The Aging Patient with Hemophilia: Complications, Comorbidities, and Management Issues

HEMOPHILIA
The Aging Patient with Hemophilia: Complications,
Comorbidities, and Management Issues
Claire Philipp1
1University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School,
New Brunswick, NJ
Improvements in hemophilia care and antiviral treatments have resulted in increases in median life expectancy for
persons with congenital hemophilia A and B. Currently, 2% of hemophilia A and B patients surveyed in US
comprehensive hemophilia treatment centers are 65 years of age or older and 15% are 45 years or older. Many of the
complications of hemophilia, including intracranial hemorrhage, joint disease, and inhibitor development, increase with
increasing age. Hepatocellular carcinoma and end-stage liver disease are increasing in the older hemophilia
population due to infection with hepatitis C (HCV) and HCV/HIV coinfection. Older hemophilia patients also now face
the same medical conditions associated with aging in the general population, including cardiovascular disease and
cancer. Complex hemostatic management, sometimes in conjunction with antithrombotic management, with extensive
cross-specialty clinical and laboratory coordination may be required for the care of the older hemophilia patient.
Because elderly hemophilia patients currently represent a small portion of the overall hemophilia population, there is
little in the way of clinical data to guide recommendations. Registry databases and cooperative group studies are
needed for the development of evidence-based guidelines for the older hemophilia population, which is anticipated to
expand in the future.
Introduction
expectancy in The Netherlands had increased to 67 years (74 years
Advances in coagulation protein replacement therapy, the develop-
excluding virally infected hemophiliacs), and by 2007, the overall
ment of specialized comprehensive care centers, and utilization of
hemophilic life expectancy was reported to be 71 years in Italy.5,11
home therapy and factor prophylaxis have led to progressive
In the United States, the utilization of specialized comprehensive
reductions in morbidity and increases in life expectancy for persons
care centers resulted in a 30% decrease in mortality for males with
with congenital hemophilia A and B.1–4 Before the 1970s, with only
hemophilia compared with those in other sources of care.2
the availability of cryoprecipitate and low-purity plasma fractions
enriched with factor VIII, patients with hemophilia had a signifi-
Males with hemophilia who are age 45 and older, meaning that they
cantly reduced life expectancy, with intracranial or other hemor-
were born in 1965 or earlier, prior to widely available factor
rhages the major cause of mortality.5 Median life expectancy in
concentrates and prior to virally safe factor concentrate products,
males with severe hemophilia was 11 years in the early 20th
are the subject of this section. The complications, comorbidities,
century, and had increased to the range of 55 to 63 years in the
and management issues confronting the clinician taking care of the
1970s, still a reduced life span compared with the overall male
older male hemophilia A or B patient are presented. Some of the
population.5,6
management issues unique to the older hemophilia patient pose
particular challenges to the clinician, with limited clinical data
Plasma-derived factor concentrate replacement therapy became
available to guide recommendations.
commercially available in the United States and Europe in the early
1970s, and by 1982, 73% of persons with hemophilia A in the
United States received factor concentrates, increasing the median
Characteristics of the Older Hemophilia Population
life expectancy by the early 1980s to almost 68 years.7,8 Specialized
Based on surveillance data from comprehensive hemophilia treat-
hemophilia treatment centers were established in the mid-1970s,
ment centers, currently in the United States, individuals 45 years
which improved medical management of hemophilia, but hemor-
and older with hemophilia A and B comprise 15% of the total
rhage still remained the major cause of death in hemophiliacs in
hemophilia population, with those older than 65 years comprising
1982.7 That same year, the first cases of HIV were identified in the
2% of the total hemophilia A and B population (Table 1). Five
hemophilia population,9 and by 1990, the median life expectancy
percent of mild (
5 U/dL factor VIII or IX) hemophilia patients are
among US hemophiliacs had dropped to 49 years and the mean age
over 65 years old, whereas only 1% of severe (
1 U/dL factor VIII
at death to 40 years.7 Clotting factor concentrates virally safe from
or IX) hemophilia patients are over 65 (Table 1). These figures
HIV have been available since 1985, and hepatitis B and C virally
contrast with the proportion of US males over 65 years (10%) and
safe concentrates have been available since 1992.10 Viral safety was
those over 45 years old (32%) (according to the 2000 US Census).
