The good, the bad and the ugly of pain in haemophilia: Recent evidence on the epidemiology, molecular mechanisms and knowledge gaps preventing optimal treatment.

INTRODUCTION: Haemophilia is an inherited, X-linked blood clotting disorder caused by the deficiency of coagulation factors VIII (FVIII, haemophilia A) or IX (FIX, haemophilia B). Spontaneous bleeds are common in severe forms of haemophilia and can also occur in moderate and mild haemophilia. Severe or repeated bleeding at a joint can evolve into chronic haemophilic arthropathy, with functional damage of the joint, disability, and intense chronic articular pain. Nonetheless, acute and chronic pain may emerge due to secondary conditions related to bleedings. AIM: This narrative review aims to critically discuss the most recent evidence about pain in haemophilia to give healthcare professionals a clear picture of current knowledge hence favouring the optimisation of clinical management of pain. METHODS: Extensive literature search with the terms 'hemophilia' AND 'pain', focusing on the time window 2021-2023. RESULTS: Acute and chronic pain is a critical aspect of haemophilia at all ages. It should be considered a multifaceted phenomenon, with a positive role as an early emergency signal of a clinical event (haemarthrosis), and numerous detrimental aspects linked to its burden that heavily affects the health-related quality of life, with psychological and social consequences. CONCLUSION: Despite its prevalence and frequency in people with haemophilia, pain is often underestimated by healthcare professionals, leading to insufficient and inadequate treatment, also due to uncertainty linked to the presence of the coagulation disorder or arthritic flares.

The value-based healthcare approach to haemophilia: Development of outcome measures for the evaluation of care of people with haemophilia.

INTRODUCTION: Considering the advances in haemophilia management and treatment observed in the last decades, a new set of value-based outcome indicators is needed to assess the quality of care and the impact of these medical innovations. AIM: The Value-Based Healthcare in Haemophilia project aimed to define a set of clinical outcome indicators (COIs) and patient-reported outcome indicators (PROIs) to assess quality of care in haemophilia in high-income countries with a value-based approach to inform and guide the decision-making process. METHODS: A Value-based healthcare approach based on the available literature, current guidelines and the involvement of a multidisciplinary group of experts was applied to generate a set of indicators to assess the quality of care of haemophilia. RESULTS: A final list of three COIs and five PROIs was created and validated. The identified COIs focus on two domains: musculoskeletal health and function, and safety. The identified PROIs cover five domains: bleeding frequency, pain, mobility and physical activities, Health-Related Quality of Life and satisfaction. Finally, two composite outcomes, one based on COIs, and one based on PROIs, were proposed as synthetic outcome indicators of quality of care. CONCLUSION: The presented standard set of health outcome indicators provides the basis for harmonised longitudinal and cross-sectional monitoring and comparison. The implementation of this value-based approach would enable a more robust assessment of quality of care in haemophilia, within a framework of continuous treatment improvements with potential added value for patients. Moreover, proposed COIs and PROIs should be reviewed and updated routinely.

Evidence of subclinical atherosclerosis in eosinophilic granulomatosis with polyangiitis.

OBJECTIVES: Patients affected by eosinophilic granulomatosis with polyangiitis (EGPA) display an increased risk of atherothrombotic events compared with the general population. An increased frequency of subclinical markers of atherosclerosis has been observed in other ANCA-associated vasculitis, but no specific study focused on EGPA. We therefore evaluated subclinical atherosclerosis in EGPA patients and in a control population. METHODS: Forty EGPA patients and 80 controls matched by age, sex and traditional cardiovascular risk factors underwent sonographic assessment of common carotid artery (CCA) intima-media thickness (IMT). The presence of plaques of the CCA was also investigated. The correlation between CCA-IMT and clinical and laboratory features was also assessed. RESULTS: Median CCA-IMT was significantly higher in EGPA patients compared with controls (P = 0.002). Also, the proportion of subjects with increased CCA-IMT and with presence of plaques was significantly higher among EGPA patients (P < 0.001 for both). Moreover, within the EGPA cohort, CCA-IMT tended to increase with disease duration (P = 0.034) and corticosteroid cumulative dose (P = 0.004). No significant associations were found between CCA-IMT, ANCA status, other clinical features and therapeutic regimens. Notably, the prevalence of traditional cardiovascular risk factors was comparable in patients with vs without an increased CCA-IMT. CONCLUSION: Ultrasound markers of subclinical atherosclerosis are increased in EGPA patients as compared with controls, independently of traditional cardiovascular risk factors.

