Hemoglobinopathies



Hemoglobinopathies


David J. Slomiany

Michael Levien



Hemoglobin (Hb) is a complex tetrameric protein composed of four polypeptide (globin) chains with prosthetic oxygen-binding heme groups. Normal Hbs in the red blood cell (RBC) are Hb A, Hb A2, and Hb F. Hb A (the major Hb) is composed of two β-globin chains and two β-globin chains. β-Chains are encoded on chromosome 16. β-Chains are encoded on chromosome 11. During embryonic and fetal development, several distinct globin chains are produced and combine in tetramers to form embryonic and fetal Hb. Mutations in the globin genes can yield:



  • Abnormal globin chains and subsequently abnormal Hb molecules (e.g., Hb S in sickle syndromes)


  • Abnormal synthesis of globin chains and subsequently decreased amounts of normal Hb (e.g., thalassemias)

The Hbs in an individual’s RBCs are characterized by electrophoresis (ELP). The screening of all newborn infants for disorders has led to early diagnosis. Early medical intervention and education have decreased morbidity and mortality in infants with sickling disorders (Table 55.1).


SICKLE CELL DISEASE


Etiology

Sickle cell diseases are a group of genetic disorders with various clinical manifestations; the common feature is that the affected individuals have at least one gene for Hb S. The disorders include homozygous Hb SS disease and disease states in which Hb S is associated with other variant Hbs (e.g., Hb SC, Hb SD, Hb S/β thalassemia) that enhance or promote the sickling phenomenon (Table 55.2). Sickle cell disease is identified in most cases by newborn screening. Confirmation of the diagnosis is by Hb ELP.

The cause of sickle cell disease is a mutation in the β-globin gene. An adenine-to-thymine substitution in codon 6 of the β-globin gene specifies the insertion of valine for glutamic acid at the sixth position of the β-globin chain to produce Hb S. Hb S occurs frequently among population in areas previously exposed to falciparum malaria, including western coastal Africa, central Africa, India, Saudi Arabia, and the Mediterranean countries. Hb S in these patients provides protection against intraerythrocytic growth of malaria.


Pathophysiology

Hb S crystallizes and polymerizes on deoxygenation, thereby distorting the RBC. Polymerization and distortion lead to destruction of the RBC membrane, decreased RBC deformability, and increased RBC adhesion to vascular endothelium. Sickling of erythrocytes is facilitated by fevers, dehydration, and acidosis.

The clinical problems associated with sickle cell disease are a consequence of hypoxia and acidosis, which are caused by tissue ischemia resulting from vaso-occlusion by irreversibly sickled RBCs. The clinical manifestations include severe hemolytic anemia, an increased frequency and severity of certain infections, tissue infarction with subsequent organ damage and failure, and recurrent episodes of pain. The clinical manifestations are acute and chronic.


Clinical Presentations and Treatments

Sickle cell disease is a chronic condition in which acute events of variable severity occur intermittently. Patients require care in specialized centers. Routine health maintenance is important, with an emphasis on nutrition, education of families, infection prophylaxis, and anticipatory guidance regarding the avoidance of extremes of temperature, dehydration, and physical activity (Table 55.3).

The clinical consequences of sickle cell disease can be broadly grouped into three categories:



  • Vaso-occlusive events


  • Hemolytic events


  • Infectious events

The damage inflicted by sickle cell disease can be acute or chronic in nature.









TABLE 55.1 HEMOGLOBIN PATTERNS ON NEWBORN SCREENING

































Newborn Screening
Hemoglobin Pattern


Interpretation


Recommended Action


FAS


Hb S trait


Hb ELP 9-12 months


FS


Homozygous sickle cell disease or Hb S trait with other variants (e.g., Hb S/β thalassemia)


Hb ELP plus CBC at initial visit, repeat Hb ELP at 9-12 months, plus CBC


FSC or FSD


Potentially serious sickling disorder


Hb ELP plus CBC at initial visit, repeat Hb ELP at 9-12 months, plus CBC


FAE


Hb E trait


Hb ELP, 9-12 months, plus CBC


FA Bart’s


α Thalassemia


Hb ELP, 9-12 months, plus CBC


FE


Homozygous Hb E or hemoglobin E/β thalassemia


Hb ELP, 9 months, plus CBC at 4-6 months. Family studies helpful


A, normal adult hemoglobin; C, hemoglobin C variant; CBC, complete blood cell count; D, D hemoglobin variant; E, hemoglobin E variant; ELP, electrophoresis; F, normal fetal hemoglobin; Hb, hemoglobin; S, sickle hemoglobin variant.



