# Cryoproteins in Non-HCV-Related Autoimmune Disorders: A Serious Cold-Induced Problem

## TL;DR

This paper reviews how cold-induced proteins affect non-HCV autoimmune diseases, highlighting their clinical impact and diagnostic challenges.

## Contribution

The paper provides a comprehensive review of non-HCV-related cryoglobulinemia and its associated cryoproteins in autoimmune disorders.

## Key findings

- Cryoglobulins and cryofibrinogen are linked to autoimmune diseases and can cause vasculitis and ischemia.
- Cold agglutinins contribute to autoimmune hemolytic anemia by agglutinating red blood cells at mild temperatures.
- Accurate laboratory detection of cryoproteins is essential for diagnosing non-HCV-related cryoglobulinemia.

## Abstract

The precipitation of cryoglobulins, serum immunoglobulins, below 37 °C 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.