A 5 year-old boy with anemia and hemoglobinuria
Prepared by.... Rawee Taweephon, M.D.
Pimlak Charoenkwan, M.D.
Patient: A 5 year-old boy with anemia and hemoglobinuria
CC: pallor and dark-colored urine for 1 day prior to admission
Present Illness:
  Three days prior to admission the patient developed low grade fever and dry cough. He had no rhinorrhea or sorethroat at that time. On the admission day his mother noticed that the patient was markedly pale and complained of malaise. She reported that his urine was dark-colored. The patient was seen at a primary hospital and subsequently was transferred to the CMU hospital. Initial CBC revealed a Hemoglobin level of 4.5 g/dL, a Hct of 14%, a WBC count of 9,100/mm3. (N76%, L14%, M8%, E1%) and a platelet count of 372,000/mm3.
Past Medical History:
> The patient had been diagnosed with Hemoglobin H disease since 18 months of age.
> He had received 2 blood transfusions when he had fever and acute anemia.
Family History: Both parents are thalassemia carriers.
Physical examination:
  Vital signs: T 38.3 C, PR 140/min, RR 36/min, BP 126/68 mmHg
GA: A boy, good consciousness, active
W/A 94.74%, H/A 102.73%
HEENT: markedly pale, no jaundice, enlarged cervical lymph nodes, 0.2-0.3 cm in diameter bilaterally, no injected pharynx and tonsils, normal tympanic membranes bilaterally
Heart: systolic ejection murmur grade II/VI at left upper sternal border
Lungs: clear, no adventitious sounds
Abdomen: soft, normal bowel sounds, enlarged liver to 4 cm. below the right costal margin, enlarged spleen to 6 cm. below the left costal margin
Extremities: no edema
Skin: no rash

Problems: acute anemia and hemoglobinuria in a 5 year-old boy with hemoglobin H disease
Laboratoy investigations:
  CBC: Hb 3.9 g/dL Hct 12.1% WBC 7,100/mm3 (N 42%, E 1%, L 57%) Platelet 186,000/mm3
MCV 68 fL MCH 21 pg MCHC 30 % RDW 31 RBC 2.8x106/mm3
PBS: hypochromia +1, microcytosis +2, anisopoikilocytosis +2, target cells +2, polychromasia +2, normal WBC with predominant lymphocyte, normal number, size and color of platelets
Reticulocyte count: 6.5% Inclusion bodies: positive
U/A: brown color, clear, no WBC, RBC
Urine heme: not done
Hb typing: AHBart'sCS; H 5.7% Bart's 11.9% CS 0.9%
 
Figure 1 Peripheral blood smear
Figure 2 Inclusion bodies
Figure 3 Hb typing by HPLC

Diagnosis:
1. Hb H/Hb CS disease with hemolytic crisis
2. Possible previous upper respiratory tract infection

Discussion 1:
What are characteristics of hemolytic anemia?
  Hemolytic anemia is a state of decreased red blood cells survival. Patients with hemolytic anemia present with pallor, increased reticulocyte count which reflects bone marrow response and indirect hyperbilirubinemia which resulls from a breakdown of red blood cells.

Discussion 2:
What is Hemoglobin H disease?
> Hemoglobin H (Hb H) disease is a result of deletions or point mutations of three alpha-globin genes, leaving only one functioning gene (genotype --/-alpha ). As a consequence, the excess alpha-globin chains make up Hb H (beta4). Patients with Hb H disease may present with symptoms of acute or chronic anemia and enlarged liver or spleen, or may be found incidentally to have a hypochromic microcytic anemia. Most patients are classified as "thalassemia intermedia" with a baseline Hb level between 8-10 g/dL, mild or absent hepatosplenomegaly and no requirement for regular red cell transfusion.
> Majority of Hb H disease results from deletion of three alpha-globin genes, which are classified as "deletional Hb H disease". The rest is caused by deletion of two alpha-globin genes combined with a point mutation of one alpha-globin gene. These are classified as "non-deletional Hb H disease". Hb H/Hb Constant Spring disease is the most common non-deletional Hb H disease in Thailand. The clinical severity of the Hb H/Hb CS patients are usually more than those with the deletional Hb H disease.
> Patients with Hb H disease may present with an acute intravascular hemolysis after certain precipitating events such as fever or infection. At that time, they may complain of sudden onset of pallor, fatigue and breathlessness. Some may experience dark-colored urine as hemoglobinuria develops. Some patients will need red blood cell transfusion during the hemolytic episode.

Discussion 3:
How would Hb H disease be diagnosed?
1. CBC and reticulocyte count: lower levels of Hb, MCH and MCV, higher RBC count, PBS: hypochromia and polychromasia with variable anisopoikilocytosis, reticulocyte count: raised to 3-6%
2. Supravital staining: precipitation of Hb H from peripheral blood red cells after incubation at room temperature in the presence of dyes such as brilliant cresyl blue or methyl violet, seen as inclusion bodies
3. History: chronic anemia, acute hemolysis precipitated by fever or infection, neonatal jaundice, family history of anemia
4. Physical examination: anemia, jaundice, enlarged liver or spleen, growth failure
5. Hemoglobin analysis: AH or AHBart's pattern seen in conventional cellulose acetate gel electrophoresis as a fast moving band before Hb A, 0.8 to 40% Hb H in adults with Hb H disease, a HPLC (High performance liquid column chromatography) also show an AH or AHBart's pattern with Hb Bart's and Hb H eluted within the first minute of analysis.
6. Genetic analysis: Southern blot, PCR-based methods or DNA sequencing will identify mutations causing the Hb H disease.

Discussion 4:
What are the managements for this patient?
1. Immediate management:
a.
 Assessment of cardiovascular status
b.
 Oxygen supplement
c.
 Intravenous fluid to maintain adequate urine output
d.
 PRC transfusion
e.
 Supportive/symptomatic treatment for URI
f.
 Patient and family education
2. Long-term management:
a.
Patient and family education about Hb H disease: genetic basis, natural course, plan of treatment and complications
b.
Folic acid supplement

Clinical course:
The patient received 10 mL/kg of PRC, 3,000 mL/m2/day of IV 5%D/N/3 and other supportive treatment. The vital signs were stable and the intake and output were balanced. The urine color was yellow after 24 hours of hydration. He was discharged home after 3 days of hospitalization.

Suggested reading:
Higgs DR, Bowden DK. Clinical and laboratory features of -thalassemia syndromes. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, editors. Disorders of Hemoglobin. Genetics, pathophysiology, and clinical management. Cambridge: Cambridge University Press;2001. p. 431-69

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