European Journal of Internal Medicine
Volume 20, Issue 5 , Pages 457-461, September 2009

Systemic manifestations of monoclonal gammopathy

  • Olivier Decaux

      Affiliations

    • Service de Médecine Interne, Hôpital Sud, CHU, 16 boulevard de Bulgarie, 35 203 Rennes, France
    • Université de Rennes 1, 1 avenue du Pr Léon Bernard, 35000 Rennes, France
    • ,
  • Elisabeth Laurat

      Affiliations

    • Service de Médecine Interne, Hôpital Sud, CHU, 16 boulevard de Bulgarie, 35 203 Rennes, France
    • ,
  • Antoinette Perlat

      Affiliations

    • Service de Médecine Interne, Hôpital Sud, CHU, 16 boulevard de Bulgarie, 35 203 Rennes, France
    • ,
  • Claire Cazalets

      Affiliations

    • Service de Médecine Interne, Hôpital Sud, CHU, 16 boulevard de Bulgarie, 35 203 Rennes, France
    • ,
  • Patrick Jego

      Affiliations

    • Service de Médecine Interne, Hôpital Sud, CHU, 16 boulevard de Bulgarie, 35 203 Rennes, France
    • Université de Rennes 1, 1 avenue du Pr Léon Bernard, 35000 Rennes, France
    • ,
  • Bernard Grosbois

      Affiliations

    • Service de Médecine Interne, Hôpital Sud, CHU, 16 boulevard de Bulgarie, 35 203 Rennes, France
    • Université de Rennes 1, 1 avenue du Pr Léon Bernard, 35000 Rennes, France
    • Corresponding Author InformationCorresponding author. Service de Médecine Interne, Hôpital Sud, CHU, 16 boulevard de Bulgarie, 35 203 Rennes, France. Tel.: +33 299267128; fax: +33 299267198.

Received 31 October 2008; accepted 4 January 2009. published online 05 February 2009.

Article Outline

Abstract 

Systemic manifestations of monoclonal gammopathies (MG) are rare but extremely varied. This general review focuses on the hyperviscosity syndrome, neurological disorders, skin changes, the POEMS syndrome, and biological manifestations, with the exception of amyloidosis AL and cryoglobulinemia. The hyperviscosity syndrome usually involves a combination of general, hemorrhagic, ocular and central neurological disorders. The principal neurological manifestations are peripheral neuropathies, mainly due to IgM with anti-MAG activity. Skin disorders include overload dermatoses (xanthomatosis, mucinosis), neutrophilic dermatosis, urticaria, edema and the AESOP syndrome. The POEMS syndrome classically consists of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasmocyte proliferation, and cutaneous manifestations. MG interference with assay methods can lead to false hyponatremia, hypoglycemia, hyperbilirubinemia, hypercalcemia and hypertransferrinemia.

These systemic manifestations can reveal classical MG-related disorders such as monoclonal gammopathy of undetermined significance (MGUS), solitary plasmocytoma, multiple myeloma, and Waldenstrom's disease. They are due either to the chemicophysical properties of the monoclonal immunoglobulin, or to its antibody activity (especially against autoantigens), with potential therapeutic implications.

Keywords: Monoclonal gammopathy, Hyperviscosity, Neuropathy, Dermatosis, POEMS syndrome

 

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1. Introduction 

Systemic manifestations of monoclonal gammopathies (MG) can be due to the physicochemical properties of the monoclonal immunoglobulin, to its antibody activity (especially against autoantigens), or to other mechanisms. Systemic manifestations linked to AL amylosis, cryoglobulinemia and tumor invasion are not considered here.

Systemic manifestations of MG are highly varied, and this review focuses on the hyperviscosity syndrome, neurological manifestations, skin changes, the POEMS syndrome, and biological disorders.

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2. Hyperviscosity syndrome 

The presence of a monoclonal immunoglobulin can increase plasma viscosity. Owing to its pentameric structure, IgM is more often involved than IgG and IgA, which are monomeric or dimeric. Plasma viscosity is normally 1.4 to 1.8 centipoise (cP). Although there is no precise cutoff, clinical signs of hyperviscosity usually appear at values above 4 or 5 cP, which correspond schematically to an IgM level of ≥30 g/l, an IgG level of ≥40 g/l and an IgA level of ≥60 g/l [1].

