Arthroscopic ankle surgery in people with haemophilia.

INTRODUCTION: People with haemophilia (PWH) not administered primary haematological prophylaxis since childhood, that is, those treated haematologically on demand or not treated at all, often experience the degeneration of the ankles, leading to pain and functional impairment. AIM: To analyse the outcomes and complications of arthroscopic ankle surgery performed on PWH. METHODS: For this narrative review of the literature, a search was conducted in PubMed on 2, December 2023, using the keywords "haemophilia", "ankle" and "arthroscopy". Of the 29 articles identified, 15 specifically related to ankle arthroscopy in PWH were selected (inclusion criterion). The remaining articles did not meet this requirement (exclusion criterion) and were therefore eliminated. RESULTS: Arthroscopic procedures (arthroscopic synovectomy, debridement and arthrodesis of the ankle) are increasingly used in the surgical treatment of haemophilic ankle arthropathy. Although arthroscopic ankle surgery offers good outcomes in patients with haemophilia, the procedure is not free of complications, which range from 7.9% for arthroscopic ankle debridement to 13.1% in arthroscopic ankle synovectomy and 17.8% in arthroscopic ankle arthrodesis, respectively. The non-union rate of arthroscopic ankle arthrodesis is 7.1% (2/28). CONCLUSION: Although arthroscopic interventions in the haemophilic ankle (synovectomy, debridement, arthrodesis) offer good functional outcomes, they are associated with a non-negligible rate of complications. Arthroscopic ankle surgery in PWH is major surgery and should be treated as such.

Hemarthrosis in a Pediatric Patient With Immune Thrombocytopenia and Lyme Arthritis.

The presentation of immune thrombocytopenia is dependent on the degree of thrombocytopenia, with no to mild bleeding symptoms, primarily mucocutaneous bleeding. Severe bleeding in other organ systems is a rare complication. Spontaneous hemarthrosis is rare in patients without hemophilia. We report a child presenting with oral and cutaneous petechial lesions and left knee hemarthrosis without trauma. Laboratory findings showed severe thrombocytopenia consistent with immune thrombocytopenia. Serologic tests were consistent with Lyme disease. Hemarthrosis was presumed secondary to Lyme disease monoarticular joint inflammation with bleeding exacerbated by severe thrombocytopenia. Hemarthrosis resolved and platelet counts normalized following immunoglobulin infusion, steroid course, and antibiotics.

Spontaneous Hemopericardium Complicated by Tamponade in a Child With Moderate Hemophilia A: Case-Based Review.

Hemophilia A is the most common severe innate bleeding disorder. It is an X-linked recessive inherited bleeding disorder characterized by a qualitative and/or quantitative deficiency of factor VIII. The clinical manifestation of this disease is hemorrhaging that can affect every organ, in particular joints (hemarthrosis) and muscles (hematoma). Some serious but rare hemorrhages can be life-threatening, in particular hemorrhage of the central nervous system and hemopericardium. We report a rare case of spontaneous hemopericardium complicated by tamponade in a child with moderate hemophilia A treated with Factor VIII replacement infusion and pericardial drainage, with a favorable outcome. To our knowledge, this is the second case described in the literature of spontaneous hemopericardium occurring in a child with hemophilia A. Our case suggests that a dose of 50 IU/kg/8 h of factor VIII maintained for up to one day after removal of the pericardial drain seems to be sufficient to ensure correct hemostasis, though further evidence is needed to confirm this impression.

Clinical, economic, and health-related quality of life burden associated with von Willebrand disease in adults and children: Systematic and targeted literature reviews.

