Search Results (16)

Background and Clinical Significance: Waldenström macroglobulinemia (WM) is a rare, indolent B-cell non-Hodgkin lymphoma, characterised by the presence of monoclonal immunoglobulin M (IgM) and lymphoplasmacytic infiltration of the bone marrow. It is often associated with various haematological and systemic disorders, including previous cold agglutinin disease (CAD), a condition where cold-sensitive antibodies lead to haemolysis. Case Presentation: A 55-year-old male patient was admitted to the Internal Diseases Ward with symptoms of weakness, reduced effort tolerance, and weight loss, along with life-threatening normoblastic anaemia (haemoglobin [Hb]: 3.90 g/dL). Initial blood tests raised suspicion of CAD due to the presence of multiple blood clots, as well as a decrease in lymphocyte and neutrophil counts. CAD was then confirmed by a cold agglutinin titre of 1:2000 and direct antiglobulin test ([DAT] 4+). Two weeks later, upon transfer to the Haematological Diseases Ward, further investigation revealed elevated IgM levels (up to 31.55 g/L). Additional diagnostic tests, including serum protein electrophoresis, imaging, multiparametric flow cytometry, and bone marrow biopsy, confirmed the diagnosis of WM. The L265P MYD88 mutation test was positive. Treatment with intravenous rituximab was initiated, followed by bendamustine/rituximab (BR) therapy protocol as first-line treatment. After two cycles, the patient’s clinical condition and laboratory results significantly improved, with a marked reduction in IgM (<0.4 g/L). Hb levels steadily rose to 12.60 g/dL, eliminating the need for further blood transfusions. Conclusions: This case highlights the importance of recognising the coexistence of CAD and WM, which may present with overlapping clinical features, including life-threatening anaemia. Extensive diagnostics and prompt treatment with combination therapy can lead to effective clinical improvement. Full article

Background and Clinical Significance: Acquired angioedema (AAE) is a rare and potentially life-threatening condition characterized by acquired deficiency of C1-inhibitor (C1-INH) resulting in hyperactivation of the classical complement pathway. AAE occurs in association with malignancies or autoimmune diseases. Infectious triggers are rarely encountered, and the underlying mechanisms have yet to be completely clarified. Case Presentation: This case involves a previously healthy 19-year-old male who was admitted with Mycoplasma pneumonia and oral ulcers, subsequently developing unilateral facial angioedema. Laboratory studies demonstrated reduced C4, decreased levels and activity of C1-INH, and reduced C1q, all consistent with acquired C1-INH deficiency. These findings were attributed to the presence of cold agglutinins, which are frequently observed in Mycoplasma pneumoniae infections. Following treatment with icatibant, a bradykinin B2 receptor antagonist, the patient’s angioedema resolved rapidly. An exhaustive workup found no evidence of underlying systemic disorders, and the patient did not experience any angioedema attacks following resolution of the infection. Conclusions: The presence of cold agglutinins, commonly associated with Mycoplasma infections, can precipitate a decline in C1-INH levels, resulting in complement pathway dysregulation. This disruption leads to an excess of bradykinin, followed by increased vascular permeability and localized edema. Full article

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. Full article

Background: Peripheral erythrophagocytosis appears to be a unique sign of acquired immune-mediated hemolytic anemia. It is said to be rare but its prevalence among patients with autoimmune hemolytic anemia has not been studied. Methods: In this retrospective study from July 2014 to June 2024, the clinical and laboratory features, treatment and outcomes of children diagnosed with autoimmune hemolytic anemia were described. The prevalence of peripheral erythrophagocytosis was compared to a group of children with hereditary spherocytosis at the time of first diagnosis seen in the same period. Results: Twelve consecutive children with autoimmune hemolytic anemia were included. There were four female patients. The mean age was 6.7 (range 0.8 to 16.6) years. The mean hemoglobin was 6.0 (range 2.5 to 8.1) g/dL. Seven patients were positive by a direct antiglobulin test, three were positive with cold agglutinins and two were positive on both tests. In seven cases, an acute infection appeared to be the precipitating factor. Mycoplasma pneumoniae infection was documented in three and suspected in another two cases. Peripheral erythrophagocytosis was present in five cases (42%) but was not found at diagnosis in any of the 16 cases of hereditary spherocytosis (p = 0.0081). Six children had pre-existing diseases, including two with hereditary hemolytic anemia. Conclusions: Peripheral erythrophagocytosis is a relatively common and characteristic finding in pediatric autoimmune hemolytic anemia and should be actively looked for in the evaluation of acute hemolysis, including in children with pre-existing hereditary hemolytic disorders. Full article

