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American Journal of Forensic Medicine & Pathology:
doi: 10.1097/PAF.0b013e3181873c90
Case Report

Sickle Cell Disease: Two Fatalities Due to Bone Marrow Emboli in Patients With Acute Chest Syndrome

Hawley, Dean A. MD*; McCarthy, Leo J. MD†

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From the *Department of Pathology and Laboratory Medicine and †Division of Transfusion Medicine, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN.

Reprints: Dean A. Hawley, MD, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 W. 11th St, CPL Bldg, Rm 4064, Indianapolis, IN 46202. E-mail: dhawley@iupui.edu.

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Abstract

Acute chest syndrome (ACS) in patients with sickle cell disease (SCD) is a common complication contributing to death. ACS can present as sudden, unexpected death, and the medical history of SCD may not be immediately available for the medical examiner. Forensic implications for ACS are more likely to be encountered in patients with the HgbSC variant of SCD because the presence of a spleen may obscure recognition of SCD. Pathologists commonly observe small bone marrow emboli within the lung vasculature postmortem after trauma or vigorous cardiopulmonary resuscitation. Consequently, the finding of pulmonary marrow emboli in ACS may be dismissed as incidental and nonpathologic. Pulmonary marrow emboli cause ACS in patients with SCD, when there is parvoviral infection with marrow necrosis. Pulmonary marrow embolism in ACS has special significance in forensic pathology. Forensic pathologists investigate sudden, unexpected deaths during exertion, such as athletics, police pursuit, or military training. A causal relationship linking sickling hemoglobinopathy with physical exertion and sudden death has been reported. In the absence of a specific and timely medical history of SCD, and with a normal or enlarged spleen in patients with HgbSC, pathologists may wrongly dismiss bone marrow emboli as consequences of cardiopulmonary resuscitation, when those emboli might actually have been causative of fatal ACS.

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Case 1.

A patient with HgbSC variant of SCD was admitted to a hospital with a 1-hour duration of severe cramping chest, back, and abdominal pains.1 He was given intravenous fluids and narcotics. Within 24 hours after admission, red blood cell transfusion was given because of increasing anemia. He developed progressive hypoxia and died in respiratory failure 30 hours after admission. IgM and IgG antibodies to parvovirus B19 were subsequently detected in his premortem blood.

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Case 2.

A patient with HgbSC variant of SCD presented to an emergency room with acute onset of shortness of breath and bone pain in the lower extremities. He was admitted for intravenous hydration, oxygen therapy, and pain management. On day 2, a red blood cell exchange was performed and antibiotics were started, due to pulmonary infiltrates shown on a chest radiograph. Within 96 hours, he had developed acute renal failure and deteriorated rapidly with profound hypoxemia requiring mechanical ventilation. He developed dialysis-dependent hypoxic multisystem organ failure and progressive jaundice. He died 8 days after admission.

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Autopsy Findings
Case 1.

A consented medical autopsy was performed within the hospital. Subsequently, a medical-legal evaluation was requested, and the autopsy report and microscopic slides were seen in consultation. A spleen was present, without infarcts. At autopsy, each lung weighed 1000 g, and the histologic sections showed several pulmonary arterial branches nearly obstructed with 4- to 10-mm fragments of necrotic bone marrow. Intravascular marrow emboli were also grossly visible in the histologic slide of vertebral bone, lying within paravertebral venous plexus vessels. Multiple large areas of necrosis were present within thoracic and lumbar vertebral bone marrow. The findings have been previously published.1

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Case 2.

The admitting hospital obtained consent for a complete autopsy examination, consultation was requested, and the body was transported for consultative examination. There were no infarcts in the 880-g spleen. The right lung weighed 1250 g and the left lung 1010 g. Several hemorrhagic and organizing pulmonary infarcts were apparent on the pleural surfaces of both lungs. Upon incising the lungs, cylindrical fragments of necrotic poorly calcified or de-mineralized bone marrow were grossly visible in both lungs, protruding from the autopsy incisions into proximal pulmonary artery branches. The fragments of marrow varied from 2 to 3mm in diameter and length, up to 5mm in diameter and 4 cm in length. Figure 1 is a gross photograph of the proximal left pulmonary artery at the hilum, with the largest embolus within a proximal branch. Figure 2 shows a smaller embolus protruding from an incision across a small branch. Figure 3 shows demarcation at the marginal edge of a pulmonary hemorrhagic infarct. Figure 4 is a composite of photomicrographs of the bone marrow emboli, with necrotic hyperplastic marrow. Parvoviral testing was never performed.

