Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Overview of cryoglobulins and cryoglobulinemia

Stanford L Peng, MD, PhD
Peter H Schur, MD
Section Editor
Mark H Wener, MD
Deputy Editor
Monica Ramirez Curtis, MD, MPH


Precipitation of blood proteins at temperatures lower than 37ºC is referred to as cryoprecipitation. Two types of cryoprecipitates are recognized. Cryoglobulin (CG) is present when proteins precipitate from an individual's serum and plasma, and cryofibrinogen refers to the precipitate from plasma only [1].

CGs are either immunoglobulins or a mixture of immunoglobulins and complement components. The nature of CGs, an overview of the clinical syndromes associated with them (cryoglobulinemia, cryoglobulinemic vasculitis), their pathogenesis, associated disorders, and prognosis are the subjects of this topic review. Treatment of cryoglobulinemia due to plasma cell disorders (monoclonal CG) and the clinical manifestations, diagnosis, and treatment of the mixed cryoglobulinemic syndromes, such as those associated with hepatitis C infection, are presented separately. (See "Treatment and prognosis of Waldenström macroglobulinemia" and "Clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome (essential mixed cryoglobulinemia)" and "Treatment of the mixed cryoglobulinemia syndrome".)

As noted above, a precipitate that develops in refrigerated plasma (cryofibrinogen) is typically composed of a mixture of fibrinogen, fibrin, fibronectin, and fibrin split products. The clinical manifestations of cryofibrinogenemia and disorders associated with the presence of circulating cryofibrinogen are discussed separately. (See "Cryofibrinogenemia".)


Cryoglobulin (CG) consists of immunoglobulins and complement components and precipitates upon refrigeration of serum and plasma. Routine laboratory testing for CG is, however, typically performed only on serum. The first description of the cryoprecipitation phenomenon has been attributed to Wintrobe and Buell, who described in 1933 a patient with signs and symptoms of hyperviscosity associated with multiple myeloma [2]. In 1947, the term "cryoglobulin" was applied to this "cold precipitable serum globulin" [3]. The appearance of precipitated CGs is illustrated in the picture (picture 1).


Although, strictly speaking, cryoglobulinemia refers to the presence of cryoglobulin (CG) in a patient's serum, this term is often used to refer to a systemic inflammatory syndrome that generally involves small-to-medium vessel vasculitis due to CG-containing immune complexes. The terms "cryoglobulinemic syndrome" and "cryoglobulinemic vasculitis" are sometimes used to make a distinction between the clinically apparent disorder and the asymptomatic presence of CGs [4-6].

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jun 14, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet 2012; 379:348.
  2. Wintrobe MM, Buell MV. Hyperproteinemia associated with multiple myeloma: with report of a case in which an extraordinary hyperproteinemia was associated with thrombosis of the retinal veins and symptoms suggesting Raynaud's disease. Bulletin of the Johns Hopkins Hospital 1933; 52:156.
  3. LERNER AB, WATSON CJ. Studies of cryoglobulins; unusual purpura associated with the presence of a high concentration of cryoglobulin (cold precipitable serum globulin). Am J Med Sci 1947; 214:410.
  4. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37:187.
  5. Dispenzieri A, Gorevic PD. Cryoglobulinemia. Hematol Oncol Clin North Am 1999; 13:1315.
  6. Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis. Arthritis Rheum 1999; 42:2507.
  7. Meltzer M, Franklin EC. Cryoglobulinemia--a study of twenty-nine patients. I. IgG and IgM cryoglobulins and factors affecting cryoprecipitability. Am J Med 1966; 40:828.
  8. Meltzer M, Franklin EC, Elias K, et al. Cryoglobulinemia--a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med 1966; 40:837.
  9. Bonnet F, Pineau JJ, Taupin JL, et al. Prevalence of cryoglobulinemia and serological markers of autoimmunity in human immunodeficiency virus infected individuals: a cross-sectional study of 97 patients. J Rheumatol 2003; 30:2005.
  10. García-Carrasco M, Ramos-Casals M, Cervera R, et al. Cryoglobulinemia in systemic lupus erythematosus: prevalence and clinical characteristics in a series of 122 patients. Semin Arthritis Rheum 2001; 30:366.
  11. Ramos-Casals M, Cervera R, Yagüe J, et al. Cryoglobulinemia in primary Sjögren's syndrome: prevalence and clinical characteristics in a series of 115 patients. Semin Arthritis Rheum 1998; 28:200.
