Uncontrolled and Recurrent Epistaxis in an Adult: The Globulin Gap Clue

INTRODUCTION

Waldenström macroglobulinemia (WM) is a rare B-cell lymphoproliferative disease that is typified by monoclonal immunoglobulin M (IgM) paraprotein synthesis. One of its most significant clinical consequences is hyperviscosity syndrome, which frequently manifests as neurological complaints, visual problems, and mucosal bleeding. The diagnosis may be delayed because of the non-specificity of these symptoms, especially if regular coagulation tests are normal. A basic liver function test may reveal an elevated globulin gap, which is a crucial indicator of an underlying monoclonal gammopathy. If not diagnosed timely, this can result in severe neurological damage and permanent vision loss also. We describe a patient with uncontrolled epistaxis in whom recognition of a marked globulin gap led to the diagnosis of WM with hyperviscosity syndrome and timely initiation of appropriate therapy.

CASE REPORT

A 49-year-old man presented with a 6-month history of intermittent epistaxis and gingival bleeding, which had worsened over the preceding month. He also reported vertigo and early satiety for 1 week, along with unintentional weight loss. On examination, he had marked pallor, hepatomegaly (4 cm below the right costal margin), and splenomegaly (8 cm below the left costal margin), without peripheral lymphadenopathy. Baseline complete blood counts showed hemoglobin of 67 g/L, a total leukocyte count of 3.43 × 10⁹/L with neutrophilic predominance, and a platelet count of 190 × 10⁹/L. Coagulation parameters were within normal limits (prothrombin time 16 s, activated partial thromboplastin time 38 s, fibrinogen 2.07 g/L). Serum urea was 8.8 mmol/L, and serum creatinine was 106 µmol/L. For severe anemia, he was transfused one unit of packed red blood cells. Following the transfusion, bleeding worsened and became persistent. There was no response to tranexamic acid, fresh frozen plasma, or platelet transfusions. Biochemical evaluation showed marked hyperproteinemia with total protein of 115 g/L and albumin of 35 g/L, suggesting a significant globulin gap. These findings raised a strong suspicion of hyperviscosity syndrome due to an underlying paraproteinemia. His fundus examination revealed superficial retinal hemorrhages in the peripheral retina in both eyes [Figure 1a]. The patient underwent urgent therapeutic plasmapheresis of 1 session, leading to rapid cessation of epistaxis and gingival bleeding, with partial improvement in vertigo. Ears, nose, throat evaluation including magnetic resonance imaging of the brain was done for vertigo, but no abnormalities were detected; thus, it was attributed to hyperviscosity.

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Figure 1: (a) Fundus examination shows superficial retinal hemorrhages in the peripheral retina. (b) Serum protein electrophoresis shows M spike, (c) Serum immunofixation shows immunoglobulin M kappa positivity in the polyclonal background.

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Further investigations demonstrated an IgM Kappa monoclonal gammopathy (IgM 32 g/L, M-spike 33.6 g/L, Immunofixation - IgM Kappa) [Figure 1b and c]. Serum β₂-microglobulin was 5.23 mg/L, and lactate dehydrogenase was 147 U/L. Bone marrow examination did not show infiltration of abnormal lymphoid cells but clonal plasma cells were identified. The negative bone marrow was likely due to focal involvement. Whole body positron emission tomography scan was done which did not show any skeletal lesions. A diagnosis of Waldenstrom Macroglobulinemia was established. MYD88 mutation testing was advised, but not done due to financial issues. Treatment was initiated due to symptomatic hyperviscosity and severe anemia. As he had already received 1 session of therapeutic plasmapheresis, we started him on rituximab and bendamustine.

DISCUSSION

The worsening of the bleeding after receiving a red blood cell transfusion was a significant aspect of this case. Transfusion can exacerbate microcirculatory flow and platelet–vessel wall interactions in IgM paraproteinemia by increasing plasma viscosity.^[1] It is crucial to distinguish WM from IgM multiple myeloma because, although both conditions exhibit IgM monoclonal gammopathy, their biology and treatment approaches are different. The characteristics of IgM myeloma include lytic bone disease, plasma cell-predominant marrow infiltration, and myeloma-defining cytogenetic abnormalities. In contrast, WM exhibits lymphoplasmacytic infiltration, no lytic lesions, and a high frequency of MYD88 L265P mutation.^[2] Even though WM is categorized as lymphoplasmacytic lymphoma, only about 15% of patients have clinically significant lymphadenopathy.^[3] Most patients present with bone marrow involvement, hepatosplenomegaly, and systemic manifestations of IgM excess. When starting rituximab in the context of hyperviscosity syndrome, there is a chance of an IgM flare, which could temporarily exacerbate symptoms. Therefore, plasmapheresis should be performed before rituximab, or treatment may be initiated with bendamustine alone for 1–2 cycles, with rituximab added subsequently once IgM levels have declined.^[4]

CONCLUSION

Early suspicion of hyperviscosity syndrome should be raised in cases of unexplained epistaxis, vertigo, or visual abnormalities (retinal hemorrhages), especially when regular coagulation tests are normal. An important and sometimes missed diagnostic hint for underlying paraproteinemia in these situations is a straightforward liver function test that shows high total protein with a preserved albumin level (globulin gap).