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DISCUSSION

Although the literature has embraced the concept of pulmonary marrow embolism as the cause for ACS and autopsy findings have been previously published in clinical medical journals, marrow embolism in ACS seems to have special significance in forensic pathology. Pathologists and hematologists have studied the apparent relationship between hemoglobinopathies and sudden unexpected death for decades. Some have reported a linkage between sickling hemoglobinopathies and an increased risk for sudden unexpected death during exertion.2–6 Others have refuted that relationship.3 Forensic medicine has contributed to some of these studies, and forensic pathologists continue to be principally involved in this debate when an unexpected death occurs and a sickling hemoglobinopathy is suggested by history or ancillary tests.4,5,7

For patients with all phenotypic variants of SCD presenting to hospitals, ACS is the most frequent potentially lethal complication of HgbSS, and somewhat less often ACS is the mechanism of death for patients with HgbSC.8 ACS occurs as a complication of the concomitant triad of SCD, parvovirus infection, and bone marrow fat embolism.1,9,10 The origin of that pulmonary “fat” embolism has been shown to be bone marrow embolism, and the origin of the systemic fat embolism remains speculative and subject to further study.1,11–14 Pulmonary bone marrow embolism is the most frequently reported causative or primal etiology for ACS. Most reported cases refer to emboli of only microscopic size.9,15 The 2 cases reported herein demonstrate gross, macroscopic bone marrow emboli in patients with ACS, one with resolving parvovirus infection, and both patients had HgbSC variant of SCD. Case 1 is the first documented autopsy case where these emboli were probably large enough to be seen during the autopsy dissection. In this case, the emboli were possibly originally thought to be thrombo-emboli, and then later proven as bone marrow emboli.1 Case 2 is an example where the marrow emboli were recognized during the gross dissection of the lungs.

In routine forensic autopsy experience, pathologists regularly encounter microscopic bone marrow and fat emboli as an artifact of vigorous CPR, and consequently, the finding of such emboli at autopsy is frequently regarded as an incidental nonpathologic peri-mortem or postmortem event.7 A history or autopsy diagnosis of SCD would be necessary for a forensic pathologist to correctly associate this finding in proper context as the cause of ACS. The specific medical history of SCD is often not available to medical examiners before conducting the postmortem examination, and the gross autopsy diagnosis of SCD can be difficult if the underlying hemoglobinopathy is HgbSC, rather than the classic HgbSS. The HgbSC variant of SCD does not cause the splenic auto-infarction commonly seen in patients with classic HgbSS. In patients with HgbSS, gross autopsy discovery of a small, fibrotic auto-infarcted spleen reflexively triggers a diagnostic suspicion of SCD, or at least that finding causes pathologists to consider SCD in a differential diagnosis. Finding a normal or even enlarged spleen commonly triggers the opposite reflex, to discount or even dismiss SCD in the differential diagnosis. But with the HgbSC variant of SCD, the spleen is not small or fibrotic, and fatal ACS is still a distinct clinical possibility.

We are not aware of any case where ACS and bone marrow embolism has been reported in a patient with sickle cell trait. Finding pulmonary bone marrow embolism in a person with proven HgbAS, especially in the presence of a history of vigorous CPR, should continue to be interpreted as a likely artifact of CPR and probably not causative of the fatal event. Fatalities of military recruits with HgbAS sickle cell trait have not been reported to show pulmonary bone marrow emboli, and the reported cases are more often associated with physiologic hyperthermia and systemic hypoxemia.2,3 An argument could be made that HgbAS does sometimes masquerade as true SCD with vaso-occlusive events.5,16 One hypothesis might be because of a concomitant occurrence of HgbAS sickle cell trait with thalassemia, but postmortem proof of thalassemia requires genetic testing, and that testing only works for a limited number of known hemoglobin defects.17,18 One such successful postmortem genomic DNA molecular diagnostic examination has been reported, and that report does include a discussion of bone marrow fat embolism.17 The value of postmortem blood for genetic testing, if there has been prior peri-mortem medical therapeutic transfusion, is debated, given the possibility of scientific or medical-legal argument that the test is merely detecting an abnormality in the donor's blood.19 Sickled-appearing red blood cells in paraffin-embedded microscopic slides of tissue removed at autopsy are a frequent artifact of tissue processing and is never sufficient proof of SCD.4 Additional testing is required. Case reports of autopsy diagnosis of “sickle cell sequestration crisis,” as a proposed cause for sudden unexpected death during exertion, and based just on the appearance of red cells in tissue sections, require further biochemical proof such as hemoglobin electrophoresis and molecular DNA genomic diagnostics to be substantiated.5,17