achieved initially using viral-inactivation methods for plasma-
The percentage of persons with hemophilia age 65 and older in Italy
derived factor concentrates before recombinant factor products were
has been reported to be 6.4%,12 higher than the percentage observed
developed. By 2001, hemophilic (all severities combined) life
in the United States.
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Table 1. Mild, moderate, and severe hemophilia (A and B combined) in
In hemophilia patients 65 years and older who received replacement
males by age group
products prior to viral-inactivation techniques, viral infection is
Severe
3983 (51%)
2918 (38%)
800 (10%)
86 (1%)
almost universal. Among 39 Italian patients 65 years of age or older
Hemophilia
with severe hemophilia A and B, 38 had blood-borne viral
(n=7787)
infections, including 13% with HIV, 92% with HCV, and 10% with
hepatitis B.12 While death from HIV-related causes has decreased
Moderate
1906 (52%)
1160(32%)
487 (13%)
117 (3%)
Hemophilia
significantly, hepatitis and other liver-related deaths have increased,
and the management of hepatitis, chronic liver disease, liver failure,
(n=3670)
and hepatocellular carcinoma represent major management chal-
Mild Hemophilia
1992(49%)
1223 (30%)
660 (16%)
234 (5%)
lenges in the older hemophiliac. Management of bleeding complica-
(n=4109)
tions in those with thrombocytopenia secondary to chronic liver
disease and/or hepatitis may entail factor replacement to normalize
All severities
7881 (51%)
5301 (34%)
1947 (13%)
437 (2%)
Hemophilia
levels.
(n=15,566)
Intracranial Hemorrhage
(From the Centers for Disease Control and Prevention, National Center on Birth
Hemorrhage is the third leading cause of mortality in hemophiliacs
Defects and Developmental Disabilities, Division of Blood Disorders. Universal
after HIV and hepatitis, with intracranial hemorrhage constituting
data collection through 2009. http://www.cdc.gov/ncbddd/blooddisorders/udc.
Accessed September 30, 2010.)
30% to 50% of hemorrhagic deaths.5,14,23 Data from the six-state
Hemophilia Surveillance System Project cohort in the United States
demonstrated that age greater than 51 years, severe hemophilia,
Viral Disease
HIV, and the presence of inhibitor were independent risk factors for
With the advent of highly active antiretroviral therapy (HAART),
intracranial hemorrhage.24 An effect of inhibitor presence on
the survival of HIV-infected individuals with hemophilia has
intracranial hemorrhage-associated mortality, however, was not
improved significantly, with 27% to 39% surviving 20 to 25
confirmed by UK hemophilia surveillance data.25 Intracranial
years.13–15 Younger age at the time of HIV seroconversion has been
hemorrhage has the highest mortality of any hemophilia-related
associated with improved survival.14,16 Most HIV-infected hemo-
bleeding, and a death rate of 30% has been reported among
philia patients are coinfected; among 458 HIV-positive hemophilia
hemophilia patients age 50 and older with intracranial hemor-
A and B patients in Canada, 96.5% were hepatitis C (HCV)
rhage.25 The majority of intracranial hemorrhages in this population
positive.14 Both cumulative incidence of end-stage liver disease and
are non-traumatic. Intracranial hemorrhage typically presents with
fatality due to liver failure have been reported to be significantly
headache, and immediate factor infusion sufficient to raise factor
increased in the dually infected hemophiliac compared with the
VIII or IX levels to 100 U/dL prior to diagnostic evaluation with a
HCV-monoinfected hemophiliac.15,17 HAART was associated with
non-contrast computed tomography (CT) scan is important. If
an increased time to end-stage liver disease in HCV/HIV positive
confirmed, factor infusion sufficient to maintain a trough of more
patients, similar to that observed in HCV positive, HIV negative
than 50 U/dL is recommended for at least 10 to 14 d.26,27 Laboratory
patients.18
monitoring of factor VIII or IX levels before and after factor
infusion is suggested in order to adjust the dose of factor concentrate
Hepatitis B and C markers are highly prevalent among older males
to maintain adequate levels. The off-label use of antifibrinolytics as
with hemophilia. Between 85% and 93% of US males with
adjunctive management has been used, but efficacy data are lacking.
