IgA plasma cell myeloma presenting as cold agglutinin-induced haemolytic transfusion reaction.

Cold agglutinins produced in the setting of B cell neoplasms, such as lymphoplasmacytic lymphoma and plasma cell myeloma, can mediate autoimmune haemolytic anemia. Transfusion of these patients can exacerbate cold agglutinin-mediated haemolysis. Moreover, the workup for these reactions represents a diagnostic challenge due in part to false negative direct antiglobulin tests (DATs). Here, we report an anaemic patient who after a red blood cell (RBC) transfusion performed without blood warming, experienced a DAT-negative haemolytic transfusion reaction, and was later diagnosed with IgA-multiple myeloma, which showed an uncommon granular pattern by CD138 immunohistochemistry. Extensive workup excluded other diagnostic possibilities, including the presence of Donath-Landsteiner antibodies and cryoglobulins. Successful treatment with CyBorD (cyclophosphamide, bortezomib and dexamethasone) achieved complete remission, and additional RBC transfusions using warmers were completed uneventfully.

Type 1 Cryoglobulinemic Vasculitis Due to Monoclonal Gammopathy of Undetermined Significance Successfully Treated by Bortezomib Plus Dexamethasone.

Cryoglobulins are immunoglobulins that precipitate in cold conditions. Type I cryoglobulinemic vasculitis is associated with hematological malignancies. We herein report a case of steroid-resistant type 1 cryoglobulinemic vasculitis associated with monoclonal gammopathy of undetermined significance (MGUS) in a 47-year-old woman. By immunofixation of cryoglobulin, we found that the main component of cryoglobulin was the M protein due to MGUS, so treatment of MGUS was needed. Bortezomib+dexamethasone therapy resulted in a rapid decrease in cryoglobulin and improvement in the symptoms of cryoglobulinemic vasculitis. In refractory type I cryoglobulinemic vasculitis, treatment of the underlying gammaglobulinopathy should be considered.

Clinical and clonal characteristics of monoclonal immunoglobulin M-associated type I cryoglobulinaemia.

Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6-239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0-10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%-84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought.

Ocular manifestations of cryoglobulinemia: a reappraisal.

BACKGROUND/OBJECTIVES: To describe frequency and type of ocular manifestations in patients with cryoglobulinemic vasculitis (CV), as well as management approaches and outcomes. SUBJECTS/METHODS: This was a retrospective, observational, cohort study of patients who were diagnosed with CV at a single center and regularly underwent a comprehensive ocular assessment. RESULTS: Ophthalmologic manifestations were recorded in 16 patients (28%). The diagnoses included dry eye disease and primary Sjögren syndrome in 5 and 2 patients, respectively; peripheral ulcerative keratitis and anterior scleritis in 1 patient each; hyperviscosity syndrome and hypertensive retinopathy in 2 patients each; and Purtscher- like retinopathy in 3 patients. Twelve patients (75%) were anti-HCV/HCV RNA-positive, 11 of whom achieved a sustained virologic response (SVR) following treatment with interferon-α2b plus ribavirin or direct-acting antivirals. All patients were treated with ocular lubricants. Systemic therapeutic measures, including glucocorticoids, immunosuppressive and biologic agents, induced the disappearance or ≥50% reduction of cryoglobulins and major signs of vasculitis in 11 patients (68.7%). In the remaining 5 patients (31.3%), cryoglobulins and CV manifestations remained unchanged or decreased by <50%. The corresponding ophthalmologic assessment showed a variable degree of improvement in the ocular symptoms in all but 2 patients (87.5%). The best corrected visual acuity following treatment improved in 26 eyes, was unchanged in 3 eyes, and worsened in 3 eyes. CONCLUSIONS: Eye involvement is not a rare event in CV patients. A timely diagnosis and the correct employment of the available therapeutic measures may result in a favorable outcome of the ocular and extra-ocular manifestations.

A multicentric and nationwide predictive study role of T cell sub-population in the prevalence and prognosis of cryoglobulinemia among genotype 4 chronic hepatitis C patients.

