Cold Hemagglutinin Research Articles

Immunoglobulin M Monoclonal Gammopathies of Clinical Significance.

Immunoglobulin M monoclonal gammopathy of undetermined significance (MGUS) comprises 15-20% of all cases of MGUS. IgM MGUS is distinct from other forms of MGUS in that the typical primary progression events include Waldenstrom macroglobulinaemia and light chain amyloidosis. Owing to its large pentameric structure, IgM molecules have high intrinsic viscosity and precipitate more readily than other immunoglobulin subtypes. They are also more commonly associated with autoimmune phenomena, resulting in unique clinical manifestations. Organ damage attributable to the paraprotein, not fulfilling criteria for a lymphoid or plasma cell malignancy has recently been termed monoclonal gammopathy of clinical significance (MGCS) and encompasses an important family of disorders for which diagnostic and treatment algorithms are evolving. IgM related MGCS include unique entities such as cold haemagglutinin disease, IgM related neuropathies, renal manifestations and Schnitzler’s syndrome. The diagnostic approach to, and management of these disorders differs significantly from other categories of MGCS. We describe a practical approach to the evaluation of these patients and our approach to their treatment. We will also elaborate on the key unmet needs in IgM MGCS and highlight potential areas for future research.

Incidentally discovered cold hemagglutinin disease with massive blood clots in the cardioplegia line and coronary artery, during coronary artery bypass graft

BackgroundCold hemagglutinin disease (CHAD) is a rare autoimmune disease, in which patients manifest symptoms when the body temperature decreases. It causes critical problems with blood clotting and hemolysis during hypothermia in cardiac surgery. Although various methods are recommended, the CHAD discovered incidentally during cardiac surgery is still a clinical challenge.Case presentationA 76-year-old male visited our hospital for chest pain. Angiography revealed unstable angina, left-main and three-vessel disease. We performed coronary artery bypass graft (CABG) with cardiopulmonary bypass after heparin injection. Shortly after aorta cross-clamping (ACC) and infusion of cold blood cardioplegia, we found massive blood clots in the cardioplegia line. Upon suspicion of CHAD, we raised the temperature and infused warm blood cardioplegia in a retrograde manner. After performing cardiac arrest, we opened the coronary artery and found blood clots in the coronary artery. We eliminated the clots and washed with warm crystalloid cardioplegia simultaneously in an antegrade and retrograde manner. During the ACC, warm cardioplegia was infused every 15 min, via retrograde and antegrade techniques simultaneously. After distal anastomosis of the saphenous venous graft (SVG) to the coronary artery, we performed a direct SVG warm cardioplegia infusion. Finally, before the proximal SVG anastomosis to the aorta, we used warm cardioplegia to eliminate the remaining microemboli. The cold reactive protein test showed a positive result. The patient was discharged without any complications.ConclusionIn this rare case, we incidentally discovered CHAD associated with massive blood clots in the cardioplegia line and the coronary artery, during CABG. However, we performed CABG without any complications using a reasonable and appropriate cardioplegia infusion technique, including direct SVG warm cardioplegia infusion.

Second-line therapy in paediatric warm autoimmune haemolytic anaemia. Guidelines from the Associazione Italiana Onco-Ematologia Pediatrica (AIEOP).

Autoimmune haemolytic anaemia (AIHA) is a rare condition in children caused by the presence of auto-antibodies directed against red blood cell surface antigens, leading to premature red cell destruction1,2. It is classified as warm, cold, including cold haemagglutinin disease and paroxysmal cold haemoglobinuria, or mixed, according to the thermal range of the auto-antibody. AIHA can be idiopathic or secondary. The overall annual incidence is reported to be 1–3 cases/100,000 people and approximately 0.2 cases/1,000,000 individuals less than 20 years of age3–7. AIHA constitutes an important issue for many paediatricians who often have to deal with the diagnosis and treatment of critical patients in the absence of consistent support from the literature. This is particularly true for the second-line therapy. Indeed, while there is an established common practice about management of the acute phase of the disease, including diagnostic work-up and first-line therapy8,9, second-line therapy is more debated. On the basis of these considerations, the Red Cell Working Group of the AIEOP (Associazione Italiana di Ematologia ed Oncologia Pediatrica) developed this consensus paper with the objective of providing shared recommendations to paediatricians.