Diagnosis and treatment of chronic synovitis in patients with haemophilia: consensus statements from the Italian Association of Haemophilia Centres.

Although synovitis is recognized as a marker of joint disease activity, its periodic assessment is not included in routine clinical surveillance of patients with haemophilia (PwH). In order to evaluate the current knowledge and to identify controversial issues, a preliminary literature search by the Musculoskeletal Committee of the Italian Association of Haemophilia Centres (AICE) has been conducted. Statements have been established and sent to the Italian AICE members to collect their level of agreement or disagreement by a Delphi process. Thirty-seven consensus recommendations have been drafted. We found a general agreement on the indication to consider the presence of synovitis as a marker of joint disease activity in PwH. Accordingly, there was agreement on the indication to search for synovitis both in patients reporting joint pain and in asymptomatic ones, recognizing ultrasound as the most practical imaging technique to perform periodic joint screening. Interestingly, after detection of synovitis, there was agreement on the indication to modify the therapeutic approach, suggesting prophylaxis in patients treated on demand and tailoring treatment in patients already under prophylaxis. Whereas the need of an early consultation with a physiotherapist is recommended for PwH affected by chronic synovitis, the exact timing for an orthopaedic surgeon consultation is currently unknown.

Volanesorsen to treat severe hypertriglyceridaemia: A pooled analysis of randomized controlled trials.

BACKGROUND: Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat subjects with sHTG. The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat sHTG. We performed a systematic review and meta-analysis of RCTs on the efficacy and safety of volanesorsen as compared to placebo treatment in patients with severe HTG. METHODS: Studies were systematically searched in the PubMed, Web of Science and Scopus databases according to PRISMA guidelines. The last search was performed on 7 February 2022. RESULTS: Four studies showed significant reduction in TG after 3 months of treatment with volanesorsen as compared with placebo (MD: -73.9%; 95%CI: -93.5%, -54.2; p < .001 I2  = 89.05%; p < .001); VLDL-C level (MD: -71.0%; 95%CI: -76.6%, -65.4%; p < .001 I2  = 94.1%; p < .001); Apo-B48 level (MD: -69.03%; 95%CI: -98.59.4%, -39.47%; p < .001, I2  = 93.51%; p < .001) and Apo-CIII level (MD: -80.0%; 95%CI: -97.5%, -62.5; p < .001 I2  = 94.1%; p < .001) with an increase in HDL-C level (MD: +45.92%, 95%CI: +37.24%, +54.60%; p < .001 I2  = 94.34%; p < .001) and in LDL-C level (MD: +68.6%, 95%CI: +7.0%, +130.1%; p < .001 I2  = 96.18%; p < .001) without a significant elevation of Apo-B100 level (MD: +4.58%, 95%CI: -5.64%, +14.79%; p = .380 I2  = 95.09%; p < .001) in 139 volanesorsen patients as compared to 100 placebo-treated controls. Most of adverse events were mild and related to local injection site reactions. CONCLUSIONS: In patients with severe HTG, volanesorsen is associated with a significant reduction in TG, VLDL-C, Apo-B48 and non-HDL-C and increment of HDL-C as compared to placebo. Documented efficacy is accompanied by an acceptable safety profile.

Enhanced Half-Life Recombinant Factor VIII Concentrates for Hemophilia A: Insights from Pivotal and Extension Studies.

The development of enhanced half-life recombinant factor VIII (EHL-rFVIII) concentrates has improved the management of hemophilia. Furthermore, the chance of maintaining higher trough levels has allowed higher protection from bleeding and, in turn, improved safely performance for certain types of physical activity. The first technology used to improve the pharmacokinetic profile of factor VIII (FVIII) was fusion with the Fc domain of immunoglobulin G. More recently, conjugation to hydrophilic polymers of polyethylene glycol (PEG) has been demonstrated to prolong plasma half-life of FVIII by means of a reduction in clearance of the molecule due to steric hindrance by PEG covering the protein. Here we report results of a systematic review of pivotal studies on EHL-rFVIII concentrates. Significant heterogeneity is observed among different studies on EHL-rFVIII concentrates, and direct comparisons should be avoided. The annualized bleeding rate has ranged between 1.2 and 1.9 in different EHL-rFVIII concentrates, with a progressive further decrease during extension phases of pivotal studies. Zero bleeding was reported by 40 to 45% of patients. Overall, the emerging treatment options seem to be highly effective and safe, associated with a decreased dosing interval to twice weekly or less, which reduces, but does not entirely eliminate, the burden of treatment. Overall, further information is needed from real-life settings to permit differentiation between EHL-FVIII concentrates and for individualizing treatment.

Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement.

Familial hypercholesterolemia (FH) is the most common genetic disease caused by variants in LDLR, APOB, PCSK9 genes; it is characterized by high levels of LDL-cholesterol and premature cardiovascular disease. We aim to perform a retrospective analysis of a genetically screened population (528 unrelated patients-342 adults and 186 children) to evaluate the biochemical and clinical correlations with the different genetic statuses. Genetic screening was performed by traditional sequencing and some patients were re-analyzed by next-generation-sequencing. Pathogenic variants, mainly missense in the LDLR gene, were identified in 402/528 patients (76.1%), including 4 homozygotes, 17 compound heterozygotes and 1 double heterozygotes. A gradual increase of LDL-cholesterol was observed from patients without pathogenic variants to patients with a defective variant, to patients with a null variant and to patients with two variants. Six variants accounted for 51% of patients; a large variability of LDL-cholesterol was observed among patients carrying the same variant. The frequency of pathogenic variants gradually increased from unlikely FH to definite FH, according to the Dutch Lipid Clinic Network criteria. Genetic diagnosis can help prognostic evaluation of FH patients, discriminating between the different genetic statuses or variant types. Clinical suspicion of FH should be considered even if few symptoms are present or if LDL-cholesterol is only mildly increased.

Clinical assessment of endothelial function in heart failure with preserved ejection fraction: A meta-analysis with meta-regressions.

BACKGROUND: Endothelial dysfunction is a key mechanism in the development of cardiac remodelling and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Flow-mediated (FMD) and nitrate-mediated dilation (NMD) are noninvasive methods to assess endothelial function. We performed a meta-analysis evaluating the impact of HFpEF on FMD and NMD. METHODS: PubMed, Web of Science, Scopus and EMBASE databases were systematically searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences were expressed as mean difference (MD) with 95% confidence intervals (95%CI). The random effects method was used. RESULTS: A total of seven studies were included in the final analysis, 7 with data on FMD (326 HFpEF patients and 417 controls) and 3 on NMD (185 HFpEF patients and 271 controls). Compared to controls, HFpEF patients showed significantly lower FMD (MD: -1.929; 95%CI: -2.770, -1.088; P < .0001) and NMD values (MD: -2.795; 95%CI: -3.876, -1.715; P < .0001). Sensitivity analyses substantially confirmed results. Meta-regression models showed that increasing differences in E/A ratio (Z-score: -2.002; P = .045), E/E' ratio (Z-score: -2.181; P = .029) and left atrial diameter (Z-score: -1.951; P = .050) were linked to higher differences in FMD values between cases and controls. CONCLUSIONS: Impaired endothelial function can be documented in HFpEF, with the possibility of a direct association between the severity of diastolic and endothelial dysfunction. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.

Effects of Bisphosphonate Treatment on Circulating Lipid and Glucose Levels in Patients with Metabolic Bone Disorders.

Bisphosphonates are the first-choice treatment of osteoporosis and Paget's disease of bone. Among the bisphosphonates, the non-amino-bisphosphonates, such as clodronic acid, are intracellular converted into toxic analogues of ATP and induce cellular apoptosis whereas the amino-bisphosphonates, such as zoledronic acid, inhibit the farnesyl-diphosphate-synthase, an enzyme of the mevalonate pathway. This pathway regulates cholesterol and glucose homeostasis and is a target for statins. In this retrospective cohort study, we evaluated the effects of an intravenous infusion of zoledronic acid (5 mg) or clodronic acid (1500 mg) on blood lipid (i.e. total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides) and glucose levels in patients with osteoporosis and Paget's disease of bone. All patients were evaluated before, 1 and 6 months after bisphosphonate treatment. Pagetic and osteoporotic patients treated with zoledronic acid showed a significant reduction in glucose and atherogenic lipids during follow-up whereas these phenomena were not observed after clodronic treatment. The effect on circulating lipid levels was similar in naïve and re-treated Pagetic patients. Zoledronic acid treatment was associated with a reduction in blood glucose and atherogenic lipids in patients with metabolic bone disorders. The extent of change was similar to that obtained with the regular assumption of a low-intensity statin. Further studies are warranted to better evaluate the clinical implications of these observations.

