BLOOD
Y P E
key updates for medical care providers
fall 2013
Developments in Sickle Cell Disease
Early detection and intervention for SCD in the U.S. began in the late
1970s through implementation of neonatal screening programs. This
has led to significant decreases in morbidity and mortality in this population.
five years of age for patients without a history of invasive pneumococcal
infection or splenectomy (5). Children with SCD should receive all routine
childhood immunizations; see Table 1 below. The 7-valent pneumococcal conjugate vaccine (PCV; Prevnar) decreases the incidence of invasive
pneumococcal infection in children younger than two years and should
be given to infants with SCD on the same schedule as other children. Because children with SCD remain susceptible to life-threatening pneumococcal infections, they should also receive the 23-valent polysaccharide
pneumococcal vaccine (PPV) if two years or older, and, if the patient is 10
years or younger, revaccination should be considered three to five years
later. (5). Other vaccination recommendations include the annual influenza immunization for patients six months of age and older and meningococcal vaccination for patients two years and older. Transcranial Doppler
ultrasonograpy is recommended for screening asymptomatic children
ages 2-16 years with SCD due to the increased risk of stroke (3). Table
2 on page 2 summarizes the recommended laboratory and radiological
screenings for asymptomatic individuals with SCD.
Complications
Hydroxyurea
Complications of SCD include: stroke, acute chest syndrome, acute vaso-occlusive crisis, avascular necrosis, leg ulcers, priapism, and pulmonary hypertension. Acute chest syndrome and acute vaso-occlusive crisis (VOC) are unique to SCD. Acute painful episodes are usually caused
by bone marrow ischemia or infarction due to vaso-occlusion. VOC are
often treated in the hospital with intravenous hydration and opioids,
although this therapy is essentially palliative until self-resolution occurs
several days later. Acute chest syndrome is a frequent cause of death
in both children and adults with sickle cell disease (4). Acute chest
syndrome resembles acute respiratory distress syndrome and may be
triggered by pneumonia, pulmonary vaso-occlusion, or embolization
to the lung of infarcted bone marrow. Acute chest syndrome is usually
managed with emergent exchange blood transfusion or exchange and
attentive supportive care.
Hydroxyurea remains the only FDA-approved, disease-modifying therapy
for SCD in adults. The Multicenter Study of Hydroxyurea for Sickle Cell
Anemia study (6) revealed decreased painful crises, fewer episodes of
acute chest syndrome, and fewer patients requiring transfusions in the
hydroxyurea group compared to the placebo group. The efficacy of hydroxyurea is generally attributed to its ability to increase fetal hemoglobin
(α2γ2); however the mechanism by which this occurs is unclear.
Sickle cell disease (SCD) is the most common inherited blood disorder
in the United States, affecting 70,000-100,000 persons, and represents
one of the most common single-gene disorders in the world (1, 2).
SCD is an autosomal recessive disorder caused by a single amino acid
substitution of a valine for a glutamic acid in position 6 of the β-globin
molecule (3). After deoxygenation of the sickle hemoglobin (HbS) molecule, HbS forms large insoluble polymers which aggregate into crystallike structures within the erythrocyte, disrupting normal function. The
most common form of SCD is homozygosity for the sickle mutation
(HbSS), classically termed sickle cell anemia; however SCD also includes
other compound heterozygous states such as HbSC, HbS β-thalassemia
(2 types) and others.
Preventative Care
Neonatal diagnostic screening allows for the timely institution of family education and antibiotic prophylaxis. Infants and children with
SCD should receive daily prophylactic penicillin V potassium starting
at two months of age. Antibiotic prophylaxis can be stopped safely at
Other mechanisms which may account for the clinical benefit of hydroxyurea include reduced marrow production of neutrophils and reticulocytes, both of which promote vaso-occlusion through vascular adhesion.