Anaesthetic management for cardiac surgery in patients with cold haemagglutinin disease.

Cold haemagglutination is a primary or acquired autoimmune disease involving antibodies that lead to agglutination of red blood cells at low temperature followed by complement fixation and haemolysis on rewarming. This disease can lead to adverse consequences in patients undergoing cardiothoracic surgery, especially when hypothermic cardiopulmonary bypass is applied. The authors discuss the management of two patients who underwent mitral valve replacement surgery while cold agglutinins were detected in the perioperative period. In the first patient, the diagnosis was made preoperatively followed by administration of glucocorticoids to achieve acceptable level of antibody titers. The second patient experienced haemoglobinuria during her intensive care unit stay. The case report describes the pathophysiology of cold agglutination, relevant laboratory investigations such as antibody titers and thermal amplitude, identification of at-risk patients, and management strategies to avoid serious complications.

Solving cases in autoimmune haemolytic anaemia

Autoimmune haemolytic anaemia (AIHA) can be classified in different types including warm AIHA (WAIHA), cold haemagglutinin disease (CHAD), mixed‐type AIHA, paroxysmal cold haemoglobinuria and drug‐induced AIHA. Warm AIHA (WAIHA) is the most common type of AHAI characterized by warm autoantibodies primarily IgG (rarely IgM or IgA) reacting best at 37°C. Most are directed against the Rh protein, and over 90% of cases have a positive Direct Antiglobulin Test (DAT). The patient's plasma contains autoantibodies that appear as a panagglutinin, and the biggest concern is that they mask the presence of alloantibodies. It is important to rule out, or identify, alloantibodies in the plasma/serum, and identification of the autoantibody specificity is rarely useful. The serologic work required to detect and identify underlying alloantibodies may include multiple autologous adsorptions and elutions, and once a patient is transfused, alloantibody identification becomes more difficult, requiring allogeneic adsorptions. Molecular testing is also being used as a valuable method to predict the extended red cell antigen profile in order to select antigen‐negative red‐blood‐cells for adsorption of autoantibodies when searching for underlying alloantibodies and to provide extended matched units to the patients. Considering that patients with AIHA become alloimmunized much more commonly than other patients, it is very important that efficient procedures for detecting underlying alloantibodies, although labour‐intensive, must be used in pretransfusion testing.

Autoimmune haemolytic anaemia

Autoimmune haemolytic anaemia (AIHA) can be classified as warm or cold type and may be either idiopathic (primary) or secondary to haematological malignancy, infection or other conditions that result in immune dysregulation. Presentation can vary from the gradual onset of symptomatic anaemia, to an acute fulminant episode of life‐threatening haemolysis. Management, which is not evidence based, largely entails the use of initial corticosteroids for primary warm‐type AIHA with either splenectomy, rituximab or alternative immunosuppression for those requiring second‐line therapy. Rituximab is now considered a first‐line therapy for primary cold haemagglutinin disease. Transfusion may be needed as a supportive measure particularly with severe acute haemolysis and requires close liaison between clinical and laboratory teams to ensure appropriate selection of red cell units in a timely manner.

Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients

AbstractThe clinical outcome, response to treatment, and occurrence of acute complications were retrospectively investigated in 308 primary autoimmune hemolytic anemia (AIHA) cases and correlated with serological characteristics and severity of anemia at onset. Patients had been followed up for a median of 33 months (range 12-372); 60% were warm AIHA, 27% cold hemagglutinin disease, 8% mixed, and 5% atypical (mostly direct antiglobulin test negative). The latter 2 categories more frequently showed a severe onset (hemoglobin [Hb] levels ≤6 g/dL) along with reticulocytopenia. The majority of warm AIHA patients received first-line steroid therapy only, whereas patients with mixed and atypical forms were more frequently treated with 2 or more therapy lines, including splenectomy, immunosuppressants, and rituximab. The cumulative incidence of relapse was increased in more severe cases (hazard ratio 3.08; 95% confidence interval, 1.44-6.57 for Hb ≤6 g/dL; P < .001). Thrombotic events were associated with Hb levels ≤6 g/dL at onset, intravascular hemolysis, and previous splenectomy. Predictors of a fatal outcome were severe infections, particularly in splenectomized cases, acute renal failure, Evans syndrome, and multitreatment (4 or more lines). The identification of severe and potentially fatal AIHA in a largely heterogeneous disease requires particular experienced attention by clinicians.

