Monday, September 25, 2023
This activity is intended for hematologists, radiologists, pediatricians, and other clinicians caring for patients with joint bleeding due to hemophilia.
The goal of this activity is to review the clinical presentation and management of hemarthrosis in patients with hemophilia.
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The development of hemophilic arthropathy is directly linked to the number of joint bleeding episodes.[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.[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.[38] However, even this lower number may be an overestimate, as plain film radiographs only visualize gross arthritic alterations.[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,[20] indicating that incipient joint damage occurs after very few bleeding events.[39] Furthermore, findings from the US Joint Outcome Study, suggest that joint deterioration can occur without clinical evidence of hemarthroses – so-called subclinical bleeding.[40]
Arthropathy, once established, is irreversible and progressive.[41] Prophylaxis, defined as long-term regular administration of FVIII or FIX to prevent joint bleeding,[42] is the lynchpin of management for children with severe hemophilia.
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.[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.[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[40] argues for starting prophylaxis before the age of 2 years and the development of clinically evident joint bleeding[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.[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.[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.[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.[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.
The clear advantages of primary prophylaxis not withstanding, this treatment strategy remains underused.[203] Nonetheless, a substantial segment of the hemophilia population can still benefit from prophylaxis when initiated after multiple joint bleeding episodes.[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.[45–47] It also allows aggressive physical rehabilitation to be undertaken in children and adolescents with chronic joint damage.[45] Although the earlier the prophylactic regimen is started, the better the benefits are, regardless of the age at initiation.[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.[49]