  12. Cicardi M, Cesana B, Del Ninno E, et al. Prevalence and risk factors for the presence of serum cryoglobulins in patients with chronic hepatitis C. J Viral Hepat 2000; 7:138.
  13. Ramos-Casals M, Muñoz S, Medina F, et al. Systemic autoimmune diseases in patients with hepatitis C virus infection: characterization of 1020 cases (The HISPAMEC Registry). J Rheumatol 2009; 36:1442.
  14. Quartuccio L, Isola M, Corazza L, et al. Validation of the classification criteria for cryoglobulinaemic vasculitis. Rheumatology (Oxford) 2014; 53:2209.
  15. Brouet JC, Clauvel JP, Danon F, et al. Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med 1974; 57:775.
  16. Musset L, Diemert MC, Taibi F, et al. Characterization of cryoglobulins by immunoblotting. Clin Chem 1992; 38:798.
  17. Tissot JD, Schifferli JA, Hochstrasser DF, et al. Two-dimensional polyacrylamide gel electrophoresis analysis of cryoglobulins and identification of an IgM-associated peptide. J Immunol Methods 1994; 173:63.
  18. Pascual M, Perrin L, Giostra E, Schifferli JA. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 1990; 162:569.
  19. Musset L, Duarte F, Gaillard O, et al. Immunochemical characterization of monoclonal IgG containing mixed cryoglobulins. Clin Immunol Immunopathol 1994; 70:166.
  20. Kyle RA, Rajkumar SV. Monoclonal gammopathies of undetermined significance. Hematol Oncol Clin North Am 1999; 13:1181.
  21. Monti G, Galli M, Invernizzi F, et al. Cryoglobulinaemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease. GISC. Italian Group for the Study of Cryoglobulinaemias. QJM 1995; 88:115.
  22. Montagnino G. Reappraisal of the clinical expression of mixed cryoglobulinemia. Springer Semin Immunopathol 1988; 10:1.
  23. Ramos-Casals M, Trejo O, García-Carrasco M, et al. Mixed cryoglobulinemia: new concepts. Lupus 2000; 9:83.
  24. Antonelli A, Ferri C, Ferrari SM, et al. Serum levels of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor alpha in mixed cryoglobulinemia. Arthritis Rheum 2009; 60:3841.
  25. Fabris P, Tositti G, Giordani MT, et al. Prevalence and clinical significance of circulating cryoglobulins in HIV-positive patients with and without co-infection with hepatitis C virus. J Med Virol 2003; 69:339.
  26. Belizna CC, Hamidou MA, Levesque H, et al. Infection and vasculitis. Rheumatology (Oxford) 2009; 48:475.
  27. Ng YC, Schifferli JA. Clearance of cryoglobulins in man. Springer Semin Immunopathol 1988; 10:75.
  28. Fornasieri A, Li M, Armelloni S, et al. Glomerulonephritis induced by human IgMK-IgG cryoglobulins in mice. Lab Invest 1993; 69:531.
  29. Grey HM, Kohler PF. Cryoimmunoglobulins. Semin Hematol 1973; 10:87.
  30. Ferraccioli GF, De Vita S, Casatta L, et al. Autoimmune connective tissue disease, chronic polyarthritides and B cell expansion: risks and perspectives with immunosuppressive drugs. Clin Exp Rheumatol 1996; 14 Suppl 14:S71.
  31. De Re V, De Vita S, Sansonno D, et al. Type II mixed cryoglobulinaemia as an oligo rather than a mono B-cell disorder: evidence from GeneScan and MALDI-TOF analyses. Rheumatology (Oxford) 2006; 45:685.
  32. Pileri P, Uematsu Y, Campagnoli S, et al. Binding of hepatitis C virus to CD81. Science 1998; 282:938.
  33. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992; 327:1490.
  34. Agnello V. The etiology and pathophysiology of mixed cryoglobulinemia secondary to hepatitis C virus infection. Springer Semin Immunopathol 1997; 19:111.
  35. Charles ED, Green RM, Marukian S, et al. Clonal expansion of immunoglobulin M+CD27+ B cells in HCV-associated mixed cryoglobulinemia. Blood 2008; 111:1344.
