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Between April and November 2010, three patients with sickle-cell-β+-thalassemia (HgbSβ+) were transferred to our tertiary care hospital for management of multiorgan failure following their first ever episodes of pain crisis, which resulted in bone marrow necrosis (BMN). The data collection methods and publication of their histories were reviewed and approved by the University of Alabama Institutional Review Board with a waiver of need for informed consent.

Patient 1 was a previously healthy, 25-year-old black male with a 2-week history of fever, back, and abdominal pain. He was brought to his local hospital after being found unresponsive and in respiratory distress. The patient was intubated and noted to have several nonblanching petechiae on his shoulders and chest. Laboratory evaluation identified microcytic anemia and thrombocytopenia. He was transferred to our institution with a presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP). On admission, his platelet count was 44 × 103/μl, and the peripheral blood smear was remarkable for numerous immature leukocytes and nucleated red blood cells with very few schistocytes (Table I). These findings were not consistent with TTP, which was later confirmed by a normal ADAMTS-13 activity.

Table I. Laboratory Values on Admission for Patients 1, 2, and 3
Laboratory valuesPatient 1Patient 2Patient 3Reference ranges
  • Abbreviations: Parvo, Parvovirus B19; Adeno, adenovirus; CMV, cytomegalovirus; EBV, Epstein–Bar virus; VZV, Varicella Zoster Virus; HIV, human immunodeficiency virus; JCV, JC virus; HSV, herpes simplex virus; NRBC, nucleated red blood cells.

  • a

    N/A, not available.

Hemoglobin (g/dl)8.4910.413.5–17.0 g/dl
Mean corpuscular volume (fl)74797580–100 fl
White cell count (×103/μl)64.43.44–11 × 103/μl
Myelocytes (%)2030%
Metamyelocytes (%)5000%
Bands (%)6000%
Neutrophils (%)71777735–73%
Lymphocytes (%)10141115–52%
Monocytes (%)5584–13%
Eosinophils (%)1410–5%
NRBC (/100 WBC)432167None
Platelets (×103/μl)443715150–400 × 103/μl
Creatinine (mg/dl)1.20.91.20.7–1.3 mg/dl
Total bilirubin (mg/dl)4.261.80.4–1.4 mg/dl
Direct bilirubin (mg/dl)2.10.60.90.1–0.3 mg/dl
Indirect bilirubin (mg/dl)2.15.40.90.1–1.3 mg/dl
Alanine aminotransferase (U/l)21548406–45 U/l
Aspartate aminotransferase (U/l)10493119≤37 U/l
Alkaline phosphatase (U/l)18713638839–117 U/l
Lactate dehydrogenase (U/l)2,1182,1142,849120–240 U/l
Blood culturesNegative for bacteria and fungiNegative for bacteria and fungiNegative for bacteria and fungiNegative
Viral testingaNegative: Parvo, Adeno, CMV, EBV, VZV, HIV, JCV, HSVNegative: Parvo, CMV, EBV, HSV, HBV, HCVN/ANegative
ADAMTS-13 activity (%)>60>60N/A>60%
Ferritin (ng/ml)9,9422,7505,09922–322 ng/ml

Patient 2 was a 53-year-old healthy black male who presented to a local emergency room (ER) with severe lower back pain. He was diagnosed with “muscle strain” and discharged with a prescription for a muscle relaxant and a narcotic. Several days later, he was brought back to the ER after being found on the ground, conscious but confused. His mental status rapidly declined, he developed respiratory insufficiency, and was intubated. Laboratory work-up showed anemia and thrombocytopenia. Like patient 1, he was transferred to our institution for the treatment of TTP and underwent one emergent plasma exchange procedure. Upon further review of his laboratory data and a peripheral blood smear (Table I), it was determined that he did not have TTP, and plasma exchange was discontinued.

Both patients presented with elevated lactate dehydrogenase (LDH), ferritin, total, and indirect bilirubin (Table I). White blood cell counts were normal on admission, and all tests for bacterial and viral infections were nonrevealing. During their prolonged ICU stays (19 and 30 days, respectively) they had persistent altered mental status (AMS) and respiratory failure and developed renal and liver insufficiency. Magnetic resonance imaging (MRI) of both patients showed numerous microhemorrhages and infarcts. The electroencephalography (EEG) tracings from the patients were consistent with encephalopathy.

