American Journal of Hematology 46:354-357 (1994)

Fat Embolism Syndrome Associated With Asthma and Sickle Cell-~+-Thalassemia

K. Johnson, J.F. Stastny, and D.L. Rucknagel Departments of Internal Medicine (K.J., D.L.R.) and Pathology (J.F.S.), University of Cincinnati School of Medicine, Cincinnati, Ohio

A 25-year-old African-American man with sickle cell-p+-thalassemia presented with acute asthma of 2 days’ duration. The asthma was well controlled by 48 hr, and parenteral medications were changed to oral bronchodilators and steroids. Sixty hours after presen- tation, he developed pain similar to that of sickle cell vasooclusion, for which he received small amounts of analgesics. He died approximately 84 hours after presentation. Autopsy showed extensive marrow necrosis and massive fat embolism. This is the first reported case of fat embolism syndrome associated with this genotype, the mildest of the clinically significant sickle cell hemoglobinopathies. The relationship between these etiologic fac- tors and indications for transfusions are discussed.

Key words: vasoocclusion, hemoglobinopathy, marrow necrosis

o 1994 Wiley-Liss, Inc.

INTRODUCTION

The fat embolism syndrome4yspnea, petechiae, and mental changes-is a common complication of long bone fracture; although infrequent, it has been reported in as- sociation with sickle cell anemia and sickle cell-hemoglo- bin C disease as far back as 193 1 [ 11. We report herein for the first time fatal fat (and marrow) embolism syndrome in a patient with sickle cell-P’-thalassemia following a brief episode of acute bronchial asthma.

CASE REPORT

A 25-year-old African-American male with sickle cell- P+-thalassemia of low morbidity and asthma of approxi- mately 15 years’ duration was admitted to the hospital because of an acute episode of wheezing of 2 days’ dura- tion. He also complained of mild left costal margin dis- comfort that was attributed to coughing. The respiratory rate was 24 per minute. Chest X-ray was normal. Subcu- taneous epinephrine injections, and metaproterenol and albuterol inhalation, and intravenous methyl pred- nisoIone were given.

Admission laboratory data were as follows: hemoglo- bin, 140 g/liter; hematocrit, 0.447; leukocytes, 13.3 X 109/liter; platelet count, 165 X 109/liter; MCV, 78.5 fl/cell. Hemoglobin electrophoretic pattern contained he- moglobin A l , 0.265; hemoglobin A2, 0.057; and hemo- globin S, 0.688. While the patient was receiving 3 liters of oxygen by nasal cannula, arterial blood pH was 7.40; 0 1994 Wiley-Liss, Inc.

p02, 73 Pa; oxygen saturation, 0.945; pCO,, 40 Pa; and total CO,, 26.3 mmol/liter.

By sixty hours after admission, the patient had im- proved, intravenous methylprednisolone was discontin- ued, and oral prednisone therapy was begun. Eighteen hours later, he complained of severe thigh and bilateral flank pain similar to previous episodes of sickle cell va- soocclusion. Acetaminophen with codeine, then intra- muscular meperidine, was given every 6 hr. The hemo- globin concentration was 135 g/liter; hematocrit, 0.425; reticulocyte count, 0.17; and platelet count, 192 X lo9/ liter. The corrected leukocyte count was 14.7 X 109/liter. The peripheral film revealed microcytes and occasional schistocytes and 50 nucleated red cells/ 100 leukocytes, suggesting that hemolysis had greatly increased. With 2 liters of nasal oxygen per minute, arterial blood pH was 7.44; pCO,, 38 Pa; PO,, 77 Pa; oxygen saturation, 0.957; total CO,, 27 mmol/liter. Chest roentgenogram was nor- mal. By 84 hours after presentation, the patient’s pain had increased, and the interval between narcotic doses was shortened to 4 hr. Hemoglobin concentration was 130 g/liter; the platelet count decreased to 85 X 10g/liter. Eight nucleated red blood cells/ 100 leukocytes were

Received for publication June 29, 1993; accepted February 9, 1994.

Address reprint requests to D.L. Rucknagel, Comprehensive Sickle Cell Center, Children’s Hospital Medical Center, Elland and Bethesda Avenues, Cincinnati, OH 45229.

Case Report: Fat Embolism Syndrome 355

Fig. 1. Markedly congested capillaries within the alveolar septa containing numerous refractile globules of fat. Oil-red-0 stain. x400.

present. Several hours later, the patient became agitated and confused and complained of headache. He became short of breath, and respirations were 50/min. Ausculta- tion of the lungs showed poor air exchange, with promi- nent diffuse expiratory wheezing. Arterial blood pH was 7.36; PCO,, 28 Pa; PO,, 49 Pa; and oxygen saturation, 0.84 on 2 liters of oxygen per minute by nasal cannula. Respiratory arrest occurred, and despite attempted resus- citation, including administration of naloxone, the pa- tient died. At the time of arrest, the hemoglobin concen- tration was 89 g/liter; hematocrit, 0.277; and platelet count, 49 x 10’~iter.