Hydroxyurea, through reducing neutrophil and reticulocyte cell numbers,
reduces surface expression of adhesion receptors (7). In addition, morphologic and physiologic changes induced by hydroxyurea include macrocytosis and increased mean corpuscular hemoglobin. These changes
lead to better hydration, more targeting, less hemolysis, fewer sickled red
blood cells, and thus improved blood flow (7).
Although the metabolic mechanism is unknown, hydroxyurea is able to
carry and release nitric oxide in the circulation. Nitric oxide has beneficial effects on the vascular endothelium, including local vasodilation,
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Table 2.
Age
Education CBC/Retic
Hb
Electro1
Chemistry
UA
RBC
Psychosocial
Phenotype3 Eval
Gallbladder
Eval4
Ophthalmology Pulse
Eval
Oximetry
Pulmonary
2-6 mos
Each visit
Every 3 mos
NBS
6-12
mos
Each visit
Every 3 mos
Every 3 mos
—
Once
Every 3 mos
—
—
Each visit
__
----
__
Every 3 mos
—
—
Each visit
__
__
12 mos2 yrs
Each visit
Every 6 mos
Repeat if
needed
Yearly
Yearly
__
Yearly
—
—
Every 6 mos
__
Yearly
2-5 yrs
Each visit
Every 6 mos
--
Yearly
Yearly
—
Yearly
As needed
—
Yearly
Baseline &
as needed
Baseline
Echocardiogram
Yearly
5-10 yrs
Each visit
Every 6 mos
--
Yearly
Yearly
—
Yearly
As needed
Beginning at 10
years
Yearly
Baseline &
as needed
Baseline
Echocardiogram
Yearly
11-18
yrs
Each visit
Every 6 mos
--
Yearly
Yearly
—
Yearly
As needed
Yearly
Yearly
As needed
As needed
Yearly
Age 19over
Each visit
Every 6 mos
Baseline
Yearly
Yearly
Baseline
As needed
As needed
Yearly
Each visit
As needed
As needed
As needed
2
—
5
5
Cardiac
6
CNS
Table 2. Notes
1.
2.
3.
4.
5.
6.
Patients without documented confirmation of diagnostic testing or for whom diagnosis is unclear.
Consider Creatinine, BUN, liver function, Ferritin and/or iron and TIBC for any patient at risk for iron deficiency or for those at risk for hemosiderosis
secondary to multiple transfusions. Consider annual vitamin D screening.
Perform once before one year and document as baseline information.
Consider on an individual basis per clinical indications
Consider Chest X-ray, PFT every other year; yearly if history of recent acute chest syndrome or evidence of chronic cardiac or pulmonary disease.
Baseline Echo between 2-10 years; thereafter as clinically indicated.
Perform annual TCD ultrasonography and neurocognitive testing. Consider CNS imaging such as MRI, MRA, for patients with poor school performance
or developmental or behavioral concerns.
References:
7. National Institutes of Health 2004. Child Heath Care Maintenance. The Management of Sickle Cell Disease. U.S. Department of Health and Human
Services. Bethesda, MD. 25-33.
8. National Institutes of Health 2004. Adolescent Health Care & Transitions. The Management of Sickle Cell Disease. U.S. Department of Health and Human Services. Bethesda, MD. 35-38.
and could help offset proposed hemolysis-related nitric oxide consumption (7). The majority of published reports regarding SCD and hydroxyurea use
patients with HbSS disease, although some HbS βo-thalassemia patients are included. In general, patients with HbS βo-thalassemia and HbSS respond
similarly to treatment. Insufficient research has specifically addressed outcomes in adults with HbSC disease. The Hydroxyurea and Magnesium Pidolate to Treat People With Hemoglobin Sickle Cell Disease (CHAMPS) study evaluated the safety and efficacy of hydroxyurea and magnesium pidolate in
people with HbSC disease but was terminated early due to inadequate enrollment.
Hydroxyurea usage is increasing in the pediatric population; however, its use in children remains off-label. At many institutions, hydroxyurea is offered
to infants, children and adolescents who have developed acute vaso-occlusive complications, recurrent painful events, or acute chest syndrome. An
emerging category for treatment consideration is early evidence of organ dysfunction, such as hypoxemia, microalbuminuria, or elevated transcranial
doppler (TCD) velocities. Although the benefits of hydroxyurea in prevention of organ damage are not yet proven, accumulating anecdotal evidence
supports this consideration (7).
