Hemophagocytic lymphohistiocytosis: review of etiologies and management

George, Melissa R

Coagulopathy is a prominent feature of HLH, as low fibrinogen is found in the majority of patients. Further coagulation studies have demonstrated normal factor V and VIII levels and an absence of fibrin split products. These findings provide evidence against disseminated intravascular coagulation, a diagnosis that may overlap with HLH due to the shared findings of thrombocytopenia and hypofibrinogenemia. 21 It is believed that macrophages may secrete plasminogen activators which accelerate the conversion of plasminogen to plasmin, subsequently degrading fibrinogen. Fibrin split products may be phagocytized by macrophages in the reticuloendothelial system. Given the normal coagulation factors measured in HLH, liver failure, while often present, is not related to the coagulopathy. The hepatomegaly, elevated transaminases, and bilirubin are believed to be the direct result of organ infiltration by lymphocytes and histiocytes. 18 Ironically, despite the fact that hemophagocytosis is prominently featured in the name of this disease, it is rarely found at presentation in secondary cases and may not be visible until late in disease progression. Bone marrow biopsies performed early in the course of secondary disease may be normal or demonstrate very nonspecific findings such as increased or decreased unilineage or multilineage hematopoiesis. Repeat studies may be necessary to show these findings. FHL, on the other hand, may demonstrate prominent hemophagocytosis from the start. An immunohistochemical stain for CD163 may be useful, as upregulation of this receptor facilitates hemophagocytosis. 22 In cases in which cerebrospinal fluid is obtained, pleocytosis is sometimes noted with lymphocytes, histiocytes, and an increased protein level. Microscopic review of spun cerebrospinal fluid may demonstrate hemophagocytosis. 6 While many of the laboratory tests are readily available, evaluation of IL-2 receptor and NK-cell activity may require sending specimens out to specialized reference laboratories and may not be a timely option for clinical diagnosis. When available, comparison of IFN-γ, IL-10, and IL-6 may be useful for distinguishing between bacterial sepsis, viral infections, and HLH. Using the criteria IFN-γ .75 pg/mL, and IL-10 60 pg/mL, sensitivity and specificity of diagnosing HLH is 98.9% and 93.0%, respectively. 23 Additionally, measuring plasma levels of CD163, a receptor for hemoglobin-haptoglobin complexes, may also be helpful in distinguishing HLH from other purely infectious diseases. 24 Flow cytometry may be used to identify and quantify levels of several useful markers involved in the