Chronic Hemophilic Arthropathy Research Articles

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

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. 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. Extensive literature search with the terms 'hemophilia' AND 'pain', focusing on the time window 2021-2023. 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. 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.

A single‐centre experience of 29 total ankle replacement in haemophiliac patients: Therapeutic management, factor consumption and cost

AbstractIntroductionIn patients with haemophilia, repeated bleeding in large joints leads to chronic haemophilic arthropathy, a rare disease that can be managed surgically with ankle arthrodesis or with total ankle replacement (TAR). TAR has been reported to provide good surgical results in the medium/long‐term and allow preservation of joint mobility but the medical therapeutic management of the patients has not been described.AimTo describe the medical therapeutic management of TAR.MethodsAll patients with haemophilia A/B, with haemophilic ankle arthropathy, and who underwent TAR between April 2006 and October 2019 were retrospectively included. Factor consumption, perioperative and early complications, volume of blood lost, and orthopaedic data were collected.ResultsA total of 25 patients underwent 29 TAR (mean age was 44.7 years [range: 26–65]). In the 17 patients with HA without history of anti‐FVIII inhibitor, the mean ± SD consumption the day of surgery was 116 ± 16 UI/kg when clotting factors were administered by continuous infusion, 106 ± 13 UI/kg when SHL factors were administered by bolus infusion, and 75 ± 22 UI/kg when EHL factors were administered by bolus infusion. During hospitalisation, the mean factor cost was €38,073 (83.7% of the total cost of surgery). Mean blood loss was significantly lower in patients treated with tranexamic acid (164 mL, range: 40–300) than in those not (300 mL, range: 70–800; p = .01). Six patients had haematoma. The 10‐year survival free of any prosthesis removal/arthrodesis was estimated to be 92.2% (95% CI [83; 100]).ConclusionThe medical therapeutic management of TAR is complex, carried out by a multidisciplinary team but effective in avoiding the occurrence of complications.

Intraarticular Delivery of AAV5-Mir-125a-5p Regulates Key Molecular Mediators of Hemophilic Arthropathy

Background: Hemophilic arthropathy (HA) is a major comorbidity in patients with hemophilia characterized by chronic inflammation of the joints, stiffness and loss of function. The expression of microRNAs are known to be altered in various joint diseases such as rheumatoid arthritis and osteoarthritis which share clinical attributes with HA. One such microRNA is miR-125a-5p, known to be involved in regulating inflammatory mediators in the arthritic joints. The current study was designed to investigate the role of miR125a-5p in HA and examine the phenotypic effect of its targeted reconstitution in the joints. Methods: We utilized a chronic arthropathy model in hemophilia A mice to study the impact of miR125a-5p in disease progression. First, we performed a targeted screen of miR125a-5p and its target genes (STAT1 and TRAF6) using digital PCR (dPCR). Further, to validate if reconstitution of miR125a-5p aids in modulating the molecular mediators of HA, we performed the Adeno-associated virus vector (AAV) serotype 5 targeted delivery of miR125a (AAV5-miR125a) either alone (2.13x10 11vgs/joint) or in combination with capsid-modified AAV8-human Factor 8 (F8)(AAV8-F8) gene therapy at a low dose (1x10 11vgs/animal) intravenously in F8 tm1kaz/Jmice. Briefly, the animals were administered with vectors (alone or in combination), and seven days post vector administration, the animals were subjected to multiple bleeding episodes in the right knee (Day 0, 14, and 30) to mimic chronic hemarthrosis. On day 45, blood samples were collected from experimental animals for FVIII specific clotting assay, and joint tissues were isolated to perform further molecular and histochemical analysis. Results: Our dPCR analysis revealed a significant reduction (2-fold) of miR125a-5p (3518 copies/µl vs 7242 copies/µl, p≤0.0001) in injured joints compared to control joints. Absolute quantification of target genes, namely STAT1 and TRAF6 showed significantly higher expression in injured joints (7.6 to 10.6 fold, respectively) when compared to control joints. Further immunohistochemical examination of joint sections from the experimental mice confirmed the elevated expression of these immunological mediators (STAT1, TRAF6). Upon administration of AAV vectors containing miR125a and/or F8, we observed a significantly increased expression of miR125a-5p (~12 fold) in only miR125a vector-administered animals while the combination vector treated group had, ~44-fold higher levels of miR125a-5p. The coagulant assay revealed an increased FVIII activity (~17%) in only F8 vector-treated animals and approximately 20% FVIII levels in mice that received both miR125a and F8 vectors at low doses. Surprisingly, the animals that received only F8 vectors also showed significantly upregulated miR125a-5p expression (~20 fold) signifying the role of miR125a-5p in HA pathology. In line with the above findings, immunohistochemical analysis of joint tissues revealed decreased expression of immunological markers STAT1, TRAF6 (direct targets of miR125a-5p), and the chondro-degenerative matrix metalloproteinases 3, 9, 13 in vector-treated groups when compared to injured joints with no treatment. Hematoxylin and Eosin (H&E) staining of joint tissues from experimental animals was performed which revealed that animals that received both miR125a and F8 vectors showed decreased synovial hyperplasia, villi formation, cartilage erosion, and reduced hemosiderin deposition signifying moderate phenotype rescue. Conclusions: Our data confirms that miR125a-5p is a major molecular target that regulates inflammatory response in chronic HA. Targeted delivery of miR125a in tandem with F8 gene augmentation had an impact on several molecular mediators like STAT1, TRAF6, MMP3,9, and 13. The reconstitution of miR125a and a higher dose of F8 vectors might be beneficial to reverse chronic HA.