Treatment of autoimmune hemolytic anemias

Autoimmune hemolytic anemia (AIHA) is a relatively uncommon disorder caused by autoantibodies directed against self red blood cells. It can be idiopathic or secondary, and classified as warm, cold (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria) or mixed, according to the thermal range of the autoantibody. AIHA may develop gradually, or have a fulminant onset with life-threatening anemia. The treatment of AIHA is still not evidence-based. The first-line therapy for warm AIHA are corticosteroids, which are effective in 70-85% of patients and should be slowly tapered over a time period of 6-12 months. For refractory/relapsed cases, the current sequence of second-line therapy is splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%), rituximab (effective in approx. 80-90% of cases), and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are intravenous immunoglobulins, danazol, plasma-exchange, and alemtuzumab and high-dose cyclophosphamide as last resort option. As the experience with rituximab evolves, it is likely that this drug will be located at an earlier point in therapy of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some cases. In CAD, rituximab is now recommended as first-line treatment.

Sustained response to low‐dose rituximab in idiopathic autoimmune hemolytic anemia

To evaluate the sustained response to low-dose (LD) rituximab in autoimmune hemolytic anemia (AIHA), the ex vivo effect on anti-RBC antibody production by mitogen-stimulated direct antiglobulin test (MS-DAT), and the in vitro dose effect of the drug on the production of anti-RBC antibodies. Thirty two patients, 18 warm (W) AIHA and 14 cold hemagglutinin disease (CHD), were treated with LD rituximab (100 mg fixed dose ×4 weekly infusions) along with a short course of oral prednisone. Complete clinical examination, blood counts, and hemolytic markers were performed at enrollment and at month 6, 12, 24, and 36. Hematological parameters significantly improved at all time points compared to enrollment. The overall response was 90%, 100%, 100%, and 89% and the relapse-free survival 87%, 79%, 68%, and 68% at 6, 12, 24, and 36 months, respectively. Response rates were slightly better in WAIHA than in CHD, and relapse risk was greater in cold than warm forms (HR 2.1, 95% CI 0.6-7.9). Four patients were retreated (one patient twice), all achieving a response, lasting a median of 18 months (range 9-30). Treatment was well tolerated without adverse events or infections. Anti-RBC antibody production by MS-DAT significantly decreased over time. In vitro studies showed that rituximab effectively inhibited anti-RBC antibody production at 50 μg/mL, 1/6 of the drug concentration after therapy with standard doses. These data confirm that LD rituximab treatment is effective and induces sustained responses in AIHA, and that a lower dose of the drug is enough to down-regulate autoantibody production.

Neumonía por Mycoplasma pneumoniae complicada con anemia hemolítica por aglutininas frías

Paciente mujer de 36 años de edad, quien consulta por síntomas respiratorios de dos semanas de&#x0D; evolución, con diagnóstico de ingreso de neumonía adquirida en la comunidad. Evolución clínica&#x0D; complicada con anemia hemolítica por hemaglutininas frías que hace sospechar infección neumónica&#x0D; por Mycoplasma pneumoniae, confirmada mediante serología. Tras curso corto de prednisona&#x0D; oral, ácido fólico y antibioticoterapia, se presenta resolución de la anemia y mejoría clínica de la&#x0D; neumonía. Este informe de caso resalta la elevada amplitud térmica de las aglutininas frías como&#x0D; condición para generar hemólisis inmune y la ausencia de reticulocitosis compensatoria de la hemólisis,&#x0D; complicaciones inusuales en neumonía por Mycoplasma pneumoniae, pero determinantes&#x0D; de la severidad de la anemia. Además, enfatiza la utilidad de los títulos de aglutininas frías en el&#x0D; diagnóstico de neumonía adquirida en la comunidad debida a Mycoplasma pneumoniae

Cold agglutinins in patients undergoing cardiac surgery requiring cardiopulmonary bypass

