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The following websites contain valuable information regarding the research and treatment of Waldenstrom's Macroglobulinemia:

Please visit our main program website: Bing Center for Waldenstrom's Research. This site contains information on the latest treatment recommendations, abstracts, news and events, current and pending clinical trials and participating institutions, basic research, and publications, as well as photos and brief bios of the Bing Center staff.

Also feel free to visit our WM Workshop Website where you will find information about our most recent conference in August, 2014 in London, UK.



Hyperviscosity syndrome

Blood hyperviscosity is effected by increased serum IgM levels leading to hyperviscosity related complications41 The mechanisms behind the marked increase in the resistance to blood flow and the resulting impaired transit through the microcirculatory system are rather complex.41–43 The main determinants are: (1) a high concentration of monoclonal IgMs, which may form aggregates and may bind water through their carbohydrate component; and (2) their interaction with blood cells. Monoclonal IgMs increase red cell aggregation (rouleaux formation) and red cell internal viscosity while also reducing deformability. The possible presence of cryoglobulins can contribute to increasing blood viscosity as well as to the tendency to induce erythrocyte aggregation. Serum viscosity is proportional to IgM concentration up to 30 g/L, then increases sharply at higher levels. Plasma viscosity and hematocrit are directly regulated by the body. Increased plasma viscosity may also contribute to inappropriately low erythropoietin production, which is the major reason for anemia in these patients.44 Clinical manifestations are related to circulatory disturbances that can be best appreciated by ophthalmoscopy, which shows distended and tortuous retinal veins, hemorrhages and papilledema45 (Figure 2). Symptoms usually occur when the monoclonal IgM concentration exceeds 50 g/L or when serum viscosity is >4.0 centipoises (cp), but there is a great individual variability, with some patients showing no evidence of hyperviscosity even at 10 cp.41 The most common symptoms are oronasal bleeding, visual disturbances due to retinal bleeding, and dizziness that may rarely lead to coma. Heart failure can be aggravated, particularly in the elderly, owing to increased blood viscosity, expanded plasma volume, and anemia. Inappropriate transfusion can exacerbate hyperviscosity and may precipitate cardiac failure.


In up to 20% of WM patients, the monoclonal IgM can behave as a cryoglobulin (type I), but it is symptomatic in 5% or less of the cases.46 Cryoprecipitation is mainly dependent on the concentration of monoclonal IgM; for this reason plasmapheresis or plasma exchange are commonly effective in this condition. Symptoms result from impaired blood flow in small vessels and include Raynaud’s phenomenon, acrocyanosis, and necrosis of the regions most exposed to cold such as the tip of the nose, ears, fingers, and toes (Figure 3), malleolar ulcers, purpura, and cold urticaria. Renal manifestations may occur but are infrequent.

Auto-Antibody Activity

Monoclonal IgM may exert its pathogenic effects through specific recognition of autologous antigens, the most notable being nerve constituents, immunoglobulin determinants, and red blood cell antigens:

IgM related neuropathy

In a series of 215 patients with WM, Merlini et al.46 reported the clinical presence of peripheral neuropathy in 24% of WM patients, although prevalence rates ranging from 5% to 38% have been reported in other series.47,48 An estimated 6.5–10% of idiopathic neuropathies are associated with a monoclonal gammopathy, with a preponderance of IgM (60%) followed by IgG (30%) and IgA (10%) (reviewed in Nemni et al49 and Ropper and Gorson50). In WM patients, the nerve damage is mediated by diverse pathogenetic mechanisms: IgM antibody activity toward nerve constituents causing demyelinating polyneuropathies; endoneurial granulofibrillar deposits of IgM without antibody activity, associated with axonal polyneuropathy; occasionally by tubular deposits in the endoneurium associated with IgM cryoglobulin and, rarely, by amyloid deposits or by neoplastic cell infiltration of nerve structures.51 Half of the patients with IgM neuropathy have a distinctive clinical syndrome that is associated with antibodies against a minor 100-kDa glycoprotein component of nerve, myelin-associated glycoprotein (MAG). Anti-MAG antibodies are generally monoclonal IgMk, and usually also exhibit reactivity with other glycoproteins or glycolipids that share antigenic determinants with MAG.52–54 The anti-MAG-related neuropathy is typically distal and symmetrical, affecting both motor and sensory functions; it is slowly progressive with a long period of stability.48,55 Most patients present with sensory complaints (paresthesias, aching discomfort, dysesthesias, or lancinating pains), imbalance and gait ataxia, owing to lack proprioception, and leg muscles atrophy in advanced stage. Patients with predominantly demyelinating sensory neuropathy in association with monoclonal IgM to gangliosides with disialosyl moieties, such as GD1b, GD3, GD2, GT1b, and GQ1b, have also been reported.56,57 Anti- GD1b and anti-GQ1b antibodies were significantly associated with predominantly sensory ataxic neuropathy.61 These antiganglioside monoclonal IgMs present core clinical features of chronic ataxic neuropathy with variably present ophthalmoplegia and/or red blood cell cold agglutinating activity. The disialosyl epitope is also present on red blood cell glycophorins, thereby accounting for the red cell cold agglutinin activity of anti-Pr2 specificity.58,59 Monoclonal IgM proteins that bind to gangliosides with a terminal trisaccharide moiety, including GM2 and GalNac-GD1A, are associated with chronic demyelinating neuropathy and severe sensory ataxia, unresponsive to corticosteroids.60 Antiganglioside IgM proteins may also cross-react with lipopolysaccharides of Campylobacter jejuni, whose infection is known to precipitate the Miller Fisher syndrome, a variant of the Guillain–Barré syndrome.61 This finding indicates that molecular mimicry may play a role in this condition. Antisulfatide monoclonal IgM proteins, associated with sensory/sensorimotor neuropathy, have been detected in 5% of patients with IgM monoclonal gammopathy and neuropathy.62 Motor neuron disease has been reported in patients with WM, and monoclonal IgM with anti-GM1 and sulfoglucuronyl paragloboside activity.63 POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome is rarely associated with WM.64

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