Targeted delivery of miR125a-5p and human Factor VIII attenuates molecular mediators of hemophilic arthropathy

Hemophilic arthropathy (HA) due to repeated bleeding into the joint cavity is a major cause of morbidity in patients with hemophilia. The molecular mechanisms contributing to this condition are not well characterized. MicroRNAs (miRs) are known to modulate the phenotype of multiple joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Since miR125a is known to modulate disease progression in OA and RA, we performed a targeted screen of miR125a-5p and its target genes in a murine model of chronic HA. A digital PCR analysis demonstrated significant downregulation of miR125a-5p (2-fold vs control joint). Further molecular evaluation revealed elevated expression of the immunological markers STAT1 (7.6-fold vs control joint) and TRAF6 (10.6 fold vs control joint), which are direct targets of miR125a-5p. We then studied the impact of targeted overexpression of miR125a-5p using an Adeno-associated virus (AAV) vector in modulating the molecular mediators of HA. AAV5-miR125a vectors were administered intra-articularly either alone or in combination with a low dose of AAV8-based human factor 8 (F8) gene in a murine model of HA. We observed significantly increased expression of miR125a-5p in AAV5-miR125a administered mice (~12 fold vs injured joint) or in combination with AAV8-F8 vectors (~44 fold vs injured joint). The activity assay revealed ~17 %–20 % FVIII levels in mice that received low dose liver-directed F8 gene therapy. Further immunohistochemical analysis, demonstrated a decrease in inflammatory markers (STAT1 and TRAF6) and cartilage-degrading matrix metalloproteinases (MMPs) 3, 9, 13 in the joints of treated animals. These data highlight the crucial role of miR125a-5p in the development of HA.

Clinical Evaluation of Balance in Children With Hemophilic Arthropathy.

Hemophilia is a hereditary coagulation disorder characterized by acute hemorrhages into the musculoskeletal system, leading eventually to arthropathy and disability. Chronic inflammation of the synovial membrane arises as a result of frequent joint hemorrhage. Proteolytic enzymes in the blood and cartilage cause deterioration after that, and joint space narrows. Chronic hemophilic arthropathy develops as a result of these unfavorable developments, which occur more quickly, especially in the target joints. Balance is a process that allows us to maintain our orientation in three-dimensional space while also regulating our body posture to avoid falling. After the central nervous system evaluates deep stimuli from sensory, visual, and auditory receptors, movement of the corresponding muscle groups is delivered. The goal of this study was to investigate how impairment to deep sensory receptors (proprioception) in the arthropathic joint structure affected hemophiliacs' balance. The study comprised 34 patients with hemophilic arthropathy, and 34 age and weight matched healthy volunteers. When balance tests of patients with hemophilic arthropathy were compared to healthy controls, hemophiliacs had a greater risk of falling. As the degree of arthropathy increased, so did the risk of falling and balance test values in individuals with hemophilic arthropathy. Treatment and coagulation factor prophylaxis to prevent the onset of arthropathy will improve patients' quality of life and reduce morbidity associated with frequent falls and bleeding. The online version contains supplementary material available at 10.1007/s12288-022-01526-0.