INTRODUCTION: Debilitating clinical complications in von Willebrand disease (VWD) can affect health-related quality of life (HRQoL), increase healthcare costs and cause long-lasting consequences. However, the magnitude of these burdens needs to be more fully explored. AIM: To estimate the prevalence and burden of clinical complications, the impact on HRQoL and the economic burden associated with VWD. METHODS: Embase® , MEDLINE® , the Cochrane Library and conference proceedings were searched for studies on VWD evaluating clinical complications, HRQoL and cost and resource use. RESULTS: Among 16 studies assessing clinical complications in VWD, the most prevalent bleeding symptoms were menorrhagia (2%-95% [n = 7 studies]), epistaxis (12%-80% [n = 6]) and easy bruising (46%-65% [n = 2]). Among 17 studies evaluating HRQoL, the most common assessment scales were the generic SF-36 (n = 8 studies) and the EQ-5D (n = 2). Bleeding symptoms were associated with reduced QoL in six of seven studies, and of six studies evaluating treatment impact, four reported improvements in one or more HRQoL components. Among 25 studies on cost and resource use, key observations included higher post-surgery healthcare costs in VWD versus non-VWD patients (n = 1 study) and higher costs and resource use in VWD patients with bleeding complications versus those without (n = 1). CONCLUSION: Although limited, available evidence suggests that VWD patients experience a high burden of clinical complications, reduced QoL and high healthcare costs. Haemarthrosis is more common in severe VWD than is often assumed, and bleeds (including haemarthrosis) can reduce QoL. Research efforts to improve QoL and other outcomes should be prioritized.

The value of radiosynoviorthesis for treatment of chronic synovitis in hemophilic joint disease.

Chronic synovitis is contributing to the development of arthropathy in hemophilia A and B. In most patients with severe and moderate hemophilia, during lifetime, joint damage progresses despite early prophylaxis and intense treatment with coagulation factor concentrates. Recurrent hemorrhages into the joints and subclinical bleeding lead to chronic inflammation of the synovium, neoangiogenesis and remodeling, sustaining a vicious circle of bleeding-remodeling-bleeding and progression of osteochondral damage. Imaging techniques including ultrasound and MRI are able to early visualize synovitis and osteochondral changes. Early detection and sustained therapy of synovitis are important preconditions to prevent further deterioration of joint status. Chronic synovitis requires intensified substitution of coagulation factors and concomitant analgetic, antiphlogistic and physical therapy. The value of early radiosynoviorthesis (RSO) as effective method to control ongoing synovitis is discussed here. RSO is recommended as first choice therapy in case of persistant chronic synovitis, recorded in both national and international guidelines.

On-demand treatment with the iron chelator deferasirox is ineffective in preventing blood-induced joint damage in haemophilic mice.

INTRODUCTION: Early intervention in the devastating process of haemophilic arthropathy (HA) is highly desirable, but no disease-modifying therapy is currently available. Considering the pivotal role of iron in the development of HA, iron chelation is considered a promising therapeutic approach. A previous study in haemophilic mice demonstrated that treatment with the iron chelator deferasirox (DFX) 8 weeks before joint bleed induction, attenuated cartilage damage upon blood exposure. However, in haemophilia patients this approach is not opportune given the unpredictable occurrence of hemarthroses. AIM: To evaluate the effectiveness of on-demand DFX treatment, initiated immediately after joint bleed induction. METHODS: A joint bleed was induced in 66 factor VIII-deficient mice by infra-patellar needle puncture. Mice were randomly assigned to treatment with either placebo (drinking water) or DFX (dissolved in drinking water) throughout the study. Five weeks after joint bleed induction, inflammation and cartilage damage were assessed histologically. Joints of ten bleed naive haemophilic mice served as controls. RESULTS: A joint bleed resulted in significant inflammation and cartilage damage in the blood-exposed joint compared with those of control animals, in both the placebo and DFX group (all p = <.05). No differences in tibiofemoral or patellar inflammation (p = .305 and p = .787, respectively) nor cartilage damage (p = .265 and p = .802, respectively) were found between the blood-exposed joints of both treatment groups. CONCLUSION: On-demand treatment with DFX does not prevent joint damage following blood exposure in haemophilic mice. DFX seems unable to reach the joint in time to exert its effect before the irreversible harmful process is initiated.

'Do not Do' Recommendations in Hemophilia.

