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A patient with hypereosinophilic syndrome that manifested with acquired hemophilia and elevated IgG4: a case report
© Nagao et al; licensee BioMed Central Ltd. 2012
Received: 12 August 2011
Accepted: 14 February 2012
Published: 14 February 2012
Hypereosinophilic syndrome is defined as a prolonged state (more than six months) of eosinophilia (greater than 1500 cells/μL), without an apparent etiology and with end-organ damage. Hypereosinophilic syndrome can cause coagulation abnormalities. Among hypereosinophilic syndrome types, the lymphocytic variant (lymphocytic hypereosinophilic syndrome) is derived from a monoclonal proliferation of T lymphocytes. Here, we describe the case of a patient with lymphocytic hypereosinophilic syndrome who presented with a coagulation abnormality. To the best of our knowledge, this is the first such report including a detailed clinical picture and temporal cytokine profile.
A 77-year-old Japanese man presented to our facility with massive hematuria and hypereosinophilia (greater than 2600 cells/μl). His eosinophilia first appeared five years earlier when he developed femoral artery occlusion. He manifested with multiple hematomas and prolonged activated partial thromboplastin time. His IgG4 level was remarkably elevated (greater than 2000 mg/dL). Polymerase chain reaction tests of peripheral blood and bone marrow identified lymphocytic hypereosinophilic syndrome. His prolonged activated partial thromboplastin time was found to be due to acquired hemophilia. Glucocorticoids suppressed both the hypereosinophilia and coagulation abnormality. However, tapering of glucocorticoids led to a relapse of the coagulation abnormality alone, without eosinophilia. Tumor necrosis factor α, interleukin-5, and/or eotaxin-3 may have caused the hypereosinophilia, and interleukin-10 was correlated with the coagulation abnormality.
To the best of our knowledge, this is the first case in which lymphocytic hypereosinophilic syndrome and IgG4-related disease have overlapped. In addition, our patient is only the second case of hypereosinophilic disease that manifested with acquired hemophilia. Our patient relapsed with the coagulation abnormality alone, without eosinophilia. This report shows that the link between eosinophilia, IgG4, and clinical manifestations is not simple and provides useful insight into the immunopathology of hypereosinophilic syndrome and IgG4-related disease.
Hypereosinophilic syndrome (HES) was originally proposed as a state of (i) blood eosinophilia with an absolute eosinophil count greater than 1500 cells/μL and persisting for more than six months, (ii) without an apparent etiology (for example, parasitic infection or allergic disease), and (iii) with eosinophil-mediated organ dysfunction . Currently, HES is classified based on etiology . For example, the lymphocytic variant (L-HES) is derived from a monoclonal proliferation of T lymphocytes. T cell clones identified in L-HES often express aberrant immunophenotypes (for example, CD3-CD4+, CD3+CD4-CD8-, CD4+CD7-, CD16+CD56+) [3–6], although no aberrancy has been identified in many patients with L-HES . In contrast, the myeloproliferative variant (M-HES) is characterized by emergence of fusion genes (for example, PDGFRa, PDGFRb, and FGFR1) originating from a chromosomal translocation in 4q12, 5q33, and 8p11, respectively . HES affects not only diverse organs, but also causes thrombotic occlusion in arteries [9, 10], veins [11–14], and capillaries . In addition, patients with HES present with coagulation abnormalities, especially disseminated intravascular coagulation (DIC), possibly due to this thrombotic tendency [9, 14, 16–18]. However, the mechanism of HES-derived coagulation abnormality is not fully understood.
Monoclonalities detected by polymerase chain reaction (PCR) in the T-cell receptor genes
Region to which PCR was applied
Vγ If, Vγ10/Jγ
Vγ 9, Vγ11/Jγ
After warfarin was stopped from day one, his PT-INR steadily normalized (Figure 1d). However, APTT continued to be prolonged (Figure 1c). Although our patient tested positive for anti-hepatitis B core (HBc) and anti-hepatitis C virus (HCV) antibodies, hepatitis B surface (HBs) antigen, hepatitis B virus (HBV) DNA and HCV RNA were all undetectable. Transaminases were consistently within the normal range. Ultrasonography, CT, and MRI scans did not detect any abnormality in the liver. Hence, the liver was not the source of the prolonged APTT. Other causes of a coagulation abnormality (such as protein C and/or S deficiencies, systemic lupus erythematosus, and anti-phospholipid antibody syndrome) were excluded (data not shown). Although the possibility of DIC was suggested (fibrin degradation products (FDP) 18 μg/mL, D-dimer 7.4 μg/mL, anti-thrombin III 66%, platelet count 117,000 cells/μL), ultrasonography detected no thrombus in the heart or veins/arteries of the lower limbs. Taken together, the findings suggested the prolonged APTT in our patient most likely originated from his HES.
