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Blood Jan 2017Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the... (Review)
Review
Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the clinical presentation and the underlying disease that triggers cryoglobulin formation. Cryoglobulinemia is categorized into two main subgroups: type I, which is seen exclusively in clonal hematologic diseases, and type II/III, which is called mixed cryoglobulinemia and is seen in hepatitis C virus infection and systemic diseases such as B-cell lineage hematologic malignancies and connective tissue disorders. Clinical presentation is broad and varies between types but includes arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. Life-threatening manifestations can develop in a small proportion of patients. A full evaluation for the underlying cause is required, because each type requires a different kind of treatment, which should be tailored on the basis of disease severity, underlying disease, and prior therapies. Relapses can be frequent and can result in significant morbidity and cumulative organ impairment. We explore the spectrum of this heterogeneous disease by discussing the disease characteristics of 5 different patients.
Topics: Adult; Connective Tissue Diseases; Cryoglobulinemia; Cryoglobulins; Female; Hepatitis C; Humans; Leukemia, B-Cell; Lymphoma, B-Cell; Male; Middle Aged; Recurrence
PubMed: 27799164
DOI: 10.1182/blood-2016-09-719773 -
Frontiers in Immunology 2020Autoimmune hemolytic anemias mediated by cold agglutinins can be divided into cold agglutinin disease (CAD), which is a well-defined clinicopathologic entity and a... (Review)
Review
Autoimmune hemolytic anemias mediated by cold agglutinins can be divided into cold agglutinin disease (CAD), which is a well-defined clinicopathologic entity and a clonal lymphoproliferative disorder, and secondary cold agglutinin syndrome (CAS), in which a similar picture of cold-hemolytic anemia occurs secondary to another distinct clinical disease. Thus, the pathogenesis in CAD is quite different from that of polyclonal autoimmune diseases such as warm-antibody AIHA. In both CAD and CAS, hemolysis is mediated by the classical complement pathway and therefore can result in generation of anaphylotoxins, such as complement split product 3a (C3a) and, to some extent, C5a. On the other hand, infection and inflammation can act as triggers and drivers of hemolysis, exemplified by exacerbation of CAD in situations with acute phase reaction and the role of specific infections (particularly and Epstein-Barr virus) as causes of CAS. In this review, the putative mechanisms behind these phenomena will be explained along with other recent achievements in the understanding of pathogenesis in these disorders. Therapeutic approaches have been directed against the clonal lymphoproliferation in CAD or the underlying disease in CAS. Currently, novel targeted treatments, in particular complement-directed therapies, are also being rapidly developed and will be reviewed.
Topics: Anemia, Hemolytic, Autoimmune; Cryoglobulins; Hemolysis; Humans
PubMed: 32318071
DOI: 10.3389/fimmu.2020.00590 -
Blood Nov 2020CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by...
CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.
Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Ataxia; Autoantibodies; B-Lymphocytes; Cryoglobulins; Female; France; Hematologic Neoplasms; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Middle Aged; Ophthalmoplegia; Paraproteinemias; Paresthesia; Retrospective Studies; Rituximab; Syndrome; Waldenstrom Macroglobulinemia
PubMed: 32959046
DOI: 10.1182/blood.2020007092 -
Mediterranean Journal of Hematology and... 2017Cryoglobulins are immunoglobulins that precipitate in serum at temperatures below 37°C and resolubilize upon warming. The clinical syndrome of cryoglobulinemia usually... (Review)
Review
Cryoglobulins are immunoglobulins that precipitate in serum at temperatures below 37°C and resolubilize upon warming. The clinical syndrome of cryoglobulinemia usually includes purpura, weakness, and arthralgia, but the underlying disease may also contribute other symptoms. Blood samples for cryoglobulin are collected, transported, clotted and spun at 37°C, before the precipitate is allowed to form when serum is stored at 4°C in a Wintrobe tube for at least seven days. The most critical and confounding factor affecting the cryoglobulin test is when the preanalytical phase is not fully completed at 37°C. The easiest way to quantify cryoglobulins is the cryocrit estimate. However, this approach has low accuracy and sensitivity. Furthermore, the precipitate should be resolubilized by warming to confirm that it is truly formed of cryoglobulins. The characterization of cryoglobulins requires the precipitate is several times washed, before performing immunofixation, a technique by which cryoglobulins can be classified depending on the characteristics of the detected immunoglobulins. These features imply a pathogenic role of these molecules which are consequently associated with a wide range of symptoms and manifestations. According to the Brouet classification, Cryoglobulins are grouped into three types by the immunochemical properties of immunoglobulins in the cryoprecipitate. The aim of this paper is to review the major aspects of cryoglobulinemia and the laboratory techniques used to detect and characterize cryoglobulins, taking into consideration the presence and consequences of cryoglobulinemia in Hepatitis C Virus (HCV) infection.