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CONCLUSION

In both of these cases of fatal ACS, macroscopic necrotic emboli arising from the patient's bone marrow, presumably caused by SCD and parvoviral infections with marrow necrosis, caused vascular occlusion within the lungs. In 1 case, the emboli caused pulmonary infarcts. Bone marrow emboli within pulmonary vessels should not be summarily dismissed as peri-mortem artifacts of trauma or resuscitation because the clinical medical history of SCD may not be immediately available to death investigators, and the classic visceral sequela of SCD (auto-infarct of the spleen) does not occur in patients with the HgbSC variant of SCD. Ancillary testing including hemoglobin electrophoresis and serologic testing for parvovirus is necessary to confirm a diagnosis in the absence of medical history. Further, if the embolic bone marrow fragments are large, hyper-cellular, and partly necrotic, it should raise suspicion that there may be an underlying sickling hemoglobinopathy, even if a spleen is present.

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REFERENCES

1. McCarthy LJ, Hawley DA. Marrow emboli in acute chest syndrome: artifact or etiology? Transfusion. 2006;46:1657–1658.

2. Kark JA, Posey DM, Schumacher HR, et al. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med. 1987;317:781–787.

3. Kark JA, Ward FT. Exercise and hemoglobin S. Semin Hematol. 1994;31:181–225.

4. Wirthwein DP, Spotswood SD, Barnard JJ, et al. Death due to microvascular occlusion in sickle-cell trait following physical exertion. J Forensic Sci. 2001;46:399–401.

5. Thogmartin JR. Sudden death in police pursuit. J Forensic Sci. 1998;43:1228–1231.

6. Murray MJ, Evans P. Sudden exertional death in a soldier with sickle cell trait. Mil Med. 1996;161:303–305.

7. Nikolic S, Savic MJ, Uzelac-Belovski Z. Post-traumatic pulmonary and systemic fat embolism in forensic practice. Prospective histological study [in Serbian]. Srpski Arhiv Za Celokupno Lekarstvo. 2000;128:90–93.

8. Platt OS. The acute chest syndrome of sickle cell disease. N Engl J Med. 2000;342:1904–1907.

9. Eckardt P, Raez LE, Restrepo A, et al. Pulmonary bone marrow embolism in sickle cell disease. South Med J. 1999;92:245–247.

10. Kolquist KA, Vnencak-Jones CL, Swift L, et al. Fatal fat embolism syndrome in a child with undiagnosed hemoglobin S/β+ thalassemia: a complication of acute parvovirus B19 infection. Pediatr Pathol Lab Med. 1996;16:71–82.

11. Lechapt E, Habibi A, Bachir D, et al. Induced sputum versus bronchoalveolar lavage during acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med. 2003;168:1373–1377.

12. Garza JA. Massive fat and necrotic bone marrow embolization in a previously undiagnosed patient with sickle cell disease. Am J Forensic Med Pathol. 1990;11:83–88.

13. Shapiro MP, Hayes JA. Fat embolism in sickle cell disease: report of a case with brief review of the literature. Arch Int Med. 1984;144:181–182.

14. Vichinsky E, Williams R, Das M, et al. Pulmonary fat embolism: a distinct cause of severe acute chest syndrome in sickle cell anemia. Blood. 1994;83:3107–3112.

15. Quinn CT, Buchanan GR. The acute chest syndrome of sickle cell disease. J Pediatr. 1999;135:416–422.

16. Bock H, Seidl S, Hausmann R, et al. Sudden death due to a haemoglobin variant. Int J Legal Med. 2004;118:95–97.

17. Hutchins KD, Ballas SK, Phatak D, et al. Sudden unexpected death in a patient with splenic sequestration and sickle cell-beta+-thalassemia syndrome. J Forensic Sci. 2001;46:412–414.

18. Tefferi A. Anemia in adults: a contemporary approach to diagnosis. Mayo Clin Proc. 2003;78:1274–1280.

19. Graham EA, Tsokos M, Rutty GN. Can post-mortem blood be used for DNA profiling after peri-mortem blood transfusion? Int J Legal Med. 2007;121:18–23.

Keywords:

acute chest syndrome; sickle cell disease; bone marrow embolism; fat embolism; hemoglobinopathy

© 2009 Lippincott Williams & Wilkins, Inc.

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