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Review

Management of joint bleeding in hemophilia

Mindy L Simpson Department of Pediatrics, Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, IL, USA. [email protected]
&
Leonard A Valentino Department of Pediatrics, Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, IL, USA
Pages 459-468 | Published online: 10 Jan 2014

Abstract

Hemarthrosis, the hallmark of severe hemophilia, is the major cause of serious bleeding events, disability and reduced quality of life in patients with factor VIII or factor IX deficiency. Joint bleeding is one of the greatest challenges confronting individuals treating hemophilia, and its economic impact is enormous. This article reviews the current management of hemophilic joint bleeding and discusses the potential impact of novel therapies.

Medscape: Continuing Medical Education Online

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert Reviews Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/expertneurothera; (4) view/print certificate.

Release date: 20 September 2012; Expiration date: 20 September 2013

Learning objectives

Upon completion of this activity, participants will be able to:

  • • Describe the clinical characteristics of joint bleeding in hemophilia

  • • Describe prophylaxis to prevent joint bleeding in hemophilia

  • • Describe management of acute hemarthrosis in patients with hemophilia

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME Author

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Authors and Credentials

Mindy L Simpson, MD

Department of Pediatrics, Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, IL, USA

Disclosure: Mindy L Simpson, MD, has disclosed no relevant financial relationships.

Leonard A Valentino, MD

Department of Pediatrics, Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, IL, USA

Disclosure: Leonard A Valentino, MD, has disclosed no relevant financial relationships.

Hemophilia is an X-linked inherited disease that affects an estimated 400,000 persons worldwide and is characterized by the deficiency or absence of coagulation factor (F) VIII (hemophilia A) or FIX (hemophilia B) that predisposes to bleeding Citation[201]. Hemophilia A occurs in approximately one in 5000 male births, whereas hemophilia B occurs in one in 30,000 male births Citation[1]. Hemophilia is categorized as severe (factor activity level: <1 IU/dl or <1%), moderate (factor activity level: 1–5%) or mild (factor activity level: >5–40%) Citation[2]. However, FVIII or FIX activity level alone does not fully represent an individual’s bleeding tendency and other disease-modifying factors are under evaluation.

FVIII & FIX genetics

The human F8 gene, cloned in 1984, is located on the most distal band (Xq28) of the long arm of the X chromosome and spans 186 kb divided into 26 exons and 25 introns Citation[3]. FVIII is primarily expressed in the liver, where sinusoidal endothelial cells are the chief source of circulating FVIII Citation[4,5], although hepatocytes also contain FVIII mRNA. The FVIII protein contains domains of internal homology, and the structure of the mature polypeptide from amino to carboxyl termini is A1-A2-B-A3-C1-C2. The large B domain is excised, and heavy and light chains form the mature FVIII, which is activated by thrombin. Hemophilia A results from multiple mutations in the F8 gene, of which approximately a third are de novo mutations in patients without a family history of the disease (this is also true for hemophilia B) Citation[6]. Gross mutations include inversions (e.g., intron 22 inversion); large deletions, which are associated with severe hemophilia and an increased risk for inhibitory antibodies; insertions; duplications and chromosomal rearrangements. Point mutations, small deletions or insertions and nonsense mutations are linked to a variety of disease phenotypes Citation[3,6,7].

The human F9 gene was cloned in 1982. Located in the subtelomeric region of the long arm of X chromosome, F9 is 34-kilobases long and is divided into eight exons and seven introns Citation[8]. FIX is synthesized exclusively in the liver by hepatocytes and is processed during its secretion into the bloodstream. The mature FIX polypeptide contains three domains in the following structure: Gla – activation peptide – catalytic domain. The activation peptide is released during the conversion to activated FIX, which is then post-translationally modified by hydroxylation and vitamin K-dependent g-carboxylation Citation[9]. Hemophilia B results from multiple mutations in the F9 gene, and patients with this bleeding disorder are classified as cross-reacting material (CRM) positive, defined as normal concentrations of the FIX antigen but reduced FIX activity; CRM reduced, defined as reduced FIX antigen and activity levels and CRM negative, defined as having no detectable FIX antigen or activity Citation[6,8]. CRM-positive patients generally have missense mutations in coding regions or splicing or transcription mutations that result in decreased quantities of FIX. CRM-negative patients typically have frameshift or missense mutations that cause protein instability. In hemophilia B (but not hemophilia A), there is a strong correlation between the presence of partial or complete gene deletions and the development of inhibitors Citation[9]. Intracellular CRM status has recently been proposed as a potential marker for alloantibody formation Citation[10].