The incidence of symptomatic hyperviscosity in multiple myeloma ranges from 2% to 6% [2]. It is much higher (10 to 30%) in Waldenstrom's disease [3]. In series of patients with a symptomatic hyperviscosity linked to monoclonal immunoglobulin, Waldenstrom's disease accounts for up to 90% of cases [4].

The clinical hyperviscosity syndrome usually combines general symptoms (fatigue), with hemorrhagic disorders (epistaxis, gingivorraghia), ocular disorders (decline in visual acuity, diplopia, fundus abnormalities: distended, tortuous or thrombotic retinal veins, retinal hemorrhage, papillary edema) and neurological disorders (headache, dizziness, ataxia, drowsiness, seizures, coma, stroke) [5], [6]. In rare cases the plasma hypervolemia can provoke heart failure. Anecdotal cases of priapism have also been reported [7]. These clinical manifestations are usually reversed by plasma exchange therapy [8].

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3. Dermatological manifestations 

Skin disorders are the most frequent systemic manifestation of gammopathies, and can also be the presenting sign (Table 1).

Table 1. Classification of dermatologic manifestations of monoclonal gammopathies.
Vascular purpura
Cryoglobulin purpura
Purpura of amyloidosis
Overload dermatoses
Xanthomatosis
Normolipemic plane xanthomatosis
Necrobiotic xantogranulomatosis
Mucinosis
Scleromyxedema
Papular mucinosis
Neutrophilic dermatosis
Sweet's syndrome
Pyoderma gangrenosum
Erythema elevatum diutinium
Urticaria
Schnitzler's syndrome
Edema
Acquired angioneurotic edema
Paroxystic capillary leak syndrome
Skin lesions due to cytokine release by proliferating plasmocytes
AESOP syndrome
POEMS syndrome

3.1. Overload dermatoses 

3.1.1. Xanthomatosis 


⁎Normolipemic plane xanthomas (NPX)

NPX consists of plane xanthomas with normal lipid parameters. Two-thirds of patients have IgG monoclonal gammopathy. The lipid deposits are due to the antilipoprotein antibody activity of the monoclonal immunoglobulin [9].

⁎Necrobiotic xanthogranulomatosis (NXG)

NXG causes raised xanthomatous deposits in the periorbital region. The main histologic features are a combination of granulomatous lesions and fat-loaded macrophages (Touton cells). The link with monoclonal gammopathy is also strong [10].

3.1.2. Mucinosis 

This rare manifestation is linked to IgGλ monoclonal gammopathy in 90% of cases, usually at a low titer [11]:

⁎ Papulous mucinosis is characterized by small, generally localized lichenoid papular lesions.

⁎ Scleromyxedema is associated with generalized cutaneous infiltration. It can be severe, owing to the extent and impact of the cutaneous changes and/or association with visceral disorders.

3.2. Neutrophilic dermatoses 

The strongest association is that between pyoderma gangrenosum and IgA monoclonal gammopathies. Aseptic organ abscesses can also be present [12]. Sweet's syndrome has been linked to MG. Although rare, the association with erythema elevatum diutinum is very strong [13].

3.3. Urticaria 

Schnitzler's syndrome consists of a combination of chronic recurrent urticaria, IgM monoclonal gammopathy and condensing bone lesions (Table 2). It can be accompanied by other manifestations such as relapsing fever, arthralgia and bone pain, hepatosplenomegaly, and adenopathies [14]. More recently, a variant of this syndrome associated with IgG monoclonal gammopathy was described [15].

Table 2. Diagnostic criteria of the Schnitzler's syndrome [14].
Major criteria
Chronic urticaria
IgM monoclonal gammopathy
Minor criteria
Relapsing fever
Arthralgia or arthritis
Bone pain
Adenopathies
Hepatomegaly and/or splenomegaly
Elevated ESR and/or leukocytosis
Bone abnormalities (radiologic or histologic)

The diagnosis is based on a combination of two major criteria and at least two minor criteria.

