First Things First

  • Inherited hemoglobinopathies caused by disordered Hb synthesis
  • Name is based on which chain subunit is underproduced; however, this underproduction leads to overproduction of other subunits.
    • So a pt with beta-thalassemia may have excess alpha, delta, gamma subunits
  • Anemia is a consequence of ineffective erythropoiesis and hemolysis combined.
  • Often the complications of iron overload syndromes prompt the complication leading to ICU admission.
  • The overall contribution of these two processes differs in various forms of thalassemia.
  • Cooley’s anemia is a severe form of beta-thalassemia that may be seen in ICU care.
  • Globin reduction contributes to diminished hemoglobin molecules (hypochromasia) and small structure (microcytosis).
  • Development of unchecked accumulation of subunits causes unstable molecules, leading to apoptosis and hemolysis and poor iron acclimation.
  • Anemia causes excess erythropoietin, but this is counteracted by ineffective production.
  • Accelerated apoptosis is major factor in dysfunctional erythropoiesis, caused by excess chain deposition in erythroid progeny.
  • Beta-thalassemia is common in Mediterranean countries, North Africa, Middle East, India, and Europe.
  • Alpha-thalassemia: usually of Asian origin but also seen in India, the Middle East, and Africa; pts with severe types rarely survive (hydrops fetalis)
  • Both types can co-exist, usually lessening the severity of disease.

History and Physical

  • Remember, vital signs are vital signs!
    • Check for tachycardia, bradycardia, fever, respiratory rate and SaO2.
  • Often, exam is complicated by co-existing disease state.
  • Specifically ask about medicines, OTC drugs, herbal remedies, EtOH and recreational drug use.
  • Ask about PMH and concurrent treatments, including chemotherapeutic drugs.
  • Inquire about ethnic, familial, and geographical background.
  • Ascertain menstrual variations and amounts, bleeding from various body sites (GI, vaginal, epistaxis, gums, bruising).
  • Exposures to toxic and marrow effective agents
  • Examine for infection, lymphadenopathy, stool blood, spleen enlargement, liver size, petechiae, purpura, murmurs, pale membranes and skin.
  • Cardiovascular, GI, skin, neuro, lymph, organ systems exam
  • Examine groin, flanks, chest and extremities for anatomical blood loss, hematomas, compartment syndromes.
  • Rectal and NGT exam of upper GI tract if melena/hematochezia exists
  • Ask specifically about RUQ pain from cholecystic disease.