Vaso-occlusive Crisis

Vaso-occlusive crisis occurs when poor RBC deformability, increased viscosity, and adherence of the “sickled” RBCs to endothelial cells cause ischemia/infarction. Vaso-occlusive crisis is also known as pain crisis. It most commonly affects bone, lung, liver, spleen, brain, and penis.

Bone infarction or ischemia of the periarticular tissues is the most common form of acute vaso-occlusive pain crisis. The pain is usually diffuse. Localized tenderness, swelling, and limited range of motion are common. Redness and warmth occur but are not prominent. Low-grade fevers usually develop. The severity and frequency of pain crisis increase with age. Initially, pain crisis is usually dactylitis (hand-foot syndrome), most common in children <2 years and involving the metacarpals, metatarsals, and phalanges of one or more extremities. Long bones, spine, clavicles, ribs, and sternum are also frequently affected by pain crisis. Treatment is supportive, with aggressive hydration, narcotic analgesics, and nonsteroidal anti-inflammatory agents. Oxygen is of little value and may actually exacerbate anemia. Infection should be sought out and treated.








TABLE 55.2 CLINICALLY IMPORTANT SICKLING DISORDERS















Hb SS


Majority (60%-70%) of the cases of sickle cell disease in the United States. Second most common form of sickle cell disease in the United States (˜20%); moderate chronic hemolytic anemia, less severe than Hb SS


Hb SD


Clinically similar to Hb SS


Hb SO Arab


Clinically similar to Hb SS


Hb S β thalassemia


Heterogeneous clinical disorders with symptoms and severity that depend on the severity of thalassemia component



Cerebrovascular Events

Two major central nervous system (CNS) complications of Hb SS disease are occlusion in large vessels and aneurysms in small vessels. Stroke occurs in up to 15% of patients with Hb SS, and the reported mortality is 15% to 20%. It is the second leading cause of death in patients with Hb SS. The risk of stroke is four times higher in patients with Hb SS disease compared with patients with Hb SC disease. Stroke is usually the result of infarction, although hemorrhagic strokes do occur. Sickling of RBCs in the vas vasorum of the large vessels leads to infarcts in the blood vessel walls causing stenosis, aneurysms, and occlusion. The distribution is typically the middle cerebral artery and watershed areas, and the stroke may be preceded by a transient ischemic attack.

The presentation is with seizures, paresis, or aphasia. Various findings are noted on magnetic resonance imaging (MRI), computed tomography (CT) scan and arteriography. The recurrence rate without treatment is 70% within 3 years.

Treatment involves reducing the concentration of Hb S to 30% to 50%; this usually requires exchange transfusion but can sometimes be accomplished by a simple transfusion. Erythrocytapheresis is the preferred treatment in an acute event to rapidly reduce the concentration of Hb S. Chronic transfusion of RBCs by hypertransfusion or erythrocytapheresis is mandatory to decrease or prevent the recurrence of stroke. Recovery varies, although children recover more fully than adults. A recent study by the National Institutes of Health has concluded that it is not safe to stop
RBC transfusions even after 5 years in this patient population due to the risk of stroke recurrence.








TABLE 55.3 HEALTH CARE MAINTENANCE













































































































Well-child immunizations


Routine childhood immunizations required


Conjugate 7-valent pneumococcal vaccine: 4 doses prior to age 2 years followed by 23-valent polysaccharide pneumococcal vaccine at ages 2 and 5 years



Yearly influenza vaccine


Initial evaluation


Physical examination, CBC with RBC indices



Reticulocyte count



Confirmatory Hb ELP



Genetic counseling



Anticipatory guidance regarding fever, hydration, pain, and acute splenic sequestration (demonstrate and teach parents how to palpate spleen)



Prophylactic penicillin from 1 month to 5 years of age



Start folic acid at 6 months (optional)