Cold agglutinins (CA) are circulating autoantibodies present in most humans. They are active below normal body temperatures. Cold hemagglutinin disease involves the presence of CA sufficiently active at temperatures in the periphery to produce hemolysis or agglutination. Systemic hypothermia and cold cardioplegia may result in agglutination or hemolysis. We reviewed the experience of a large referral center in managing patients with CA and cold hemagglutinin disease undergoing cardiac surgery requiring cardiopulmonary bypass. The electronic medical records from 2002 to 2010 were searched to identify patients with CA or cold hemagglutinin disease who underwent cardiac surgery requiring cardiopulmonary bypass. Information related to preoperative CA testing and treatment, surgery, cardiopulmonary bypass, postoperative complications, and mortality was recorded. Sixteen patients underwent 19 procedures requiring cardiopulmonary bypass. Six patients had cold hemagglutinin disease. The identification of CA was made intraoperatively in 3 patients. One patient underwent preoperative plasma exchange. Cold blood cardioplegia was used in 2 of 16 procedures using cardioplegia, with the remaining using warmer blood cardioplegia. The lowest recorded intraoperative core temperature was less than 34 °C in 1 case. CA-related postoperative hemolysis requiring transfusion was present in 1 patient, which was resolved with active warming. No patient had evidence of permanent myocardial dysfunction, had a neurologic event, required dialysis, or died within 30 days. All patients with CA/cold hemagglutinin disease at the Mayo Clinic College of Medicine safely underwent cardiac surgery without major adverse morbidity or mortality. Patients with CA but without evidence of cold hemagglutinin disease can safely undergo normothermic cardiopulmonary bypass at 37°C and warm cardioplegia without further testing. Patients with cold hemagglutinin disease should undergo laboratory testing including CA titers and thermal amplitude and hematology consultation before cardiac surgery.

Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies

AbstractThis prospective study investigated the efficacy, safety, and response duration of low-dose rituximab (100 mg fixed dose for 4 weekly infusions) together with a short course of steroids as first- or second-line therapy in 23 patients with primary autoimmune hemolytic anemia (AIHA). The overall response was 82.6% at month +2, and subsequently stabilized to ∼ 90% at months +6 and +12; the response was better in warm autoimmune hemolytic anemia (WAIHA; overall response, 100% at all time points) than in cold hemagglutinin disease (CHD; average, 60%); the relapse-free survival was 100% for WAIHA at +6 and +12 months versus 89% and 59% in CHD, respectively, and the estimated relapse-free survival at 2 years was 81% and 40% for the warm and cold forms, respectively. The risk of relapse was higher in CHD and in patients with a longer interval between diagnosis and enrollment. Steroid administration was reduced both as cumulative dose (∼ 50%) and duration compared with the patient's past history. Treatment was well tolerated and no adverse events or infections were recorded; retreatment was also effective. The clinical response was correlated with amelioration biologic markers such as cytokine production (IFN-γ, IL-12, TNF-α, and IL-17), suggesting that low-dose rituximab exerts an immunomodulating activity. This study is registered at www.clinicaltrials.gov as NCT01345708.

Case report: retinopathy in a patient with cold hemagglutinin disease.

We describe abnormalities of retinal vasculature and blood flow in a patient with cold hemagglutinin disease. Case report and literature review using the PubMed database. A man with cold hemagglutinin disease and no visual symptoms was referred to the Eye Department with retinal abnormalities found during a routine optometrist examination. He was found to have scattered retinal hemorrhages, abnormal retinal vasculature resembling neovascularization (but that did not show leakage on fundus fluorescein angiography), and aggregated material flowing visibly in the retinal vessels. No specific descriptions of retinopathy related to cold hemagglutinin disease have been previously published. We suggest that the abnormalities are secondary to areas of retinal ischemia, resulting in the development of a form of collateral circulation.