Postoperative bleeding complications in patients with hemophilia undergoing major orthopedic surgery: A prospective multicenter observational study

BackgroundPersons with hemophilia (PWH) are at risk for chronic hemophilic arthropathy (HA). Joint replacement surgery may be used to relieve intractable pain and/or restore joint function. ObjectivesThis multicenter, prospective, observational cohort study evaluated the rate of bleeding during the postoperative period after total hip (THA) or knee arthroplasty (TKA). Patients/MethodsWe included PWH of any severity ≥18 years of age who were undergoing THA or TKA. Clinical decisions were made at the discretion of the treating physician according to local standards of care. Clinical data were prospectively recorded. Major bleeding was defined as bleeding in a critical site, bleeding that resulted in either a 2 g/dl or greater decrease in hemoglobin during any 24‐h period, or transfusion of two or more units of packed red blood cells. ResultsOne hundred thirty‐one procedures (98 TKA and 33 THA) were performed, 39 (29.8%) of which were complicated by major bleeding, including 46% of THA and 25% of TKA. The risk of major bleeding was increased in THA compared to TKA (OR 2.50, p = .05), and by the presence of an inhibitor (OR 4.29, p = .04), increased BMI (OR 4.49 and 6.09 for overweight and obese, respectively, compared to normal BMI, each p < .01), and non‐use of an antifibrinolytic medication (OR 3.00, p = .03). Neither continuous clotting factor infusion (versus bolus infusion) nor pharmacologic thromboprophylaxis were associated with bleeding risk. ConclusionsThe bleeding risk remains substantial after THA and TKA in PWH, despite factor replacement. Use of antifibrinolytic medications is associated with decreased risk.

Soft tissue releasing and serial casting for management of flexion contracture after primary total knee arthroplasty in a patient with hemophilia.

Introduction and importanceFlexion contracture following total knee arthroplasty (TKA) in patients with hemophilia is not uncommon, and this complication reduces knee range of motion and produces morbidity for the patient. This report states the success of treatment of flexion contracture after primary TKA in a patient with hemophilia; by open soft tissue contracture releasing and serial casting.Case presentationA 20-year-old-man presented with hemophilia type A. He had undergone TKA for treatment of secondary osteoarthritis, following chronic hemophilic arthropathy of his right knee. After surgery, the patient had progressive flexion contracture posture, until he had 45 degrees of knee flexion contracture at his 3 month follow up. The patient received open soft tissue releasing, then serial casting for 6 weeks. After this, the cast was removed and he continued with a home rehabilitation program. At 1 year follow, his knee flexion contraction contracture had improved up to 10 degrees. The patients function had recovered and he was satisfied with this treatment.Clinical discussionThe complications after TKA in patients with hemophilia are very challenging in there management; with flexion contracture after TKA being a common complication in patients with hemophilia.ConclusionIn severe flexion contracture following TKA, soft tissue releasing combined with serial casting is effective, and might be an option that is less invasive than revising all of the TKA components.

Low rate of subclinical venous thrombosis in patients with haemophilia undergoing major orthopaedic surgery in the absence of pharmacological thromboprophylaxis.

Deep venous thrombosis (DVT) is a common postoperative complication in patients undergoing major orthopaedic surgery of the lower limbs, such as total hip or knee replacement (THR, TKR). Routine pharmacological thromboprophylaxis with low-molecular-weight heparin (LMWH) or a direct oral anticoagulant agent is strongly recommended in this setting. THR and TKR as well as ankle arthrodesis are frequently performed in people with haemophilia (PWH) and chronic haemophilic arthropathy. Pharmacological thromboprophylaxis in this population remains controversial. We report the results of a single-centre prospective study initiated in 2002 evaluating by systematic Doppler ultrasound the incidence of subclinical DVT in consecutive PWH referred for major orthopaedic surgery and not receiving pharmacological thromboprophylaxis. We included 46 different PWH (39 Haemophilia A, 7 Haemophilia B, 27 severe, 15 moderate and 4 mild forms) undergoing 67 orthopaedic procedures. Most (89.5%) were performed with continuous infusion of clotting factor concentrates. Rehabilitation was usually started on day 1 post-op. No clinical DVT or pulmonary embolism was suspected. In total, there were 5 cases (3 severe, 1 moderate HA and 1 moderate HB) of subclinical DVT which were all distal. Two patients were treated with a short course (10-14days) of LMWH. The overall incidence of DVT was 7.5%. These data provide imaging-based evidence that the risk of DVT following major orthopaedic surgery among PWH is low. Identified DVTs were distal and resolved spontaneously in most cases. Systematic pharmacological thromboprophylaxis in this specific population is probably for most patients not required.