Evolution of hemophilia therapy

Hemophilia has been recognized since at least the second century, when it was described in the Talmud Citation[11], but the management of this coagulopathy is a far newer concept. In 1840, Lane reported the benefits of blood transfusion for controlling hemophilia-related bleeding Citation[12]; in 1923, Feissly demonstrated the superiority of plasma for this purpose Citation[13] and in 1964, Pool discovered cryoprecipitate, ushering in the modern era of hemophilia treatment Citation[14]. The introduction of plasma-derived factor concentrates in the 1970s made it possible for patients to infuse at home at the first sign of bleeding Citation[15], resulting in a reduction in bleeding-associated morbidity and mortality Citation[16–18]. This impressive forward momentum in treatment was temporarily derailed in the early 1980s, when 70–80% of patients with severe hemophilia became infected with HIV, and virtually all were infected with HCV transmitted from contaminated plasma concentrates Citation[15,19]. In the ensuing decades, the safety of products used for the treatment of hemophilia became an overarching concern of patients, treaters and manufacturers. Today, the availability of recombinant factor concentrates, and plasma-derived products that now undergo two different viral inactivation procedures has minimized or nearly eliminated infectious risk, and inhibitor development is considered the most serious treatment-related complication.

Joint bleeding is the hallmark of hemophilia. In patients with severe FVIII or FIX deficiency, more than 90% of all bleeding episodes occur in the joints, and 80% of these represent hemarthroses of the ankles, knees and elbows Citation[20]. Recurrent bleeding into the same joint, termed a target joint, is when there is recurrent bleeding into the same joint four or more times within a 6-month period of time, results in progressive damage and the development of hemophilic arthropathy, characterized by synovial hypertrophy, cartilage damage, loss of joint space and bony changes Citation[21,22]. Decreased use of a target joint leads to ongoing muscle atrophy, ankylosis, osteoporosis, bone cysts and eventually, crippling arthritis Citation[21,23,24]. The deteriorating health-related quality of life (HRQoL) associated with progressive joint disease Citation[25,26] and the high cost of hospitalization and orthopedic interventions to relieve pain and improve joint function make the prevention of arthropathy a major goal of hemophilia treatment.

Mechanisms of blood-induced joint disease

The progression from normal joint to synovitis and then to arthropathy is attributed to undefined mediators in blood Citation[27,28], which is not normally found in the joint space Citation[29]. Following an isolated hemarthrosis, blood in the joint cavity is gradually resorbed by synovial tissue over a period of 3–4 weeks, resulting in complete resolution of the hemorrhage Citation[30]. By contrast, recurrent bleeding into a joint overwhelms the synovium. Iron (hemosiderin), the degradation product of red blood cells, accumulates in the tissue, leading to synovial hypertrophy and hyperplasia and the proliferation and persistence of inflammatory cells Citation[31]. Chronic inflammation triggers the release of tissue-destructive enzymes and cytokines that contribute to progressive joint damage Citation[32,33].

Vascular development and angiogenesis are an essential component of blood-induced joint disease. Just as angiogenesis is required for tumor growth, angiogenesis also appears to be necessary for synovial expansion Citation[34]. Neovascularization causes the synovial membrane to thicken and develop friable fronds and villous projections. A network of capillaries forms under the hypertrophied synovium in response to joint irritation and in an effort to increase blood flow to remove blood breakdown products Citation[30]. Any attempt at joint rehabilitation may cause the synovial fronds and villi to become trapped in the joint space and torn with joint motion, severing the subsynovial vessels and causing bleeding. New hemorrhaging further irritates the synovium, increasing the likelihood of subsequent synovial entrapment and bleeding directly resulting in a self-perpetuating cycle of bleeding, synovitis and joint bleeding Citation[30].

