Frontiers in Arthritis

Joint damage due to recurrent bleedings in Haemophilia is the cause for long-term disabilities. The pathogenetic mechanism of haemophilic arthropathy is multifactorial and includes inflammatory synovium-mediated and degenerative cartilage-mediated phenomenons, in addition to neoangiogenesis and bone loss. Free blood in the joint has a direct effect on cartilage and synovium, and the deposit of iron appears to play a pivotal role. Iron may promote the apoptosis of chondrocytes by catalyzing the formation of oxygen metabolites. Iron may also act on the synovial membrane by favouring its proliferation through the induction of proto-oncogenes involved in cellular proliferation and stimulation of inflammatory cytokines. Such degenerative and inflammatory processes occur concomitantly, but also independently. A reduction of bone mineralization is usually present as a part of the articular damage associated to a multifactorial mechanism: it seems that the molecular triad (osteoprotegerin/Receptor activator of nuclear factor kB/Receptor activator of nuclear factor kB ligand) probably plays a major role, inducing osteoclastic differentiation and maturation. These processes finally result in a fibrotic and irreversible altered joint, feature of haemophilic arthropathy.

Pharmacokinetic (PK) has improved our knowledge about the most appropriate dosing and timing of administration of FVIII/FIX concentrates in patients with Haemophilia. However, although several studies have recently addressed the relevance of PK of clotting factors, usual practice is still mostly based on empiric approaches since individual PK estimation is difficult to obtain unless the patient is formally enrolled in a study. In fact, several plasma samples collected over several hours and/or days are required to establish a half-life curve confidently and this may be a relevant problem, especially in children. Recently however population PKs has emerged as an important tool to overcome this drawback. Targeted prophylaxis could take advantage of knowing the individual response to factor concentrate administration. On the clinical ground, age and body weight (BW) are roughly used to guide dosing because usually in vivo recovery is lower and clearance is faster in children than in adults.

Haemophilia A and B are X-linked recessive coagulation disorders resulting from the deficiency or abnormal function of either factor VIII or IX, respectively. Musculoskeletal bleedings, particularly joint bleeding, are the hallmark of severe Haemophilia. Recurrent joint bleedings lead to arthropathy and functional disability. Haemophilia can be treated either on demand to stop bleeding or with prophylaxis to prevent joint damage. A variety of high-quality clotting concentrates are available for patients with Haemophilia and long-acting concentrates are becoming available, with further improvements in the treatment of this potentially disabling disease. Also gene therapy is an impressive promise of cure for the patients, especially those with Haemophilia B. Currently, the development of alloantibodies directed against FVIII or FIX, able to neutralize their clotting activity, and making replacement therapy ineffective represents the most serious challenge of the treatment. A comprehensive care of patients with Haemophilia should be provided by a multidisciplinary team, offering the more appropriate and innovative therapies for Haemophilia and its complications.

The haemostatic process is characterized by a series of biochemical reactions aiming at preventing blood loss through blood clot formation. This latter process is mediated by the interaction of platelets on the surface of the injured vessel wall which in turn induces the coagulative phase requiring the activation of inactive zymogen into active proteases. Haemophilia A and B are rare disorders in which the coagulation cascade is affected due to the lack of blood clotting FVIII and FIX, respectively. In order to provide the appropriate therapy for patients with these bleeding disorders, several laboratory tests have to be performed. The initial screening is conducted by screening global tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) but only this latter is prolonged in hemophilia. Next, the measurement of factor activity is required for the diagnostic assessment and classification of the disease severity. Three methods can be performed for evaluating FVIII activity including one-stage, two-stage and chromogenic assays. Approximately 30% of severe Haemophilia patients develop FVIII inhibitors which neutralize the clotting activity. The most common assay employed for the detection of inhibitors is the Bethesda assay that combines plasma containing normal amount of FVIII with same volume of patient plasma. Problems in Haemophilia diagnosis or inhibitor detection can occur at any stage in the clinical diagnosis/laboratory phase, from the pre-analytical to the analytical to postanalytical. Therefore, the aim of this chapter is to summarize the diagnostic approaches, pitfalls and interpretation of coagulation assay in Haemophilia.

The management of nursing consists in the performance of leadership functions of governance and decision-making within organizations employing nurses. It includes many processes common to all management as planning, organizing, directing, and controlling. In case of rare bleeding disorders, nurses may encounter patients who are experiencing acute bleedings or receiving treatments for another condition. In Haemophilia, the nurse is not only a professional figure but also a teacher of daily actions, as self-injections of substitutive factors, and a confidant reference point for patients and their family.

Haemophilic arthropathy one of the most severe cause of disability in patients affected by severe Haemophilia. The identification of early signs of arthropathy and the assessment of osteochondral damage is fundamental in the management of such patients. Different imaging modalities can be useful to detect haemophilic arthropathy at various stages. Conventional radiography demonstrates bone alterations and indirectly osteochondral damages, and still remains the basis to plan a surgical treatment. Magnetic resonance imaging better detects soft tissues and cartilage abnormalities at every stages, while ultrasonography especially by the colorpower Doppler modality has became crucial for the monitoring of underage subjects and for the clinical follow-up. Computed tomography is nowadays just used for the detection of invading pseudotumors, bone erosions, and some extra-musculoskeletal complications of Haemophilia.