The patients were also noted to have persistent anemia and thrombocytopenia for which bone marrow biopsies were performed. Histologic sections from both patients demonstrated complete necrosis of hematopoeitic elements (Fig. 1). Further clinical work-up failed to identify malignant, infectious, or drug-induced causes for BMN. However, hemoglobin electrophoresis revealed that both patients had hereto unknown HgbSβ+ disease (Table II). Although patient 1 received two units of packed RBCs four days before hemoglobin electrophoresis, the findings of increased Hgb A2 (4.4%) and decreased mean corpuscular volume (74 fl) were consistent with β-thalassemia (Table I). Abdominal imaging (ultrasound and computed tomography in patients 1 and 2, respectively) demonstrated moderate splenomegaly, both measuring 15 cm, with evidence of acute splenic infarcts. Of note, neither patient had had any clinical manifestation of hemoglobinopathy before the events described in this report.

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Figure 1. Histologic sections of bone marrow biopsies from Patients 1 and 2 (A and B, respectively). A: Low power (10×) view of bone marrow necrosis (BMN) denoted by pale eosinophilic coagulum surrounded by regions of hemorrhage. B: High power view (40×) of BMN demonstrating numerous sickle cells. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Table II. Hemoglobin Electrophoresis
Laboratory valuesPatient 1aPatient 2Patient 3Expected range in HgbSb+ thalassemia (%)
  • a

    Electrophoresis performed on post-transfusion blood sample.

Hemoglobin A (%)36.918.321.85–30
Hemoglobin A2 (%)4.45.35.3>3.5
Hemoglobin S (%)51.866.766.965–90
Hemoglobin F (%)6.99.76.02–10

Patient 1 underwent red cell exchange 5 days after admission, but showed no clinical improvement. After 19 days, he remained ventilator-dependent. He was transferred to a long-term care facility with permanent devastating neurologic deficits. Patient 2 did not receive red cell exchange and was subsequently transferred to an inpatient rehabilitation facility with persistent cognitive impairment and paralysis after 30 days in the ICU.

One month after patient 2 presented, a 42-year-old black male with a 2-week history of severe back pain, fatigue, and weakness was found unresponsive at home and brought to an ER (patient 3). He had been in good health before this event, but had a history of HgbSβ+ diagnosed during a routine military physical exam. Upon arrival to the ER, the patient was noted to be hypoxic and was emergently intubated due to respiratory failure. Laboratory tests showed anemia and thrombocytopenia, increased LDH, and rare schistocytes (Table I). Given these findings, he was transferred to our institution also with a diagnosis of TTP. However, based on his history of HgbSβ+ and our recent experience with patients 1 and 2, we elected to perform an emergent red cell exchange upon admission. A bone marrow biopsy was not performed due to the presumptive diagnosis of BMN from clinical and laboratory data. His ICU course was complicated by pneumonia, renal failure, cardiac insufficiency, and neurologic impairment. An MRI showed mild multifocal white matter lesions, which could not be definitively characterized as hemorrhages/infarcts. An EEG was consistent with encephalopathy. He was discharged to a rehabilitation facility on day 15 with clinical status near baseline and a good prognosis for recovery.

Commentary

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The goal of this report is to increase awareness of the clinical syndrome of BMN and multiorgan failure in adults with phenotypic variants of sickle-cell disease (SCD). The presenting clinical and laboratory features of the three patients described here were initially interpreted as TTP by the medical staff that first evaluated them. After admission to our institution, patients 1 and 2 were given a presumptive diagnosis of macrophage activation syndrome due to their high ferritin levels in the setting of multiorgan failure (Table I). These cases highlight the difficulty of making a clinical diagnosis of BMN, especially in adult patients unaware of having a hemoglobinopathy.

SCD results from the inheritance of two hemoglobin S (HgbS) genes. A Glu-Val substitution at the sixth position of the β-globin gene produces hemoglobin that is poorly soluble in the deoxygenated state. Deoxy-HgbS can polymerize into fibers that distort the shape of the RBC into the classic sickle form [1]. Anemia and vaso-occlusive disease are hallmarks of SCD [2]. β-Thalassemia is characterized by impaired production of β-globulin chains resulting in a relative excess of α-globulin chains. The vast majority of β-thalassemia mutations in African-Americans are due to promoter region mutations resulting in a mild phenotype [3]. Patients with compound heterozygous HgbSβ+ disease tend to have a more benign lifetime clinical course than those who are homozygous SCD. Such patients are more likely to have an incidental diagnosis of HgbSβ+ at a later age; indeed, patients 1 and 2 went undiagnosed until adulthood, and patient 3 had only been diagnosed incidentally during previous military evaluation. Of note, we later discovered that patient 1 had two half-siblings with SCD. However, interviews with family members failed to elicit a history of sickle cell hemoglobinopathy in this patient.