Articular cartilage is composed of chondrocytes embedded in an extracellular matrix that produce collagen, proteoglycans and metabolism-regulating enzymes Citation[35]. The continuous presence of blood in a joint changes the composition of the articular cartilage, possibly owing to the loss of proteoglycans and the production of degradative enzymes from iron-laden synovial or subsynovial macrophages Citation[36]. As joint disease progresses, bone remodeling occurs, and osteoclastic activity increases, resulting in a loss of bone mineral density that culminates in osteoporosis Citation[27,28].

Rationale for prophylaxis

The development of hemophilic arthropathy is directly linked to the number of joint bleeding episodes Citation[37,38]. Among 378 patients enrolled in the landmark Orthopaedic Outcome Study, published in 1994, Pettersson radiologic scores (a measure of joint status) increased by 1 point for every 40 joint bleeds Citation[37]. A subsequent evaluation of 117 patients with severe hemophilia found that just 13 bleeds were necessary to cause a 1-point increase in the Pettersson score Citation[38]. However, even this lower number may be an overestimate, as plain film radiographs only visualize gross arthritic alterations Citation[20]. When children with hemophilia who had no obvious clinical signs of arthropathy underwent MRI, early changes in the soft tissues (e.g., synovium and cartilage) were apparent Citation[20], indicating that incipient joint damage occurs after very few bleeding events Citation[39]. Furthermore, findings from the US Joint Outcome Study, suggest that joint deterioration can occur without clinical evidence of hemarthroses – so-called subclinical bleeding Citation[40].

Arthropathy, once established, is irreversible and progressive Citation[41]. Prophylaxis, defined as long-term regular administration of FVIII or FIX to prevent joint bleeding Citation[42], is the lynchpin of management for children with severe hemophilia.

Primary prophylaxis

The US Joint Outcome Study, which randomized 65 boys younger than 30 months of age with hemophilia A to prophylaxis or intensive on-demand therapy (referred to as enhanced episodic therapy), established that prophylaxis initiated early in life protects against joint damage and decreases the frequency of hemarthroses and other hemorrhages Citation[40]. Similar conclusions were reached in the ESPRIT study, a randomized controlled trial of prophylaxis versus on-demand therapy conducted in Italy that enrolled 40 children aged 1–7 years with severe hemophilia A Citation[25]. While there is general agreement about the benefits of primary prophylaxis, clinicians continue to debate the timing of treatment initiation. The possibility of subclinical bleeding Citation[40] argues for starting prophylaxis before the age of 2 years and the development of clinically evident joint bleeding Citation[42] and for using the high-dose regimen recommended by the National Hemophilia Foundation Medical and Scientific Advisory Committee: FVIII 25–50 IU/kg three-times weekly or every other day or FIX 40–100 IU/kg 2- to 3-times weekly Citation[202]. However, initiating prophylaxis at a very young age is costly, can result in overtreatment in children who are not prone to joint bleeding, and often requires insertion of a central venous access device to administer factor infusions Citation[42]. Individualized dosing that is adjusted according to a patient’s bleeding pattern offers an opportunity to provide adequate prophylactic coverage while reducing factor concentrate consumption and the need for central venous access devices Citation[43].

A recent survey of current prophylaxis practices at 62 US hemophilia treatment centers showed large variability regarding when to initiate prophylaxis and which regimen (i.e., standard high-dose or individualized treatment) to use Citation[44]. Only 25% of the Hemophilia Treatment Centers surveyed started prophylaxis after the first bleeding episode (of any type), and just 16% began after the second hemorrhage. Nearly a third reported beginning prophylaxis with once-weekly infusions to avoid the need for central venous access and increasing the dosing frequency if bleeding incidence escalates.