hemophilia born before 1975 have been found to be positive for
Hemophilia patients who have had an intracranial hemorrhage are
HCV infection, and 27% to 51% of similar birth cohorts have been
candidates for long-term prophylaxis with factor concentrates or
found to be positive for hepatitis B infection.10 A significant
prophylaxis for 2 years at a minimum.26,27
difference between HCV-infected hemophilia patients and non-
hemophilia patients is the duration of their infection. Hemophilia
patients usually acquired their HCV infection in the first year of life
Joint Disease
with their first factor infusion, and pre-liver transplant survival in
The US Joint Outcome study demonstrated the benefits of factor
hemophilia patients has been reported to be much shorter than in
concentrate prophylaxis in preventing joint damage and bleeding
non-hemophilia patients.19 HCV antiviral treatment consists of
episodes compared with on-demand factor use in children.4 Individu-
therapy with pegylated interferon and ribavirin, which achieves a
als age 65 and older with hemophilia did not have access to regular
50% response in hemophilic patients with genotype 1 (most
replacement therapy until well into adulthood, and those 45 and
common) or genotype 4, compared with an 80% to 90% response in
older did not have ready access during significant portions of their
genotypes 2 and 3. Coinfection with HIV also adversely affects the
childhood. Joint disease remains a major cause of morbidity in the
effectiveness of treatment.20 If an assessment of fibrosis is needed
older hemophilia patient. The majority of severe hemophilia
for determination of treatment, a transjugular liver biopsy with
patients age 65 and older have arthropathy in four to six of the six
adequate factor coverage is preferred over a percutaneous biopsy to
joints most commonly affected by bleeding (i.e., knees, ankles, and
reduce the risk of bleeding. Factor VIII or IX replacement to achieve
elbows).12,28 Arthropathy is also associated with reduced bone
levels 80 to 100 U/dL prior to biopsy, with continued factor
mineral density in severe hemophilia. Pain management includes
replacement to maintain levels
50 U/dL for 2 to 4 d following
acetaminophen, cyclooxygenase 2 (COX2) inhibitors, and narcot-
biopsy, has been associated with a 1% to 2% rate of clinically
ics.29 Managing painful arthropathy with nonaddictive medications
significant bleeding.21 Recently, transient elastography has been
is difficult in the older hemophilia patient because of increased risks
proposed as a noninvasive tool for the assessment of liver fibrosis in
of nonsteroidal anti-inflammatory agent (NSAID)-associated gastro-
hemophilia patients.22 Liver transplantation is an option for hemo-
intestinal bleeding and acetaminophen-associated liver dysfunc-
philia patients with end-stage liver disease who are infected with
tion.30,31 In one study, the use of nonselective NSAIDs was
HCV or HCV-/HIV and corrects the factor deficiency.
associated with an increased likelihood of bleeding, whereas
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selective COX2 inhibitors were not.30 The extent of use of
moderate hemophilia A has been reported to be higher in patients
long-term continued factor prophylaxis initiated after multiple joint
exposed to continuous infusion and in those with certain missense
bleeds and established joint damage, so-called “secondary” prophy-
mutations, especially Arg531Cys.35 Hemophilia patients emigrating
laxis, in adults over 45 is unknown; its effectiveness in mitigating
from countries where factor concentrates are not readily available
hemophilic arthropathy is also unknown. A European survey found
may be at increased risk for inhibitor development when first
that 23% (58 out of 251) of severe hemophiliacs over 50 years of
exposed to factor concentrates in the United States.