Rituximab in Lymphoma Associated Auto-Immune Haemolytic Anemia

AbstractAbstract 4923The association of Autoimmune hemolytic and Non Hodgkin's lymphoma is a known phenomenon. Cold hem agglutinin disease (CHD), is an uncommon Autoimmune hemolytic anemia, mediated by cold reactive auto antibodies that bind to erythrocyte carbohydrate antigen causing hem agglutination and complement mediated hemolysis. Cold agglutinin–mediated hemolysis occurs at low temperature which may be severe and difficult to treat.CHD may be primary when it is idiopathic or secondary as in lympho-proliferative disorder of bone marrow associated with clonal proliferation of CD20 B cells that produce monoclonal 1g M cold agglutinin (kappa /lamda). Rituximab has been used as an as a novel treatment option in Autoimmune hemolytic anemia. Rituximab is a genetically engineered chimeric monoclonal antibody that targets the CD20 antigen on B cells.Rituximab in autoimmune conditions possibly acts by destruction of CD20_clonotypic precursor B cells and/or CD20 plasma cells, thus is effective in controlling immunoglobulin-mediated diseases of B lymphocytes.We analysed four patients of lymphoma with severe CHD who were successfully treated with the chimeric anti-CD20 monoclonal Rituximab (375mg/ m2) intravenously every three weeks for four to six cycles, till the Agglutinins disappeared from the serum. Patient and methodIn this study patients diagnosed with lymphoma associated CHD were treated with Rituximab with a dose of 375mg/ meter square given every three weeks for four to six cycles, till the primary aim was achieved. The primary aim was correction of anemia, disappearance of cold hem-agglutinins from serum, assessed by complete blood counts and measuring cold agglutinins in serum.Four such patients were studied, all of them had NHL-DLBCL (IHC proven), with severe hemolysis and jaundice with Hemoglobin <5 gm/ dl. All had presence of cold agglutinins in the serum and were positive for direct and indirect coomb's test. ResponseAll the patients showed significant improvement in the symptoms due to anemia and there was a rise in hemoglobin detected within the first week of Rituximab treatment. They achieved normal levels of hemoglobin with four to six weeks of treatment and in three patients cold agglutinins disappeared after completion of five cycles and the fourth patients had it after the sixth cycle. None of the patients was given any transfusion because of incompatibility issues. ConclusionOur experience with Rituximab was excellent in this indication and patients had a good overall outcome. Further trials need to be done for more evidence in this regard. Disclosures:No relevant conflicts of interest to declare.

Low-Dose Rituximab In Idiopathic Autoimmune Hemolytic Anemia: Biological Studies

AbstractAbstract 3206 Background:Conventional therapy of warm autoimmune hemolytic anemia (WAIHA) include administration of corticosteroids and immunosuppressive agents, or splenectomy, whereas no effective treatment exists for cold hemagglutinin disease (CHD). A substantial proportion of patients with WAIHA do not respond to or relapse after corticosteroid therapy and may experience clinically relevant side effects. Favorable responses to rituximab at standard doses (375 mg/m2 weekly for 4–6 courses) have been reported in both WAIHA and CHD, idiopathic or secondary, as well as in other autoimmune diseases, such as rheumatoid arthritis and primary immune thrombocytopenia. Recently, low dose (LD)-rituximab (100 mg fixed dose weekly for 4 courses) has been proven effective in patients with autoimmune cytopenias, particularly immune thrombocytopenia. Aims:To evaluate the safety, activity and the duration of the response of LD-rituximab associated with standard oral prednisone (PDN) as first line therapy in newly diagnosed WAIHA and CHD, and as second line therapy in WAIHA relapsed after standard oral PDN. To correlate the clinical response to biological parameters (cytokine and anti-erythrocyte antibody production). Methods:In this single-arm prospective pilot study, LD-rituximab was administered at 100 mg fixed dose weekly on days +7, +14, +21, +28 along with standard oral PDN (1 mg/kg/die p.o. from day +1 to + 30, followed by quick tapering: 10 mg/week until 0.5/mg/kg/die, then 5 mg/week until stop). Complete and partial initial responses (iCR and iPR) were defined as Hb >/= 12 g/dL and >/= 10 g/dL at month +2 from the beginning of therapy, respectively; sustained response (SR) was defined as Hb >/= 10 g/dL at month +6 and +12, in the absence of any treatment. Mitogen stimulated cultures were performed to measure anti-RBC antibodies (at enrolment and month +1, +3, +6 and +12) and cytokines (at enrolment and month, +3, and +6) by ELISA. Results:Twenty-one patients (14 female, 7 male; median age 52 yrs, range 28–77) were enrolled after informed consent. The median follow-up was 11 months (range 2–25). An iCR and iPR were observed in 14 (67%) and 4 (19%) out of 21 patients, respectively; the median Hb level increased from 9.1 g/dL (range 4.4–12.3) at enrolment to 12.5 g/dL (range 9.1–15.3) at month +2. A SR at month +6 was observed in 13/14, and at month +12 in 11/11 evaluable patients. A total of 3 patients relapsed: one at month +16 (retreated with the same protocol with iPR at month +18), another at month +7 (retreated with a SR at month +13), ad the last at month +5 (splenectomy planned). No side effects or serious adverse events were observed. For 10 relapsed AIHA patients (with a follow-up post treatment of at least 12 months) laboratory data (Hb, LDH, reticulocytes) and steroid administration were available before LD-rituximab treatment: a lower cumulative dose (roughly 50%) of steroid was administered to patients during LD-rituximab study compared with previous therapy, without significant differences in the general trend of Hb, LDH, and reticulocytes. Biological studies showed that anti-RBC antibody production decreased until month +6 (from 556 ng/ml at enrolment to 125 ng/ml) and slightly increased at month +12 (307 ng/ml). Regarding cytokine production, at enrolment TNF-α, IFN-γ, IL-12 and TGF-β were lower in patients vs controls, and increased at month +6, without reaching normal values. IL-17 was 10-fold normal values at enrolment, and diminished during the follow-up without reaching normal values. These preliminary results seem to indicate that the addition of LD-rituximab to standard corticosteroid therapy is a feasible and active treatment in AIHA. Data on SR are intriguing, particularly regarding the possible steroid sparing effect of LD-rituximab. Cytokine and anti-erythrocyte antibody production offer new insights into the immunomodulating activity of the drug. Disclosures:No relevant conflicts of interest to declare.