Secondary prophylaxis & limited prophylaxis

The clear advantages of primary prophylaxis not withstanding, this treatment strategy remains underused Citation[203]. Nonetheless, a substantial segment of the hemophilia population can still benefit from prophylaxis when initiated after multiple joint bleeding episodes Citation[45]. Long-term secondary prophylaxis can reduce joint and other bleeding episodes, slow the progression of – although not reverse – existing joint damage and permit participation in sports and other activities Citation[45–47]. It also allows aggressive physical rehabilitation to be undertaken in children and adolescents with chronic joint damage Citation[45]. Although the earlier the prophylactic regimen is started, the better the benefits are, regardless of the age at initiation Citation[48]. The bottom line is that it is never too late to start prophylaxis.

Limited or episodic prophylaxis, defined as a short period of factor replacement, is a frequently used strategy for preventing joint bleeding in specific situations, usually sports or other strenuous activities. The goal of limited prophylaxis is to completely prevent bleeding. To this end, aggressive dosing to achieve 100% correction may be necessary Citation[49].

Management of acute hemarthrosis

An acute hemarthrosis is characterized by rapid joint swelling that may be preceded by a prodrome of tingling, reduced range of motion and pain Citation[50]. The joint is often held in a flexed position, and the overlying tissues may be warm to palpation and extremely tender when touched or moved. Pain from bleeding into the ankles, knees or hips may make weight bearing impossible. In the absence of trauma, the presentation of acute joint bleeding is generally straightforward and does not require radiographic imaging.

On-demand therapy

On-demand therapy with a plasma-derived or recombinant FVIII or FIX concentrate is first-line treatment for acute bleeding events in patients with hemophilia. Dosing is largely based on uncontrolled, observational studies Citation[51] and ranges from approximately 5 Citation[52] to 30 IU/kg Citation[53] administered until bleeding stops. In the US Joint Outcome Study, acute hemarthrosis in the on-demand cohort was treated at a substantially higher dose and for an extended period of time: FVIII 40 IU/kg at the time of joint hemorrhage and 20 IU/kg at 24 and 72 h after the first dose. Parents were then encouraged to continue infusions of 20 IU/kg every other day, until joint pain and impairment of mobility had completely resolved. The benefits of this more aggressive therapy have yet to be determined in a rigorous way. An outstanding issue facing patients and clinicians alike is the objective determination of the cessation of joint bleeding. At this time, the patient’s or caregiver’s judgment must be relied on, as no objective test (i.e., ultrasonography or biomarker) has been demonstrated to be more informative.

Adjunctive treatment

Pain control

Pain is a universal symptom of acute joint bleeding and chronic arthropathy, yet there is little evidence to guide therapy Citation[54]. NSAID, such as ibuprofen, are effective analgesics Citation[55], but the potential for gastric bleeding is problematic Citation[56]. Opioids, frequently used to relieve pain associated with chronic, noncancerous conditions Citation[57], have not been systematically evaluated for hemarthrosis, and concerns about abuse and addiction likely result in underuse of these drugs in the hemophilia population Citation[58]. Little data are available regarding the efficacy of intra-articular corticosteroid injections to control hemophilic pain Citation[59–61].

Rest, ice, compression & elevation

Rest, ice, compression and elevation are generally recommended as an adjunct to factor replacement therapy during acute hemarthrosis Citation[62,63], but here again, the benefits of these conservative measures are not well established. Rest, with or without splinting, limits further injury and reduces pain, but prolonged rest poses a risk for muscle atrophy and contracture formation. While ice decreases pain, inflammation and tissue damage, it also slows blood flow, platelet function and enzymatic reactions, including conversion of prothrombin to thrombin Citation[64–66]. Consequently, ice should be applied only after adequate factor replacement is administered (if factor concentrate is not readily available, ice can be used immediately). Swelling and edema are indicative of blood filling the joint space and inflaming the surrounding tissues. A compression bandage may help reduce soft tissue swelling, but it has little impact on bleeding. Finally, elevation of the affected limb to limit swelling is a good idea in theory but is not practical for young, active children.