3.4. Edema 


⁎ Acquired angioneurotic edema (AANE)

AANE consists of recurrent exacerbations of subcutaneous and/or mucosal edema. It can be life-threatening, especially in case of laryngeal edema. Monoclonal gammopathy, through its antibody activity, reduces the activity of the C1 esterase inhibitor [16].

⁎ Paroxystic capillary leak syndrome

The clinical manifestations are severe, combining generalized edema and cardiovascular collapse. Biologically, the diagnosis is raised by signs of hemoconcentration (elevated hemoglobin and hematocrit), contrasting with a marked lowering of the protinemia and especially the albuminemia. Monoclonal gammopathy (usually IgG Kappa) is found in over 90% of cases [17].

3.5. AESOP syndrome 

This syndrome combines regional adenopathies with violaceous cutaneous patches overlying a skeletal or extraskeletal plasmocytoma. The skin lesions are due to cytokine release by the plasmocyte tumor, and can be the first manifestation of the POEMS syndrome [18].

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4. Neurological manifestations 

The neurological manifestations of monoclonal gammopathies consist mainly of peripheral neuropathies. In series of patients with MGUS, the prevalence of symptomatic neuropathy is 8% to 36% [19]. IgM monoclonal gammopathy is more frequent (60%) than IgG or IgA MG (10%). Conversely, the monoclonal gammopathy is mainly of the IgM type in 10% of cases of apparently isolated peripheral neuropathies.

4.1. Neuropathies and IgM monoclonal gammopathy 

Symptomatic neuropathy is reported in up to 50% of patients with IgM monoclonal gammopathies. MGUS is far more frequent than Waldenstrom's disease in this setting. The manifestations usually consist of symmetrical and predominantly distal peripheral neuropathies. In at least two-thirds of cases the neuropathy is linked to IgM antibody activity against neuronal antigens (usually MAG, but also sulfatides or gangliosides).

⁎ Neuropathies associated with anti-MAG activity.

Anti-MAG activity is found in nearly 50% of neuropathies associated with IgM MG [20]. Nearly 80% of cases involve MGUS. The neuropathy is distal, symmetrical and mainly sensory, with altered deep sensitivity and upper limb tremor. Progression is gradual. Electrophysiological studies show a demyelinating neuropathy. Nerve biopsy shows segmental demyelinisation with abnormally spaced myelin sheets and monoclonal IgM and complement deposition on myelin [21].

⁎ Neuropathies associated with antisulfatide activity.

The antisulfatide activity of IgM is associated with axonal neuropathies (mainly sensory) and sensory-motor demyelinising neuropathies.

⁎ Neuropathies associated with antiganglioside activity (CANOMAD syndrome).

IgM MG can have antibody activity against disialylated gangliosides (GQ1B, GD1B, GT1B, GD3 and GD2). In these cases the neuropathy is sensory with predominant ataxia, mild or absent motor involvement, recurrent ophthalmoplegia and cold agglutinin activity of the monoclonal immunoglobulin directed against antigen Pr2 of the erythrocyte membrane. The acronym CANOMAD (Chronic Ataxic Neuropathy with Ophthalmoplegia, M protein, Cold Agglutinins and anti-Disyalosil antibodies) has been proposed for this syndrome [22].

⁎ Neuropathies without antibody activity

These represent about one-third of the neuropathies associated with IgM MG. In this setting the IgM MG is linked to Waldenstrom's disease or malignant lymphoma in two-thirds of cases. Other mechanisms can be involved, such as vasculitis of the vaso nervorum, and cryoglobulin, hyperviscosity, amyloidosis, or lymphoplasmocytic nerve infiltration. The clinical manifestations tend to consist of mononeuritis or multineuritis rather than polyneuropathy.

4.2. Neuropathies and IgG monoclonal gammopathies 

The relationship between neuropathies and IgG MG is far less evident than that with IgM MG. Antibody activity against nerve glycoproteins has very rarely been demonstrated; in practice, it is not therefore necessary to search for such activity in a patient with IgG MG-related neuropathy.