At autopsy, small alveolar septa1 capillaries were markedly congested with sickled red blood cells and nu- merous refractile globules identified as fat by ’ oil-red-0 stain (Fig. 1) . Occasionally, fat extruded into the alveolar spaces. Larger muscular vessels were congested with sickled cells but were not thrombosed. Other pulmonary changes compatible with the history of longstanding asthma were thickened basement membranes surround- ing large bronchi, bronchial muscular hypertrophy, and hyperplasia of mucus glands. Fat emboli were seen

within small capillaries and vessels of various organs. Capillaries within glomeruli were markedly congested by sickled red cells and fat globules. Small blood vessels within the brain showed similar changes.

The bone marrow was hypercellular with scattered foci of necrosis, including necrosis in various portions of ver- tebrae. The amount of fat was moderately decreased compared with that of persons of similar age.

DISCUSSION

Only approximately 25 cases of fat embolism syn- drome associated with sickle cell syndromes have been reported in the past 60 years. One-third were associated with homozygous sickle cell anemia [ 1-61, the remainder with sickle cell-hemoglobin C disease [3,4,7-141, one- third of whom were pregnant [3,9,11,12]. In the last dozen years, only three such cases have been reported [6,13,14]. Most often the embolization has been the cul- mination of a several-days course of vasoocclusion. In a few instances, however, it occurred suddenly after only a brief illness. Only two of the previously reported cases

356

have survived [5, 121. It is possible, however, that the fat embolism syndrome is more common than the number of reported cases suggests but that the diagnosis is fre- quently overlooked.

In this case, as in the sickle hemoglobinopathies in general, the clinical signs that might suggest the fat em- bolism syndromeAyspnea, petechiae, and altered men- tal status-might have been obscured by the other condi- tions present, namely, by the acute asthma that may have deflected attention from dyspnea and by the use of narcot- ics, to which this patient’s mental changes were attrib- uted (even though he had received only small amounts). In some cases skin pigmentation may obscure the pete- chiae, unless they are also present in the conjunctivae or fundi. A diagnostic test for fat embolism is needed to lend objectivity to the diagnosis. The presence of fat globules in urinary sediment [ 151 or in macrophages in sputum [5] or brochial washings [16,17] has been reported, but at- tempts to confirm both have failed [ 18,191. Increased concentration of free fatty acids in plasma has also been suggested [20], as have fat-laden macrophages in the pulmonary microvascular bed via pulmonary artery wedge catheterization [21,22].

Infarction of bone marrow is common in sickle cell syndromes [4], as is evident from bone scintigraphy [23- 251. A special case of bone infarction is involvement of the bony thorax, to which the acute chest syndrome has been attributed [25]. Why some bone infarcts result in fat emboli and most do not is an enigma; the previously reported cases offer no clues other than the possibility that the amount of marrow infarcted may be important. Whether the terminal thrombocytopenia and anemia are a result of sequestration in the areas of infarction or are manifestations of a more disseminated intravascular co- agulation is also conjectural.

This is the first case of fat embolism associated with sickle cell-~+-thalassemia, the mildest of the clinically significant sickle hemoglobinopathies. Given the paucity of reports of fat embolism syndrome in those with this genotype, which is nearly as common among the Afri- can-American population as sickle cell-Hb C disease, the association of this case with an attack of acute asthma suggests (but does not prove) that the resultant hypoxia may have initiated the vasoocclusion that caused the inf- arction; hemoconcentration may also have played a role. It is impossible to ascertain the time of occurrence of the initiation of the event within the 4-6 days of hypoxia; indeed, the lower rib cage pain present on admission may have indicated that it began during the 2 days prior to hospitalization, when hypoxia may have been maximal. However, the course for the subsequent 2 days was not typical of rib infarction [25].

Specific therapy for the syndrome in nonsickle cell patients is lacking. The use of steroids to block the re-

Case Report: Johnson et al.

lease of complement is controversial [18,26]. The au- thors of the two reports of survivors [5,12] attributed the survival to the transfusions that had been given. Although dilution of sickle cells by transfusion may allow affected persons to withstand the effects of the hypoxia that fol- lows, there are no reasons to think that transfusions will prevent fat emboli after infarction has occurred.

This case raises a number of questions regarding ther- apy of the combination of acute asthma and sickle cell hemoglobinopathies. Should transfusions be given pro- phylactically to prevent infarction or fat embolism? If so, when or at what level of hypoxia? The combination of asthma and a sickle cell syndrome should not be rare. The lack of prior evidence of a relationship between asthma and vasoocclusion suggests that it would be superfluous to transfuse at the onset of each episode of broncho- spasm. If transfusion is not given until after the fat ernbo- lism syndrome is recognized, how effective will it be? Is simple transfusion adequate or should an exchange be given?

This case does not answer these questions. However, it does illustrate how premorbid conditions creating hy- poxia may mask and perhaps exacerbate sickle cell syn- dromes. We report this case in the hope that other cases may help provide answers to the questions posed above.

ACKNOWLEDGMENTS

This study was supported by USPHS 5P60-HL- 15996, Comprehensive Sickle Cell Center.

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