Comparative analysis of the pivotal studies of extended half-life recombinant FVIII products for treatment of haemophilia A.

The need to reduce the burden of injections, and improve adherence and clinical outcomes in haemophilia A led to the development of recombinant FVIII products endowed with an extended plasma half-life (EHL-rFVIII) in comparison with standard half-life products (SHL-rFVIII). Lack of head-to-head studies makes difficult to grasp the relative value of each treatment option. We conducted a combined evaluation of the individual pivotal trials in order to assess between-product differences regarding the reported efficacy results and FVIII consumption. We evaluated 4 EHL-rFVIII products available to treat patients with haemophilia A without inhibitors and also a SHL-rFVIII as a comparator. In the frame of these clinical studies, all the EHL-rFVIII products showed a decrease in the injection burden coupled with good clinical efficacy, even though there were between-product differences in terms of reduction in injection frequencies. Further, between-product differences in terms of weekly/yearly consumption of rFVIII expressed in IU/Kg were identified, suggesting a different economic impact for the different EHL-rFVIII products in the context of comparable clinical efficacy. The present findings based upon the review of pivotal studies done in the frame of a highly selected clinical scenario should be integrated with real-life data.

COVID-19 and Venous Thromboembolism: A Meta-analysis of Literature Studies.

Coronavirus disease 2019 (COVID-19) may have a wide spectrum of clinical presentations, leading in some cases to a critical condition with poor long-term outcomes and residual disability requiring post-acute rehabilitation. A major concern in severe COVID-19 is represented by a concomitant prothrombotic state. However, contrasting data are available about the prevalence of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and/or pulmonary embolism (PE). A detailed search on the association of COVID-19 with thromboembolic complications was conducted in the main electronic databases (PubMed, Web of Science, and Scopus) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The weighted mean prevalence (WMP) with 95% confidence interval (95% CI) was calculated with the random-effects model. Twenty studies enrolling 1,988 COVID-19 patients were included. The WMP of VTE was 31.3% (95% CI: 24.3-39.2%). The WMP of DVT was 19.8% (95% CI: 10.5-34.0%), whereas the WMP of PE was 18.9% (95% CI: 14.4-24.3%). Similar results were obtained when specifically analyzing studies on patients admitted to intensive care units and those on patients under antithrombotic prophylaxis. Regression models showed that an increasing age was associated with a higher prevalence of VTE (Z-score: 3.11, p = 0.001), DVT (Z-score: 2.33, p = 0.002), and PE (Z-score: 3.03, p = 0.002), while an increasing body mass index was associated with an increasing prevalence of PE (Z-score = 2.01, p = 0.04). Male sex did not impact the evaluated outcomes. The rate of thromboembolic complications in COVID-19 patients is definitely high. Considering the risk of fatal and disabling complications, adequate screening procedures and antithrombotic strategies should be implemented.

Association of systemic lupus erythematosus with peripheral arterial disease: a meta-analysis of literature studies.

OBJECTIVE: SLE patients have an increased cardiovascular morbidity and mortality. Contrasting data are available about the association between peripheral arterial disease (PAD) and SLE. We aimed to perform a meta-analysis of studies evaluating the association between SLE and PAD. METHODS: Studies were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases according to preferred reporting items for systematic reviews and meta-analyses guidelines. RESULTS: Eight studies reporting on 263 258 SLE patients and 768 487 controls showed that the prevalence of PAD was 15.8% (95% CI: 10.5%, 23.2%) in SLE patients and 3.9% (95% CI: 1.8%, 7.9%) in controls with a corresponding odds ratio of 4.1 (95% CI: 1.5, 11.6; P <0.001). In addition, five studies reporting on ankle-brachial index showed significantly lower values in 280 SLE patients as compared with 201 controls (mean difference: -0.018; 95% CI: -0.034, -0.001; P =0.033). Meta-regression models showed that age, hypertension and diabetes were inversely associated with the difference in the prevalence of PAD between SLE patients and non-SLE controls, whereas no effect for all the other clinical and demographic variables on the evaluated outcome was found. CONCLUSION: SLE patients exhibit an increased prevalence of PAD and lower ankle-brachial index values as compared with non-SLE controls. This should be considered when planning prevention, interventional and rehabilitation strategies for these chronic patients with functional disability and poor long-term outcomes.