Most patients with neuropathy and IgG MG have IgG MGUS. The prevalence of symptomatic neuropathy is about 3% [23]. Half the patients have signs of chronic demyelinising neuropathy very similar to those of chronic inflammatory polyneuritis [19]. It is crucial to look for an apparently solitary bone plasmocytoma, because of the therapeutic implications. Some cases are linked to multiple myeloma. The most typical aspect is that of a neuropathy secondary to osteocondensing myeloma; in this rare form of myeloma the neuropathy is present in up to 50% of cases and is often the initial manifestation [24]. These patients have a rapidly progressive initially sensory neuropathy, with axonal involvement leading to a severe disabling motor deficit. The possibility of the POEMS syndrome should be borne in mind (see below).

4.3. Neuropathies and IgA monoclonal gammopathies 

This is a rare situation, and the link has not been formally established.

Independently of the type of MG, MGUS associated with a peripheral neuropathy appears to carry a higher risk of malignant transformation than in the general MGUS population. Indeed, in a series of 176 patients, the annual rate of malignant transformation was 2.7%, compared to 1% in the general population [25].

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5. POEMS syndrome 

Initially called the Crow-Fukase syndrome, the POEMS syndrome classically combines polyneuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal plasmocyte proliferation (M) and skin changes. Three large series [26], [27], [28] have described the main features of the POEMS syndrome (Table 3).

Table 3. Diagnostic criteria of the POEMS syndrome [30].
Obligatory criteria
Polyneuropathy
Monoclonal plasmocyte proliferation
Major criteria
Condensing bone lesions
Castleman's disease
Elevated VEGF
Minor criteria
Organomegaly
Edema
Endocrine manifestations
Cutaneous manifestations
Papillary edema
Thrombocytosis/polyglobulia

The diagnosis is based on a combination of polyneuropathy and monoclonal plasmocyte proliferation, plus at least one major criterion and one minor criterion.

Onset generally occurs in the 5th or 6th decade of life. Polyneuropathy is the main clinical manifestation and is frequently the presenting symptom. It is initially sensory and peripheral, subsequently affecting the motor nerves. It is mainly distal, bilateral and symmetrical, and frequently leads to a major loss of autonomy. The electromyogram shows an aspect compatible with demyelinising neuropathy, with evidence of axonal involvement. On nerve biopsy the most characteristic finding is non compacted myelin sheets [29]. The cranial nerve pairs are spared, except for papillary edema. Cutaneous manifestations include hyperpigmentation, hypertrichosis, profuse angioma, acrocyanosis, skin thickening, flushes, white nails and clubbing. Hepatomegaly is present in nearly half the patients, while splenomegaly and peripheral adenopathies are rarer. Node biopsy can show angiofollicular hyperplasia compatible with Castleman's disease. Between 11% and 30% of patients have Castleman or Castleman-like disease [30], [31]. Edema of the lower limbs is frequent, and is sometimes associated with serous effusion (pleurisy, ascites). Arterial and/or venous thromboembolism is possible and sometimes severe (stroke, myocardial infarction, Budd-Chiari syndrome) [32].

The monoclonal component is generally moderate (<30 g/l in most cases). It is usually IgA or IgG (almost always λ). The medullary plasmocytosis is generally low (<5%). Bone radiography shows condensation in 95% of cases. Blood analysis frequently shows an elevated platelet count and, more rarely, polyglobulia. The VEGF level is often high. The serum concentration is far higher than the plasma concentration [31]. Endocrine abnormalities are frequent, and include hypogonadism leading to impotence and gynecomastia, hypothyroidism, adrenal insufficiency, and altered carbohydrate metabolism. Renal involvement (renal failure, proteinuria) is rare. Pulmonary hypertension is the most frequent pulmonary manifestation, and was found in 25% of 20 patients monitored for 10 years [32].