In haemophilic arthropathy (HA), a spontaneous joint bleeding may trigger and perpetuate synovitis, and cartilage damage may follow even after a single exposure to blood, leading to a progressive and permanent joint damage. Ultrasonography (US) may detect articular and periarticular structures, muscles, tendons, tendon-sheats and enthesys. While power Doppler (PDUS) detects synovial inflammation and local blood flow. The US is based on technique, concepts and method widely accepted. We describe a US protocol to study the typical target joint (elbows, knees, and ankles). Knees, elbows, and ankles can be systematically and easily evaluated by means of conventional US machines, including portable machines, with a linear probe 13-4 MHz. The presence of haemarthrosis and the evidence of a synovial neoangiogenesis is assessed by PDUS in longitudinal scan. In the last decade, some scoring methods were proposed. Our scoring system requires a practice of US technique without necessarily being expert sonographers and allow to study all joints in static and dynamic position through nine items. This scoring method is applied to each target joint with a range from 0 to 21 and with cut off ≤ 5 or >5 useful to define the early stage of arthropathy.

The combination of bleeding control strategies associated with lifestyle modifications, gentle physical activity, and the eventual use of ortheses are the basic principles to prevent the haemophilic arthropathy in its severe stages that represent the most common clinical manifestation of Haemophilia. Several conservative treatments may be also useful. Intraarticular injections of hyaluronic acid (viscosupplementation), Rifampicine (chemical synoviorthesis), and radioactive colloids (radiosynoviorthesis) with their different indications have been associated with good results. Other approaches as platelet-rich-plasma injections or synovial endovascular embolization have still to be validated and understood to ensure their safety or effectiveness.

Haemophilia is a condition that has to be kept under full control. A “3 M’s” approach aiming to the patient’s Mindfulness, Muscles and physical activity Maintenance is nowadays suggested. In association, an appropriate program of physical therapy with strategies fitting all needs and abilities of patients is mandatory and reasonable, particularly when acute or chronic musculoskeletal affections occur.

Arthroscopy in haemophilic subjects is nowadays considered a procedure associated with good clinical outcomes and a low rate of complications. Once addressed as the minimally invasive way to obtain a synovectomy, to date it is performed for several other procedures, as loose bodies removal and joint debridement. It is also useful as assistance for a mini-open ankle fusion. The modern aim of an arthroscopy in a target joint is to delay a more aggressive surgical approach. Thus, critical are the indications: early to moderate or mild arthropathies, in adult or young subjects after failure of conservative treatments. Knees and ankles are the most arthroscopically treated joints, followed by elbows and shoulders.

Total Knee Arthroplasty is one of the most performed procedures in the haemophilic population. Several series have been released over the last decades: despite good clinical outcomes, high rates of complications such as infection and loosening have been reported. Such complications have been mainly related to coinfected patients (HIV-positive) and subjects with inhibitors frequently affected by uncontrolled bleedings. Moreover, almost all arthroplasties have been performed using standard cemented Cobalt-Chrome knee implants and generally high constraints to ensure the stability of the prostheses. Recently new biomaterials with a better tribology and implants with less constraints have been used in haemophiliacs with encouraging results. The present mean survivorship is more than 90% at a mid-term follow-up while it was about 82.5% (range: 68%-96%) in the period ’70-‘90s. Dedicated multidisciplinary teams, appropriate bleeding management, and modern modular implants may ensure even better outcomes than the last decades with rates of success and complications very close to those of the non-haemophilic population.

Hip arthropathy in patients with Haemophilia may be disabling. In early stages a conservative treatment may be useful, as in late stages a Total Hip Arthroplasty is indicated. During the ‘80s and ‘90s clinical outcomes after a hip arthroplasty were variable given the use of first generation cemented implants, and the significantly high rates of complications, as for other types of surgery. In the last decades modern cementless implants with high performing materials and less invasive surgical techniques have been introduced with expected improved results. Recently several series have been reported with very satisfactory outcomes, and longer survival rates of implants with respect to the past. A combination of multidisciplinary teams dedicated to haemophilic subjects, the use of modern cementless implants, and less invasive surgical approaches may represent the key to achieve good outcomes, fewer complications, and better prosthetic survivorship in such difficult patients.