Diagnostic Tests

  • Order standard CBC with differential, peripheral smear for schistocytes, reticulocyte count, PT/PTT, LFTs, metabolic profile, TSH, iron, TIBC, folate, ferritin, B12, transferrin, blood type/screen, ESR, CRP, lactate, DIC panel, haptoglobin, LDH.
    • Try to obtain these before blood is given.
    • Serum iron level is unreliable, with ~78% sensitivity and 36% specificity in ICU management.
  • Reticulocyte index (see “Anemia” chapter for specifics)
  • Iron levels and other serum studies may be inaccurate if recent transfusions have been given.
  • Pan-culture for infection
  • Urine analysis, creatinine, BUN, glucose
  • CPK and troponin (for rhabdomyolysis and ongoing ischemia from anemia)
  • CXR, EKG, ABG, SvO2 (if CVC above diaphragm)
  • Low MCV with high reticulocyte count may be the first indirect evidence for thalassemia.
  • Hb-electrophoresis evaluation usually confirms the diagnosis in beta-thalassemia but can be normal in alpha-subtypes, transfusions or acute anemia.
  • Hemoglobin/hematocrit (H/H): In worse forms levels can be extremely low (< 5 g/dL) but usually levels are 8-9 g/dL.
  • Indices (MCV/MCH): Considerably low
  • RDW: Thalassemia trait normal, major has marked elevation from notable anisocytosis
  • Reticulocytes: High
  • WBC: Leukocytosis with left shift and bands usually present in beta-thalassemia major from both the hemolysis-induced cell shift and inappropriate counting of excess RBC types by automated machines
  • Platelets: Often low, reflective of concomitant disease state or splenic enlargement, but can be normal
  • Serum iron studies: High, with extremely elevated saturation levels, >70-80%; TIBC elevated
  • Ferritin: High, but levels need to be taken into consideration in face of acute illness. Some patients may have iron overload.
  • Peripheral smear: Usually done by automated systems in lab, but ask for specific hemolysis and anemia profiling. Great source for identification of abnormal cell types, inclusion bodies (Heinz), morphology.
  • Other: Complete RBC phenotype, hepatitis screen, folic acid level, and human leukocyte antigen (HLA) typing are recommended before initiation of blood transfusion therapy.
  • Hemoglobin electrophoresis: Patients with silent carrier genotypes may have “normal” levels and usually don’t have an ICU presentation based on their genotype.
  • Both alpha-thalassemia and beta-thalassemia trait are similar. Both should be differentiated from iron deficiency anemia (IDA; see below).
  • Elevated levels of Hb A2, F, or both are seen in beta-thalassemia.
  • Alpha-thalassemia, electrophoresis is usually normal; other tests may be needed to differentiate IDA or AAI from thalassemia.
  • EZP levels are usually elevated in patients with IDA or AAI, not with thalassemia.
  • Soluble transferrin receptors levels are high in patients with IDA but not in those with AAI or thalassemia.
  • Adequate H&P usually allows for proper identification of thalassemia patients when labs are inconclusive.
  • Hemoglobin levels are usually ≥9 g/dL. Levels less than this indicate a confounding process.
  • RBC count is usually higher in patients with thalassemia compared with IDA.
  • RDW is normal.
  • May have stippling pattern (basophilic)
  • Mentzer index: In non-critical care settings, to differentiate IDA from thalassemia
    • Not generally useful in an acute setting, especially if multifactorial anemias present
    • Divide the MCV by RBC count (MCV/RBC).
    • 13 suggests thalassemia, < 13 indicates IDA.

General Management Principles

  • Pts usually present with overwhelming infections, cardiomyopathy or endocrine failures.
  • Depending on the geno- and phenotypical profile, patients may have low-grade, asymptomatic, compensated anemia, or symptomatic, decompensated disease.
  • Patients may have admission associated with thalassemia or concomitant disease processes; this makes treatments and diagnosis difficult.
  • Endocrine dysfunction
    • DM
    • Hypothyroidism
    • Hypoparathyroidism
  • Cardiomyopathy from iron overload or chronic hyperdynamic state
  • Arthropathies
  • Organomegaly
  • Thrombophilia with DVT/PE
  • Pulmonary hypertension
  • Proclivity for severe overwhelming infections secondary to splenic dysfunction or loss, transfusion-related infections, including Yersinia
  • Severe forms of alpha-thalassemia and beta-thalassemia intermedia (Hb H disease) can be characterized by moderately severe anemia, splenic enlargement, jaundice, bone changes due to expansion of marrow. In these situations, Hb electrophoresis is diagnostic.
  • Unstable and dysfunctional Hb can be detected on peripheral smears as Heinz bodies.
  • Remember, Hb electrophoresis will be inaccurate if transfusions have been given in face of IDA.

Specific Treatments

  • Directed toward specific complications as above
  • Transfuse only when necessary
  • Desferal (chelation therapy) -- pts may have a pump to deliver
  • BMT
  • Splenectomy may be necessary.

Ongoing Assessment

  • IDA depresses production of all Hb molecules. Consider repeating confirmatory tests when acute illness is over.
  • Check for iron overload.
  • Evaluate for common complications as noted above.
  • Source control for sepsis
  • CI, hemodynamic monitoring for cardiac decompensation


  • As disease progresses, pt can suffer from the consequences of long-term therapy, notably iron overload syndromes, infections, gallstones.
  • Typical ICU complications


  • Steven Zanders, MD

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