Fat Embolism Syndrome Mimicking Thrombotic Thrombocytopenic Purpura in a Patient With Hemoglobin S/Beta-Thalassemia

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104

Case Report

J Hematol. 2024;13(3):104-107

Fat Embolism Syndrome Mimicking Thrombotic

Thrombocytopenic Purpura in a Patient With

Hemoglobin S/Beta-Thalassemia

Bobby Se

a, c

, Austin Frisch

, Min Woo Hwang

, Faran Polani

Najeebah Bade

Abstract

Thrombotic microangiopathies cause ischemic organ damage and re-

quire urgent management for a favorable prognosis. Fat embolism

syndrome from bone marrow necrosis is a rare and unique pathology

that carries a high mortality rate. It can mimic thrombotic microangi-

opathies such as thrombotic thrombocytopenic purpura (TTP). Here-

in, we present a patient with sickle cell-beta-thalassemia who initially

presented with a vaso-occlusive crisis, lab evidence of hemolysis,

schistocytes and thrombocytopenia who developed acute encepha-

lopathy with respiratory distress, consistent with TTP. She was found

to have multiple infarcts in the brain. She was intubated and under-

went plasma and red cell exchange. Bone marrow biopsy confirmed

marrow necrosis from her vaso-occlusive crisis and subsequently, fat

embolism syndrome. Here, we discuss the complex presentation and

the complications of fat embolism from bone marrow necrosis and

how it can mimic TTP.

Keywords: Fat embolism; Hemolytic anemia; Thalassemia; Throm-

bocytopenia

Introduction

Thrombotic microangiopathies (TMAs) are a group of disor-

ders defined by the presence of microangiopathic hemolytic

anemia, thrombocytopenia, and microthrombi, which lead to

organ damage through ischemia. Thrombotic thrombocyto-

penic purpura (TTP) is a TMA pathology that requires quick

identification and treatment to avoid severe complications

and death [1]. TTP is defined by the presence of the classic

TMA features of hemolytic anemia, schistocytes on peripheral

smear, and thrombocytopenia in addition to low ADAMTS-13,

and can present with signs of organ damage such as neuro-

logical impairment, renal dysfunction, or cardiac ischemia [2].

Similarly, fat embolism syndrome (FES) is characterized by

pulmonary insufficiency, neurologic symptoms, thrombocyto-

penia, and anemia [3]. FES is most commonly seen after trau-

matic injuries such as long bone fractures, but other risk fac-

tors can include non-traumatic etiologies such as pancreatitis,

liver disease, and sickle cell disease [4]. There have been case

reports of TTP clinically mimicking FES and thus, making the

diagnosis challenging [5]. Table 1 outlines the similarities and

differences in the clinical and laboratory features between TTP

and FES. We review the clinical presentation, pathophysiol-

ogy, and current literature on the intersection between TTP and

FES in sickle cell patients while highlighting the diagnosis and

treatment needed to quickly differentiate these diseases and

prevent death.

Case Report

Investigations

A 40-year-old female with a history of sickle-beta-thalassemia

who presented to an outside hospital with severe back and bi-

Manuscript submitted April 12, 2024, accepted May 28, 2024

Published online June 28, 2024

Inova Fairfax Hospital Department of Internal Medicine, Falls Church, VA

22042, USA

Inova Schar Cancer Institute, Fairfax, VA 22031, USA

Corresponding Author: Bobby Se, Inova Fairfax Hospital Department of In-

ternal Medicine, Falls Church, VA 22042, USA.

Email: [email protected]

doi: https://doi.org/10.14740/jh1274

Table 1. Clinical and Laboratory Features Differentiating Be-

tween TTP and FES

Clinical/laboratory features TTP FES

Thrombocytopenia Common Common

Acute kidney injury Common Common

Altered mental status Common Common

Fever > 100.4 °F or 38 °C Common Common

Respiratory failure Less likely More likely

Bone marrow necrosis Less likely More likely

Schistocytes More likely Less likely

ADAMTS-13 < 10% Normal

FES: fat embolism syndrome; TTP: thrombotic thrombocytopenic purpura.