On day 28, our patient developed a subcutaneous hematoma in his hip, which spread rapidly to the thighs, and he was admitted to our hospital. His APTT was further prolonged (83 seconds; Figure 1c). Hematomas appeared on his trunk and upper limbs. His oral mucosa and a scar in his ear began to bleed. Although a large amount of fresh frozen plasma and red blood cells were infused between days 31 and 34, his APTT reached a high of 93 seconds on day 36, and the hemoglobin level decreased to 7.9 g/dL (Figure 1c,f). On day 36, prednisolone was started at 60 mg/day (Figure 1b). His peripheral eosinophils decreased quickly (Figure 1a). The APTT and platelet count gradually normalized (Figure 1c,e), while bleeding, subcutaneous hematomas, hematuria, and anemia subsided steadily (Figure 1f). Renal damage improved (β2-macroglobulin decreased to 3.4 mg/L). A CT scan revealed that the lymph nodes around the abdominal aorta had shrunk to a normal size (data not shown). His γ-globulinemia normalized (Figure 1g). He was discharged on day 55. Prednisolone was continuously tapered in the out-patient setting (Figure 1b).
On day 122, when the dose of prednisolone was down to 3 mg/day, a subcutaneous hematoma developed in his thigh. Although his eosinophil count was normal at 64 cells/μL (0.4% of the total white blood cells), his APTT was again prolonged (76 seconds, Figure 1c). He was admitted to our hospital again, where prednisolone was raised to 40 mg/day (Figure 1b). Since his APTT then normalized and hematoma diminished steadily, he was discharged on day 141. To date, he has been kept on prednisolone at 10 mg/day, with no further relapses of coagulopathy or peripheral hypereosinophilia.
We report a case of a patient with L-HES who manifested with a coagulation abnormality. Glucocorticoids effectively suppressed hypereosinophilia and corrected the coagulation abnormality. However, excessive subsequent tapering of the glucocorticoid brought about a relapse of the coagulation abnormality, but not the eosinophilia.
It has been reported that HES can manifest with thrombotic tendency. Our patient had developed femoral artery occlusion, a frequent manifestation of HES-induced thrombosis, five years prior to the episode reported here. The thrombotic tendency had been controlled effectively by warfarin. In the episode reported here, factor VIII activity was remarkably decreased, which was most likely due to acquired hemophilia. Hypereosinophilia complicated with acquired hemophilia has been reported only once previously in the literature . In our patient, DIC, a frequent complication of HES [9, 14, 16–18], possibly exacerbated the bleeding tendency. These findings remain to be generalized to other cases of HES-derived coagulopathy.
Our patient's case, featuring an extremely high value of IgG4, is likely to be an example of IgG4RD. IgG4RD, first reported in 1993 , is characterized by elevated serum IgG4 and/or tissue infiltration by IgG4+ plasma cells [25, 26]. IgG4RD has been recognized as a systemic illness which affects numerous organs including lymph nodes , pancreas , salivary gland [24, 26], retroperitoneum , and kidney . Its pathogenesis, however, remains to be elucidated . IgG4RD has been often associated with eosinophilia [29–31], and responds well to glucocorticoid . These characteristics are consistent with our patient, supporting the diagnosis of IgG4RD in this case. To the best of our knowledge, the presented case is the first reported example in which L-HES and IgG4RD have overlapped.
The cytokines measured in our patient's sera can be classified into three groups in relation to the illness (Figure 4). First, tumor necrosis factor α (TNFα), interleukin (IL)-5, and eotaxin-3 increased to very high levels immediately before the first episode, and decreased to low levels after the glucocorticoid was started on day 36. Therefore, these cytokines were correlated with eosinophilia. Second, IL-10 was present at very high levels until glucocorticoid was started on day 36, and peaked again at the onset of relapse. Hence, IL-10 exhibited a strong correlation with prolonged APTT and anticoagulant to factor VIII. Third, other cytokines in Figure 3 rose to high levels immediately after day 36. These peaks may possibly be reactions to substances released from dying eosinophils [9, 18]. Among the cytokines in this group, granulocyte colony stimulating factor (G-CSF) and eotaxin-1 showed second elevations in the relapse phase, suggesting heterogeneity within this group. The roles of these cytokines in the pathogenesis are difficult to explain. Collectively, TNFα, IL-5, and eotaxin-3 appeared to play an important role in generating peripheral hypereosinophilia, while IL-10 was most closely correlated with prolonged APTT and anticoagulant. Indeed, eosinophilic diseases have been associated with TNFα [32, 33], IL-5 , IL-10 , and eotaxin-3 [36, 37], while IL-10 was overexpressed in IgG4RD [38, 39]. The causal relationship between these cytokines, eosinophilia, IgG4, and clinical manifestations remains to be elucidated.
To the best of our knowledge, this is the first case of L-HES overlapped with IgG4RD, and the second reported case of hypereosinophilic disease complicated by acquired hemophilia. Furthermore, this is the first case of L-HES or IgG4RD in which the cytokine profile was described during the phases of onset and relapse. Although the clinical manifestation (that is, coagulopathy) presented twice (in the first episode and in the relapse), the underlying immunological profiles were dissimilar between these two periods. These findings imply that the interaction between HES and IgG4RD is a complex process.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
We are grateful to Yasushi Teranishi, Kazuyuki Yoshizaki, Ayalew Tefferi, and Masayuki Miyata for their cooperation and advice. We are happy to provide the sera from our patient to those who may wish to validate our results. All the laboratory data, from which the identification information was deleted, are available from the corresponding author upon request.
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