Fat embolism syndrome due to bone marrow necrosis in patients with hemoglobinopathies: A life‐threatening complication mimicking thrombotic thrombocytopenic purpura
Authors: Radhika Gangaraju, Jori E. May, Lance A. Williams, Vishnu B. Reddy, Paul MacLennan, Marisa B. Marques
Journal: American Journal of Hematology (2018)

Bone marrow necrosis (BMN) and embolization of fat and necrotic marrow is a rare, life-threatening condition in patients with sickle cell disorders (SCD).1 Fat emboli cause multiorgan failure with anemia and thrombocytopenia, often mimicking thrombotic thrombocytopenic purpura (TTP) and posing a diagnostic challenge. In the last 8 years, we have diagnosed BMN/FES in 16 patients with SCD at our institution, some of whom were unaware of their hemoglobinopathy prior to this presentation. Although the etiology and precipitating factors of FES are poorly understood and require further investigation, we discuss important distinguishing features that can facilitate rapid recognition and treatment. We retrospectively reviewed medical records of all BMN/FES patients diagnosed at our institution between April 2010 and January 2018 to obtain histories, laboratory data, treatment, and clinical outcome. We compared each FES patient with 2 TTP patients matched for age, gender and race. We analyzed presenting symptoms and laboratory results aiming at identifying characteristics that differentiate FES from TTP. A univariate exact conditional logistic regression was used to examine significant differences in likelihood of FES for continuous and categorical variables. A Friedman test was used to check for significant differences in schistocytes on admission. Ordinal values were created based off the value of the dependent variable, that is, presence of schistocytes (none = 0, rare = 1, few = 2, occasional = 3, moderate = 4, and many = 5 per high power field). This test accounts for the 1:2 matching and the null hypothesis is that there is no difference in ranks by patient group. We also attempted to calculate fat embolism risk scores (Gurd and Wilson's criteria, and Schonfeld's criteria) for FES patients, to test their applicability in this context.2 The Institutional Review Board at our institution approved this study and granted a waiver of informed consent. Sixteen patients (8 males and 8 females) with BMN/FES were seen at our institution between April 2010 and January 2018. Their mean age was 40.6 years (SD ± 12.1) compared with 41.1 years (SD ± 11.5) for the 32 patients with TTP (P = 0.5834). Ten patients with FES had HbSβ+, 4 HbSC and 2 HbSS disease; 4 patients were unaware of having hemoglobinopathy prior to presentation. Their most common complaints were severe back pain (69%), respiratory compromise (69%) and altered mental status (56%; Supporting Information Figure S1). Laboratory data for both groups are shown in Supporting Information Table S1. On admission, all patients with FES were anemic, with a mean hemoglobin of 9.2 g/dL (SD ± 2 g/dL) and thrombocytopenia was present in 12 patients (75%). The remainder developed thrombocytopenia during hospitalization. TTP patients had significantly lower platelet count on admission and at the nadir. Six (38%) FES patients had a leukoerythroblastic picture on admission, and seven (total, 81%) developed it during hospitalization. There were no differences in terms of hemoglobin, lactate dehydrogenase (LDH) and creatinine. In terms of nucleated red blood cells (NRBCs), there was a change in the reporting of this parameter in our laboratory in 2015, and only patients seen since that time could be compared. Figure 1A shows that the peak number of NRBCs/100 leukocytes was >100 in 4 of 6 patients with FES but in none with TTP. Conversely, FES patients were less likely to have moderate/many schistocytes on peripheral smear compared to TTP patients (P = 0.035; Figure 1B). Of the 10 FES patients who had ferritin measured, all had a markedly increased level (mean 5792 ng/mL, SD 4296 ng/mL; reference: 10-291 ng/mL). The first 4 FES patients had a bone marrow biopsy during the diagnostic evaluation, revealing extensive necrosis, stromal hemorrhage, microvascular thrombi and many sickle cells in marrow sinuses and stroma. The next 12 patients were diagnosed based on our experience recognizing the clinical and laboratory presentation of FES and published descriptions.3, 4 Our third patient received 3 units of RBC within 6 hours of admission for a hemoglobin of 4.5 g/dL and had rapid reversal of symptoms, prompting us to treat all subsequent patients with red cell exchange (RCE) as soon as FES was suspected. Unfortunately, patients #9, #13, and #15 died prior to RCE due to delayed diagnosis, and patients #11 and #12 had the procedure many days from initial presentation at other institutions. Overall, 12 patients