Autoimmune hemolytic anemias (AIHAs) are conditions involving the production of antibodies against one’s own red blood cells (RBCs). These can be primary with unknown cause or secondary (by association with diseases or infections). There are several different categories of AIHAs recognized according to their features in the direct antiglobulin test (DAT). (1) Warm-antibody AIHA (wAIHA) exhibits a pan-reactive IgG autoantibody recognizing a portion of band 3 (wherein the DAT may be positive with IgG, C3d or both). Treatment involves glucocorticoids and steroid-sparing agents and may consider IVIG or monoclonal antibodies to CD20, CD38 or C1q. (2) Cold-antibody AIHA due to IgMs range from cold agglutinin syndrome (CAS) to cold agglutin disease (CAD). These are typically specific to the Ii blood group system, with the former (CAS) being polyclonal and the latter (CAD) being a more severe and monoclonal entity. The DAT in either case is positive only with C3d. Foundationally, the patient is kept warm, though treatment for significant complement-related outcomes may, therefore, capitalize on monoclonal options against C1q or C5. (3) Mixed AIHA, also called combined cold and warm AIHA, has a DAT positive for both IgG and C3d, with treatment approaches inclusive of those appropriate for wAIHA and cold AIHA. (4) Paroxysmal cold hemoglobinuria (PCH), also termed Donath–Landsteiner test-positive AIHA, has a DAT positive only for C3d, driven upstream by a biphasic cold-reactive IgG antibody recruiting complement. Although usually self-remitting, management may consider monoclonal antibodies to C1q or C5. (5) Direct antiglobulin test-negative AIHA (DAT-neg AIHA), due to IgG antibody below detection thresholds in the DAT, or by non-detected IgM or IgA antibodies, is managed as wAIHA. (6) Drug-induced immune hemolytic anemia (DIIHA) appears as wAIHA with DAT IgG and/or C3d. Some cases may resolve after ceasing the instigating drug. (7) Passenger lymphocyte syndrome, found after transplantation, is caused by B-cells transferred from an antigen-negative donor whose antibodies react with a recipient who produces antigen-positive RBCs. This comprehensive review will discuss in detail each of these AIHAs and provide information on diagnosis, pathophysiology and treatment modalities. Full article

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition characterized by the presence of low levels of a monoclonal protein in the serum and a low percentage of clonal plasma cells in the bone marrow. MGUS may progress to multiple myeloma or other plasma cell disorders at a rate of 1% annually. However, MGUS may also have adverse effects on the cardiovascular system independent of its malignant potential. Emerging data have shown that MGUS is associated with cardiovascular disease. The mechanisms underlying this association are not fully understood but may involve genetic abnormalities, vascular calcification, cryoglobulinemia, cold agglutinin disease, autoantibodies and the direct or indirect effects of the monoclonal protein on the vascular endothelium. Herein, we review current evidence in this field and we suggest that patients with MGUS may benefit from regular cardiovascular risk assessment to prevent severe cardiovascular complications, in parallel with close hematological follow-up to monitor potential disease progression. Full article

The last 2 decades have seen great progress in understanding the pathogenesis of cold agglutinin disease (CAD) and development of effective therapies. Cold agglutinins can cause hemolytic anemia as well as peripheral circulatory symptoms such as acrocyanosis. We distinguish CAD, a well-defined clinicopathologic entity, from secondary cold agglutinin syndrome. This review addresses the histopathologic, immune phenotypic, and molecular features that allow CAD to be classified as a distinct clonal lymphoproliferative disorder of the bone marrow, recently recognized in the WHO classification. We discuss recent data on the possible overlap or distinction between CAD and Waldenström’s macroglobulinemia. Two major steps in the pathogenesis of CAD are identified: clonal B-cell lymphoproliferation (leading to monoclonal IgM production) and complement-mediated hemolysis. Each of these steps constitutes a target for treatment. Established as well as novel and experimental therapies are reviewed. Full article

