Page 2270 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 135 Hemophilia A and B 2017

patient. Thus some patients prefer to treat themselves with a small are very expensive, and prophylaxis regimens can cost as much as
amount of clotting factor every day (e.g., 500 IU of FVIII/daily), while $300,000 per patient per year. However, the cost has decreased in
others prefer a once- or twice-weekly regimen with additional infusions countries with tendering systems. In the next few years, widespread
before high-risk activities, such as sports. Prophylaxis should be used introduction of extended half-life factor concentrates will likely
in patients with a target joint into which repeated bleeding is docu- have a major impact on the price of factor concentrates—both the
mented. In this instance, prophylactic concentrate infusions at regular newer products and the current products.
intervals (three times a week for FVIII and twice a week for FIX) should 2. Inhibitor development: Management of patients with inhibitors
be initiated and continued for several months or longer. remains a challenge. Although inhibitor development is more
If an on-demand regimen is used, patients must be carefully common in patients with hemophilia A (particularly severe
counseled. Treatment should be started as soon as possible after the forms), patients with hemophilia B are difficult to manage because
first signs of bleeding and, if appropriate, adjunctive measures such they often develop anaphylaxis and nephrotic syndrome. Although
as rest, ice, compression, or limb elevation should be used to hasten the genetic and environmental risk factors for inhibitor develop-
symptom control. ment are increasingly well understood, our capacity to prevent
inhibitor development remains limited.
3. CVADs: These are useful for the management of young children
Complications of Treatment with severe hemophilia. They are of particular benefit in children
who develop inhibitors and require immune tolerance therapy
Until the mid-1970s, the biggest impediment to the management of (ITT). Most ITT regimens call for daily administration of factor,
patients with hemophilia was the lack of readily administered treat- which can rarely be given by repeated peripheral venipuncture in
ment, which virtually guaranteed that patients with severe hemophilia young children. CVAD complications include infections and
would develop hemophilic arthropathy, and many would die from thrombosis. Catheter infections caused by skin organisms can
bleeding, including ICH. By the 1980s, treatments were available, produce considerable morbidity, and the CVAD often needs to be
and prophylaxis programs were initiated in many countries. Unfor- removed. In a meta-analysis of studies evaluating CVAD compli-
tunately, the 1980s was the era of HIV and hepatitis C, and most cations, Valentino and colleagues reported a 40% CVAD infection
patients with hemophilia treated before 1985 became infected with rate with a mean of one CVAD infection for every four patients
both, with smaller numbers also becoming infected with hepatitis A with a CVAD in place for 1 year. Thrombosis associated with
and B. Many of these patients have died. This tragedy prompted CVADs varies in significance from small fibrin sheaths to thrombi
widespread implementation of blood donor screening programs and that occlude large vessels and can lead to pulmonary embolism or
viral inactivation processes and accelerated the development of death. Several studies have shown that radiographically proven
recombinant clotting factor concentrates. CVAD-associated thrombosis develops in up to 50% of patients
The management of HIV since the 1980s has undergone tremen- with hemophilia with these devices. Such thrombi may impair
dous advances. Currently, patients with HIV who are treated with CVAD function, thereby necessitating their removal. Because of
highly active antiretroviral therapy live almost normal life spans. the complications associated with CVAD implantation, some
Infection with hepatitis C has been more problematic because it institutions recommend AVFs as an alternative. However, experi-
results in chronic disease in approximately 60% of those infected. A ence with AVFs is still limited.
combination of interferon and ribavirin has been used with good
results in patients with certain hepatitis C genotypes 2 and 3 and less
satisfactory results in those with genotype 1. Several new-generation Immune Responses to Exogenous
anti–hepatitis C virus therapies are now available, and these may Factor VIII and Factor IX
facilitate the cure of increasing numbers of infected patients with
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hemophilia. Nonetheless, many patients still develop long-term Adverse immunologic responses to replacement products are a major
complications of chronic hepatic infection, including hepatocellular complication for patients with hemophilia who have access to
carcinoma. Co-infection with HIV and hepatitis C together with replacement factor concentrates. These responses occur because the
alcohol use increases the risk of liver complications. All noninfected infused factors contain foreign epitopes. However, not all patients
persons with hemophilia should routinely receive hepatitis A and B develop an immune response to replacement; the reasons for this are
vaccination to reduce the risk of infection. unknown.
Immune responses include anaphylactic reactions and nonana-
phylactic antibody-producing responses. The latter are classified
Other Comorbidity in Patients With Hemophilia according to their effects in vitro: whereas immunoglobulin (Ig) G
antibodies that “inhibit” the coagulant function of the replacement
With progressive improvements in hemophilia care, persons with factor are referred to as inhibitors, those that do not interfere with
hemophilia are living longer, and morbidities associated with aging are coagulant activity are called nonneutralizing antibodies. Catalytic
now complicating the clinical management of hemophilia. Although antibodies directly hydrolyze the target protein.
patients with hemophilia are somewhat protected from atherothrom-
botic events, there are increasing numbers of older patients with
coronary artery disease. This problem is necessitating the development Anaphylactic Reactions
of guidelines to safely introduce antiplatelet regimens for secondary
prevention in patients with coronary artery disease. Type I hypersensitivity reactions are rare in patients with hemophilia
There is also an increased prevalence of hypertension in hemo- A but have been reported with infusion of either plasma-derived or
philia, the pathogenic mechanism of which is currently unresolved. recombinant FVIII concentrates. Rarely, there is evidence of IgE
mediation, suggesting that in some cases, these reactions may reflect
complement activation, immune complex formation, or other
Limitations to Treatment for Hemophilia mechanisms.
Approximately 3% of patients with hemophilia B experience ana-
Currently, the major impediments in the management of patients phylactic reactions to FIX products; these occur with equal frequency
with hemophilia are cost, inhibitor development, and the need for with plasma-derived and recombinant products. The median number
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CVADs. of FIX exposure days at the time of anaphylactic reactions is 11. These
reactions often occur in patients who have FIX inhibitors and show
1. Cost: Worldwide, cost is the major issue. Currently available evidence of IgE mediation. In some cases, transient IgG1 antibodies to
factor concentrates, particularly recombinant factor concentrates, FIX have been detected near the time of the allergic reaction. Because