  36. Knight GB, Gao L, Gragnani L, et al. Detection of WA B cells in hepatitis C virus infection: a potential prognostic marker for cryoglobulinemic vasculitis and B cell malignancies. Arthritis Rheum 2010; 62:2152.
  37. Charles ED, Brunetti C, Marukian S, et al. Clonal B cells in patients with hepatitis C virus-associated mixed cryoglobulinemia contain an expanded anergic CD21low B-cell subset. Blood 2011; 117:5425.
  38. Schott P, Polzien F, Müller-Issberner A, et al. In vitro reactivity of cryoglobulin IgM and IgG in hepatitis C virus-associated mixed cryoglobulinemia. J Hepatol 1998; 28:17.
  39. Boyer O, Saadoun D, Abriol J, et al. CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. Blood 2004; 103:3428.
  40. Kunkel HG, Winchester RJ, Joslin FG, Capra JD. Similarities in the light chains of anti-gamma-globulins showing cross-idiotypic specificities. J Exp Med 1974; 139:128.
  41. Zinneman HH. Cryoglobulins and pyroglobulins. Pathobiol Annu 1980; 10:83.
  42. Saha A, Chowdhury P, Sambury S, et al. Studies on cryoprecipitation. IV. Enzymic fragments of a human cryoglobulin. J Biol Chem 1970; 245:2730.
  43. Haakenstad AO, Mannik M. Saturation of the reticuloendothelial system with soluble immune complexes. J Immunol 1974; 112:1939.
  44. Hamburger MI, Gorevic PD, Lawley TJ, et al. Mixed cryoglobulinemia: association of glomerulonephritis with defective reticuloendothelial system Fc receptor function. Trans Assoc Am Physicians 1979; 92:104.
  45. Berliner S, Weinberger A, Zamir R, et al. Familial cryoglobulinemia and C4 deficiency. Scand J Rheumatol 1984; 13:151.
  46. McLean RH, Weinstein A, Chapitis J, et al. Familial partial deficiency of the third component of complement (C3) and the hypocomplementemic cutaneous vasculitis syndrome. Am J Med 1980; 68:549.
  47. Trejo O, Ramos-Casals M, García-Carrasco M, et al. Cryoglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine (Baltimore) 2001; 80:252.
  48. Terrier B, Karras A, Kahn JE, et al. The spectrum of type I cryoglobulinemia vasculitis: new insights based on 64 cases. Medicine (Baltimore) 2013; 92:61.
  49. Payet J, Livartowski J, Kavian N, et al. Type I cryoglobulinemia in multiple myeloma, a rare entity: analysis of clinical and biological characteristics of seven cases and review of the literature. Leuk Lymphoma 2013; 54:767.
  50. Della Rossa A, Trevisani G, Bombardieri S. Cryoglobulins and cryoglobulinemia. Diagnostic and therapeutic considerations. Clin Rev Allergy Immunol 1998; 16:249.
  51. Geltner D. Therapeutic approaches in mixed cryoglobulinemia. Springer Semin Immunopathol 1988; 10:103.
  52. Gorevic PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med 1980; 69:287.
  53. Cohen SJ, Pittelkow MR, Su WP. Cutaneous manifestations of cryoglobulinemia: clinical and histopathologic study of seventy-two patients. J Am Acad Dermatol 1991; 25:21.
  54. Giuggioli D, Manfredi A, Lumetti F, et al. Cryoglobulinemic vasculitis and skin ulcers. Our therapeutic strategy and review of the literature. Semin Arthritis Rheum 2015; 44:518.
  55. Rossi D, Mansouri M, Baldovino S, et al. Nail fold videocapillaroscopy in mixed cryoglobulinaemia. Nephrol Dial Transplant 2004; 19:2245.
  56. Weinberger A, Berliner S, Pinkhas J. Articular manifestations of essential cryoglobulinemia. Semin Arthritis Rheum 1981; 10:224.
  57. Ferri C, La Civita L, Cirafisi C, et al. Peripheral neuropathy in mixed cryoglobulinemia: clinical and electrophysiologic investigations. J Rheumatol 1992; 19:889.
  58. Gemignani F, Pavesi G, Fiocchi A, et al. Peripheral neuropathy in essential mixed cryoglobulinaemia. J Neurol Neurosurg Psychiatry 1992; 55:116.
  59. Garcia-Bragado F, Fernandez JM, Navarro C, et al. Peripheral neuropathy in essential mixed cryoglobulinemia. Arch Neurol 1988; 45:1210.