BACKGROUND: It is important to discard those practices that do not add value. As a result, several initiatives have emerged. All of them try to improve patient safety and the use of health resources. PURPOSE: To present a compendium of "do not do recommendations" in the context of hemophilia. METHODS: A review of the literature and current clinical guidelines has been made, based on the best evidence available to date. RESULTS: The following 13 recommendations stand out: 1) Do not delay the administration of factor after trauma; 2) do not use fresh frozen plasma or cryoprecipitate; 3) do not use desmopressin in case of hematuria; 4) do not change the product in the first 50 prophylaxis exposures; 5) do not interrupt immunotolerance; 6) do not administer aspirin or NSAIDs; 7) do not administer intramuscular injections; 8) do not do routine radiographs of the joint in case of acute hemarthrosis; 9) Do not apply closed casts for fractures; 10) do not discourage the performance of physical activities; 11) do not deny surgery to a patient with an inhibitor; 12) do not perform instrumental deliveries in fetuses with hemophilia; 13) do not use factor IX (FIX) in patients with hemophilia B with inhibitor and a history of anaphylaxis after administration of FIX. CONCLUSION: The information mentioned previously can be useful in the management of hemophilia, from different levels of care. As far as we know, this is the first initiative of this type regarding hemophilia.

Clinical gait features are associated with MRI findings in patients with haemophilic ankle arthropathy.

INTRODUCTION: Haemophilic ankle arthropathy due to repeated joint bleeds often leads to altered gait in adult patients with haemophilia. AIM: To investigate the association between clinical gait features and blood-induced ankle joint damage scored using MRI findings in patients with haemophilic ankle arthropathy. METHODS: This observational study investigated 48 ankles of 24 patients with severe haemophilia (median age of 33 years). Blood-induced ankle joint damage was scored by an experienced radiologist using the International Prophylaxis Study Group (IPSG-)MRI score which evaluates the presence or absence of effusion, synovial hypertrophy, haemosiderin, surface erosions, subchondral cysts and cartilage degeneration. Using 3D gait analysis, peak ankle joint power generation and absorption (W/kg) were measured for each ankle since these are surrogate measures for joint loading during walking. Associations between MRI findings and these two clinical gait features were calculated using Spearman's ρ correlation with an α-level correction (α = 0.01) for multiple tests. RESULTS: We found large negative associations between ankle joint peak power generation and IPSG-MRI score (ρ = -0.631; P = <.001), IPSG-MRI osteochondral subscore (ρ = -0.701; P = <.001), severity of synovial hypertrophy (ρ = -0.507; P = <.001) and haemosiderin (ρ = -0.400; P = .005). Associations were also found for ankle joint peak power absorption and IPSG-MRI score (ρ = -0.425; P = .003) and IPSG-MRI osteochondral subscore (ρ = -0.556; P = <.001). CONCLUSION: Severe blood-induced ankle joint damage relates to a lowered tolerance towards ankle joint mechanical loading during walking in patients with haemophilia.

TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding.

Excessive vascular remodeling is characteristic of hemophilic arthropathy (HA) and may contribute to joint bleeding and the progression of HA. Mechanisms for pathological vascular remodeling after hemophilic joint bleeding are unknown. In hemophilia, activation of thrombin-activatable fibrinolysis inhibitor (TAFI) is impaired, which contributes to joint bleeding and may also underlie the aberrant vascular remodeling. Here, hemophilia A (factor VIII-deficient; FVIII-deficient) mice or TAFI-deficient mice with transient (antibody-induced) hemophilia A were used to determine the role of FVIII and TAFI in vascular remodeling after joint bleeding. Excessive vascular remodeling and vessel enlargement persisted in FVIII-deficient and TAFI-deficient mice, but not in transient hemophilia WT mice, after similar joint bleeding. TAFI-overexpression in FVIII-deficient mice prevented abnormal vessel enlargement and vascular leakage. Age-related vascular changes were observed with FVIII or TAFI deficiency and correlated positively with bleeding severity after injury, supporting increased vascularity as a major contributor to joint bleeding. Antibody-mediated inhibition of uPA also prevented abnormal vascular remodeling, suggesting that TAFI's protective effects include inhibition of uPA-mediated plasminogen activation. In conclusion, the functional TAFI deficiency in hemophilia drives maladaptive vascular remodeling in the joints after bleeding. These mechanistic insights allow targeted development of potentially new strategies to normalize vascularity and control rebleeding in HA.

Radiosynovectomy in haemophilia.