The primary prophylaxis is the best way to protect haemophilic patients from synovitis and arthropathy in foot and ankle. By the replacement of the deficient factor, haemophiliacs requiring orthopedic surgery of the foot and ankle may successfully and safely undergo such type of surgery. Radiosynovectomy is a very effective procedure able to induce the decrease of frequency and intensity of bleedings related to synovitis. On average, the number of haemarthroses may diminishes up to 65%. If three consecutive radiosynovectomy procedures, repeated at six-month intervals, fail to lessen the synovitis, arthroscopy should be performed. In such cases, large osteophytes may develop on the anterior aspect of distal, causing severe pain and impingement. Open or arthroscopic osteophyte removal (queilectomy) should be considered. Achilles tendon lengthening in cases of fixed equinus deformity represents another common procedure in haemophilic subjects. In the case of advanced haemophilic arthropathy of the ankle, the first option is the arthroscopic debridement. In severe cases three further options are available: ankle distraction by means of external fixation (arthrodiastasis), ankle fusion (tibiotalar and/or subtalar), and total ankle replacement.

The elbow is the second most commonly affected joint in haemophilic patients. As for other target joints, the strategy of treatment starts from a medical management, and in case of failure, more specific approaches have to be chosen. Radioactive or chemical synovectomy represent valid options but may not be adequate in moderate arthropathies. In such cases, surgical procedures as arthroscopic or open synovectomy are useful. Advanced haemophilic arthropathy of the elbow may be severely disabling, particularly for younger patients. In these conditions, a total elbow replacement may be a good option. Thanks to modern implant designs and materials, this procedure has shown excellent clinical outcomes and an acceptable survival rate. Nevertheless, it remains a complex surgery and considering the postoperative restrictions and risks, it requires a careful selection of patients.

The management of a failed orthopaedic implant is potentially complex in haemophilic patients. Several critical aspects have to be considered ranging from a tailored haematological care and rehabilitative period to high technically demanding surgical procedures and type of implants needed for the management of the compromised joint. Hip and knee are the most involved joints needing a substitution after a prosthetic failure. All these interventions are delicate and expensive, particularly when the failure is not a simple aseptic loosening but it is represented by an infection or a case with severe bone defects, pseudotumours, and soft tissue mortification. Only specific facilities and specialized teams may be able to manage such these conditions in a safe manner.

The proposal of a comprehensive rehabilitation program after major orthopaedic surgery, specifically Total Hip Arthroplasty (THA) and Total Knee arthroplasty (TKA), is a key event in the management of patients affected by haemophilia arthropathy. Rehabilitative protocols should be carried out by a multidisciplinary team. This is a modern approach consists of three main stages: preoperative evaluation and education, in-hospital rehabilitation, and out-patient rehabilitation. The primary purposes are the control of pain, the recovery and maintenance of range of movement, and the muscle strengthening. In-hospital rehabilitation usually starts the day after surgery, using specific protocols in order to gradually counteract joint stiffness and pain. After the discharge haemophilic patients should improve their training with task-oriented exercises. An adequate and individually-tailored rehabilitation program could optimize the result of major orthopaedic surgery, improving the functional ability of haemophiliacs, and resulting in a better quality of life.

The knowledge regarding the management of complications related to orthopaedic surgery in Haemophilia is still limited due to the lack of published data and several concerns about the possible catastrophic damage to patients. A quote of 12% to 17% of haemophilic patients need a hospital admission to undergo orthopaedic surgery and more than one procedure is often needed for some subjects. Complications in haemophilic patients occur from 2% to 66% and are strictly related to the severity of disease, type of orthopaedic procedure, and patient comorbidities. Bleeding, haematoma, wound complications, infection, inhibitors development, deep venous thromboembolism, and intraoperative fractures are the most frequently reported complications. The management of complications of the orthopaedic surgery in haemophiliacs is a challenging task, requiring complex treatment performed in a highly specialized centre by a multidisciplinary team.

Microsurgery is increasing popularity among plastic surgeons, creating new alternative solutions for patients that until few years ago only had amputation as final option. Muscles are supplied by several vascular pedicles and the knowledge of their anatomy may allow the use of myocutaneos islands and a rotation on its axis (propeller flap), or a complete detaching from the rest of the body (free flap) and its anastomosis with a recipient vessel to cover soft tissue defects. These procedures are very similar in patients affected by Haemophilia: the only specific issue in such patients is the attention paid to the maintenance of an adequate vascularization that represents the key for the survival of any type of flap.

A standard replacement treatment by FVIII or FIX concentrates is in most cases ineffective in haemophilic patients with inhibitors. To overcome this problem, the so-called bypassing agents (BPAs) have been introduced in the market and patients may be efficaciously treated also in the orthopaedic setting. However not all patients with inhibitors need to be treated at the same manner. In a proportion of patients a standard replacement therapy by FVIII and FIX concentrates may be useful for the postoperative period or just for a part of it. Ancillary therapy by tranexamic acid may significantly contribute to the bleeding control while anti-thrombotic drugs seem unnecessary differently from non haemophilic patients. Brand new drugs are now being studied representing a potential actual revolution in the treatment of patients with haemophilia and inhibitors.

Haemophilia as other complex diseases deserves several peculiar orthopaedic conditions that may not be classified in specific routinary categories. A multidisciplinary approach and a full information of the patients may be useful to treat such usually difficult cases. An overview of unusual clinical settings regarding joints, bones, and muscles are reported. Finally, a brief summary of the gene therapies and novel approaches is presented.