Successful rituximab therapy in the treatment of refractory cold haemagglutinin disease with long‐term disease control

Successful rituximab therapy in the treatment of refractory cold haemagglutinin disease with long‐term disease control

Low-Dose Rituximab in Idiopathic Autoimmune Hemolytic Anemia.

Abstract 4027Poster Board III-963 BackgroundConventional therapy of warm autoimmune hemolytic anemia (WAIHA) include administration of corticosteroids and immunosuppressive agents, or splenectomy, whereas no effective treatment exists for cold hemagglutinin disease (CHD). A substantial proportion of patients with WAIHA do not respond to or relapse after corticosteroid therapy and may experience clinically relevant side effects. Favorable responses to rituximab at standard doses (375 mg/m2 weekly for 4-6 courses) have been reported in both WAIHA and CHD, idiopathic or secondary, as well as in other autoimmune diseases, such as rheumatoid arthritis and primary immune thrombocytopenia. Recently, low dose (LD) rituximab (100 mg fixed dose weekly for 4 courses) has been proven effective in patients with autoimmune cytopenias, particularly immune thrombocytopenia. AimsTo evaluate the safety, activity and the duration of the response of LD rituximab associated with standard oral prednisone (PDN) as first line therapy in newly diagnosed WAIHA and CHD, and as second line therapy in WAIHA relapsed after standard oral PDN. MethodsIn this single-arm prospective pilot study, LD-rituximab was administered at 100 mg fixed dose weekly on days +7, +14, +21, +28 along with standard oral PDN (1 mg/kg/die p.o. from day +1 to + 30, followed by quick tapering: 10 mg/week until 0.5/mg/kg/die, then 5 mg/week until stop). Complete and partial initial responses (iCR and iPR)) were defined as Hb ≥ 12 g/dL and ≥ 10 g/dL at month +2 from the beginning of therapy, respectively; sustained response (SR) was defined as Hb ≥ 10 g/dL at month +6 and +12, in the absence of any treatment. ResultsTwelve patients (6 female, 6 male; median age 49 yrs, range 28-65) were enrolled. A iCR and iPR were observed in 6 and 4 out of 12 patients, respectively; the median Hb level increased from 9.9 g/dL (range 6.1-12.3) at enrolment to 12.3 g/dL (range 9.5-14.9) at month +2. A SR at month +6 was observed in 7 out of 7 evaluable patients, and in the first 2 patients enrolled at month +12. No side effects or serious adverse events were observed. For 9 relapsed AIHA patients laboratory data (Hb, LDH, reticulocytes) and steroid administration were available before LD rituximab treatment: a lower cumulative dose (roughly 50%) of steroid was administered to patients during LD rituximab study compared with previous therapy, without significant differences in the general trend of Hb, LDH, and reticulocytes. ConclusionsThese preliminary results seem to indicate that the addition of LD rituximab to standard corticosteroid therapy is a feasible and active treatment in AIHA. Data on SR are intriguing, particularly regarding the possible steroid sparing effect of LD rituximab, but need to be confirmed in larger survey and after longer follow up. Disclosures:No relevant conflicts of interest to declare.