Primary prophylaxis was associated with lower arthropathy in Colombian men with haemophilia B: A longitudinal analysis (2015‐2019)

The risk of chronic haemophilic arthropathy (CHA) is related to severity. Evidence suggests that primary prophylaxis (PPr) could reduce CHA incidence and its impact on quality of life. To evaluate the association between PPr and CHA in Colombian males with haemophilia B (HB) during 2015 to 2019. A panel-time analysis was performed with data provided by the National Health System to update a nationwide open cohort of people with congenital coagulopathies. The association was evaluated in a logistic random-effect regression model (LRERM), adjusted by age at diagnosis, prophylaxis dose and frequency, severity, haemarthrosis and high-titre inhibitors. During 2015-2019, a total of 362 men with HB and treated with either, primary, secondary or tertiary prophylaxis were identified. At baseline, CHA prevalence in the cohort was 36.84% (n=133), median age was 19.0years (IQR: 10.0-27.0), and median age at diagnosis was 1.0year (IQR: 0.0-4.0). PPr was prescribed in 37.85% (n=137), and median dose (IU/Kg/dose) was almost the same for primary vs. secondary/tertiary prophylaxis. Patients in PPr had a lower frequency of severe HB, CHA, haemarthrosis, infectious complications and high-titre inhibitors than those in secondary or tertiary prophylaxis (STPr). In the LRERM, PPr was associated with a significant reduction of 89.70% in the odds of CHA (aOR=0.103, IC 95%: 0.040, 0.270; P<.001), compared with STPr. PPr decreased the odds of CHA by 89.70% in males with HB in Colombia. Our findings are consistent with previous studies and support the strategy to prescribe PPr to our patients.

Inhibition of Fenton reaction is a novel mechanism to explain the therapeutic effect of intra-articular injection of PRP in patients with chronic haemophilic synovitis.

Haemarthroses cause major morbidity in haemophilia resulting in chronic haemophilic synovitis (CHS) and arthropathy. Oxidation of haemoglobin-coupled iron released in synovium after haemolysis induces chondrocytes death and cartilage damage, allowing postulate using iron-chelating drugs as potential therapeutic tool for haemophilic joint damage. Considering that albumin, the most abundant plasma protein, is a physiologic iron chelator, we aim to demonstrate that impediment of haemoglobin oxidation is exerted by plasma as a mechanism involved in the therapeutic effect of intra-articular injection of platelet-rich plasma in CHS. Oxidation of haemoglobin (Hb) to methaemoglobin (MeHb) through Fenton reaction was induced in vitro by addition of potassium ferricyanide in the presence or absence of peripheral blood-derived platelets-rich or platelets-poor plasma (PRP/PPP) or albumin. The relevance of in vitro findings was analysed in synovial fluid (SF) samples from one patient with CHS obtained before and after 6months of PRP intra-articular injection. MeHb formation was completely impaired either by of PPP, PRP or albumin indicating that PRP exerts an anti-oxidative effect, probably due by plasma albumin. Analysis of SF samples revealed the presence of MeHb levels and haemosiderin-laden macrophages in SF obtained before PRP treatment. Reduction of synovial MeHb, normalization of cellular composition and improvement of health joint haemophilic score, pain and bleeding episodes were registered after 6months of PRP intra-articular injection. Inhibition of Fenton reaction and the consequent normalization of joint cellular composition is a noncanonical mechanism underlying the therapeutic effect of PRP intra-articular injection in CHS.

Quantitative Measurements of Hemophilic Joint Tissues By Point-of-Care Musculoskeletal Ultrasound Are Associated with Clinical and Functional Joint Outcome Parameters