All three patients developed BMN as their first manifestation of HgbSβ+ disease. BMN is morphologically defined as the destruction of hematopoeitic cells and stroma with preservation of cortical bone [4]. The pathologic mechanism of BMN is thought to be ischemia due to vaso-occlusive crisis secondary to impaired circulation in the bone marrow microvasculature [5]. BMN appears to be a rare phenomenon as evidenced by the paucity of reports in the literature. When reported, BMN is most commonly seen in the setting of hematologic malignancy. Occasionally, cases of BMN and SCD, infections, and drug toxicity have also been published [6–9]. The most common presenting symptom of BMN is bone pain that may be disseminated or localized in the lower back, followed by fever and fatigue [5]. Anemia and thrombocytopenia are present in >80% of cases [7]. A leukoerythroblastic picture on the peripheral blood, elevation of LDH, and alkaline phosphatase are also common findings [5]. The three patients described in this report complained of severe bone pain, which they described as severe “back pain”, and demonstrated laboratory abnormalities consistent with BMN. In addition, histologic evaluation of bone marrow biopsies from patients 1 and 2 revealed sickle cells and hemorrhage in the marrow stroma (Fig. 1). The persistent anemia and thrombocytopenia in these patients were likely due to a combined effect of severe bone marrow insult and splenic sequestration.

An uncommon, but serious complication of BMN is the embolization of fat and necrotic marrow into the systemic circulation causing damage to multiple organs [10–14]. Although acute chest syndrome, cerebrovascular accidents, and pain episodes are known to occur in HgbSβ+ [2], acute multiorgan failure has rarely been reported [10]. Even those with more severe SCD (i.e., HgbSS and HgbSC) rarely experience multiorgan failure during vaso-occlusive crises in the absence of serious comorbidities [11, 15]. The fat embolism syndrome is prominently characterized by AMS, petechiae, and progressive respiratory failure [16]. Fat emboli activate clotting factors and precipitate disseminated intravascular coagulation and microvascular infarcts, which may lead to multiorgan failure [6]. The primary features of multiorgan failure manifesting in the three patients were AMS and respiratory failure followed by renal and liver dysfunction. The combination of AMS and thrombocytopenia was initially interpreted as TTP resulting in the patients' transfer to our institution for plasma exchange. Although TTP has been described in the context of BMN and solid organ malignancy [17–19], one must speculate that the mental status changes, anemia, thrombocytopenia, and increased LDH, and alkaline phosphatase were consequences of BMN alone, because none of the reported patients with TTP and BMN were evaluated for ADAMTS-13 activity [20, 21]. Two of our patients had normal ADAMTS-13.

Treatment of patients with BMN and multiorgan failure is mainly supportive. Some reports suggest clinical improvement with both simple transfusion and automated red cell exchange [10, 16]. Red cell exchange is an effective therapy for both acute and chronic complications of SCD (both homozygous and compound heterozygous forms). The American Society for Apheresis advises that red cell exchange be used as first-line or adjunctive second-line therapy for cerebrovascular accidents and acute chest crisis, respectively [22]. However, the role for red cell exchange in multiorgan failure has not been established, and treatment should be decided on a case-by-case basis [22]. Patient 3, who was treated early with red cell exchange, demonstrated a more complete and quicker recovery when compared with the two other patients who were provided with supportive care only or red cell exchange later in the presentation (Patient 1). Of note, a patient with HgbSC disease and BMN (confirmed by biopsy) was admitted to our institution for pain crisis, pancytopenia, and AMS soon after patient 2. She received four units of packed red cells on admission and with supportive care she experienced complete recovery. Although her clinical outcome was presumed to have resulted from early intervention, we cannot prove it.

One of the most perplexing mysteries about the three patients described in this report is the unknown precipitating event(s) resulting in BMN and the subsequent clinical consequences. Bacterial and viral studies, including Parvovirus B19, which has been associated with BMN [7, 12], were all negative (Table I). We suspect that an “environmental” exposure may be responsible for these cases due to the fact that all three patients were transferred to our institution in a period of 7 months and that they hailed from the same general geographic location.

Our experience shows that BMN and multiorgan failure can occur as the first manifestation of HgbSβ+ disease in previously undiagnosed and otherwise healthy adults with nonspecific complaints such as severe low back pain and AMS accompanied by anemia, thrombocytopenia, and increased LDH. Although intravascular hemolysis and microthromboses can also cause anemia and thrombocytopenia, in the setting of multiorgan failure, BMN should be considered. Because of the extensive degree of BMN in patients 1 and 2 (and presumably patient 3), it is likely that fat embolism syndrome accounted for the development of catastrophic multiorgan failure. Interestingly, fat embolism syndrome is more commonly reported in patients with HgbSC and HgbSβ+ than in patients who are homozygous for HgbSS [16]. We suggest that establishing the correct diagnosis early in the clinical course may improve prognosis if rapid intervention with red cell exchange or simple transfusion is instituted.

References

  1. Top of page
  2. Commentary
  3. References