Obstetric antiphospholipid syndrome is not associated with an increased risk of subclinical atherosclerosis.

OBJECTIVES: The persistent positivity of aPLs, either isolated or associated with thrombotic and/or obstetric events (APS), has been associated with the increase of intima-media thickness (IMT) and carotid plaques. Despite the fact that aPLs can promote both thrombotic and obstetric complications, some pathogenic differences have been documented between the two entities. This study aimed to evaluate whether the atherosclerotic risk differs between subjects with obstetric and thrombotic APS. METHODS: A total of 167 APS women (36 obstetric and 131 thrombotic) were compared with 250 aPLs negative controls. IMT of the common carotid artery (CCA) and of the bulb and the prevalence of carotid plaques were assessed. RESULTS: CCA- and bulb-IMT were significantly higher in women with thrombotic APS, while being similar between the obstetric APS and the controls [CCA-IMT: mean (s.d.) 0.97 (0.49), 0.78 (0.22) and 0.81 (0.12) mm for the thrombotic, obstetric and control groups, respectively, P < 0.001 between thrombotic and controls, P = 0.002 between thrombotic and obstetric; bulb-IMT: mean (s.d.) 1.38 (0.79), 0.96 (0.27) and 0.96 (0.51) mm for the thrombotic, obstetric and control groups, P < 0.001]. Women with thrombotic APS had significantly increased risk of presenting carotid plaques. This risk was significantly lower in obstetric APS. CONCLUSION: Unlike thrombotic APS, obstetric APS is not associated with an increase of markers of subclinical atherosclerosis. If confirmed on wider populations, these results could suggest different pathogenetic role of aPLs in promoting atherosclerosis in vascular and obstetric APS, and raise questions on the risk-benefit profile of thromboprophylaxis in obstetric APS outside pregnancy periods.

Clinical application of nasal nitric oxide measurement in allergic rhinitis: A systematic review and meta-analysis.

BACKGROUND: Nasal nitric oxide (nNO) is considered a biomarker of nasal inflammation. OBJECTIVE: To perform a systematic review with meta-analysis and meta-regressions on the association between nNO levels and allergic rhinitis (AR). METHODS: PubMed, Web of Science, Scopus, and EMBASE databases were systematically searched. Differences between cases and controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). RESULTS: Overall, 39 articles were included: 30 containing data on nNO measured by nasal aspiration (1881 patients with AR and 1337 controls) and 12 assessing nNO by nasal exhalation (525 patients with AR and 350 controls). Compared with controls, AR presented significantly higher nNO values both during nasal aspiration (SMD, 1.309; 95% CI, 0.841-1.777; P < .001) and nasal exhalation (SMD, 0.708; 95% CI, 0.303-1.114; P = .001). Sensitivity and subgroup analyses confirmed that the results for the evaluated outcomes were not affected by the presence of clinical confounding factors (asthma, nasal polyps, inhaled corticosteroids, smoking history), this being valid for both perennial and seasonal diseases during exposure to allergens. For the aspiration method, meta-regressions indicated that older age and a better pulmonary function were associated with a lower difference in nNO levels between patients with AR and controls, whereas an increasing aspiration flow was associated with a high effect size. CONCLUSION: nNO levels are higher in AR, particularly when using high aspiration flows and in younger patients, who often perceive this condition as a source of disability. Further studies are needed to evaluate the usefulness of this biomarker for monitoring airway disorders and optimizing strategies in different settings (community, hospital, rehabilitation).

The Progression of Hemophilic Arthropathy: The Role of Biomarkers.