More recently the national BABY HUG trial enrolled 9-18 month old children with sickle cell disease (HbSS or HbS b zero thalassemia) to be randomly
assigned to receive either daily hydroxyurea or an identical tasting placebo. The results published in 2011 showed safety of hydroxyurea administration and as well as decreased pain events and evidence of decreased hospitalizations and transfusions in the group of children taking hydroxyurea.
Transfusion therapy
Transfusions are used to raise the oxygen-carrying capacity of blood and decrease the proportion of sickled red cells. In general, simple transfusions
should not be used for uncomplicated, acute, painful episodes; minor surgical procedures; chronic anemia without symptoms; or uncomplicated
pregnancies. For patients with severe symptomatic anemia, a simple transfusion is often given. For major surgery, a transfusion to correct anemia to a
hemoglobin level of 10g/dL is often performed (8). Acutely ill patients are often transfused, by either simple or exchange transfusion, based on illness
severity and availability of exchange transfusion. Chronic transfusion therapy is indicated when avoidance of potentially serious medical complications
justifies the risks of alloimmunization, infection and iron overload. Simple transfusions are often used for primary and secondary prevention of stroke.
Transfusions may also be suggested for conditions in which efficacy is unproven, but may be considered under extreme circumstances, such as: chronic debilitating pain, pulmonary hypertension, chronic heart failure, anemia associated with chronic renal failure, priapism, and leg ulcers. Exchange
transfusion is used to remove sickle cells and replace them with normal red cells without increasing whole blood viscosity. A post-transfusion hematocrit level of ≤36% is recommended, as a higher value theoretically causes hyperviscosity, which is dangerous to patients with SCD (8).
As patients with SCD have special requiring special red blood cell antigen matching, and given that they are at an increased risk for transfusion reactions, blood banks should be notified immediately. Delayed hemolytic transfusion reactions may be difficult to recognize because the symptoms may
overlap with those of a severe painful episode. All blood should be screened for the absence of sickle hemoglobin. The red blood cell antigen testing
should be determined in all patients > 6 months of age. A permanent record of the phenotyping should be maintained in the blood bank to optimize
matching, and a copy of the record should be given to the patient or family. All patients with a history of prior transfusion should be screened for the
presence of alloantibodies. Prestorage leukodepletion of red cells is standard practice to reduce complications associated with transfusion (8).
Iron Overload
Because human beings lack effective means to excrete excess iron, long-term treatment with blood transfusions produces the clinical problem of iron
overload. Initially, most of the excess iron can be stored in the reticuloendothelial macrophages. However, over time and with continued transfusions,
the capacity of macrophages to retain iron results in the release of excess iron into the plasma (9). Transferrin binds the released iron, with an increase
in the plasma iron concentration and transferrin saturation. As transferrin saturation increases, hepatocytes are recruited to serve as storage sites
for the excess iron. With continued transfusions, macrophages and hepatocytes are no longer able to retain surplus iron. As a result, iron enters the
plasma in amounts that exceed the transport capacity of circulating transferrin and non-transferrin-bound iron appears in the plasma.
Plasma non-transferrin bound iron enters specific cells, particularly hepatocytes, cardiomyocytes, anterior pituitary cells, and pancreatic beta-cells.
Iron accumulation leads to the generation of reactive oxygen species, resulting in damage to lipids, proteins, DNA, and subcellular organelles, including lysosomes and mitochondria. This injury may result in cellular dysfunction, apoptosis and necrosis. (9). Therapy with chelating agents that form a
complex with iron and promote its excretion can clear plasma non-transferrin-bound iron, remove excess iron from cells, and maintain, or return, iron
to safe levels. Two iron-chelating agents approved for use in the United States are parenteral deferoxamine mesylate (Desferal®) and oral deferasirox
(Exjade®).