The infection caused by the hepatitis C virus (HCV) is a significant global health concern. The prevailing genotype of HCV in Egypt is 4a, commonly referred to as GT-4a. A significant proportion exceeding 50% of patients infected with HCV experience extrahepatic manifestations (EHMs), encompassing a diverse range of clinical presentations. These manifestations, including essential mixed cryoglobulinemia (MC), can serve as initial and solitary indicators of the disease. The complete understanding of the pathogenesis of EHM remains unclear, with autoimmune phenomena being recognized as the primary causative factor. In this study, we examined the predictive significance of T-cell subpopulations in relation to the occurrence and prognosis of cryoglobulinemia in HCV patients. A total of 450 CHC genotype four treatment naïve patients were enrolled in this analytic cross-sectional study after thorough clinical, laboratory, and radiological examinations. All patients underwent laboratory investigations, including testing for cryoglobulin antibodies and measurements of CD4 and CD8 levels; two groups were described according to their test results: Group 1 consists of patients who have tested positive for cryoglobulin antibodies and Group 2 consists of patients who have tested negative for cryoglobulin antibodies. The exclusion criteria encompassed individuals with HIV infection or chronic HBV infection. Additionally, pelvi-abdominal ultrasonography was performed. Our study included 450 treatment naïve CHC patients (59% male, mean age 50.8 years). The patients were categorized according to their cryoglobulin antibodys test results into two groups: group A, CHC patients with cryoglobulin antibodies (Abs) negative (364 patients), and group B, CHC patients with cryoglobulin Ab positive (86 patients). Group B demonstrated a higher average age, elevated international normalized ratio, more prolonged duration of HCV infection, lower albumin, higher alanine aminotransferase, higher aspartate aminotransferase, higher bilirubin, lower CD8, lower CD4, and lower CD4:CD8 ratio. In contrast, 27 out of 86 (31.40%) patients in group B had symptoms; 85.8% had purpura and arthralgia, 74.3% had paresthesias, 86.7% had weakness, and 12.2% had non-Hodgkin's lymphoma. The levels of CD4 and CD8 were found to be decreased in chronic HCV patients with MC. T-cell subpopulation serves as a reliable indicator for assessing the prevalence and prognosis of MC in individuals with genotype 4 chronic hepatitis C. However, additional research is needed to further understand the development and spread of various emerging infectious diseases. Nevertheless, it is noteworthy that a critical threshold may exist beyond which EHM reaches a point of no return.

Waldenström's Macroglobulinemia and Cryoglobulinemic Glomerulonephritis: An Unusual Case of Monoclonal Gammopathy of Renal Significance.

Cryoglobulins are immunoglobulins that precipitate at temperatures below 37 °C and dissolve upon reheating. They can induce small-vessel vasculitis with renal involvement. Cryoglobulinemic glomerulonephritis is a rare manifestation that occurs in patients with monoclonal gammopathy, specifically Waldenström's macroglobulinemia. We present the case of a 52-year-old patient with a history of cutaneous vasculitis and hypothyroidism, who presented with generalized edema, moderate anemia, hypercholesterolemia, nephrotic range proteinuria of 12.69 g/day, microhematuria, arterial hypertension, and hypocomplementemia via the classical pathway, without acute kidney injury and with negative serological studies and positive cryoglobulins in the second determination. Serum and urine protein electrophoresis and immunofixation studies showed a monoclonal band of IgM and kappa light chain. Renal biopsy was consistent with cryoglobulinemic glomerulonephritis. In the context of dysproteinemia and cryoglobulinemic glomerulonephritis, bone-marrow aspiration and biopsy were performed, leading to the diagnosis of Waldenström's macroglobulinemia. Monoclonal gammopathies have been described in association with type I cryoglobulinemias. This described association is uncommon, which is why we present this case, along with a review of the literature.

Lupus nephritis with cryoglobulinemic glomerulonephritis features: a diagnostic conundrum.

