study shows that a moderate thrombocytopenia is a risk factor for PPH, especially in blood group O carriers.

Current and Emerging Approaches for Pain Management in Hemophilic Arthropathy.

INTRODUCTION: Hemophilia is an inherited bleeding hematological disorder characterized by the partial or complete deficiency of clotting factor VIII or IX. Hemophilic arthropathy is the consequence of repeated joint bleeding (hemarthrosis) and its management is based on the prevention of acute bleeding through the administration of the deficient clotting factor concentrate or non-factor therapies. In addition, the management of acute and chronic pain is pivotal in hemophilic arthropathy in order to restore function and allow rehabilitation of the joint. METHODS: We conducted a qualitative review of the literature regarding current and emerging strategies for pain treatment in hemophilic arthropathy. This review considers systemic and local pharmacological and non-pharmacological interventions for acute and chronic pain management. RESULTS: In hemophilic arthropathy, pain management is based on analgesics such as paracetamol, which represents the first choice for acute and chronic pain in adults and children, in association with opioids for adults. Non-steroidal anti-inflammatory drugs inhibit platelet function, so that the currently preferred drugs are short courses of cyclooxygenase 2 inhibitors. Local treatment with intra-articular injections of corticosteroids is an option for refractory cases and physiotherapy has an important role after hemarthrosis and for the long-term management of chronic pain for both pediatric and adult patients. CONCLUSIONS: The management of pain in hemophilia requires more standardization. Meanwhile, the safest drugs should be used at the lowest effective dosage and for periods as short as possible. For the non-pharmacological management of pain in these patients, a multidisciplinary team including hematologists, orthopedic surgeons, rheumatologists, and physiotherapists is warranted.

Risk of diagnostic delay in congenital thrombotic thrombocytopenic purpura.

Essentials Congenital thrombotic thrombocytopenic purpura (cTTP) is a very rare thrombotic microangiopathy. Its rarity and great phenotype heterogeneity may account for misdiagnosis. We report the history of a middle-aged woman with cTTP, misdiagnosed until adulthood. Accurate clinical history is crucial for early diagnosis to prevent long-term sequelae. SUMMARY: Thrombotic thrombocytopenic purpura (TTP) is an acute life-threatening disorder characterized by multiple organ ischemia due to disseminated thrombus formation in the microvasculature. The congenital form of the disease (Upshaw-Schulman syndrome) is related to ADAMTS13 mutations. Adulthood-onset of TTP does not exclude the congenital form of the disease and a diagnostic delay may account for a great morbidity burden in these patients. We describe the case of a middle-aged woman who presented to our attention with a clinical diagnosis of a chronic relapsing form of TTP. The medical history of the patient raised the suspicion of a congenital form of TTP. Phenotype and genotype tests were performed, and clinical diagnosis was confirmed. Upshaw-Schulman syndrome is a rare congenital disease with a great phenotype heterogeneity that can be diagnosed also in adulthood. Accurate clinical history is crucial. Early diagnosis can prevent recurrences and long-term organ damage with long-term sequelae.

Prevention of relapse in patients with acquired thrombotic thrombocytopenic purpura undergoing elective surgery: a case series.

Essentials Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease. Surgery is a possible trigger of acute TTP episodes and no guidelines are available. Six patients with severe ADAMTS-13 deficiency during remission underwent elective surgery. Patients were prophylactically treated to restore ADAMTS-13 activity and no relapses occurred. SUMMARY: Background Severe ADAMTS-13 deficiency has been recognized as the main risk factor for recurrence of thrombotic thrombocytopenic purpura (TTP). Several conditions, including surgery, may influence the levels of ultra-large von Willebrand factor and ADAMTS-13, acting as a trigger for an acute TTP event. Objectives To report our experience of management of six patients with acquired TTP who underwent elective surgery after prophylactic treatment to restore ADAMTS-13 activity levels. Patients Six patients followed for acquired TTP with severe ADAMTS-13 deficiency during remission were candidates for seven elective surgeries (inguinal hernioplasty, cholecystectomy, laparoscopic hysterectomy, oophorectomy, parotidectomy and two total hip arthroplasties). Results Four patients were treated with prophylactic plasma exchange (PEX) therapy immediately before surgery. One patient was treated with PEX therapy before her first surgery and with preemptive rituximab once her second surgery was scheduled. Because rituximab increased ADAMTS-13 levels only partially, she required one PEX procedure the day before her second surgery. One patient was treated with azathioprine after rituximab failure, obtaining a progressive increase of ADAMTS-13 activity to more than 40%. This level allowed her to undergo total hip arthroplasty without additional treatment. All surgeries were successful and no complications or relapses occurred. Conclusions Six patients with acquired TTP underwent seven successful surgical procedures using prophylaxis to restore ADAMTS-13 activity. Further observational studies or randomized clinical trials are needed to confirm whether prophylactic PEX could be the key factor in preventing relapse.

Persistent and severe hypoglycemia associated with trimethoprim-sulfamethoxazole in a frail diabetic man on polypharmacy: A case report and literature review
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OBJECTIVE: Trimethoprim-sulfamethoxazole (co-trimoxazole) is a commonly used broad-spectrum antibiotic, but it can be associated with potentially serious adverse effects, often not recognized by clinicians. This is a relevant problem in elderly patients, who are particularly susceptible to adverse drug reactions. Moreover, multiple medications taken by older people increase the risk for adverse drug reactions and drug-drug interactions. CASE REPORT: We report the case of an 85-year-old man with diabetes mellitus who attended the emergency room with severe hypoglycemia that persisted despite multiple intravenous bolus doses and continuous infusion of glucose. He needed hospital admission to stabilize glycemia. The patient, a nursing home resident, was being treated with co-trimoxazole for an uncomplicated urinary tract infection, but was also taking multiple additional drugs for his co-morbidities. After co-trimoxazole was discontinued, plasma glucose levels slowly stabilized within the normal range. A diagnosis of prolonged and refractory hypoglycemia induced mainly by the antimicrobial agent was made, with additional contribution from multiple other drugs. No further episodes of hypoglycemia occurred during the next 6 months of follow-up. CONCLUSION: This case study illustrates once more the critical importance of prescription appropriateness in elderly patients with multiple morbidities in terms of type and dosage of drugs, in order to avoid serious adverse reactions.
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Cognitive status in the oldest old and centenarians: a condition crucial for quality of life methodologically difficult to assess.

Human life expectancy and the number of the oldest old are rapidly increasing worldwide. Advanced age is the main risk factor for dementia, representing one of the major causes of disability/dependency among older people with a strong impact on their families/caregivers. Centenarians have reached the extreme limits of human life escaping or delaying the major age-related diseases. Thus, these extraordinary individuals embody the best model to answer the crucial question if cognitive decline and dementia are progressive and unavoidable occurrences of increasing age. Despite a growing amount of data underlines the importance of cognitive function for quality of life and survival in old age, studies on centenarians have paid more attention to their physical condition rather than the assessment of their actual cognitive abilities. Accordingly, this work aims to summarize available data on the prevalence of dementia in centenarians and to critically address topics which can have a relevant impact on the cognitive assessment/status of the oldest old: (i) lack of standardized tools for cognitive assessment; (ii) criteria and threshold to establish the presence of dementia; (iii) influence of birth cohort and education; (iv) role of depression or positive attitude towards life; (v) gender differences.