Physiotherapy

Physiotherapy is an essential adjunct to factor replacement therapy in hemophilia patients with acute and chronic joint bleeding Citation[201]. Hydrotherapy, for example, not only reduces pain but also decreases bleeding frequency and instability in target joints and improves range of motion and muscle girth Citation[67]. Isometric and isotonic exercise, ultrasound, pulsed short-wave diathermy and transcutaneous electrical nerve stimulations are other modalities of physiotherapy used both acutely and chronically in the rehabilitation of hemophilia patients following hemarthrosis Citation[68].

Joint aspiration

Arthrocentesis of intra-articular blood may be indicated in acute and profuse hemarthrosis to prevent long-term joint damage Citation[68]. To be effective, joint aspiration should be performed within 2 days of bleeding onset, and before the procedure, factor concentrate must be administered to achieve 100% correction Citation[68]. In general, however, the application of this procedure should be limited to episodes of extreme bleeding except for when the hip is involved in a young child where there is a risk of avascular necrosis.

Synovectomy

For individuals with pre-existing joint disease, prophylaxis may not sufficiently reduce the frequency of hemarthrosis, and, as mentioned, it cannot reverse progressive joint damage. When joint bleeding and synovitis are poorly controlled, synovectomy is effective in removing inflamed and hypertrophic synovium Citation[69], thus decreasing the propensity for repeated joint hemorrhage Citation[70,71]. Surgical synovectomy, either open or arthroscopic, and radionuclide synovectomy, which involves the intra-articular injection of a radionuclide to induce fibrosis Citation[72], are all options for synovectomy. Success rates are similar for all three procedures, with synovectomy decreasing the frequency of joint bleeding by a reported 70–100% Citation[70,71].

Outcome measurement

Questionnaires

A major limitation in the use of questionnaires to assess outcomes following episodes of joint bleeding is that most scales are dependent on patient reports Citation[73] and lack objective measures, such as data from tools for evaluating psychometrics Citation[74] or HRQoL Citation[75]. One tool developed specifically to evaluate the functional wellbeing of hemophilia patients is the Hemophilia Joint Health Score, an 11-item measure administered by a physical therapist Citation[76]. Objective findings assessed include the presence or absence of joint swelling, preservation or loss of flexion and extension and gait changes. The outcome-predicting power of the Hemophilia Joint Health Score has been validated in boys. Other tools under study include questionnaires that assess independence Citation[77] and the ability to participate in regular Citation[78,79] and sporting activities Citation[80]. The use of multiple scales improves the precision of questionnaires used to assess joint outcome posthemarthroses Citation[81].

Imaging modalities

Patient-reported outcomes have traditionally been used to determine when bleeding has stopped because it has been quite difficult to detect joint bleeding with radiography. However, this situation is changing. MRI has advantages over radiography because of its ability to visualize soft tissue and cartilage changes in hemophilia joints Citation[20]. Two MRI scoring systems – one is a progressive system that displays the most severe joint changes, the other an additive system that depicts osteochondral and soft tissue-related changes Citation[82] – may enable the comparison of pathologic joint findings.

MRI has some distinct limitations, including its ability to differentiate synovial hypertrophy and hemosiderin deposition Citation[83]. These deficiencies may be overcome with the use of ultrasound, which has been shown to provide objective evidence of bleed resolution and can also assess joint damage Citation[84]. A recent study that evaluated and scored the joints of 62 consecutive patients with hemophilia A or B and compared the findings with those from 20 healthy subjects and 20 subjects with rheumatoid arthritis found the correlation between ultrasound score and the number of hemorrhages to be highly significant (p < 0.01). Furthermore, ultrasound was effective in detecting synovitis and bone and cartilage alterations, and power Doppler ultrasound identified bleeding in asymptomatic joints.