age were on a regimen of regular concentrate administration,32 but
this may not be similar in the United States, given the variation
The management of inhibitors in the older hemophilia patient poses
between the United States and some European countries in prophy-
challenges, not only because of the increased risk of bleeding, but
laxis practice patterns for pediatric hemophilia patients. Orthopedic
also because of the potential increase in thrombotic risk with the use
surgical procedures, including ankle arthrodesis and hip and knee
of bypassing agents. The role of immune tolerance induction for
arthroplasty, are frequently performed to reduce the pain and
inhibitor eradication in this age group is not known. A recent report
disability of hemophilic arthropathy when conservative manage-
analyzing the use of rituximab among cases reported in the
ment fails.
literature, which included 9 out of 46 patients over age 50,
demonstrated an increased response to rituximab with age and with
Hemostatic management of the older severe hemophilia patient
mild/moderate hemophilia.36
undergoing major orthopedic surgery is challenging, and should
take into account inhibitor status and risk of venous thromboembo-
lism.33 In a literature review of replacement therapy for invasive
Cardiovascular Disease
procedures, 35 clinical studies, which included 707 orthopedic
Hemophilia seems to protect against cardiovascular disease.5,6,37,38
surgeries, were identified.34 Sixteen percent of major surgical
Several European studies have documented a 38% to 80% de-
procedures were managed by continuous infusion of factor concen-
creased mortality from ischemic heart disease in males with
trate (off-label) and the rest by bolus infusion. The preoperative
hemophilia compared with the non-hemophilia male popula-
target factor VIII or IX level was
80 U/dL in 26 out of 31 studies,
tion.5,6,38 One US study, however, reported an increased mortality
and among 27 studies addressing postoperative trough levels, 19 out
for acute myocardial infarction in hemophilia patients compared
of 27 targeted troughs of
50 U/dL in the first postoperative week.
with the general US male population.2 Based on hospital discharge
The majority of studies targeted a trough level of
30 U/dL in the
data from six US states from 1993 to 1998, ischemic heart disease
second postoperative week. Factor concentrate may need to be
was found to be reduced in hemophilic males ages 45 to 64 and
continued beyond the second postoperative week prior to physical
those 65 and older compared with normal US males.37 It has been
therapy sessions. Preoperative pharmacokinetic evaluation for deter-
postulated that hypocoagulability protects against thrombus forma-
mination of factor recovery and half-life is performed in many
tion in the hemophiliac, but whether it also protects against
hemophilia treatment centers34 for planning perioperative hemo-
atherosclerosis is not clear. In hemophilia patients, age, hyperten-
static management, and the availability of factor VIII or IX
sion, diabetes, and hyperlipidemia have been independently associ-
laboratory assessment during the postoperative period is important
ated with the risk of ischemic heart disease.37 However, a study
for factor concentrate adjustment. Hemostatic management of
comparing hemophilic patients with age-, gender-, and race-
hemophilia patients with inhibitors who are undergoing major
matched controls demonstrated no differences in intraluminal
surgery involves the extensive use of bypassing agents.33 The risk of
coronary artery stenosis at autopsy, or in cardiovascular risk factors
venous thromboembolism in older hemophiliacs undergoing major
including hypertension, hypercholesterolemia, smoking, or diabe-
orthopedic surgery is not well established. Furthermore, the impact
tes.39 Routine cardiovascular preventive care and risk-reduction
that elevated factor VIII levels due to excessive factor concentrate
measures are indicated in individuals with hemophilia29,40
replacement have on thrombosis risk in this population is not
known. The use of anticoagulant thromboprophylaxis following
HIV is an additional risk factor that has been found to be
major orthopedic surgery in the patient with hemophilia is controver-
independently associated with non-ischemic heart disease in males
sial. Some advocate the use of prophylactic low-molecular-weight
with hemophilia.37 A recent study in non-hemophilic HIV patients
heparin in the hemophiliac without an inhibitor,33 but this should
demonstrated that diastolic dysfunction and left ventricular mass
only be considered during periods of factor concentrate replacement
were independently associated with HIV infection.41 Other explana-
with close factor level monitoring and only when trough factor VIII
tions for an increased cardiovascular risk with HIV include the
or IX levels are within the normal or near-normal range. Mechanical
association of some antiretrovirals with dyslipidimia (and indepen-
methods of thromboprophylaxis and early ambulation are otherwise
dently with cardiovascular risk) and the association of HIV with
recommended.