PubMed: 28101312
DOI: 10.4084/MJHID.2017.007 -
Archives of Pathology & Laboratory... Feb 1999Cryoglobulins are immunoglobulins that precipitate as serum is cooled below core body temperatures. A cryoglobulin screen is the observation of a serum specimen... (Review)
Review
Cryoglobulins are immunoglobulins that precipitate as serum is cooled below core body temperatures. A cryoglobulin screen is the observation of a serum specimen collected and separated while warm for cryoprecipitation over a period of up to 7 days. Values of the screening may be reported as a cryocrit, which is the volume percent of the precipitate compared with the total volume of serum. Further proof that the precipitate is indeed a cryoglobulin can be obtained by demonstrating resolubilization with warming and immunochemical analysis by immunofixation. Detailed characterization of cryoglobulins may also require rigorous washing of the precipitate, quantitation of total protein and immunoglobulins, and evaluation of serum for monoclonal gammopathy, rheumatoid factor activity, evidence of complement activation, and presence of hepatitis C virus seroreactivity or hepatitis C virus RNA. The single most important variable confounding standardization of cryoglobulin testing is the frequently improper separation of warm serum from other blood elements prior to screening and characterization.
Topics: Chemical Precipitation; Cryoglobulins; Humans; Immunoglobulins; Laboratories, Hospital; Paraproteinemias
PubMed: 10050784
DOI: 10.5858/1999-123-0119-EOC -
Canadian Medical Association Journal May 1976A 40-year-old woman had cryocrystalglobulinemia with IgG2(K1). To date, 27 other cases of spontaneous crystallization of a plasma protein have been reported. In all, the...
A 40-year-old woman had cryocrystalglobulinemia with IgG2(K1). To date, 27 other cases of spontaneous crystallization of a plasma protein have been reported. In all, the protein, a cryoglobulin, has been found to be an IgG molecule. The disease most commonly associated with this phenomenon has been multiple myeloma. None of the patients have had Raynaud's phenomenon, but many have had purpuric skin lesions made worse by exposure to cold. In the two cases of essential cryocrystalglobulinemia, crystals were found in the peripheral blood film. Immunologic, biochemical and ultrastructural studies have so far not demonstrated any property common to all cryocrystalglobulins.
Topics: Adult; Cryoglobulins; Crystallization; Cyclophosphamide; Female; Hematologic Diseases; Humans; Melphalan; Prednisone
PubMed: 1268777
DOI: No ID Found -
British Journal of Haematology Jan 2008
Topics: Adult; Cryoglobulinemia; Cryoglobulins; Female; Fibrinogens, Abnormal; Humans
PubMed: 17916105
DOI: 10.1111/j.1365-2141.2007.06823.x -
World Journal of Gastroenterology Jun 2014Hepatitis C virus (HCV) infection is a systemic disorder which is often associated with a number of extrahepatic manifestations including glomerulopathies. Patients with... (Review)
Review
Hepatitis C virus (HCV) infection is a systemic disorder which is often associated with a number of extrahepatic manifestations including glomerulopathies. Patients with HCV infection were found to have a higher risk of end-stage renal disease. HCV positivity has also been linked to lower graft and patient survivals after kidney transplantation. Various histological types of renal diseases are reported in association with HCV infection including membranoproliferative glomerulonephritis (MPGN), membranous nephropathy, focal segmental glomerulosclerosis, fibrillary glomerulonephritis, immunotactoid glomerulopathy, IgA nephropathy, renal thrombotic microangiopathy, vasculitic renal involvement and interstitial nephritis. The most common type of HCV associated glomerulopathy is type I MPGN associated with type II mixed cryoglobulinemia. Clinically, typical renal manifestations in HCV-infected patients include proteinuria, microscopic hematuria, hypertension, acute nephritis and nephrotic syndrome. Three approaches may be suggested for the treatment of HCV-associated glomerulopathies and cryoglobulinemic renal disease: (1) antiviral therapy to prevent the further direct damage of HCV on kidneys and synthesis of immune-complexes; (2) B-cell depletion therapy to prevent formation of immune-complexes and cryoglobulins; and (3) nonspecific immunosuppressive therapy targeting inflammatory cells to prevent the synthesis of immune-complexes and to treat cryoglobulin associated vasculitis. In patients with moderate proteinuria and stable renal functions, anti-HCV therapy is advised to be started as pegylated interferon-α plus ribavirin. However in patients with nephrotic-range proteinuria and/or progressive kidney injury and other serious extra-renal manifestations, immunosuppressive therapy with cyclophosphamide, rituximab, steroid pulses and plasmapheresis should be administrated.