Radiosynovectomy (RS) is a simple, effective and safe procedure for the control of haemophilic synovitis that causes repetitive haemarthrosis. It must be done after confirming clinically (hard and painless mass on palpation) and by ultrasonography the existence of synovitis in a joint with recurrent haemarthrosis. RS should be the first invasive option (instead of arthroscopic synovectomy) for treatment of chronic synovitis. The technique is highly cost effective in comparison to arthroscopic synovectomy. The indication for RS is the presence of repeated haemarthroses associated with synovitis (confirmed clinically and by imaging techniques) that cannot be controlled by means of haematological treatment. No increase in the risk of cancer has been published and the dose of radiation utilized in RS is minimal. In haemophilic patients with recurrent haemarthrosis, RS should be performed under factor coverage as soon as possible, once the existence of synovitis has been confirmed by ultrasonography. RS should really be considered as a useful adjunctive procedure to the primary intervention, which is intensive replacement therapy.

Severe Ankle Arthritis After Multiple Hemarthrosis Secondary to Factor XI Deficiency: A Case Report.

Hemophilic arthropathy of the ankle is an extremely unique condition that affects a small subset of the population in the United States. We present the case of a 66-year-old male with factor XI deficiency, which, over years of repetitive microtrauma as a professional soccer player, led to multiple hemarthrosis and severe arthropathy of his right ankle. The patient successfully underwent total ankle replacement arthroplasty and was able to return to recreational sports and competitive road cycling.

Surgical Treatment of Neglected Bilateral Hemophilic Equinus Contracture With External Fixation: A Case Report.

Hemophilia is a disorder of blood coagulation with X-linked recessive inheritance. It is characterized by uncontrollable hemorrhage, and 80% of these occur intraarticularly. With recurrent hemarthrosis, recurrent synovitis occurs, which eventually leads to the formation of articular contractures. The key to the prevention of hemophilic joint complications is successful prevention of bleeding and management of the initial hemarthrosis. However, after the development of a rigid contracture, surgical correction remains the only method to correct the deformity. Achilles tendon lengthening, synovectomy, anterior osteophyte resection, corrective osteotomies, external fixators, or arthrodesis should be considered as surgical options. In the present report, we describe our experience using hybrid-type external fixators to manage bilateral neglected rigid equinus contractures in a hemophilic patient, with 78 months of follow-up data.

Continuous infusions of B domain-truncated recombinant factor VIII, turoctocog alfa, for orthopedic surgery in severe hemophilia A: first case report.

Continuous infusions (CI) of factor (F)VIII are preferable to the conventional bolus injections for the maintenance of consistent FVIII levels during surgery in patients with severe hemophilia A. A third generation, B domain-truncated recombinant FVIII (turoctocog alfa, Novo Nordisk, NovoEight®), was approved for clinical use in 2014. The hemostatic efficacy and safety of bolus injections of turoctocog alfa in patients undergoing surgery have been reported, but no reports on CI therapy have been published. We describe a 43-year-old patient with severe hemophilia A who required arthroscopic synovectomy of the right elbow and arthrodesis of the right ankle. He was treated with a bolus injection of turoctocog alfa (36 IU/kg) immediately before operation, followed by CI (infusion rate; 2.9 IU/kg/h) to maintain FVIII activity > 80 IU/dl throughout the perioperative period. Surgery was completed successfully with uncomplicated hemostatic control. CIs were continued until post-operative day (POD) 4. Further bolus injections were given from POD5. No anti-FVIII inhibitor has been detected post-operation. This case provides important information on CI therapy using turoctocog alfa during surgery for patients with severe hemophilia A.

Connective tissue growth factor (CTGF/CCN2) in haemophilic arthropathy and arthrofibrosis: a histological analysis.

