Cryoglobulinemia and Cryofibrinogenemia: Ten years of experience and diagnostic perspectives from a large laboratory-based cohort

Objectives: Cryoproteins include cryoglobulins (CG), detectable in serum and plasma, and cryofibrinogen (CF), detectable only in plasma. Although they share clinical features, CG and CF differ in pathogenesis and diagnostic management. Cryofibrinogenemia remains poorly characterized and likely underdiagnosed. Methods: We retrospectively analyzed CG tests performed between 2015 and 2024 and CF tests between 2020 and 2024 at the Laboratory of the Public Health Hospital of Modena, evaluating clinical and epidemiological characteristics. Results: Among 10,874 patients tested for CG, 14% were positive: type III (50%), type II (45%), and type I (5%). Mean age at first detection differed significantly between males (60 years) and females (66 years; p < 0.001). Since 2020, male predominance was observed. Cryocrit levels were higher in HCV-positive patients (p < 0.001), with a marked reduction in HCV-related cases and cryocrit values over time. In patients achieving sustained virological response, cryocrit levels were comparable to HCV-negative patients. No temporal differences of cryocrit were observed in HCV-negative cases. In the 2020–2024 cohort (n = 628), CF was detected in 47%. Among 574 patients tested for both CG and CF, cryoprotein positivity was observed in 54%: isolated CF in 70%, combined CF/CG in 23%, and isolated CG in 7%. In systemic sclerosis patients (n = 239), isolated CF was significantly more frequent (p = 0.022; OR = 1.82). Conclusions: Parallel CG and CF testing improves diagnostic accuracy in cryoproteinemias. CF determination should be systematically included in diagnostic protocols, as CG testing alone may be insufficient in complex clinical scenarios.