Topics: Antiviral Agents; Cryoglobulinemia; Diabetic Nephropathies; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Treatment Outcome
PubMed: 24976695
DOI: 10.3748/wjg.v20.i24.7544 -
Advances in Clinical Chemistry 2021Cryoglobulins consist of serum immunoglobulins that precipitate below 37°C and resolubilize upon warming. The clinical triad of cryoglobulinemia usually includes... (Review)
Review
Cryoglobulins consist of serum immunoglobulins that precipitate below 37°C and resolubilize upon warming. The clinical triad of cryoglobulinemia usually includes purpura, weakness, and arthralgia. Cryoglobulinemic syndrome, clinically defined as a systemic vasculitis, is associated with chronic infection with hepatitis C virus (HCV) and autoimmune disorders and can evolve into B-cell malignancies. While the current literature about HCV-associated cryoglobulinemia is not very limited, little is known about the immunologic and serologic profiles of affected patients. Therefore, comprehension of the pathogenetic mechanisms underlying cryoprecipitation could be very helpful. Due to the persistence of viral antigenic stimulation, biomarkers to use after the worsening progression of HCV infection to lymphoproliferative and/or autoimmune diseases are widely needed. Laboratory methods used to detect and characterize low concentrations of cryoprecipitates and immunotyping patterns could improve patient management. The most critical factor affecting cryoglobulin testing is that the pre-analytical phase is not fully completed at 37°C.
Topics: Animals; Autoantibodies; Biomarkers; COVID-19; Chemical Precipitation; Cryoglobulinemia; Cryoglobulins; Hepatitis C; Humans; Vasculitis
PubMed: 34462057
DOI: 10.1016/bs.acc.2020.09.006 -
Kidney360 Apr 2021Cryoglobulinemia is a systemic disease and the clinical involvement is variable. The long-term renal outcome of cryoglobulinemia remains unclear, and most published...
BACKGROUND
Cryoglobulinemia is a systemic disease and the clinical involvement is variable. The long-term renal outcome of cryoglobulinemia remains unclear, and most published series are from the Western world, with a high proportion of chronic hepatitis C. The objective is to determine the prevalence, causes, and renal outcome of cryoglobulinemia in Hong Kong.
METHODS
We reviewed 289 patients with cryoglobulinemia in the public hospital database of Hong Kong between 2000 and 2019. The renal event-free survival, dialysis-free survival, and overall survival were analyzed according to the underlying etiologies, and compared with 7483 patients who tested negative for cryoglobulinemia during the same period.
RESULTS
Among the patients with cryoglobulinemia, 68 (24%) had chronic hepatitis B, 69 (24%) had hepatitis C, and 14 (5%) paraproteinemia. They were followed for 62.7±58.0 months. The 5-year dialysis-free survival was 68%, 70%, 67%, and 83% for patients with cryoglobulinemia attributed to hepatitis B, hepatitis C, paraproteinemia, and unknown etiology, respectively (=0.05), and their 5-year overall survival was 61%, 58%, 22%, and 72%, respectively (=0.002). Among patients with hepatitis B, the group with cryoglobulin had a worse renal event-free survival than those without (36% versus 43%, =0.005), although their dialysis-free survival and all-cause mortality were similar. For patients with hepatitis C or paraproteinemia, the presence of cryoglobulin did not affect the renal outcome.
CONCLUSIONS
Hepatitis B is a common cause of cryoglobulinemia in southeast Asia, and the presence of cryoglobulinemia is associated with a worse renal event-free survival. The renal prognosis of cryoglobulinemia appears to be affected by the underlying cause, with hepatitis B having a worse renal outcome and patients with paraproteinemia having a worse overall survival than those with other causes of cryoglobulinemia.
Topics: Cryoglobulinemia; Cryoglobulins; Hepatitis C; Hong Kong; Humans; Renal Dialysis
PubMed: 35373043
DOI: 10.34067/KID.0007532020