{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:52:18Z","timestamp":1783385538698,"version":"3.54.6"},"reference-count":125,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universit\u00e0 Cattolica del Sacro Cuore Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>The precipitation of cryoglobulins, serum immunoglobulins, below 37 \u00b0C defines the clinical cryoglobulinemic syndrome, a systemic vasculitis usually characterized by purpura, weakness, and arthralgia. In most cases, this condition is associated with chronic infection by the hepatitis C virus (HCV) and can evolve into B-cell dysregulation and malignancies. The current literature on non-HCV-associated cryoglobulinemia is very limited, and little is known about the immunological and serological profile of affected patients. The cryoglobulinemic syndrome not associated with HCV infection is often found concomitantly with other infections, autoimmune diseases, and B-cell lymphoproliferative disorders. The cryoprecipitation of fibrinogen has been described as a rare disorder, perhaps underestimated and not fully understood, causing thrombotic occlusion and ischemia in different rheumatic disorders. Cold temperature plays a pathogenetic role in autoimmune hemolytic anemias, in which the presence of cold agglutinins produced by B cells at the lymphoplasmacytic cell stage may promote agglutination of red blood cells in the coldest parts of the circulation, even at mild room temperatures, undergoing hemolysis. Laboratory methods for the detection and quantification of cryoproteins are downright critical, and their concurrent detection is pivotal for the diagnosis. In this review, we summarize the clinical involvement of cryoglobulins, cryofibrinogen, and cold agglutinins in non-HCV autoimmune diseases, underlining the crucial steps of the most employed analytic methods.<\/jats:p>","DOI":"10.3390\/diagnostics15151933","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T08:51:41Z","timestamp":1754038301000},"page":"1933","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cryoproteins in Non-HCV-Related Autoimmune Disorders: A Serious Cold-Induced Problem"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2456-5308","authenticated-orcid":false,"given":"Krizia","family":"Pocino","sequence":"first","affiliation":[{"name":"Unit\u00e0 Operativa Complessa di Patologia Clinica, Ospedale San Pietro Fatebenefratelli, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9730-5836","authenticated-orcid":false,"given":"Annunziata","family":"Stefanile","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Complessa di Patologia Clinica, Ospedale San Pietro Fatebenefratelli, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8568-0866","authenticated-orcid":false,"given":"Patrizia","family":"Natali","sequence":"additional","affiliation":[{"name":"Dipartimento Interaziendale Integrato di Medicina di Laboratorio, Azienda Unit\u00e0 Sanitaria Locale e Azienda Ospedaliero-Universitaria di Modena, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8720-6284","authenticated-orcid":false,"given":"Cecilia","family":"Napodano","sequence":"additional","affiliation":[{"name":"Dipartimento Interaziendale Integrato di Medicina di Laboratorio, Azienda Unit\u00e0 Sanitaria Locale e Azienda Ospedaliero-Universitaria di Modena, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9716-070X","authenticated-orcid":false,"given":"Valerio","family":"Basile","sequence":"additional","affiliation":[{"name":"Clinical Pathology Unit and Cancer Biobank, Department of Research and Advanced Technologies, Regina Elena National Cancer Institute IRCCS, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Ciasca","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u201cA. Gemelli\u201d I.R.C.C.S., 00168 Rome, Italy"},{"name":"Sezione di Fisica, Dipartimento di Neuroscienze, Universit\u00e0 Cattolica del Sacro, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9155-6378","authenticated-orcid":false,"given":"Mariapaola","family":"Marino","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u201cA. Gemelli\u201d I.R.C.C.S., 00168 Rome, Italy"},{"name":"Sezione di Patologia Generale, Dipartimento di Medicina e Chirurgia Traslazionale, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8328-2570","authenticated-orcid":false,"given":"Umberto","family":"Basile","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Santa Maria Goretti Hospital, 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"ref_1","first-page":"156","article-title":"Hyperproteinemia Associated with Multiple Myeloma, Bull. Johns Hopkins Hosp","volume":"52","author":"Wintrobe","year":"1933","journal-title":"Mult. MYELOMA JAMA Intern. 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