Articles © The authors | Journal compilation © J Hematol and Elmer Press Inc™ | www.thejh.org

105

Se et al J Hematol. 2024;13(3):104-107

lateral lower extremity pain was transferred for management

of acute sickle cell crisis. Upon arrival, lab work was largely

unremarkable with hemoglobin of 12.8 g/dL, white blood cell

counts of 12.9 × 10

/µL, and platelet count of 253 × 10

/µL. The

patient was initially managed with fluids and pain medication

for vaso-occlusive crisis but then developed acute encephalopa-

thy. Follow-up lab work showed worsening hemolytic anemia

and new onset thrombocytopenia with platelets of 105 × 10

µL. Laboratory testing showed elevated lactate dehydrogenase

(LDH) to 1,070 U/L, low haptoglobin of < 8 mg/dL, elevated

indirect bilirubin of 2.8 mg/dL and schistocytes were seen on the

peripheral smear. She was intubated for airway protection given

her worsening mental status and transferred to the intensive care

unit (ICU). The following day, thrombocytopenia worsened to

79 × 10

/µL. At this time, a computed tomography (CT) angio-

gram and CT of head were both negative. Her PLASMIC score

was 6, which corresponds to a 72% risk of severe ADAMTS-13

deficiency. Therefore, the leading diagnosis at this time was

TTP with other differential being fat embolism progressing to

FES from non-traumatic bone marrow necrosis given the hemo-

globinopathy and vaso-occlusive crisis.

Diagnosis

The patient underwent emergent plasma exchange and was

started on high-dose steroids (1 g of solumedrol). Subsequent-

ly, ADAMTS-13 level was normal, and follow-up brain mag-

netic resonance imaging (MRI) showed multiple, scattered in-

farcts, highly suspicious for fat emboli. Bone marrow biopsy

showed marrow necrosis (Fig. 1). Given these findings, FES

became the established diagnosis.

Treatment and outcomes

The patient therefore underwent red cell exchange (RCE) im-

mediately which reduced the hemoglobin S levels to 17%.

Throughout her stay in the ICU, the patient continued to have

minimal neurologic recovery and electroencephalogram con-

tinued to show cerebral dysfunction in a non-specific man-

ner. Hospital course was further complicated by continued

fevers and tachycardia with leukocytosis prompting infectious

workup and anti-microbial coverage. Her neurological status

continued to show minimal recovery and eventually, tracheos-

tomy and peg procedure were pursued prior to discharge to a

long-term care facility.

Thrombocytopenia is defined as platelet levels < 150 × 10

U/L. Acute kidney injury is defined as an increase in serum cre-

atinine by 0.3 mg/dL within 48 h, increase in serum creatinine >

1.5 times the baseline level within 7 days, or a decrease in urine

output < 0.5 mL/kg/h for > 6 h. These definitions are consist-

ent with the 2012 KDIGO clinical practice guidelines. Respira-

tory failure is defined as either hypoxemic or hypercapnic with

PaO

< 60 mm Hg or PaCO

> 50 mm Hg, respectively. Altered

mental status is defined as an acute change in cognitive func-

tion, psychological function, and/or level of consciousness in

the form of behavior changes, alertness or confusion.