INTRODUCTION: Joint haemorrhage is the principal clinical manifestation of haemophilia frequently leading to advanced arthropathy and arthrofibrosis, resulting in severe disability. The degree and prevalence of arthrofibrosis in hemophilic arthropathy is more severe than in other forms of arthropathy. Expression of connective tissue growth factor (CTGF) has been linked to many fibrotic diseases, but has not been studied in the context of haemophilic arthropathy. AIM: We aim to compare synovial tissues histologically from haemophilia and osteoarthritis patients with advanced arthropathy in order to compare expression of proteins that are possibly aetiologic in the development of arthrofibrosis. METHODS: Human synovial tissues were obtained from 10 haemophilia and 10 osteoarthritis patients undergoing joint surgery and processed for histology and immunohistochemistry. RESULTS: All samples from haemophilia patients had synovitis with hypertrophy and hyperplasia of synovial villi. Histologically, synovial tissues contained hyperplastic villi with increased cellularity and abundant haemosiderin- and ferritin-pigmented macrophage-like cells (HMCs), with a perivascular localization in the sub-surface layer. CTGF staining was observed in the surface layer and sub-surface layer in all haemophilia patients, exclusively co-localizing with HMCs. Quantification showed that the extent of CTGF-positive areas was correlated with the degree of detection of HMCs. CTGF was not observed in any of the samples from osteoarthritis patients. CONCLUSION: Using histological analysis, we showed that CTGF expression is elevated in haemophilia patients with arthrofibrosis and absent in patients with osteoarthritis. Additionally, we found that CTGF is always associated with haemosiderin-pigmented macrophage-like cells, which suggests that CTGF is produced by synovial A cells following the uptake of blood breakdown products.

Arthroscopic knee debridement can delay total knee replacement in painful moderate haemophilic arthropathy of the knee in adult patients.

The role of arthroscopic debridement of the knee in haemophilia is controversial in the literature. The purpose of this study is to describe the results of arthroscopic knee debridement (AKD), with the aim of determining whether it is possible to delay total knee replacement (TKR) for painful moderate haemophilic arthropathy of the knee in adult patients. In a 14-year period (1998-2011), AKD was performed for moderate haemophilic arthropathy of the knee in 27 patients with haemophilia A. Their average age at operation was 28.6 years (range 26-39 years). Indications for surgery were as follows: more than 90° of knee flexion, flexion deformity less than 30°, good axial alignment of the knee, good patellar alignment, and pain above >60 points in a visual analogue scale [0 (no pain) to 100 points]. Secondary haematological prophylaxis and rehabilitation (physiotherapy) was given for at least 3 months after surgery. Follow-up was for an average of 7.5 years (range 2-14 years). We assessed the clinical outcome before surgery and at the time of latest follow-up using the Knee Society pain and function scores, the range of motion, and the radiological score of the World Federation of Haemophilia. Knee Society pain scores improved from 39 preoperatively to 66 postoperatively, and function scores improved from 36 to 52. Range of motion improved on an average from -15° of extension and 90° of flexion before surgery, to -5° of extension and 110° of flexion at the last follow-up. A radiological deterioration of 2.8 points on average was found. There were two (7.4%) postoperative complications (haemarthroses resolved by joint aspiration). One patient (3.7%) required a TKR 12.5 years later. AKD should be considered in painful moderate haemophilic arthropathy of the knee in adult patients to delay TKR.

Clinical, instrumental, serological and histological findings suggest that hemophilia B may be less severe than hemophilia A.

Recent evidence suggests that patients with severe hemophilia B may have a less severe disease compared to severe hemophilia A. To investigate clinical, radiological, laboratory and histological differences in the arthropathy of severe hemophilia A and hemophilia B, 70 patients with hemophilia A and 35 with hemophilia B with at least one joint bleeding were consecutively enrolled. Joint bleedings (<10, 10-50, >50), regimen of treatment (prophylaxis/on demand), World Federation of Hemophilia, Pettersson and ultrasound scores, serum soluble RANK ligand and osteoprotegerin were assessed in all patients. RANK, RANK ligand and osteoprotegerin expression was evaluated in synovial tissue from 18 hemophilia A and 4 hemophilia B patients. The percentage of patients with either 10-50 or more than 50 hemarthrosis was greater in hemophilia A than in hemophilia B (P<0.001 and P=0.03, respectively), while that with less than 10 hemarthrosis was higher in hemophilia B (P<0.0001). World Federation of Hemophilia (36.6 vs. 20.2; P<0.0001) and ultrasound (10.9 vs. 4.3; P<0.0001) score mean values were significantly higher in hemophilia A patients. Serum osteoprotegerin and soluble RANK ligand were decreased in hemophilia A versus hemophilia B (P<0.0001 and P=0.006, respectively). Osteoprotegerin expression was markedly reduced in synovial tissue from hemophilia A patients. In conclusion, the reduced number of hemarthrosis, the lower World Federation of Hemophilia and ultrasound scores, and higher osteoprotegerin expression in serum and synovial tissue in hemophilia B suggest that hemophilia B is a less severe disease than hemophilia A. Osteoprotegerin reduction seems to play a pivotal role in the progression of arthropathy in hemophilia A.