  60. Stricker RB, Sanders KA, Owen WF, et al. Mononeuritis multiplex associated with cryoglobulinemia in HIV infection. Neurology 1992; 42:2103.
  61. Stricker RB, Kiprov DD. Mononeuritis and cryoglobulins. Neurology 1993; 43:2159.
  62. Bombardieri S, Paoletti P, Ferri C, et al. Lung involvement in essential mixed cryoglobulinemia. Am J Med 1979; 66:748.
  63. Viegi G, Fornai E, Ferri C, et al. Lung function in essential mixed cryoglobulinemia: a short-term follow-up. Clin Rheumatol 1989; 8:331.
  64. Bertorelli G, Pesci A, Manganelli P, et al. Subclinical pulmonary involvement in essential mixed cryoglobulinemia assessed by bronchoalveolar lavage. Chest 1991; 100:1478.
  65. Levo Y, Gorevic PD, Kassab HJ, et al. Association between hepatitis B virus and essential mixed cryoglobulinemia. N Engl J Med 1977; 296:1501.
  66. Schena FP. Survey of the Italian Registry of Renal Biopsies. Frequency of the renal diseases for 7 consecutive years. The Italian Group of Renal Immunopathology. Nephrol Dial Transplant 1997; 12:418.
  67. Tarantino A, De Vecchi A, Montagnino G, et al. Renal disease in essential mixed cryoglobulinaemia. Long-term follow-up of 44 patients. Q J Med 1981; 50:1.
  68. Nash JW, Ross P Jr, Neil Crowson A, et al. The histopathologic spectrum of cryofibrinogenemia in four anatomic sites. Skin, lung, muscle, and kidney. Am J Clin Pathol 2003; 119:114.
  69. Cohen P, Nguyen QT, Dény P, et al. Treatment of mixed cryoglobulinemia with recombinant interferon alpha and adjuvant therapies. A prospective study on 20 patients. Ann Med Interne (Paris) 1996; 147:81.
  70. Chad D, Pariser K, Bradley WG, et al. The pathogenesis of cryoglobulinemic neuropathy. Neurology 1982; 32:725.
  71. Nemni R, Corbo M, Fazio R, et al. Cryoglobulinaemic neuropathy. A clinical, morphological and immunocytochemical study of 8 cases. Brain 1988; 111 ( Pt 3):541.
  72. Tredici G, Petruccioli MG, Cavaletti G, et al. Sural nerve bioptic findings in essential cryoglobulinemic patients with and without peripheral neuropathy. Clin Neuropathol 1992; 11:121.
  73. Bonetti B, Invernizzi F, Rizzuto N, et al. T-cell-mediated epineurial vasculitis and humoral-mediated microangiopathy in cryoglobulinemic neuropathy. J Neuroimmunol 1997; 73:145.
  74. Cavaletti G, Petruccioli MG, Crespi V, et al. A clinico-pathological and follow up study of 10 cases of essential type II cryoglobulinaemic neuropathy. J Neurol Neurosurg Psychiatry 1990; 53:886.
  75. Ben-Bassat M, Boner G, Rosenfeld J, et al. The clinicopathologic features of cryoglobulinemic nephropathy. Am J Clin Pathol 1983; 79:147.
  76. Beddhu S, Bastacky S, Johnson JP. The clinical and morphologic spectrum of renal cryoglobulinemia. Medicine (Baltimore) 2002; 81:398.
  77. Dammacco F, Sansonno D. Mixed cryoglobulinemia as a model of systemic vasculitis. Clin Rev Allergy Immunol 1997; 15:97.
  78. Tarantino A, Campise M, Banfi G, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int 1995; 47:618.
  79. Karras A, Noël LH, Droz D, et al. Renal involvement in monoclonal (type I) cryoglobulinemia: two cases associated with IgG3 kappa cryoglobulin. Am J Kidney Dis 2002; 40:1091.
  80. Su CF, Chen HH, Yeh JC, et al. Ultrastructural 'fingerprint' in cryoprecipitates and glomerular deposits: a clinicopathologic analysis of fingerprint deposits. Nephron 2002; 90:37.
  81. Monteverde A, Ballarè M, Bertoncelli MC, et al. Lymphoproliferation in type II mixed cryoglobulinemia. Clin Exp Rheumatol 1995; 13 Suppl 13:S141.