Newborn-2 years


Every 2-3 months for physical examination



CBC, reticulocyte count every visit



G6PD at 6 months



Confirmatory Hb ELP at 9-12 months



Anticipatory guidance



Blood chemistries at 12 months, as needed



Iron and lead studies


2-6 years


Every 6 months for physical examination, if clinically well



CBC, reticulocyte count every visit



Blood chemistries yearly, p.r.n



Transcranial Doppler ultrasonography every 6 months to 1 year



Ophthalmology exam yearly



Urinalysis yearly



ECHO/ECG at 3-5 years



Anticipatory guidance


6-18 years


Every 6 months for physical examination, if clinically well



CBC, reticulocyte count every visit



Blood chemistries yearly, p.r.n



Transcranial Doppler ultrasonography every 6 months



Ophthalmology exam yearly



Urinalysis yearly



ECHO/ECG every 3-5 years



Pulmonary functions age 10, p.r.n or with history of acute chest syndrome



Hip/shoulder x-rays age 10-14 years



Anticipatory guidance


CBC, complete blood cell; ECHO/ECG, echocardiography/electrocardiography; ELP, electrophoresis; G6PD, glucose-6-phosphate dehydrogenase; Hb, hemoglobin; p.r.n, as needed; RBC, red blood cell.


It is important to note that 30% of asymptomatic patients with Hb SS disease have “silent” infarcts on MRI surveillance. These patients have never had clinical evidence of stroke. Children with Hb SS disease should have transcranial Doppler (TCD) ultrasonography every 6 months or at least once a year starting at the age of 2 years. TCD measures the velocity of blood flow through the internal carotid and middle cerebral arteries. More frequent studies should be done on patients with borderline high velocities (180-199 cm/second). If the velocity is ≥200 cm/second on two separate occasions 1 to 2 months apart, magnetic resonance arteriography and venography should be done to assess the patient’s risk for stroke. If the patient has tortuous vessels with or without stenosis, moyamoya disease (basal arterial occlusion with telangiectasia), and/or “silent” infarct(s), then commencing a chronic RBC transfusion program is strongly recommended.

The long-term consequences of chronic transfusion program are the result of iron overload and alloimmunization. Iron chelation therapy should be administered in children 3 years and older when the serum ferritin is >1000 ng/mL (although serum ferritin alone is not a reliable measure of total body iron burden). Deferoxamine is currently the standard chelating agent. Partial RBC exchange transfusions are another approach to reducing iron overload.


Acute Chest Syndrome

Patients present with chest pain, tachypnea, shortness of breath, cough, fever, leukocytosis, unilateral or bilateral
infiltrates, and possibly hypoxemia. Bony tenderness over the ribs, sternum, or spine may occur. Bloody or purulent cough is not prevalent. Increased incidence of acute chest syndrome occurs in patients with low fetal hemoglobin, high steady-state hemoglobin (increased blood viscosity), high white blood cell counts, and in the winter months when the frequency of respiratory infections are increased. Acute chest syndrome may develop after vaso-occlusive pain crisis, which is a consequence of infarcts in long bones creating pulmonary fat emboli. The Hb level can be significantly decreased from baseline at presentation. The respiratory status can quickly deteriorate as hypoxia and acidosis further promote sickling.

Causes of acute chest syndrome include infection, bone infarction, and the formation of fat emboli secondary to bone marrow necrosis. The fatality rate is 10% to 20%; acute chest syndrome is reported to be the leading cause of death in patients with Hb SS disease who are >10 years. It is the most common complication of anesthesia. Repeated episodes can lead to chronic restrictive pulmonary disease, pulmonary hypertension, and cor pulmonale. Early recognition is important. Treatment includes:



  • Correction of the hypoxemia with oxygen


  • Administration of antibiotics and analgesics


  • Transfusion (simple or exchange)


  • Incentive spirometry to prevent hypoventilation

Priority should be given to administering RBC transfusions to rapidly decrease Hb S. Intravenous fluids should not exceed maintenance rate. A rapidly deteriorating patient should have exchange transfusion (erythrocytapheresis). These patients can progress to respiratory failure and require tracheal intubation and ventilator support. A multicenter acute chest syndrome trial conducted by the National Institutes of Health accrued 538 patients with 671 episodes of acute chest syndrome. Analysis of bronchial alveolar lavage samples from these patients revealed the following:



  • 30%: negative for viral, bacterial, and fungal infection


  • 16%: positive for lipid-laden macrophages (pulmonary fat emboli)


  • 54%: positive for infection (Chlamydia 13%), (Mycoplasma 12%), (viruses 12%), (Staphylococci, Streptococci, and Haemophilus 8%)

Empiric intravenous antibiotic therapy should include a 3rd generation cephalosporin, such as ceftriaxone or cefotaxime and a macrolide.

Jul 5, 2016 | Posted by in CRITICAL CARE | Comments Off on Hemoglobinopathies

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