Aging
The prognosis in those with SCD has dramatically improved over the past 30 years. Improved survival provides unique challenges in health maintenance. Complications such as retinopathy, renal glomerular disease, chronic pulmonary disease, leg ulcers, and osteonecrosis increase with age. Geriatric challenges in patients with SCD are not well studied. Persons with hypertension and SCD have an increased risk of strokes and increased mortality,
therefore treatment for hypertension is imperative. Currently, there are no trials in patients with SCD that assist in decisions regarding time to begin
antihypertensive treatment; agents most effective; blood pressure goals; and whether blood pressure reduction decreases stroke incidence or prolongs
life.
The NIH publication recommends a general approach to consider when beginning antihypertensive treatment; systolic blood pressure increases by
20mmHg or diastolic blood pressure increases by 10mmHg. If there is evidence of target organ damage from heart disease, nephropathy and/or peripheral vascular disease, treatment may begin at pressures >130/85 mmHg. Treatment at pressures of 120/75 mmHg may be indicated when proteinuria is > 1 gram/day (4). ACE inhibitors and calcium antagonists may be especially useful treatments. ACE inhibitors appear to reduce proteinuria and
preserve renal function. Calcium antagonists may induce a higher rate of response in black patients. Diuretics may increase vaso-occlusion by causing
hemoconcentration however in practice it is not clear whether this occurs, and their use is not contraindicated. Patients with SCD are not protected
from developing cancer as they age and require the same age-appropriate cancer screenings. Routine dental care is important to prevent loss of teeth
and infections that may lead to other SCD-related complications.
Stem Cell Transplants
Although the genetic and molecular pathophysiology of SCD are well described and understood, there has been disappointing progress toward definitive, curative therapy. Stem cell includes bone marrow and cord blood transplantation offers a cure but currently requires an HLA-matched sibling
donor for best results. This requirement limits the number of patients who can benefit from this approach. Moreover, even using a matched sibling
donor, stem cell transplantation remains associated with considerable morbidity (primarily graft-versus-host disease) and low, but not negligible, mortality (7).
Newborn screening in Indiana
There are approximately thirty infants born each year in Indiana with SCD or other hemoglobinopathy. Since 2009, all infants testing positive for SCD
and other hemoglobinopathies are referred to the Sickle-SAFE Program. The Sickle-SAFE Program, a collaboration between the Indiana Hemophilia and
Thrombosis Center (IHTC) and Riley Children’s Hospital, was implemented to address and resolve gaps in care for patients with hemoglobinopathies
living in Indiana, and to optimize outcomes. The program ensures timely notification of affected patients, educates families about the confirmed diagnosis and proper management of the disease, and links families of a newborn to a hematologist and other needed resources. The program is carried
out through home visits, family assessments and continued follow-up through one and a half years of age.
Another unique feature of Sickle-SAFE program is the early non-invasive red blood cell (RBC) antigen testing offered to newly diagnosed patients with
SCD who may be at increased risk for red blood cell alloimmunization. RBC alloimmunization is a common clinical sequelea of transfusion therapy
that contributes to morbidity in children and adults with SCD and other hemoglobinopathies. Alloimmunization results in part from racial difference
between the blood-donor and recipient populations (10). In patients who are transfused regularly, including patients with SCD, the frequency of alloimmunization and the development of antibodies can be as high as 10-38% compared to the usual 0.1-2%. It is believed that early, non-invasive antigen
testing in at-risk infants will result in a lower incidence of first-blood-transfusion-prior to testing for red blood cell antigens.
IHTC Resources
The IHTC currently offers a Sickle Cell Registry. This is for a long term (5 years), prospective, observational study of sickle cell disease patients in the US
that will enhance the understanding of the disease patterns, current transfusions practices, treatments and outcomes in sickle cell disease. Contact the
IHTC Research Department at 877-256-8837.
The IHTC has a sickle cell management book available upon request. To request your copy, contact the IHTC at 877-256-8837.
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