Complement-mediated diseases or complementopathies, such as Paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), and transplant-associated thrombotic microangiopathy (TA-TMA), demand advanced complement diagnostics and therapeutics be adopted in a vast field of medical specialties, such as hematology, transplantation, rheumatology, and nephrology. The miracle of complement inhibitors as “orphan drugs” has dramatically improved morbidity and mortality in patients with otherwise life-threatening complementopathies. Efficacy has been significantly improved by upstream inhibition in patients with PNH. Different molecules may exert diverse characteristics in vitro and in vivo. Further studies remain to show safety and efficacy of upstream inhibition in other complementopathies. In addition, cost and availability issues are major drawbacks of current treatments. Therefore, further developments are warranted to address the unmet clinical needs in the field of complementopathies. This state-of-the-art narrative review aims to delineate novel insights into factor D inhibition as a promising target for complementopathies. Full article

Autoimmune hemolytic anemia (AIHA) is a rare disorder characterized by the autoantibody-mediated destruction of red blood cells, and treatments for it still remain challenging. Traditional first-line immunosuppressive therapy, which includes corticosteroids and rituximab, is associated with adverse effects as well as treatment failures, and relapses are common. Subsequent lines of therapy are associated with higher rates of toxicity, and some patients remain refractory to currently available treatments. Novel therapies have become promising for this vulnerable population. In this review, we will discuss the mechanism of action, existing data, and ongoing clinical trials of current novel therapies for AIHA, including B-cell-directed therapy, phagocytosis inhibition, plasma cell-directed therapy, and complement inhibition. Full article

Cold agglutinin disease (CAD) is a distinct clinicopathologic entity characterized by clonal B-cell lymphoproliferative disorder in the bone marrow. B-cell gene mutations affect NF-ΚB as well as chromatin modification and remodeling pathways. Clonal immunoglobulins produced by B cells bind to red cells (RBCs) at cold temperatures causing RBC aggregation, complement cascade activation and cold-autoantibody autoimmune hemolytic anemia (cAIHA). The clinical picture shows cold-induced symptoms and cAIHA. Therapeutic options include “wait and watch”, rituximab-based regimens, and complement-directed therapies. Steroids must not be used for treating CAD. New targeted therapies are possibly identified after recent molecular studies. Full article

Chronic lymphocytic leukemia (CLL) patients have a greater predisposition to develop autoimmune complications. The most common of them is autoimmune hemolytic anemia (AIHA) with a frequency of 7–10% of cases. Pathogenesis is multifactorial involving humoral, cellular, and innate immunity. CLL B-cells have damaged apoptosis, produce less immunoglobulins, and could be responsible for antigen presentation and releasing inflammatory cytokines. CLL B-cells can act similar to antigen-presenting cells activating self-reactive T helper cells and may induce T-cell subsets imbalance, favoring autoreactive B-cells which produce anti-red blood cells autoantibodies. Treatment is individualized and it depends on the presence and severity of clinical symptoms, disease status, and comorbidities. Corticosteroids are the standardized first-line treatment; second-line treatment comprises rituximab. Patients not responding to corticosteroids and rituximab should be treated with CLL-specific drugs as per current guidelines according to age and comorbidities. New targeted drugs (BTK inhibitors and anti BCL2) are recently used after or together with steroids to manage AIHA. In the case of cold agglutinin disease, rituximab is preferred, because steroids are ineffective. Management must combine supportive therapies, including vitamins; antibiotics and heparin prophylaxis are indicated in order to minimize infectious and thrombotic risk. Full article

An 83-year-old woman was admitted to the emergency department for a 7-day history of fatigue and progressive cyanosis in the feet and hands after cold exposure despite physical protective measures. Upon arrival, the patient presented with necrotic cutaneous lesions in both hands and distal lower extremities. Upon admission, hemoglobin was 7.6 g/dL and laboratory tests were consistent with cold agglutinin disease (CAD), the presence of monoclonal IgM, and flow cytometry consistent with lymphoplasmacytic lymphoma, but MYD88 L265P mutation was negative. The patient required blood transfusion, resulting in stabilized hemoglobin and a decrease in markers of hemolysis. Treatment with aspirin 250 mg daily and intravenous iloprost 0.5 mL/h was initiated with a poor clinical response at day 4. Amputation was required. Plasma exchange was performed and chemotherapy with rituximab and bendamustine was initiated. The clinical course was marked by further necrosis, prompting discussions regarding an additional amputation that was not performed considering the high surgical risk and refusal by the patient. Supportive treatment was initiated, and the patient expired one month after hospital admission. Full article

