Warm-antibody Hemolytic Anemia Research Articles

Discovery of Sovleplenib, a Selective Inhibitor of Syk in Clinical Development for Autoimmune Diseases and Cancers.

Herein we describe the medicinal chemistry efforts that led to the discovery of the clinical-staged Syk inhibitor sovleplenib (41) via a structure-activity relationship investigation and pharmacokinetics (PK) optimization of a pyrido[3,4-b]pyrazine scaffold. Sovleplenib is a potent and selective Syk inhibitor with favorable preclinical PK profiles and robust anti-inflammation efficacy in a preclinical collagen-induced arthritis model. Sovleplenib is now being developed for treating autoimmune diseases such as immune thrombocytopenic purpura and warm antibody hemolytic anemia as well as hematological malignancies.

A Rare Case of Bleeding - Acquired Factor Inhibitors with Normal Coagulation Tests

Introduction: Acquired Factor XIII deficiency due to an antibody inhibitor (AIFXIII) is a rare but life-threatening bleeding disorder. Factor XIII is a fibrin stabilizing enzyme that crosslinks fibrin monomers. Deficiency of Factor XIII results in destabilization of formed clots within 24-48 hours, resulting in delayed hemorrhage. Because the standard coagulation tests are normal, the diagnosis of this disease requires a high degree of suspicion and specialized testing. We report a case of an 88-year-old female presenting with severe hemorrhage of unknown origin.Goal: We aim to heighten the awareness amongst clinicians of the possibility of acquired FXIII deficiency when a patient presents with bleeding symptoms and normal routine coagulation tests.Case: An 88-year-old female with a recent diagnosis of autoimmune hemolytic anemia (AIHA) on oral Prednisone developed left arm swelling, pain, and ecchymosis. She denied anticoagulation and history of abnormal bleeding. CT scan of the arm showed a biceps muscle hematoma measuring 17cm in length. On day 4, she developed hematoma on the contralateral forearm, which prompted bilateral fasciotomies and evacuation. Patient continued to have bleeding from her right forearm hematoma, requiring further exploration and evacuation of multiple clots.Laboratory Tests: Her Hg dropped from 9.2 g/dl to 6.6 g/dl requiring RBC transfusions. Peripheral blood smear revealed features of chronic hemolysis. She had a normal coagulation profile including PT (11.1 sec), INR (1.05), PTT (24.4 sec), fibrinogen (295mg/dL) and normal platelet function assay. Her D-dimer was elevated at 371 ng/ml. She had a normal CRP (3.3mg/L), ANA antibody (<1:40) and ESR (23 mm/hr). SPEP showed hypoproteinemia without monoclonal bands. The patient's FVIII (307%), VWF ag (307%), VWF activity (369%), VWF collagen binding assay (412%) and alpha-2-antiplasmin (101%) were normal. Patient's Factor XIII levels were measured at 8%. We suspected this to be a case of AIFXIII. Testing for inhibitor with serial dilutions showed an antibody titer of 1:40.Results: She was started on 100 mg/d of Cyclophosphamide and continued on 20mg of Prednisone. No further hematomas developed. Patient was discharged on day 29 with a close follow up. On day 66, patient had AIHA flare (Hg: 6.6g/dL) and was treated with PRBCs, Rituximab 375mg/m^2 for 4 infusions and prednisone 40mg daily. Her Factor XIII activity on day 68 was 12% and inhibitor titer 1:10. On day 98, patient developed large ecchymoses on the right knee, thigh and buttock. Her Factor XIII activity dropped to < 10% again and inhibitor titer went up to 1:20 on serial dilution. She was transfused with PRBCs and was started on IVIG at 1000 mg/kg X 5. Cyclophosphamide was stopped and Prednisone was decreased to 10mg daily. Her Factor XIII is still <10% but inhibitor titer is down to 1:10. Patient is not actively bleeding.Discussion: There are less than 60 reported cases of AIFXIII in the literature. This is the first reported case presenting with warm antibody hemolytic anemia. Various treatments have been employed in the past for AIFXIII. It involves two strategies: hemostasis to treat acute bleeding symptoms and inhibitor eradication. Use of steroids and immunosuppressants such as Cyclophosphamide, Rituximab, and Cyclosporine has been prevalent in most of the cases to obtain inhibitor eradication. It is hard to define what combination of therapy works because most of the cases involve use of combination of these strategies and spontaneous remissions have also been seen. In this case, we suspect that patient presented with higher than expected factor XIII activity (8%) at the onset because she was already on immunosuppression for her AIHA for 2 months prior. She was refractory to first-line therapy with Rituximab and Cyclophosphamide in combination with steroids for complete inhibitor eradication. Second line therapy with IVIG was recently given and we are hopeful of a response.Conclusion: AIFXIII is a rare but life-threatening bleeding disorder that should be suspected especially when elderly patients present with hemorrhage of unknown origin and normal screening coagulation studies. Characterization of the factor XIII activity and detection of antibodies should be undertaken promptly in order to provide the best anti-hemorrhagic and inhibitor eradication treatment. DisclosuresNo relevant conflicts of interest to declare.