  82. Zignego AL, Giannelli F, Marrocchi ME, et al. Frequency of bcl-2 rearrangement in patients with mixed cryoglobulinemia and HCV-positive liver diseases. Clin Exp Rheumatol 1997; 15:711.
  83. Luzar MJ, Camisa C, Neff JC. Essential mixed cryoglobulinemia (type II) with pseudoleukocytosis. Arthritis Rheum 1984; 27:353.
  84. Tarantino A, Anelli A, Costantino A, et al. Serum complement pattern in essential mixed cryoglobulinaemia. Clin Exp Immunol 1978; 32:77.
  85. Hebert LA, Cosio FG, Neff JC. Diagnostic significance of hypocomplementemia. Kidney Int 1991; 39:811.
  86. Ferri C, Mannini L, Bartoli V, et al. Blood viscosity and filtration abnormalities in mixed cryoglobulinemia patients. Clin Exp Rheumatol 1990; 8:271.
  87. Wener MH, Hutchinson K, Morishima C, Gretch DR. Absence of antibodies to cyclic citrullinated peptide in sera of patients with hepatitis C virus infection and cryoglobulinemia. Arthritis Rheum 2004; 50:2305.
  88. Misiani R, Bellavita P, Fenili D, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 1992; 117:573.
  89. Levo Y. Hepatitis B virus and essential mixed cryoglobulinemia. Ann Intern Med 1981; 94:282.
  90. Popp JW Jr, Dienstag JL, Wands JR, Bloch KJ. Essential mixed cryoglobulinemia without evidence for hepatitis B virus infection. Ann Intern Med 1980; 92:379.
  91. Vermeersch P, Gijbels K, Mariën G, et al. A critical appraisal of current practice in the detection, analysis, and reporting of cryoglobulins. Clin Chem 2008; 54:39.
  92. Trendelenburg M, Schifferli JA. Cryoglobulins are not essential. Ann Rheum Dis 1998; 57:3.
  93. Della Rossa A, Tavoni A, D'Ascanio A, et al. Mortality rate and outcome factors in mixed cryoglobulinaemia: the impact of hepatitis C virus. Scand J Rheumatol 2010; 39:167.
  94. Kay J, McCluskey RT. Case records of the Massachusetts General Hospital. Case 31-2005. A 60-year-old man with skin lesions and renal insufficiency. N Engl J Med 2005; 353:1605.
  95. Kallemuchikkal U, Gorevic PD. Evaluation of cryoglobulins. Arch Pathol Lab Med 1999; 123:119.
  96. Shihabi ZK. Cryoglobulins: an important but neglected clinical test. Ann Clin Lab Sci 2006; 36:395.
  97. Vermeersch P, Gijbels K, Knockaert D, et al. Establishment of reference values for immunoglobulins in the cryoprecipitate. Clin Immunol 2008; 129:360.
  98. Invernizzi F, Pietrogrande M, Sagramoso B. Classification of the cryoglobulinemic syndrome. Clin Exp Rheumatol 1995; 13 Suppl 13:S123.
  99. Invernizzi F, Pioltelli P, Cattaneo R, et al. A long-term follow-up study in essential cryoglobulinemia. Acta Haematol 1979; 61:93.
  100. La Civita L, Zignego AL, Monti M, et al. Mixed cryoglobulinemia as a possible preneoplastic disorder. Arthritis Rheum 1995; 38:1859.
  101. Saadoun D, Sellam J, Ghillani-Dalbin P, et al. Increased risks of lymphoma and death among patients with non-hepatitis C virus-related mixed cryoglobulinemia. Arch Intern Med 2006; 166:2101.
  102. Terrier B, Carrat F, Krastinova E, et al. Prognostic factors of survival in patients with non-infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey. Ann Rheum Dis 2013; 72:374.
  103. Alberico S, Mazza S, Grimaldi E, et al. Essential mixed type II cryoglobulinemia in a HCV positive pregnant woman: case report. Clin Exp Obstet Gynecol 1998; 25:129.
  104. Sibilia J, Feugeas O, Laugel V, et al. Successful management of neonatal cryoglobulinaemia after a gemellar pregnancy in a woman with symptomatic type I cryoglobulinaemia. Ann Rheum Dis 2004; 63:217.
  105. Laugel V, Goetz J, Wolff S, et al. Neonatal management of symptomatic transplacental cryoglobulinaemia. Acta Paediatr 2004; 93:556.