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6. Biological manifestations 

6.1. Artifacts due to MG interference with some assay methods 

MG can interfere with a wide range of automated nephelemetric, turbidimetric and immunological assays [33], through a variety of mechanisms, including precipitate formation, MG binding to an assay reagent, and incomplete antibody binding. These abnormalities are usually observed with IgM and IgG MG. Pseudohyponatremia is observed when sodium is measured with a technique such as flame photometry or indirect potentiometry; it is corrected when direct potentiometry is used [34]. The possibility of false hyperbilirubinemia [35] and false hyperphosphatemia [36] has also been reported. In a series of 74 patients with IgM MG, a false rise in the CRP was found in 12.2% of cases [37]. In two patients with IgG MG, very high transferrin and transferrin coefficient values have been described in the absence of hyperferritinemia and signs of visceral iron overload. These abnormalities are due to the anti-transferrin antibody activity of the MG [38].

Several strategies can be used to avoid these artifacts, such as eliminating MG from the sample, using another assay method, or diluting the serum.

6.2. Clotting abnormalities 

Monoclonal gammopathies can be associated with a hemorrhagic syndrome. Acquired von Willebrand disease was reported in three patients with MGUS [39], [40], [41], [42]. Acquired hemophilia has been described in association with myeloma [43] and MGUS [44]; the latter patient also had a circulating lupus anticoagulant.

Prothrombotic abnormalities have also been described, above all in myeloma [45] but also in MGUS and Waldenstrom's disease [46]. They consist mainly of an increase in factor VIII and von Willebrand factor. Moreover, acquired resistance to activated protein C has been observed in myeloma patients [47]. These disturbances can partly account for the increased frequency of deep venous thrombosis reported in multiple myeloma, particularly early after diagnosis and at treatment initiation, although other mechanisms often coexist (immobilization, hyperviscosity, adverse effects of chemotherapy, steroids and antiangiogenic drugs) [48]. They could also be involved in MGUS: in a series of 310 patients, 6.1% developed deep venous thrombosis during a mean follow-up of 44 months [49].

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7. Learning points 


•Systemic manifestations can reveal monoclonal gammopathy.

•Dermatological manifestations are numerous and consists of xanthomatosis, mucinosis, neutrophilic dermatosis, urticaria, purpura or edema.

•Neurological manifestations are mostly observed with IgM monoclonal gammopathy and are often related to antibody activity (anti MAG, antisulfatide, antiganglioside).

•The diagnosis of POEMS syndrome is based on a combination of polyneuropathy and monoclonal proliferation with major criteria and minor criteria.

•Monoclonal gammopathy can interfere with several biological assays.