inflammation and immune activation.42 These risks may be impor-
tant in the hemophilia population over 45 years of age given the
Inhibitors
prevalence of HIV in this group.
Cumulative inhibitor risk increases with age.25 According to UK
surveillance data, the cumulative risk of hemophilia A inhibitor at
Managing cardiovascular disease and associated risks in the hemo-
15 years of age is 20%, at 50 years 30%, and at 75 years 36%. In
philia patient is a challenge, and there are few clinical studies
moderate and mild hemophilia A, the cumulative risk is 6%, 10%,
beyond case reports or small series to guide treatment. In one case
and 12% at 15, 50, and 75 years of age, respectively. For hemophilia
series, cardiac surgery in six hemophilia A patients, including four
B, the cumulative risk is much lower at age 75 (8%) and at all ages
mild, one moderate, and one severe hemophiliac, undergoing aortic
compared with hemophilia A.25 Older individuals with mild hemo-
valve replacement and/or coronary artery bypass graft with extracor-
philia A may be at increased risk for inhibitor development when
poreal circulation were managed with recombinant factor VIII
receiving intensive perioperative factor concentrates, and should be
replacement for between 11 and 24 d. All valve replacements were
monitored for the presence of inhibitor subsequent to factor
tissue valves to avoid the need for long-term anticoagulation. All
exposure.28,35 The risk of inhibitor development in mild and
received factor replacement by bolus infusion, 4 out of 6 received
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antifibrinolytics postoperatively, and 4 out of 6 received low-
Table 2. Approach to management of selected procedures in older
molecular-weight heparin for up to 3 months postoperatively.
hemophilia patients*
Postoperative morbidity was reported to be similar to patients
Procedure
Management Reference
†
without hemophilia.43Some have suggested using continuous infu-
Liver biopsy
Factor replacement: 80-100 U/dl prior, > 50
21
sion (off-label) recombinant factor VIII or IX over bolus factor
U/dl 2-4 days post
infusion perioperatively to avoid peaks of factor VIII or IX activity,
Approach: transjugular > percutaneous
to maintain stable factor levels, and to reduce thrombosis risk.29,40
Major orthopedic surgery
Factor replacement: 80-100 U/dl prior; trough
34
Because of the bleeding risks in patients with hemophilia, cardiac
>50 U/dl first postop wk; trough > 30 U/dl 2nd
bypass surgery may be preferred over percutaneous coronary
postop wk; prior to physical therapy sessions
intervention with stenting given the requirement for dual antiplatelet
Mechanical thromboprophylaxis
agents for extended periods of time, the risk of re-stenosis, and the
Anticoagulant thromboprophylaxis considered
when factor levels >50 U/dl
potential need for repeated procedures.29 Bare metal stents are
preferred over drug-eluting stents because of the considerably
Cardiac surgery
Factor replacement: 80-100 U/dl prior; trough
33,43,44
>60-70 U/dl post surgery until wound healing;
shorter duration of antiplatelet therapy required with bare metal
consider continuous infusion
stents. Factor replacement to maintain a trough plasma factor level
Valve replacement: tissue > mechanical
of at least 30 U/dL for the duration of the antiplatelet therapy has
Percutaneous cardiac
Factor replacement: 80 U/dl prior and 48 hrs
44
been recommended.33,44 Close laboratory monitoring of factor
catheterization
post; trough >30 U/dl during dual antiplatelet
levels periprocedurally, perioperatively, and during the use of
tx
anticoagulants and/or antiplatelet agents is required.