Elective total knee arthroplasty in haemophilic patients. Proposal for a clinical pathway.

UNLABELLED: Total knee arthroplasty (TKA) provides significant pain relief and better function in patients with end-stage haemophilic knee arthropathy. Peri- and postoperative care tends to be more complex than in non-haemophilic patients undergoing TKA and requires a multidisciplinary team approach. AIM: The implementation of standardized clinical pathways in non-haemophilic patients undergoing TKA has been shown to increase quality of care and to reduce postoperative complication rates. Consequently, the use of clinical pathways in haemophilic patients undergoing TKA may be beneficial to this particular subpopulation of patients. METHODS: A clinical pathway for TKA for haemophilic patients was designed in a consensus process involving all participating departments. RESULTS: We propose a specifically adjusted clinical pathway for TKA for haemophilic patients to show that standardization of elective orthopaedic surgery in haemophilia is feasible. CONCLUSION: The authors emphasize that there are limitations on categorizing haemophilic patients and stress that individual interdisciplinary treatment should take precedence over a standardized approach.

Radiosynovectomy in haemophilia: long-term results of 500 procedures performed in a 38-year period.

BACKGROUND: Radiosynovectomy (RS) can reduce the number of haemarthroses in chronic haemophilic synovitis. The purpose of this study was to assess the effectiveness of RS in terms of the objective improvement of five parameters (number haemarthroses, articular pain, degree of clinical synovitis, clinical score of the World Federation of Haemophilia (WFH), and radiological score of the WFH. METHODS: In a 38-year period (1976-2013), five hundred radiosynovectomies were performed in 443 joints of 345 patients with haemophilia diagnosed with chronic synovitis. The mean patient age was 23.7 years (range, 6-53). The mean follow-up was 18.5 years (range: 6 months-38 years). The RS was carried out with either yttrium-90 or rhenium-186. We performed 1 to 3 injections (RS-1, RS-2, RS-3), with a 6-month interval between them. RESULTS: RS resulted in significant improvement in all the parameters studied, except in the WFH radiologic score that showed no improvement. On average, the number of haemarthroses decreased by 64.1% and articular pain decreased by 69.4%. The degree of synovitis showed a reduction of 31.3%. The WFH clinical score revealed an improvement of 19%. The WFH radiological score showed no improvement. There were four complications (0.9%) of RS. Twenty-eight (6.3%) joints eventually had to be subjected to arthroscopic synovectomy or total knee replacement (TKR). No cancer was observed in this group of patients during the 38-year period. CONCLUSIONS: Radiosynovectomy (RS) is an effective, safe, minimally invasive, well tolerated procedure in the long-term for the treatment of chronic haemophilic synovitis. Moreover, it is very easy to perform. The knee required more injections than the elbow or the ankle and more severe synoviums required a higher number of RS procedures.

The acutely swollen knee. Part 1: Management of atraumatic pathology.

The acutely swollen knee is a common presentation of knee pathology in the Emergency Department and the primary care setting whether on board ship, a Regimental Aid Post or Medical Centre. The swollen knee has both traumatic and atraumatic (systemic) causes, all of which can be accurately diagnosed with an understanding of the underlying injury patterns and patho-anatomy. In Part One, we will be examining the management of non-traumatic causes, followed by Part Two, looking at traumatic causes, in the next issue of the Journal. A detailed clinical history combined with thorough clinical examination will establish the diagnosis, or at least the narrow differential diagnosis in the majority of cases. The uses of specialist examination techniques, diagnostic imaging and arthrocentesis can further assist the clinician in confirming the correct diagnosis and thus prescribing the appropriate treatment. This review will endeavour to give a consensus of opinion and structured guidelines in the diagnosis and initial management of patients presenting with acute or recent-onset swelling of the knee related to atraumatic pathology.