Introduction: Recurrent joint bleeding in patients with congenital hemophilia causes progressive arthropathy, characterized by reduced range of motion, synovial proliferation and osteochondral damage. Chronic hemophilic arthropathy remains a leading disabling complication affecting activity and quality of life. Clinical scoring systems, such as the Hemophilia Joint Health Score (HJHS), along with semi-quantitative imaging modalities (radiographs, magnetic resonance, ultrasound) can aid in the evaluation of joint health. However, scores exhibit ceiling effects and lack the opportunity to provide tissue measurements reflecting subtle dynamic changes of intra-articular structures that may be important in monitoring progression of hemophilic arthropathy. Point-of-care (POC) musculoskeletal ultrasound (MSKUS) has emerged as a rapid and sensitive imaging modality to evaluate not only acute bleeding episodes but also the extent of hemophilic arthropathy at the tissue level in the clinic setting. The Joint Tissue Activity and Damage Exam (JADE) has been developed as a concise, quantitative (not semi-quantitative) MSKUS protocol, validated per Outcomes Measures in Rheumatology guidelines for accurate tissue recognition, with high intra/inter-rater and inter-operator reliability, to quantify (1/10th of millimeter) soft tissue expansion, osteochondral alterations and cartilage thickness in hemophilic joints. We aimed to explore to what extent measurable structural intra-articular tissue changes, evaluated by JADE, correlate with clinical and functional joint assessments. If the value of JADE can be established in this context, such information would enable the use of JADE as a POC precision imaging tool to guide management of hemophilic arthropathy. Methodology: From May 2016 to April 2019, we assessed baseline joint characteristics in a prospective multicenter study in patients with congenital hemophilia and arthropathy (age ≥18 years; n=44 patients; n = 264 joints [bilateral elbows, ankles and knees]). HJHS (a clinical assessment tool) and total arc (a functional assessment tool measuring the sum of flexion and extension degrees of motion) were also evaluated. Each joint was examined using the MSKUS JADE protocol. We analyzed the association between joint HJHS and each JADE variable (comprising measurements of soft tissue expansion, osteochondral alterations and cartilage thickness in validated sentinel positions), and between total arc and each JADE variable, by fitting random intercept models that accounted for intra-individual correlation. The outcomes were transformed to ensure normal residuals, and when necessary polynomial terms were added to fit the curve associations between outcomes and JADE variables. Results: A wide range of joint HJHS values (Elbow: 0 - 13, Knee: 0 - 14; Ankle: 0 - 18 [normal=0; highest abnormal 20]) and total arc values (Elbow: 48 - 158, Knee: 22 - 160; Ankle: 5 - 76) were recorded in the cohort, enabling analyses over a broad range of arthropathic changes. Increasing HJHS and declining total arc were associated with increasing age which is consistent with deteriorating joints. Worsening arthropathy (increasing HJHS or declining total arc) of each joint were associated with JADE measurements in the expected direction including increasing soft tissue expansion, increasing length of osteochondral alterations and decreasing cartilage thickness. This is exemplified for the elbow in Figure 1, showing the associations of worsening HJHSs and arcs with increasing osteochondral alterations and decreasing cartilage thickness. Conclusions: This study demonstrated convincing relationships between direct ultrasonographic measurements using the JADE protocol, clinical HJHS and functional arc in a broad range of arthropathic manifestations in hemophilic patients. Interestingly, changes in arc, limiting joint flexion and extension, appeared often to be closer related to ultrasound tissue measurements than HJHS, highlighting the relevance of JADE towards joint function, a parameter of particular patient interest. These findings confirm the clinical value of POC ultrasonographic direct joint tissue measurements as a precision tool to guide timely changes in the management of hemophilic arthropathy. Disclosures von Drygalski: University of California San Diego: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties; UniQure, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, Biomarin, Shire, CSL Behring: Consultancy; Hematherix Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Founder.

Opioid dependence among people with haemophilia in a low-resource tropical setting: prevalence and risk factors in northern Nigeria

Abstract Background In tropical countries such as Nigeria, where factor VIII (FVIII) is scarce, severe pain due to musculoskeletal bleeding complications, leading to frequent opioid prescription, is not uncommon in poorly managed people with haemophilia (PWH). The relationship between opioid use and dependence is intensively studied in other painful diseases, such as cancer and rheumatoid arthritis, but surprisingly little is known about opioid dependence in haemophilia. We hypothesise that the risk of opioid dependence among PWH in tropical countries like Nigeria is multi-factorial, encompassing demographic (age), clinical (haemophilia severity and chronic arthropathy) and biological (ABO blood groups and haemoglobin (Hb) phenotypes) factors that may directly or indirectly increase incidence of bleeding and/or pain. Aims To determine the prevalence of opioid dependence and relative risks (RR) associated with age, haemophilia severity, chronic arthropathy, ABO blood groups and Hb phenotypes, and to elucidate the pathophysiological roles of each risk factor in the development of opioid dependence among haemophilia-A patients in five hospitals in northern Nigeria. Methodology A retrospective review of the medical records of 88 PWH seen between 1996 and 2012 was used to collate data on age, sex, haemophilia severity, painful chronic haemophilic arthropathy, ABO blood group, haemoglobin phenotypes, presence or absence of opioid dependence, and the types of opioids on which the patients were dependent. The prevalence of opioid dependence among the cohort was expressed as a percentage. The frequency of each putative risk factor for opioid dependence in patients with and without opioid dependence were compared using Fisher’s exact test; RR associated with each risk factor was determined by regression analysis. P&lt;0.05 was taken as significant. Results Of the 88 PWH studied,15 (17%) were shown to be opioid-dependent. Compared with PWH who were not opioid-dependent, this group had higher frequencies of severe haemophilia (86.7% vs. 49.3%: RR= 5.2, p=0.02), survival to adulthood (73.3% vs. 12.3%: RR= 9.5, p=0.0001), chronic arthropathy in one or more joints (86.7% vs. 21.9%: RR= 13.2, p=0.0004), blood group-O (80% vs. 49.3%: RR= 3.3, p=0.04), and HbAA phenotype (86.7% vs. 54.8%: RR= 4.3, p=0.04). Conclusion Prevalence of opioid dependence among PWH treated at five hospitals in northern Nigeria was 17% during the study period. Significant risk factors were directly or indirectly associated with increased rates of bleeding and/or pain, which can only be prevented or treated through optimal application of FVIII. There is a need for the Nigerian government to establish standard haemophilia care centres with adequate FVIII for optimal prophylaxis and treatment in order to minimise painful complications, thereby helping to prevent undue opioid use and dependence.