Discussion

The pathophysiology behind marrow necrosis causing FES is

not yet fully understood. Classically, FES presents after long

bone or pelvic trauma and only 10% of these cases have clinical

manifestations such as anemia, thrombocytopenia, neurologic

symptoms, and pulmonary insufficiency [6]. In patients with

acute chest syndrome, circulating phospholipids from bone

marrow necrosis have been found to activate the inflammatory

cascade leading to fat emboli formation [7]. This observation

agrees with the biochemical theory that explains non-traumatic

causes of FES [8]. Therefore, patients with hemoglobinopa-

thies are at increased risk for bone marrow necrosis leading to

fat embolism and subsequently, FES [9]. Furthermore, there

seems to be an increase in prevalence with sickle cell patients

that have heterozygous genotypes compared to their homozy-

gous counterparts. This correlation is poorly understood but

patients with hemoglobin Sβ

compared to SC and SS have

a higher rate of developing FES [5, 9, 10]. The mortality rate

for FES in the reported literature for sickle patients is 46%.

Twenty percent of these patients that died also tested positive

for parvovirus B19 [11, 12]. Therefore, hemoglobin Sβ

, SC

and SS along with parvovirus are risk factors for the develop-

ment of FES in patients with sickle cell disease.

Figure 1. Bone marrow biopsy with evidence of bone marrow necrosis (a, × 4 magnification; b, × 20 magnification) (arrows).

Articles © The authors | Journal compilation © J Hematol and Elmer Press Inc™ | www.thejh.org

106

FES Mimicking TTP J Hematol. 2024;13(3):104-107

While this disease is severe and life-threatening, diagnos-

ing FES can be a challenge given clinically similar presentation

as TTP. Distinguishing between the two diagnoses can be more

complex in the setting of hemoglobinopathy due to chronic he-

molysis. FES can rarely cause a triad of neurological impair-

ment, thrombocytopenia, and organ failure making presentation

nearly identical to TTP [13, 14]. Respiratory distress appears to

be a distinguishing feature between the two as it is more com-

mon in FES; however, as demonstrated with our patient, relying

on clinical presentation can be deceiving in these cases.

FES treatment is generally supportive care with a level of

definitive management in sickle cell patients. This is because

FES can cause acute chest syndrome in sickle cell patients,

thus lending to RCE as an option. This exchange prevents the

removed sickled cells from propagating more vaso-occlusive

events and thus minimizing bone marrow necrosis [15]. Other

treatment options include trialing high-dose steroids in pa-

tients with life-threatening FES which theoretically prevents

more formation [16]. However, high-dose steroids can have

adverse effects like infection like in our case thus making it a

controversial treatment decision [17].

Given the high mortality rate of TTP and clinical findings

in this case, it is reasonable to treat as TTP with plasma ex-

change while waiting on ADAMTS-13 levels on initial presen-

tation. In the rare cases where FES was misdiagnosed as TTP,

initial plasma exchange did not seem to negatively affect these

patients [11, 18, 19]. However, it is important to re-evaluate

the diagnosis based on clinical progression and new lab re-

sults. Here, our patient had a normal ADAMTS-13 level with

MRI findings of multiple infarcts suggestive of fat emboliza-

tion. Bone marrow biopsy to corroborate bone marrow necro-

sis confirmed our diagnosis of FES. While RCE is definitive

in FES caused by sickle cell disease, the primary treatment

modalities are supportive which further emphasizes the impor-

tance of prevention.

Learning points

FES resulting from bone marrow necrosis is an uncommon and

distinctive pathology characterized by a significant mortality

risk. Patients with sickle cell variant Hb Sβ

who test positive

for parvovirus B19 are at an increased risk of developing FES

from bone marrow necrosis.

FES can imitate TMAs like TTP. Thus, plasma exchange

is a reasonable initial therapy while waiting for ADAMTS-13

level to result before starting RCE.

Acknowledgments

None to declare.

Financial Disclosure

The authors have no funding source to disclose for this case

report.

Conflict of Interest

The authors have no conflict of interest.

Informed Consent

Not applicable.

Author Contributions

Bobby Se: original draft preparation with literature review

(lead); Austin Frisch: original draft preparation with literature

review (support); Min Woo Hwang: review and editing; Faran

Polani: review and editing; Najeebah Bade: review, editing,

visualization of concept.

Data Availability

The authors declare that the data supporting the findings of this

study are available withing the article.

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