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References 

  1. Somer T. Rheology of paraproteinaemias and the plasma hyperviscosity syndrome. Baillieres Clin Haematol. 1987;1:695–723
  2. Riccardi A, Gobbi PG, Ucci G, Bertoloni D, Luoni R, Rutigliano L, et al. Changing clinical presentation of multiple myeloma. Eur J Cancer. 1991;27:1401–1405
  3. MacKenzie MR, Babcock J. Studies of the hyperviscosity syndrome. II. Macroglobulinemia. J Lab Clin Med. 1975;85:227–234
  4. Tichy M. Viscosity of paraproteinemic sera. Acta Medica (Hradec Kralove). 1996;39:41–43
  5. Kwaan HC, Bongu A. The hyperviscosity syndromes. Semin Thromb Hemost. 1999;25:199–208
  6. Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Semin Thromb Hemost. 2003;29:467–471
  7. Rosenbaum EH, Thompson HE, Glassberg AB. Priapism and multiple myeloma. Successful treatment with plasmapheresis. Urology. 1978;12:201–202
  8. Reinhart WH, Lutolf O, Nydegger UR, Mahler F, Straub PW. Plasmapheresis for hyperviscosity syndrome in macroglobulinemia Waldenstrom and multiple myeloma: influence on blood rheology and the microcirculation. J Lab Clin Med. 1992;119:69–76
  9. Williford PM, White WL, Jorizzo JL, Greer K. The spectrum of normolipemic plane xanthoma. Am J Dermatopathol. 1993;15:572–575
  10. Jeziorska M, Hassan A, Mackness MI, Woolley DE, Tullo AB, Lucas GS, et al. Clinical, biochemical, and immunohistochemical features of necrobiotic xanthogranulomatosis. J Clin Pathol. 2003;56:64–68
  11. Dinneen AM, Dicken CH. Scleromyxedema. J Am Acad Dermatol. 1995;33:37–43
  12. Andre MF, Piette JC, Kemeny JL, Ninet J, Jego P, Delevaux I, et al. Aseptic abscesses: a study of 30 patients with or without inflammatory bowel disease and review of the literature. Medicine (Baltimore). 2007;86:145–161
  13. Bayer-Garner IB, Smoller BR. The spectrum of cutaneous disease in multiple myeloma. J Am Acad Dermatol. 2003;48:497–507
  14. de Koning HD, Bodar EJ, van der Meer JW, Simon A. Schnitzler syndrome: beyond the case reports: review and follow-up of 94 patients with an emphasis on prognosis and treatment. Semin Arthritis Rheum. 2007;37:137–148
  15. Nashan D, Sunderkotter C, Bonsmann G, Luger T, Goerdt S. Chronic urticaria, arthralgia, raised erythrocyte sedimentation rate and IgG paraproteinaemia: a variant of Schnitzler's syndrome?. Br J Dermatol. 1995;133:132–134
  16. Fremeaux-Bacchi V, Guinnepain MT, Cacoub P, Dragon-Durey MA, Mouthon L, Blouin J, et al. Prevalence of monoclonal gammopathy in patients presenting with acquired angioedema type 2. Am J Med. 2002;113:194–199
  17. Amoura Z, Papo T, Ninet J, Hatron PY, Guillaumie J, Piette AM, et al. Systemic capillary leak syndrome: report on 13 patients with special focus on course and treatment. Am J Med. 1997;103:514–519
  18. Lipsker D, Rondeau M, Massard G, Grosshans E. The AESOP (adenopathy and extensive skin patch overlying a plasmacytoma) syndrome: report of 4 cases of a new syndrome revealing POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome at a curable stage. Medicine (Baltimore). 2003;82:51–59
  19. Hadden RD, Nobile-Orazio E, Sommer C, Hahn A, Illa I, Morra E, et al. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of paraproteinaemic demyelinating neuropathies: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2006;13:809–818
  20. Nobile-Orazio E, Latov N, Wokke JH, Kelly JJ. Neuropathies associated with anti-MAG antibodies and IgM monoclonal gammopathies. In: Immunological and infectious diseases of the peripheral nerve, C. UK. Cambridge University Press; 1998;p. 169–189
  21. Lozeron P, Adams D. Monoclonal gammopathy and neuropathy. Curr Opin Neurol. 2007;20:536–541
  22. Willison HJ, O'Leary CP, Veitch J, Blumhardt LD, Busby M, Donaghy M, et al. The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies. Brain. 2001;124:1968–1977
  23. Nobile-Orazio E, Casellato C, Di Troia A. Neuropathies associated with IgG and IgA monoclonal gammopathy. Rev Neurol (Paris). 2002;158:979–987
  24. Kelly JJ. The electrodiagnostic findings in peripheral neuropathy associated with monoclonal gammopathy. Muscle Nerve. 1983;6:504–509
  25. Eurelings M, Lokhorst HM, Kalmijn S, Wokke JH, Notermans NC. Malignant transformation in polyneuropathy associated with monoclonal gammopathy. Neurology. 2005;64:2079–2084