Autoimmune hemolytic anemia (AIHA) is a rare disease in children, presenting with variable severity. Most commonly, warm-reactive IgG antibodies bind erythrocytes at 37 °C and induce opsonization and phagocytosis mainly by the splenic macrophages, causing warm AIHA (w-AIHA). Post-infectious cold-reactive antibodies can also lead to hemolysis following the patient’s exposure to cold temperatures, causing cold agglutinin syndrome (CAS) due to IgM autoantibodies, or paroxysmal cold hemoglobinuria (PCH) due to atypical IgG autoantibodies which bind their target RBC antigen and fix complement at 4 °C. Cold-reactive antibodies mainly induce intravascular hemolysis after complement activation. Direct antiglobulin test (DAT) is the gold standard for AIHA diagnosis; however, DAT negative results are seen in up to 11% of warm AIHA, highlighting the need to pursue further evaluation in cases with a phenotype compatible with immune-mediated hemolytic anemia despite negative DAT. Prompt supportive care, initiation of treatment with steroids for w-AIHA, and transfusion if necessary for symptomatic or fast-evolving anemia is crucial for a positive outcome. w-AIHA in children is often secondary to underlying immune dysregulation syndromes and thus, screening for such disorders is recommended at presentation, before initiating treatment with immunosuppressants, to determine prognosis and optimize long-term management potentially with novel targeted medications. Full article

Autoimmune hemolytic anemia is a rare condition characterized by destruction of red blood cells with and without involvement of complement. It is associated with significant morbidity and mortality. In warm autoimmune hemolytic anemia, less than 50% of patients remain in long-term remission following initial steroid therapy and subsequent therapies are required. Cold agglutinin disease is a clonal hematologic disorder that requires therapy in the majority of patients and responds poorly to steroids and alkylators. Rituximab has a favorable toxicity profile and has demonstrated efficacy in autoimmune hemolytic anemia in first-line as well as relapsed settings. Rituximab is the preferred therapy for steroid refractory warm autoimmune hemolytic anemia (wAIHA) and as part of the first- and second-line treatment of cold agglutinin disease. This article reviews the mechanism of action of rituximab and the current literature on its role in the management of primary and secondary warm autoimmune hemolytic anemia and cold agglutinin disease. Full article

Autoimmune hemolytic anemia (AIHA) is a highly heterogeneous disease due to increased destruction of autologous erythrocytes by autoantibodies with or without complement involvement. Other pathogenic mechanisms include hyper-activation of cellular immune effectors, cytokine dysregulation, and ineffective marrow compensation. AIHAs may be primary or associated with lymphoproliferative and autoimmune diseases, infections, immunodeficiencies, solid tumors, transplants, and drugs. The direct antiglobulin test is the cornerstone of diagnosis, allowing the distinction into warm forms (wAIHA), cold agglutinin disease (CAD), and other more rare forms. The immunologic mechanisms responsible for erythrocyte destruction in the various AIHAs are different and therefore therapy is quite dissimilar. In wAIHA, steroids represent first line therapy, followed by rituximab and splenectomy. Conventional immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine) are now considered the third line. In CAD, steroids are useful only at high/unacceptable doses and splenectomy is uneffective. Rituximab is advised in first line therapy, followed by rituximab plus bendamustine and bortezomib. Several new drugs are under development including B-cell directed therapies (ibrutinib, venetoclax, parsaclisib) and inhibitors of complement (sutimlimab, pegcetacoplan), spleen tyrosine kinases (fostamatinib), or neonatal Fc receptor. Here, a comprehensive review of the main clinical characteristics, diagnosis, and pathogenic mechanisms of AIHA are provided, along with classic and new therapeutic approaches. Full article