BACKGROUND: Hemophilia A and B are X-linked congenital bleeding disorders characterized by recurrent hemarthroses leading to specific changes in the synovium and cartilage, which finally result in the destruction of the joint: this process is called hemophilic arthropathy (HA). This review highlights the most prominent molecular biomarkers found in the literature to discuss their potential use in the clinical practice to monitor bleeding, to assess the progression of the HA and the effectiveness of treatments. METHODS: A review of the literature was performed on PubMed and Embase, from 3 to 7 August 2020. Study selection and data extraction were achieved independently by two authors and the following inclusion criteria were determined a priori: English language, available full text and articles published in peer-reviewed journal. In addition, further articles were identified by checking the bibliography of relevant articles and searching for the studies cited in all the articles examined. RESULTS: Eligible studies obtained at the end of the search and screen process were seventy-three (73). CONCLUSIONS: Despite the surge of interest in the clinical use of biomarkers, current literature underlines the lack of their standardization and their potential use in the clinical practice preserving the role of physical examination and imaging in early diagnosis.

Impact of Genetic Variations and Epigenetic Mechanisms on the Risk of Obesity.

Rare genetic obesity disorders are characterized by mutations of genes strongly involved in the central or peripheral regulation of energy balance. These mutations are effective in causing the early onset of severe obesity and insatiable hunger (hyperphagia), suggesting that the genetic component can contribute to 40-70% of obesity. However, genes' roles in the processes leading to obesity are still unclear. This review is aimed to summarize the current knowledge of the genetic causes of obesity, especially monogenic obesity, describing the role of epigenetic mechanisms in obesity and metabolic diseases. A comprehensive understanding of the underlying genetic and epigenetic mechanisms, with the metabolic processes they control, will permit adequate management and prevention of obesity.

Cardiac Manifestations of Antiphospholipid Syndrome: Clinical Presentation, Role of Cardiac Imaging, and Treatment Strategies.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies, vascular thrombosis (venous, arterial, or small vessels), and/or pregnancy morbidity. Diagnosis of APS is based on the presence of at least one clinical criterion (thrombotic events or pregnancy morbidity) and at least one of the laboratory criteria (persistently medium/high titer immunoglobulin G [IgG]/immunoglobulin M [IgM] anticardiolipin antibodies, and/or medium/high titer IgG/IgM anti-ß2-glycoprotein I antibodies, and/or a positive lupus anticoagulant test), confirmed after repetition at least 12 weeks apart. The clinical spectrum of APS encompasses additional (extracriteria) clinical manifestations, including cardiac diseases. Heart involvement may become evident as a consequence of direct (autoimmune-mediated) or indirect (thrombosis) mechanisms, and include valve heart disease (vegetations and/or thickening associated with functional abnormalities) and intracardiac thrombosis, coronary, and vascular accelerated atherosclerosis, along with ischemic heart disease. APS can also cause pulmonary arterial hypertension, left ventricular dysfunction, and heart failure. This review describes the major cardiac manifestations of APS and illustrates the role of cardiac imaging for diagnosing subclinical and overt heart involvement and addressing management of these patients. The possible role of therapeutic strategies in cardiac manifestations of APS is also discussed.

Assessment of Hemophilic Arthropathy by Ultrasound: Where Do We Stand?

Joint hemorrhages represent the most common type of bleeding episode in persons with hemophilia, and recurrent hemarthrosis triggers chronic arthropathy, which is the most frequent chronic complication in these patients. In recent years, in the frame of a comprehensive care approach, a growing attention has been given to the periodic assessment of the joint status in hemophilia patients with the aim to identify early arthropathic changes and to prevent the development of a clinically overt arthropathy. Besides clinical examination, X-ray and magnetic resonance imaging (MRI) are currently used to evaluate joint status and to monitor the disease progression in hemophilia. Considering the limitations of X-ray and MRI, growing interest has been given to ultrasound (US) as a possible tool to assess joint status and identify early arthropathic changes in hemophilia patients. In the present review, we summarize major literature evidence on the use of joint US for the evaluation of markers of disease activity (joint effusion and synovial hypertrophy) and of degenerative damages (osteochondral changes) in patients with hemophilia. On the whole, being able to identify the presence of intra- or extra-articular fluid, US examination is the fastest and most reliable technique to identify acute conditions, such as hemarthrosis. In addition, the information on joint involvement provided by US in the patient follow-up may influence treatment decisions on a personalized basis. The use of US as part of a routine clinical examination by hemophilia experts may optimize the diagnostic workflow, avoiding additional costs and long waiting lists for patients referred to imaging departments. In the frame of a comprehensive care approach, US might represent a strategy to early detect and monitor synovial hypertrophy and osteochondral changes in hemophilia, thus extending the clinical examination and helping identify joints to be studied with a second-level examination such as MRI.