  26. Nakanishi T, Sobue I, Toyokura Y, Nishitani H, Kuroiwa Y, Satoyoshi E, et al. The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology. 1984;34:712–720
  27. Soubrier MJ, Dubost JJ, Sauvezie BJ. POEMS syndrome: a study of 25 cases and a review of the literature. French Study Group on POEMS Syndrome. Am J Med. 1994;97:543–553
  28. Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR, et al. POEMS syndrome: definitions and long-term outcome. Blood. 2003;101:2496–2506
  29. Vital C, Vital A, Ferrer X, Viallard JF, Pellegrin JL, Bouillot S, et al. Crow-Fukase (POEMS) syndrome: a study of peripheral nerve biopsy in five new cases. J Peripher Nerv Syst. 2003;8:136–144
  30. Dispenzieri A. POEMS syndrome. Blood Rev. 2007;21:285–299
  31. Tokashiki T, Hashiguchi T, Arimura K, Eiraku N, Maruyama I, Osame M. Predictive value of serial platelet count and VEGF determination for the management of DIC in the Crow-Fukase (POEMS) syndrome. Intern Med. 2003;42:1240–1243
  32. Lesprit P, Godeau B, Authier FJ, Soubrier M, Zuber M, Larroche C, et al. Pulmonary hypertension in POEMS syndrome: a new feature mediated by cytokines. Am J Respir Crit Care Med. 1998;157:907–911
  33. Bakker AJ, Mucke M. Gammopathy interference in clinical chemistry assays: mechanisms, detection and prevention. Clin Chem Lab Med. 2007;45:1240–1243
  34. Nanji AA, Blank DW. Pseudohyponatremia and hyperviscosity. J Clin Pathol. 1983;36:834–835
  35. Pantanowitz L, Horowitz GL, Upalakalin JN, Beckwith BA. Artifactual hyperbilirubinemia due to paraprotein interference. Arch Pathol Lab Med. 2003;127:55–59
  36. Cohen AM, Magazanik A, van-der Lijn E, Shaked P, Levinsky H. Pseudohyperphosphataemia incidence in an automatic analyzer. Eur J Clin Chem Clin Biochem. 1994;32:559–561
  37. Gallou G, Legras B, Ruelland A, Grosbois B, Cloarec L. Problems of C-reactive protein determination in patients with monoclonal immunoglobulins. Clin Chem. 1993;39:918
  38. Alyanakian MA, Taes Y, Bensaid M, Segovia B, Aucouturier P, Rain JD, et al. Monoclonal immunoglobulin with antitransferrin activity: a rare cause of hypersideremia with increased transferrin saturation. Blood. 2007;109:359–361
  39. Mahapatra M, Mishra P, Makharia G, Kumar R, Saxena R. Acquired von Willebrand's disease associated with gastrointestinal angiodysplasia and monoclonal gammopathy. J Assoc Physicians India. 2006;54:963
  40. Agarwal N, Klix MM, Burns CP. Successful management with intravenous immunoglobulins of acquired von Willebrand disease associated with monoclonal gammopathy of undetermined significance. Ann Intern Med. 2004;141:83–84
  41. Huang YW, Saidi P. Acquired von Willebrand disease in a patient with monoclonal gammopathy of undetermined significance. Am J Med Sci. 2004;327:98–101
  42. Sailler L, Ecoiffier M, Cadroy Y, Couret B, Sie P, Mazurier C, et al. Association maladie de Willebrand acquise-gammapathie monoclonale-angiodysplasie du grêle: une indication rare des immunoglobulines intraveineuses à forte dose. Rev Med Interne. 1996;17:929–932
  43. Loftus LS, Arnold WN. Acquired hemophilia in a patient with myeloma. West J Med. 1994;160:173–176
  44. Taher A, Abiad R, Uthman I. Coexistence of lupus anticoagulant and acquired haemophilia in a patient with monoclonal gammopathy of unknown significance. Lupus. 2003;12:854–856
  45. Zangari M, Saghafifar F, Mehta P, Barlogie B, Fink L, Tricot G. The blood coagulation mechanism in multiple myeloma. Semin Thromb Hemost. 2003;29:275–282
  46. Auwerda JJ, Sonneveld P, de Maat MP, Leebeek FW. Prothrombotic coagulation abnormalities in patients with paraprotein-producing B-cell disorders. Clin Lymphoma Myeloma. 2007;7:462–466
  47. Jimenez-Zepeda VH, Dominguez-Martinez VJ. Acquired activated protein C resistance and thrombosis in multiple myeloma patients. Thromb J. 2006;4:11
  48. Zangari M, Elice F, Fink L, Tricot G. Thrombosis in multiple myeloma. Expert Rev Anticancer Ther. 2007;7:307–315
  49. Sallah S, Husain A, Wan J, Vos P, Nguyen NP. The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance. Ann Oncol. 2004;15:1490–1494

PII: S0953-6205(09)00002-8

doi:10.1016/j.ejim.2009.01.001

European Journal of Internal Medicine
Volume 20, Issue 5 , Pages 457-461, September 2009

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