An IgM Lambda Monoclonal Antibody in a Patient with Anti-Pr Cold Agglutinin Causing Erythrocyte Agglutination and Catastrophic Thrombosis

Erythrocyte agglutination causing microvascular occlusion is a rare albeit clinically significant event. This is seen in cold agglutinin disease and in cerebral malaria caused by Plasmodium falciparum. We studied a patient with autoimmune hemolytic anemia, characterized by massive hemolysis and the presence of both an anti-Pr antibody and a cold hemagglutinin. In addition, he suffered from catastrophic mesenteric ischemia necessitating surgical resection and extensive and multiple ischemia strokes. His surgical specimens, including colon, ileum and gall bladder, were studied with informed consent. Eluate from his agglutinated erythrocytes showed that he had an IgM lambda monoclonal antibody against the Pr antigen. The patient's peripheral blood showed extensive erythrocyte agglutination that was worse at cold temperatures. H&E staining of the colon and ileum showed ischemia and necrosis with widespread microvascular occlusion caused by agglutinated erythrocytes. To characterize the intravascular agglutinated erythrocytes, immunoperoxidase staining was done and positive for IgM and lambda light chain and negative for IgG and kappa light chain. We thus concluded that the cold agglutinin on the intravascular agglutinated erythrocytes was an IgM lambda. To investigate why the circulating agglutinated erythrocytes resulted in widespread microvascular occlusion, we studied adhesive molecules including CD 62E (E-selectin), CD62P (P-selectin), CD54 (ICAM-1) and CD 106 (VCAM-1) and found all of them expressed on the agglutinated erythrocytes within the occluded vessels and on the endothelial cells of the involved vessels. The data suggests that the endothelial cells were activated at the site of vascular occlusion, thereby promoting adhesion of the agglutinated erythrocytes to the vascular endothelium.

Cold haemagglutinin disease misdiagnosed as hand-arm vibration syndrome

A patient with a diagnosis of hand-arm vibration syndrome was referred for a second opinion. He worked as a multi-skilled operative in the housing department of a local authority, a job not normally associated with high levels of exposure to hand-transmitted vibration ( > 2.5 m/s(2) A(8)). He described blanching of his fingers and a blue discolouration of his extremities in cold weather. On examination, his fingertips, toes and pinnae were acrocyanotic, the fingers were patchily pale and sensation was subjectively impaired in all of the digits. Investigations revealed a haemolytic anaemia and haemagglutination. He was diagnosed with idiopathic cold haemagglutinin disease. Exposure to vibration may confound with exposure to cold in which case the differential diagnoses of cold haemagglutinin disease or cryoglobulinaemia should be excluded before diagnosing hand-arm vibration syndrome.

Management of Cold Agglutinin–Immune Hemolytic Anemia in Pregnancy

Cold hemagglutinin disease is an acquired autoimmune hemolytic anemia caused by an immunoglobulin M autoantibody directed against the polysaccharide antigens on the red blood cell surface. This case presents the challenges surrounding the management of cold hemagglutinin disease in pregnancy. A pregnant woman in her thirties with type-2 diabetes, reporting shortness of breath and productive cough, was found to have anemia, reticulocytosis, bilirubinemia, positive direct Coombs test result, positive cold agglutinin antibody, and raised lactate dehydrogenase levels. As the infection screen and autoimmune serology results were negative, she was diagnosed as having idiopathic cold hemagglutinin disease. The management included keeping the patient warm and hydrated and treating the anemia with warm packed red blood cell transfusion. Cold hemagglutinin disease is a rare condition. Investigations to rule out infections help determine the diagnosis of cold hemagglutinin disease of unknown origin.