Bone marrow necrosis and fat embolism syndrome in sickle cell disease: Increased susceptibility of patients with non-SS genotypes and a possible association with human parvovirus B19 infection

Abstract

Fat embolism syndrome (FES) due to extensive bone marrow necrosis (BMN) in sickle cell disease (SCD) is a potentially under-diagnosed complication associated with severe morbidity and mortality. We identified 58 cases reported in the world literature to date. Typically, patients presented with a seemingly uncomplicated vaso-occlusive crisis (VOC) and subsequently deteriorated rapidly with a drop in their haemoglobin and platelets, development of respiratory failure, encephalopathy and varying degrees of involvement of other systems. Overall mortality in the reported cases was 64% but differed according to the use of transfusion and was 29%, 61% and 91% for patients receiving exchange, top-up or no transfusion respectively. Patients most at risk appear to be those with a “milder” form of SCD as 81% of patients had a genotype other than HbSS and the majority had no history of significant sickle-related complications. Human parvovirus B19 (HPV B19) infection was documented in 24% of cases.

Introduction

Fat embolism syndrome (FES) results from the release of fat globules into the venous circulation and is associated with distinct clinical features comprising respiratory, neurological, cutaneous and haematological manifestations [1]. It is a complication mostly described in the context of long bone fractures or orthopaedic surgery; non-traumatic FES is very rare and is attributed to bone marrow necrosis (BMN) [2].

BMN refers to necrosis of myeloid tissue and medullary stroma in large areas of the haemopoietic bone marrow. Extensive BMN is associated with the development of pancytopenia with a leucoerythroblastic peripheral blood smear; characteristically, a striking number of circulating nucleated red blood cells (NRBCs) have been described. The bone marrow trephine shows disruption of normal marrow architecture with loss of fat spaces but generally preservation of the spicular architecture [3]. Up to 90% of cases of BMN occur in the context of cancer, most often haematological malignancy. Much rarer causes of BMN include autoimmune conditions, infections and sickle cell disease (SCD) [4]. Failure of the marrow microcirculation has been thought to be the common underlying feature [5].

FES due to extensive BMN was first described in 1941 in a woman with previously undiagnosed SCD who presented with pain, deteriorated rapidly and died [6]. Several case reports and small case series involving patients with SCD have been published since. The largest review to date from 2005, identified 24 cases in the literature. One third of those patients had HbSS and the remainder were associated with other genotypes, mostly HbSC. In one third of cases the diagnosis of SCD was not made until autopsy. A quarter presented comatose, all of whom had HbSC or HbSβ-thalassaemia. Nearly half of the female patients were pregnant [7].

In light of the limited published literature on this rare but often fatal syndrome, we undertook the present review to make as complete as possible a list of all reported cases to date, to describe clinical presentations and outcomes, to explore potential links with specific characteristics of SCD and to identify potential triggering factors.