Haemophilia and ageing.

Advances in the development of effective and safe treatments for haemophilia over the last 50years have resulted in a significant increase in the life expectancy of persons with haemophilia (PWH). The management of this new cohort of middle-aged and elderly PWH is challenging because of the opposing risks of haemophilia and age-related cardiovascular disease and malignancy. Furthermore, this cohort of ageing PWH has the additional comorbidities of human immunodeficiency virus/hepatitis C and chronic haemophilic arthropathy. This article reviews the prevalence, underlying mechanisms and treatment strategies for managing these comorbidities. International collaboration is essential for registry data and further prospective trials to inform optimal evidence-based management for this rare disorder in the future.

Bilateral, Simultaneous Total Knee Replacement (TKR) Surgery for Hemophilia a with Eloctate (Extended Half Life Product)—A Feasible and Cost Effective Approach

Abstract INTRODUCTION: The majority of bleeds experienced by people with Haemophilia occur into the joints or muscles.The joints most frequently involved are the knees, ankles, and elbows. The consequences of recurrent bleeding into a joint leads to chronic hemophilic arthropathy. Knee arthropathy is crippling situation affecting Quality of Life (QOL) for Patient with Hemophilia (PWH).With the advent of the availability of Clotting Factor Concentrates (CFC), Total Knee Replacement (TKR) can now be performed safely. TKR is performed using Total 2000IU/kg of Plasma Derived (PD) or Recombinant CFC. Literature recommends 1000-1200IU/kg of Total Eloctate for TKR. METHODS: Aim for feasible, safe &amp; cost effective CFC replacement policy for TKR 1) Use lower dose Eloctate during TKR 2) Perform Simultaneous Bilateral TKR Patients and Methods: Total 24 Severe Hemophilia A patients underwent 48 bilateral, simultaneous TKR. Age range was 28-51 years. Pre-operative 50IU/Kg Eloctate was infused. Pre-operative FVIIIc Level was median 108IU/kg (86-126 IU/dl). Post-operative Eloctate replacement was 40-50IU/kg once daily till day 5, then 30IU/kg once daily till Day15. FVIIIc assay was monitored at least once daily till day 10. Dose was tailored according to FVIIIc levels. Trough FVIIIc level was maintained above 60iu/dl for first 5 days. Average duration of surgery was 4 hours. Drains were removed after 48 hours. LMWH Thromboprophylaxis &amp; physiotherapy was started from post-operative Day 2. Clips were removed on Day 14. Eloctate was received through Humanitarian Aid Program of WFH. RESULTS: Total of 48 bilateral, simultaneous TKR were performed on 24 patients. 23 patients had no significant intra or post-operative bleeding &amp; no transfusion support was needed . One patient underwent pseudo tumour excision and TKR in the same sitting &amp; required extra 50IU/kg Eloctate+ 8 packed red cells + 8 FFP + 10 Cryoprecipitate intra operative during excision of Pseudo Tumour for total blood loss of 2200 ml as expected . He also experienced no post-operative bleeding till discharge. No wound or prosthesis infection was noted. Prosthesis survival was 100%. Total Eloctate used was 510- 640 IU/kg over 14 days. DISCUSSION: There was no excess bleeding in our patients. The results from our assessment are quite similar to the overall prosthetic survival rates reported for TKAs performed on patients without hemophilia.In our study there were no periprosthetic infections reported. Other studies have showed rates of periprosthetic infection after primary TKA in patients with hemophilia are much higher (up to 11%). Late infection is a major concern after TKA in patients with hemophilia, an important factor is the high rate of HIV-positive patients (3).Another important complication of TKA surgery is aseptic loosening of the prosthesis. Aseptic loosening was not found in any of our patients. Rates of this complication increase over follow-up (4). In our data the ROM improved and flexion contracture reduced significantly after arthroplasty following the scheduled physiotherapy.As mentioned in an article by Schild FJA et al the Median amount of CFC (Plasma derived &amp; recombinant) used for multi-joint procedure per patient was 57,680 IU; in another retrospective study by A Thes et al where the median CFC (Plasma derived &amp; recombinant) usage per patient was 1,500 IU/kg; whereas we used Total Eloctate of 510- 640 IU/kg and hence reduced CFC usage compared to western protocol. CONCLUSIONS : Low dose Eloctate replacement is safe and cost effective for TKA in PWH. Bilateral TKA in same sitting is feasible and increases cost effectiveness in PWH. Thrombo-prophylaxis with LMWH can be done safely in PWH. Bleeding events did not increase with low dose Eloctate &amp; LMWH. At these doses, total Eloctate replacement was 40-50% lower than previously reported for TKR surgery for PWH. Our protocol offers a cost effective and safe option in resource constraint countries. Disclosures No relevant conflicts of interest to declare.

