Teaching Topics | July 11, 2019
Hemolytic Transfusion Reactions: What are some of the features of delayed hemolytic transfusion reactions?
A 31-Year-Old Woman with Vision Loss: Is there an effective medical therapy for Leber’s hereditary optic neuropathy?
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Teaching Topic
Hemolytic Transfusion Reactions
REVIEW ARTICLE
S. Panch, C. Montemayor‑Garcia, and H.G. Klein
Although technical and administrative controls to prevent transfusion of ABO-mismatched blood have reduced transfusion-related deaths, immune-mediated hemolysis remains an important, if underappreciated, risk.
Clinical Pearls
 What signs and symptoms suggest that an acute hemolytic transfusion reaction has occurred?
Although fever, flank pain, and reddish urine represent the classic triad of an acute hemolytic transfusion reaction, this type of reaction may also be suspected if one or more of the following signs or symptoms appears within minutes to 24 hours after a transfusion: a temperature increase of 1°C or more, chills, rigors, respiratory distress, anxiety, pain at the infusion site, flank or back pain, hypotension, or oliguria. One fascinating early symptom, a “sense of impending doom,” has been reported by numerous patients and should not be ignored.
Describe some of the steps taken when an acute hemolytic transfusion reaction is suspected.
When an acute hemolytic transfusion reaction is suspected, the transfusion should be stopped immediately, and the blood being transfused should be saved for analysis. Laboratory testing should include repeat ABO and Rh compatibility testing, along with additional antibody testing for non-ABO incompatibility. Visual inspection of urine and plasma, as well as testing for urine and plasma free hemoglobin, is standard. Timing is critical, since free hemoglobin is cleared rapidly from the circulation. Simultaneously, alternative causes, including infectious agents, must be ruled out by means of Gram’s staining and cultures of the remaining transfused component.
Morning Report Questions
Q. What are some of the features of delayed hemolytic transfusion reactions?
A. Delayed hemolysis, occurring days to a month after transfusion, is less evident than an acute hemolytic reaction, since the temporal relationship to transfusion is often overlooked. Unlike acute hemolytic transfusion reactions, delayed hemolytic transfusion reactions are almost invariably caused by secondary (anamnestic) immune responses in patients immunized by previous transfusions, allogeneic stem-cell transplants, or pregnancy. These reactions rarely constitute a medical emergency. In many instances, alloantibodies appear on routine testing in the blood bank (reported as “delayed serologic transfusion reactions”) and are not associated with clinical events. Clinical manifestations, if they occur, include anemia and jaundice due to extravascular red-cell destruction, followed by hemoglobin degradation and liberation of bilirubin into the plasma. Fever, hemoglobinuria, and hemoglobinemia are even less frequent.
Q. Does management of an acute hemolytic transfusion reaction include the routine use of intravenous immune globulin?
A. An acute hemolytic transfusion reaction is considered to be a medical emergency. Management must occur in an intensive care unit, along with a renal consultation, since dialysis may be required. Once an immune-mediated acute hemolytic transfusion reaction has been recognized, management is mainly supportive. Vigorous hydration with isotonic saline to maintain urine output at a rate above 0.5 to 1 ml per kilogram of body weight per hour is recommended to minimize the effects of free heme-mediated renal and vascular injury. The common practice of mannitol administration is not evidence based and should be used cautiously, if at all, in patients with anemia and limited cardiac reserve. No evidence supports the routine use of therapeutic high-dose glucocorticoids, intravenous immune globulin, or plasma exchange.
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Teaching Topic
A 31-Year-Old Woman with Vision Loss
CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
M. Matiello and Others
Leber’s hereditary optic neuropathy was the first human disease linked to a mutation in mitochondrial DNA; it is more common in men than in women and typically occurs between 15 and 35 years of age.
Clinical Pearls
What is Leber’s hereditary optic neuropathy (LHON)?
LHON is a maternally inherited mitochondrial disorder that is caused primarily by mutations in mitochondrial genes encoding the NADH dehydrogenase subunits and that causes decreased activity of complex 1 of the mitochondrial electron transport chain. Three mutations account for more than 95% of cases of LHON: m.11778G→A (the most common), m.3460G→A, and m.14484T→C. These mutations all ultimately lead to decreased ATP production.
What are some of the features of LHON?
LHON causes painless, subacute, severe vision loss in one eye, followed by vision loss in the contralateral eye within several weeks or months. Up to 50% of affected patients do not have a family history of vision loss. Since inflammation is not driving the process, the administration of glucocorticoids does not lead to improvement. MRI typically shows only hyperintensity in the posterior portion of the optic nerve, but enhancement of the optic nerve has been reported during the acute phase. Spontaneous vision recovery can occur in some cases and is most often associated with the m.14484T→C point mutation.
Morning Report Questions
Q. Is LHON caused by the presence of a relevant mitochondrial mutation alone?
A. LHON-related mutations are more likely to occur in males than in females, at ratios of 2.1:1.0 to 7.7:1.0. However, the mutations alone are not sufficient to cause the disease, and other genetic modifiers (mitochondrial DNA copy number, haplotype, and nuclear modifiers), environmental factors (tobacco, alcohol, and toxin exposure), and sex hormone levels play a role in the pathophysiology. In patients with LHON, a combination of these factors is thought to cause an increase in free radicals, a decrease in ATP production, and a disruption in the oxidation–reduction (redox) balance, ultimately leading to retinal ganglion-cell apoptosis and optic-nerve degeneration.
Q. Is there an effective medical therapy for LHON?
A. Unfortunately, there is no Food and Drug Administration–approved therapy for LHON. Multiple supplements and medications have been proposed as potential treatments. These agents use various mechanisms to boost mitochondrial mass and number, circumvent dysfunction in the respiratory chain complex, or prevent oxidative damage to retinal ganglion cells. One promising medication that has been prescribed is idebenone. This short-chain coenzyme Q analogue acts as an electron carrier to directly deliver electrons to complex 3 of the respiratory chain, bypassing the dysfunctional complex 1 of LHON. Idebenone has been approved by the European Medicines Agency for the treatment of LHON. Gene therapy is a potential future treatment. In clinical trials of intravitreal injection of an adenovirus-associated vector that contains wild-type mitochondrial genes encoding functional NADH subunits, preliminary data suggest the potential for some vision recovery in patients with LHON.
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