received RBCs (10 RCEs and 2 simple transfusions) and 9 had full recovery, while 2 had neurologic impairment and 1 died (Table S2). When we applied the criteria to diagnose FES in trauma patients, 13 fulfilled the Gurd and Wilson's criteria, and 13 others fulfilled Schonfeld's, with only one patient meeting neither one (Table S2). Two major theories, a mechanical and biochemical theory, exist to explain the pathophysiology of FES.5 Several reports have shown an association with Parvovirus B19 infection, with an incidence as high as 24% in the review by Tsitsikas et al.4 Among our patients, 7 were tested by PCR (1 positive), and 2 by serology (1 positive). Patients with FES presented with non-specific symptoms such as back pain, fever, fatigue, respiratory distress and altered mental status. Laboratory data showed anemia, thrombocytopenia, increased LDH and ferritin, and evidence of end-organ damage, most commonly renal failure, mimicking another life-threatening hematologic emergency, TTP. For this reason, the majority of patients in our study were transferred to our institution with a presumed diagnosis of TTP, and had even undergone therapeutic plasma exchange but had further clinical deterioration. While both disorders have mortality ~90% if untreated and therapeutic plasma exchange is life-saving in TTP, FES patients appear to benefit from RCE. Hence, identifying early signs that differentiate them is essential. Peripheral smear review can be useful; FES patients predominantly have a leukoerythroblastic picture with left shift and abundant NRBCs, whereas TTP patients have microangiopathic hemolytic anemia with schistocytes. Although schistocytes may be present in patients with FES, and leukoerythroblastosis in critically ill patients with TTP, FES patients were less likely to have moderate/many schistocytes. FES patients also had markedly high ferritin, which quickly decreased and even normalized upon clinical recovery (data not shown), suggesting that ferritin may be a sensitive (albeit not specific) marker of FES. BMN/FES is likely an under-recognized disease entity in SCD, as many cases are fatal and diagnosed at autopsy. For reasons that are not clear, the majority of FES patients have compound heterozygous SCD.4 It has been postulated that increased blood viscosity due to higher baseline hematocrits may play a role in this susceptibility, but the reason remains elusive.6 The mortality rates in patients with BMN/FES who received RCE, simple transfusions and no transfusion were 29%, 61% and 91%, respectively.4 While bone marrow biopsy is diagnostic, treatment with transfusion should not wait for biopsy confirmation based on our experience.2 Dramatic clinical improvement in oxygen requirement, encephalopathy, renal failure and blood parameters was observed when our patients were treated promptly with either multiple RBC transfusions or automated RCE. Based on our observations, we propose that RCE should be performed emergently in patients with suspected or confirmed FES. Admittedly, we do not understand how RCE or transfusion improves the prognosis, but it is perhaps attributed to dilution of sickled red cells with normal RBC, decreasing viscosity and/or improving circulation. Since some patients appear to improve during the procedure, one could also speculate that RCE removes fat globules or bone marrow elements avoiding further end organ damage. In conclusion, FES should be suspected when an African American patient complains of new onset severe back pain and is found to have anemia and thrombocytopenia, even in the absence of known hemoglobinopathy. Supporting Information Figure S2 shows our proposed diagnostic algorithm to guide treatment decisions in such cases. Since the majority of patients with FES have a rapidly deteriorating clinical course, calculation of the Fat Embolism Index scores can also help increase diagnostic certainty. Maintaining a high index of suspicion for FES, increasing physician awareness and instituting rapid intervention with RCE or simple transfusion are paramount to prevent permanent dysfunction or death. RG, JEM, and MBM contributed to the study design, data collection, analyses and interpretation of results; PM provided statistical analysis. RG, JEM and MBM wrote the manuscript; VBR and LAW critically revised the manuscript for intellectual content. All authors critically revised the manuscript for important intellectual content and approved the final manuscript. The authors declare no competing financial interests. Table S1. Comparison of laboratory characteristics of FES and TTP patients on admission Table S2. Underlying hemoglobinopathy, fat embolism scores, treatment and outcomes of FES patients Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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