A number of novel techniques are under evaluation for soft tissue and cartilage imaging that are as follows:

  • • Blood oxygen level-dependent MRI, which relies on MRI contrast resulting from changes in the microvascular ratio of oxyhemoglobin to deoxyhemoglobin, may determine how hypoxia affects synovial changes as arthropathy progresses Citation[85].

  • • Ultrasmall superparamagnetic iron oxide contrast-enhanced MRI, which uses nanoparticle contrast media that appear to localize in synovial macrophages, may be able to quantify hemosiderin in a joint Citation[86];

  • • Microbubble contrast-enhanced ultrasonography may increase the sensitivity of the color and power of the Doppler signal, making it possible to detect changes in low-velocity blood flow in the hemophilic synovium Citation[87];

  • • PET, which may detect arthritis-related inflammation Citation[83];

  • • T1 Citation[88] and T2 Citation[89] mapping MRI, which are sensitive to changes in cartilage composition, may help to characterize the structural integrity of cartilaginous tissue and quantitatively assess the degree of cartilage degeneration;

  • • Ultrasound biomicroscopy, which uses high-frequency probes that allow evaluation of hyaline cartilage, intra-articular fibrocartilage and ligaments Citation[90].

Although not an imaging strategy, biomarkers of synovium, cartilage and bone turnover and resorption (e.g., cartilage oligomeric matrix proteins, bone-specific alkaline phosphatase, C-terminal telopeptides type 1 collagen) have the potential to monitor subclinical bleeding and early joint disease Citation[91].

Expert commentary

The management of joint bleeding in hemophilia has evolved from reactive therapy initiated after the onset of bleeding symptoms to prophylaxis to prevent hemarthroses and the subsequent arthropathy Citation[28]. Despite the effectiveness of prophylaxis Citation[37,40], there are significant barriers to its widespread implementation, in particular the need for frequent dosing/frequent venous access, which can result in poor adherence Citation[49,92], and the high cost of factor concentrate. New drugs and drug delivery systems currently in development may overcome some of these obstacles Citation[93]. For example, the development of FVIII and FIX concentrates with an extended duration of action will reduce the frequency of intravenous injections, and oral agents will obviate the need for venous access all together. Ultimately, correction of the gene defect will cure hemophilia, although such therapy remains on the distant horizon Citation[94]. Until that time, patients will continue to experience joint bleeding and will require appropriate interventions, including replacement of the deficient clotting factor, analgesia and physiotherapy.

Five-year view

Over the next 5 years, one or more drugs with a prolonged biological activity and/or novel mechanism of action will be approved for use in the USA Citation[93,95–97]. The advantages of these drugs in preventing joint and other bleeding are likely to be substantial Citation[98], but their efficacy must be established through rigorous clinical trial programs. In addition to these new therapies, the next half century is likely to provide individuals treating hemophilia with an enhanced understanding of the benefits and risks of adjuvant therapies and better tools for measuring outcomes. Sensitive, noninvasive modalities for detecting subclinical joint bleeding are desperately needed now, and this need will become more urgent following the introduction of sustained-activity products, as patients may have prolonged periods with FVIII or FIX levels in the mild or moderate range. Such strategies are under investigation, and some may reach the clinic within 5 years.

Despite this optimistic perspective, one must keep in mind that only about 25% of the estimated 400,000 people with hemophilia worldwide receive adequate treatment. The World Federation of Hemophilia is attempting to close the gap in care for the remaining 75% by promoting proper diagnosis, management and care together with the provision of safe, effective treatment products. However, in many countries, the high cost of clotting factor concentrates for replacement therapy make this goal impossible, and the provision of prophylaxis, recommended as optimal care, unrealistic. Advocacy efforts for adequate product supplies are ongoing through the World Federation of Hemophilia and its national patient organizations. Cost-efficacy studies to identify the minimum effective dose to prevent bleeding and other initiatives are necessary to expand access to prophylaxis and to better understand how the conservation of precious products can be achieved in parts of the world where resources are limited. Novel approaches to care, such as once-weekly prophylactic dosing, will require multicenter, international prospective studies that compare efficacy with standard therapy.