Hemofilia

Hemophilia A and B are X-linked recessive diseases that are caused by gene mutations in factors VIII adan IX of the blood clotting cycle. Hemophilia C is an autosomal recessive disease caused by a mutation in factor XI, and acquired hemophilia is largely is an autoimmune process. Hemophilia A and B cannot be distinguished clinically, and severe cases can cause bleeding in the joints and lead to chronic hemophilic arthropathy. The main treatment of hemophilia is infusions of factor VIII and IX, and DDAVP in less severe cases. The main complication that can rise from the use of clotting factors is the appearance of specific inhibitor antibodies that can neutralize the work of the factors. Severe cases of hemophilia A and B by itself carries a poor prognosis, but proper treatment throught the use of clotting factors can give a very good prognosis

T28. Neuropathies in haemophylics: Preliminary evaluation of four cases and literature review

Peripheral neuropathy is an uncommon complication in patients with hemophilia, usually characterized by mononeuropathies, caused by hematoma and compartmental syndrome. The femoral nerve is the most affected, but several other locations have been described. The purpose of this article is to describe four cases of peripheral nerve injury in hemophiliacs comparing with data from the literature. This is a descriptive study, carried out by reviewing the medical record of four hemophiliac patients diagnosed with peripheral nerve injury, performed at a hematology and hemotherapy center in the state of Ceara, Brazil. The literature review was performed on the PubMed platform. All four patients underwent imaging and electromyography studies. The data collected were compared with those of the literature. The first case involves a male patient, twenty-nine years old, with a massive hematoma encapsulated in the right thigh (pseudotumor), and associated with paresthesia and a sensory and motor NCS evidencing sciatic nerve involvement. The second case refers to a male patient, forty-seven years old, with chronic hemophilic arthropathy at the right elbow, presenting with tactile-painful hypoesthesia at the medial border of the hand and the fifth finger. The study of nerve conduction revealed ulnar neuropathy at the elbow. In this case, the probable pathophysiology involves the stretching of the ulnar nerve by the pronounced valgus of the elbow. The last two patients were a man of forty-two and a boy of sixteen, both with left iliopsoas hematoma, accompanied by paresthesia in the anterior and lateral aspect of the thigh. The evaluation of the sensory e motor NCS revealed the involvement of the sensory branch of the femoral nerve (saphenous) and acute denervation in quadriceps muscle on needle EMG. Even in a limited sample, the four reported cases are in accordance with the literature data. The main publications on the subject indicate the nerves of the lower limbs as the most affected ones, predominating the femoral nerve, followed by the sciatic nerve.

Knee and Ankle Arthroplasty in Hemophilia.

Today, major surgical procedures can be safely performed in hemophilic patients with chronic arthropathy, using available factor concentrates. In this setting, total knee replacement is considered the “gold standard”, while the use of total ankle replacement is still debated. Indeed, the unsatisfactory results obtained with the previous available design of implants did not raise enthusiasm as knee or hip replacement. Recently, the introduction of new implant designs and better reported outcomes have renewed the interest in total ankle replacement in people with hemophilia. In this review, the role of replacement surgery in the treatment of chronic hemophilic arthropathy will be described.