In this clinical case, we report an atypical and unique presentation of systemic lupus erythematosus (SLE) in a 39-year-old female with nephrotic syndrome. The patient exhibited class IV plus V lupus nephritis and extensive immune complex deposition within the intracapillary and arteriolar regions suggestive of cryoglobulinemic glomerulonephritis, despite no detectable circulating cryoglobulins. Electron microscopy revealed cryoglobulin-like deposit distribution in all glomerular examined compartments, namely subendothelial, intramembranous, subepithelial, and mesangial, apparently extending from the capillary hyaline thrombi. The case highlights the possibility of severe renal injury in SLE without circulating cryoglobulins and the diverse kidney manifestations associated with the disease. However, the impact on patient outcome was minimal, as classical treatment (id est National Institute of Health regimen) remained effective.

Cardiopulmonary bypass surgery-cold alert!

The term "cold agglutinin (CA)" refers to a group of disorders caused by anti-erythrocyte autoantibodies that preferentially bind RBCs at cold temperatures (4°C-18°C). CAs contribute to 10 to 15% of autoimmune hemolytic anemia. We report a case of CAs diagnosed intraoperatively during emergency mitral valve replacement.

Serological and Molecular Characterization of Hepatitis C Virus-Related Cryoglobulinemic Vasculitis in Patients without Cryoprecipitate.

Prolonged B cells stimulation due to the Hepatitis C virus (HCV) can result in autoimmunity, stigmatized by rising levels of cryoglobulins (CGs), the rheumatoid factor (RF), and free light chains (FLC) of immunoglobulins (Ig) associated with a range of symptoms, from their absence to severe cryoglobulinemic vasculitis and lymphoma. Here, we aimed to identify an immunological signature for the earliest stages of vasculitis when cryoprecipitate is still not detectable. We firstly analyzed the IgG subclasses, FLC, and RF in 120 HCV-RNA-positive patients divided into four groups according to the type of cryoprecipitate and symptoms: 30 asymptomatic without cryoprecipitate (No Cryo), 30 with vasculitis symptoms but without CGs that we supposed were circulating but still not detectable (Circulating), 30 type II and 30 type III mixed cryoglobulinemia (Cryo II and Cryo III, respectively). Our results revealed that patients with supposed circulating CGs displayed a pattern of serological parameters that closely resembled Cryo II and Cryo III, with a stronger similarity to Cryo II. Accordingly, we analyzed the groups of Circulating and Cryo II for their immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) gene rearrangements, finding a similar mixed distribution of monoclonal, oligoclonal, and polyclonal responses compared to a control group of ten HCV-RNA-negative patients recovered from infection, who displayed a 100% polyclonal response. Our results strengthened the hypothesis that circulating CGs are the origin of symptoms in HCV-RNA-positive patients without cryoprecipitate and demonstrated that an analysis of clonal IGH and TCR rearrangements is the best option for the early diagnosis of extrahepatic complications.

The role of the laboratory in the diagnosis of an unusual case of Waldenstrom's macroglobulinaemia that lacked the common clinical features: A case report.

Lymphoplasmacytic lymphoma (LPL) is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes and plasma cells usually involving the bone marrow (BM). A subset of LPL which is associated with IgM monoclonal gammopathy is called Waldenstrom's macroglobulinaemia (WM), and usually requires therapeutic intervention when a patient becomes symptomatic (Bone Marrow failure characterised by cytopenia or hyperviscosity syndrome). Here, we report the case of an 80-year-old female with clinically unsuspected WM who initially presented to the Emergency Department (ED) with nausea and vomiting. The patients' gastrointestinal symptoms subsequently settled and was awaiting discharge. Non-specific, borderline size significant lymph nodes on CT chest was the only substantial past medical history. The diagnosis of WM was made after the Biochemistry Biomedical Scientist (BMS) detected the presence of a Type I monoclonal cryoglobulin. A potential cryoprecipitate was suspected when repeated 'clotting' error flags occurred during routine laboratory analyses; the sample aspiration difficulties being attributed to the viscous nature of the sample. The investigation of inaccessible low volume lymphadenopathy in the elderly should include serum protein electrophoresis and immunoglobulins as this may have established an earlier diagnosis in this case. The application of good scientific principles informed the laboratory investigation and resulted in the identification of a large IgM monoclonal cryoglobulin that prompted further appropriate investigations resulting in the diagnosis of WM. This case also highlights the importance of good communication between the laboratory and clinical staff.