Palliative approaches to blood-induced joint disease, such as joint fusion and joint replacement therapy, will continue to play an important role in the overall care of patients with hemophilia for the foreseeable future. Nonetheless, new strategies that can be undertaken before the development of end stage arthropathy are needed to improve HRQoL. To that end, it is imperative that targeted biological therapies directed at the earliest molecular and biochemical changes invoked by intra-articular blood be identified. Clinical trials of biological agents that use antibodies to block TNF-a (e.g., infliximab, adalimumab, golimumab and certolizumab) are approved for use in rheumatoid arthritis and other chronic inflammatory diseases Citation[99,100]. The efficacy and safety of this class of agents in controlling the inflammatory response of synovial tissues to blood in hemophilia patients must also be studied. Synovial membrane vascularization is a prominent feature of blood-induced joint damage, and antiangiogenesis drugs (e.g., bevacizumab) may be helpful in this setting, as they are in some forms of cancer Citation[101]. However, a cautionary note is warranted regarding the use of biological agents in hemophilia, since the patients most likely to benefit are young children who have experienced a first hemarthrosis. Pediatric trials of these drugs can only be considered after their efficacy and safety have been clearly demonstrated in preclinical models and dose-finding studies in adults.

Key issues

  • • Joint bleeding is the hallmark of severe hemophilia, begins early in life and accounts for significant morbidity and cost.

  • • In the absence of prophylaxis, joint damage is common in persons with severe hemophilia and may result in crippling arthropathy at a young age.

  • • The optimal dose and regimen to control acute hemarthrosis and to prevent the development of arthropathy remains unknown.

  • • Evidence supporting the use of ancillary therapies (in addition to factor replacement) is lacking.

  • • Over the next 5 years, one or more new drugs with prolonged biological activity and/or novel mechanisms of action will be approved for use in hemophilia.

  • • The development of biological agents to target the earliest molecular and biochemical changes associated with intra-articular bleeding may minimize the impact of hemarthrosis in hemophilia patients.

Acknowledgements

The authors wish to acknowledge Michele Grygotis for her expert review of the manuscript and helpful comments.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Management of joint bleeding in hemophilia

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

1. Based on the review by Drs. Simpson and Valentino, which of the following statements about the clinical characteristics of joint bleeding in hemophilia is most likely correct?

  • □ A In patients with severe factor (F)VIII (hemophilia A) or FIX (hemophilia B) deficiency, about half of all bleeding episodes occur in the joints

  • □ B The hip joint is most often affected by bleeding

  • □ C Hemophilic arthropathy is characterized by synovial hypertrophy, cartilage damage, loss of joint space, and bony changes

  • □ D Joint deterioration does not occur without repeated acute hemarthrosis, with rapid joint swelling that may be preceded by tingling, reduced range of motion, and pain

2. Your patient is an 18-month-old male with hemophilia A. Based on the review by Drs. Simpson and Valentino, which of the following statements about prophylaxis to prevent joint bleeding is most likely correct?

  • □ A The US Joint Outcome Study and ESPRIT study showed no benefit of prophylaxis over intensive on-demand therapy for protecting against joint damage and hemarthroses

  • □ B There is no rationale for starting prophylaxis before age 2 years and before joint bleeding is clinically evident

  • □ C High-dose prophylaxis is definitely recommended and has no drawbacks

  • □ D Long-term secondary prophylaxis can reduce joint bleeding, slow progression of existing joint damage, and allow participation in sports and other activities

3. The patient described in question 2 develops acute hemarthrosis in his right knee. Based on the review by Drs. Simpson and Valentino, which of the following statements about management would most likely be correct?

  • □ A On-demand therapy with a plasma-derived or recombinant FVIII or FIX concentrate is first-line treatment

  • □ B Dosing is standardized and based on controlled, randomized trials

  • □ C There are objective tests to accurately determine when bleeding stops

  • □ D Joint aspiration is standard therapy

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