The impact of chronic hemophilic arthropathy on children school life

The impact of chronic hemophilic arthropathy on children school life

FREQUENCY AND DEGREE OF CHRONIC ARTHROPATHY IN HEMOPHILIA A PATIENTS ON PROPHYLACTIC AND ON-DEMAND TREATMENT

hemophilia A is the most common congenital bleeding disorder caused by a deficiency in coagulation factor VIII activity, characterized by a marked bleeding tendency. It is inherited recessively. The most common complication of the disease is chronic arthropathy. In the prophylactic treatment regimen, the subjects receive preventative F VIII infusions every second day or three times a week. In an on-demand regimen, bleeds are treated as they occur. Analysis of the frequency and degree of chronic hemophilic arthropathy in patients with moderate and severe hemophilia A. Analysis of involvement of individual joints, and their score values by the treatment regimen (prophylaxis vs. on-demand treatment.) The study included 23 patients - 15 patients on 'on-demand' regimen and 8 patients who had prophylaxis, all being treated at the Clinic of Hematology and Clinical Immunology, Clinical Center Nis. In the assessment of frequency of complications we used descriptive statistics: the number, proportion and mean. The comparison of arithmetic means of the two samples was performed using the t-test. The comparison of frequency values was performed using the chi-square test or Fisher's test. In the group without prophylaxis, the knee and hip were the most commonly affected sites (73.33% and 53.33%), and in the group with prophylaxis, the elbow joint was mostly affected (37.50%). The knee was statistically more often affected in patients without prophylaxis compared to those on prophylaxis. The knee score had the highest value in both groups. It was statistically significantly higher in patients without prophylaxis compared to those on prophylaxis. The hip score was the second highest value in the examined groups, the third was the elbow joint score, followed by the ankle score, and the lowest score was observed for the shoulder joint. Elbow and ankle scores were statistically significantly higher in patients without prophylaxis compared to those on prophylaxis. Chronic arthropathy is the most common complication in patients with severe and moderate Haemophilia A, with maximum involvement of the knee joint in both groups of patients (with or without prophylaxis), but with a statistically significantly higher score in patients without prophylaxis.

Phase 1-2 Clinical Trial of a Recombinant AAV5 Vector Containing the Human FIX Gene in Patients with Severe or Moderately Severe Haemophilia B

Gene therapy has been successfully used in a research setting in a limited number of patients with severe haemophilia B, primarily using vectors based on adeno-associated virus (AAV) serotype 2 and 8. Several research groups and companies are exploring new developments to improve current treatment strategies to eventually make gene therapy available for a larger number of patients. Pre-existing immunity to AAV capsid proteins may limit the availability of such therapies to small sub-groups of patients. A low prevalence of natural neutralizing antibodies against AAV5 compared with other serotypes has been demonstrated (Calcedo et al., Clin Vaccine Immunol 2009, 18:1586-1588). We use a recombinant AAV5 containing the codon optimized human factor IX gene (AAV5-hFIX), using a baculovirus production process that allows commercial scale manufacturing of the AAV5-hFIX drug product. Human FIX expression levels in macaques treated i.v. with AAV5-hFIX at a dose of 5 × 10^12 gc/kg were high enough to expect therapeutic effect on the haemophiliac phenotype in haemophilia B patients. Such levels were achieved in humans during AAV8-hFIXco clinical study (Nathwani et al., NEJM 2011, 365:2357-2365). hFIX levels in dose-escalating GLP toxicity studies in cynomolgus monkeys and mice showed linear dose responses using doses up to 1 × 10˄14 and 2.3 × 10^14 cg/kg, respectively, and no specific safety concerns. In human studies with AAV5 containing the human porbilinogen deaminase (PBGD) gene, administered in doses up to 2 x 10^13 gc/kg to patients with acute intermittent porphyria, no safety concerns were raised (D’Avola et al., ASGCT, Washington DC, 2014). Importantly, in this study no liver enzyme perturbations were observed following administration of AAV5.The primary objective of the proposed study is to investigate the safety of systemic administration of AAV5-hFIX to adult patients with severe or moderately severe haemophilia B. The multicentre trial has an open-label, uncontrolled, single-dose, dose-ascending design and consists of two cohorts. The study population consists of male patients, aged ≥18 years, with severe or moderately severe haemophilia B and a severe bleeding phenotype [i.e. known FIX deficiency with plasma FIX activity level <1% (severe), or plasma FIX activity level ≥1% and ≤2% (moderately severe) and currently on prophylactic FIX replacement therapy for a history of bleeding, or currently on on-demand therapy with a current or past history of frequent bleeding defined as four or more bleeding episodes in the last 12 months, or chronic haemophilic arthropathy. Patients should have had more than 150 previous exposure days of treatment with FIX protein. Subjects are allocated to one of two cohorts with the following planned dose levels: Cohort 1 (5 subjects) with AAV5-hFIX 5.0 × 10^12 gc/kg and Cohort 2 (5 subjects) with AAV5-hFIX 2.0 × 10^13 gc/kg. Key efficacy assessments include factor IX plasma levels, the need for FIX replacement therapy, incidence of spontaneous bleedings and health-related quality of life measurements.In conclusion, AAV5-hFIX produced in commercial scale represents a novel approach to gene therapy of haemophilia B. DisclosuresMiesbach:uniQure: Consultancy; Bayer: Research Funding; Baxter: Research Funding; CSL Behring: Research Funding; Biotest: Research Funding; Octapharma: Research Funding. Meyer:uniQure B. V.: Employment. Nijmeijer:uniQure B. V.: Employment. Salmon:uniQure B. V.: Employment. Grosios:uniQure B. V.: Employment. Petry:uniQure B. V,: Employment. Leebeek:uniQure B. V.: Consultancy; CSL Behring: Research Funding; Baxter: Research Funding.