Access site: Radial > femoral
Stent: bare metal > drug-eluting
Long-term antithrombotic therapy for the management of coronary
unfractionated heparin (w/80-100 U/dl factor
artery disease or atrial fibrillation in persons with hemophilia is
replacement) > bivalirudin; avoid thrombolysis
largely based on opinion, because risk-stratification models have not
Low dose aspirin > clopidogrel
yet been determined in this population.33,44,45 The long-term use of
Severe hemophilia: avoid use of antiplatelet tx
low-dose aspirin in patients with mild or moderate hemophilia has
w/out factor replacement;
been proposed, but extended use in patients with severe hemophilia
Other invasive procedures
Factor replacement: 80-100 U/dl prior; trough
46
(ie colonoscopy w/ bx;
>50 U/dl minimum 3-4 days
may be difficult, even with factor prophylaxis and close monitoring
prostate biopsy; other
Consider adjunctive antifibrinolytics
for bleeding.44 The use of warfarin has generally not been
diagnostic bx)
recommended.
*Based on case studies or opinion; no randomized clinical trial data available.
†Management not applicable to hemophilia patients with inhibitors
Cancer
Older hemophilia patients are at increased risk for HCV-associated
cardiovascular disease in this population. Age-related comorbidities
hepatocellular carcinoma and HIV-associated non-Hodgkin’s lym-
in hemophilia patients may require complex treatment and extensive
phoma, despite substantial reductions in HIV-associated malignan-
cross-specialty clinical and laboratory coordination. With little in
cies with HAART.5,46 Hepatocellular carcinoma is an increasingly
the way of evidence-based guidelines, the management of older
important cause of mortality, with a reported standardized mortality
patients with hemophilia remains a challenge for hematologists.
ratio of 17.2 (95% confidence interval 5.2–35.9).5 Age over 45
Registry databases and collaborative studies are needed to establish
years, older age at the time of HCV infection, elevated alpha
evidence-based guidelines for the care of this emerging population.
fetoprotein, and the presence of cirrhosis are risk factors for
hepatocellular carcinoma.47 Regular surveillance with alpha fetopro-
Disclosure
tein levels and ultrasonography and/or contrast-enhanced imaging
Conflict-of-interest disclosure: The author has received research
has been recommended in this age group, particularly in individuals
funding from Baxter, Pfizer, Octapharma, Bayer, and CSL Behring.
with cirrhosis, in order to improve detection of earlier-stage
The author has received an honorarium and been a member of an
hepatocellular carcinoma.29,48 Most studies have not found an
advisory board for CSL Behring.
increased incidence of other malignancies in hemophiliacs com-
pared with the general population, but the studies have not been
Off-label drug use: Factor administration by continuous vs. bolus
uniform.45,46 The elderly hemophiliac with cancer should be man-
infusion (not product-specific discussion).
aged similarly to the non-coagulopathic individual; however, factor
replacement is needed for invasive procedures, and prophylactic
Correspondence
factor replacement may be indicated when platelet counts are
Claire Philipp, MD, Division of Hematology, MEB 378, UMDNJ-
low.33,45 Just as in the general population, age-appropriate screening
Robert Wood Johnson Medical School, New Brunswick, NJ 08903;
for malignancies such as colon and prostate cancer is indicated in
Phone: (732) 235-7682; Fax: (732) 235-7115; e-mail: philipp@
patients with hemophilia, with prophylactic factor replacement for
umdnj.edu
invasive screening procedures (Table 2).
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