Cryofibrinogen-Characteristics and Association with Cryoglobulin: A Retrospective Study Out of a Series of 1,712 Samples over 7 Years.

OBJECTIVE: Cryofibrinogens (CFs) and cryoglobulins (CGs) are cryoproteins responsible for obstructive vasculopathy and vasculitis. The aim of this study was to compare the characteristics of CF and CG, and to define the conditions of their association. METHODS AND RESULTS: This retrospective study was conducted at the Lyon University Hospitals, and included patients with at least one sample tested for CF and/or CG between September 2013 and April 2021. Serum and plasma samples were analyzed in very strict conditions of temperature. After cold precipitation, CF and CG were characterized and quantified in the cryoprecipitates. CRP and plasma fibrinogen levels were also investigated. Over this 7-year period, 1,712 samples for CF detection and 25,650 samples for CG detection were sent to the laboratory. Simultaneous testing of CF and CG was performed in 1,453/1,712 samples (85%). CF was less often positive than CG (8.3 vs. 13.5%, p < 0.0001). In positive CF samples, CG was associated in 28.9% of cases. In CF, fibrinogen was associated with fibronectin in 98/142 (69%) samples, especially in highly concentrated CF. CF concentration was independent of C-reactive protein and plasma fibrinogen concentrations. CONCLUSION: The simultaneous detection of CF and CG is essential for the diagnosis of vasculitis or thromboembolic events and their treatment.

The wide spectrum of cryoglobulinemic vasculitis and an overview of therapeutic advancements.

Immunoglobulins that reversibly precipitate at temperatures below 37 °C are called cryoglobulins (CGs). Cryoglobulinemia often manifests as cryoglobulinemic vasculitis (CV), whose symptoms range in severity from purpuric eruptions to life-threatening features. The majority of CV patients are infected with hepatitis C virus (HCV), whereas lymphoproliferative disorders or connective tissue diseases (CTD) are commonly diagnosed among patients with CV of non-infectious origin. In the absence of detectable associated disease, cryoglobulinemia is classified as "essential" (EMC). All HCV-positive CV patients should be given direct-acting antiviral agents (DAAs) that are consistently able to induce a sustained virologic response (SVR). Glucocorticoids (GCs) can mitigate CV-associated vasculitis, but they have no role as maintenance therapy. Cyclophosphamide restrains the hyperactive phase(s) of the disease and the post-apheresis rebound of newly synthesized CGs. Its use has been largely replaced by rituximab (RTX) in patients unresponsive to DAAs, patients progressing to B-cell non-Hodgkin lymphoma (B-NHL) and patients in whom CV persists or reappears after clearance of HCV. Therapeutic apheresis is an emergency treatment for CV patients with hyperviscosity syndrome. HCV-positive CV patients are at an increased risk of developing NHL, but the achievement of SVR can effectively prevent HCV-related NHL or induce the remission of an already established lymphoma, even without chemotherapy. The treatment of patients with IgM or IgG monoclonal cryoglobulins and an underlying immunoproliferative disorder is based on the regimens adopted for patients with the same B-cell malignancies but without circulating CGs. For patients with CTD, GCs plus alkylating agents or RTX are similarly effective as first-line therapy and in the relapse/refractory setting. In patients with EMC, treatment should consist of GCs plus RTX, with the dose of GCs tapered as soon as possible to reduce the risk of infectious complications.

Cutaneous Pedal Manifestations in Patient With Hepatitis C Virus-Associated Cryoglobulinemia: Case Report and Review of Literature.

Cryoglobulinemia is an uncommon blood dyscrasia that can manifest itself in the lower extremity. Due to the insidious nature of this disease, dermatological symptoms and ulcerations can easily be mistaken for more common entities. The authors present an overview of cryoglobulinemia and a case report of a patient with lower extremity manifestations of this disorder. This can provide specific guidance on the steps necessary to accurately establish the diagnosis of cryoglobulinemia or rule it out and pursue other etiologies causing lower extremity ulceration.