The role of rituximab in adults with warm antibody autoimmune hemolytic anemia

AbstractWarm antibody hemolytic anemia is the most common form of autoimmune hemolytic anemia. When therapy is needed, corticosteroids remain the cornerstone of initial treatment but are able to cure only a minority of patients (<20%). Splenectomy is usually proposed when a second-line therapy is needed. This classical approach is now challenged by the use of rituximab both as second-line and as first-line therapy. Second-line treatment with rituximab leads to response rates similar to splenectomy (∼70%), but rituximab-induced responses seem less sustained. However, additional courses of rituximab are most often followed by responses, at the price of reasonable toxicity. In some major European centers, rituximab is now the preferred second-line therapy of warm antibody hemolytic anemia in adults, although no prospective study convincingly supports this attitude. A recent randomized study strongly suggests that in first-line treatment, rituximab combined with steroids is superior to monotherapy with steroids. If this finding is confirmed, rituximab will emerge as a major component of the management of warm antibody hemolytic anemia not only after relapse but as soon as treatment is needed.

Splenic infarction, warm autoimmune hemolytic anemia and antiphospholipid antibodies in a patient with infectious mononucleosis

An 18-year-old woman with infectious mononucleosis developed splenic infarction and severe anemia. Evaluation of her anemia revealed a warm autoantibody and a persistently prolonged partial thromboplastin time that ultimately led to the identification of antiphospholipid antibodies. Although the warm autoantibody disappeared after 2 months, the antiphospholipid antibodies remained persistently positive. To our knowledge, this is the first case report in the literature of this specific constellation of findings, with infectious mononucleosis, warm antibody hemolytic anemia, splenic infarction and persistently positive, high-titer antiphospholipid antibodies occurring in an individual patient.

Induction of Heme Oxygenase-1 and Ferritin in the Kidney in Warm Antibody Hemolytic Anemia

Warm antibody autoimmune hemolytic anemia usually is associated with extravascular hemolysis. We report a case of a 42-year-old man with sustained and moderately severe warm antibody autoimmune hemolytic anemia, hemoglobinuria, hemosiderinuria, and acute kidney injury. We show marked induction of heme oxygenase-1 and increased ferritin expression in renal tubules, along with increased iron deposition in renal proximal tubules. These findings in this clinical case thus recapitulate those observed in experimental models of heme protein-induced kidney injury in which a coupled induction of heme oxygenase-1 and ferritin occurs in the kidney. We discuss the pathobiological significance of these findings and suggest that this linked response confers cytoprotection to the kidney exposed to hemoglobin and mitigates the severity of acute kidney injury that may otherwise occur. Finally, this case report documents that nephrotic-range proteinuria can occur in patients with autoimmune hemolytic anemia complicated by hemoglobinuria.

Autoimmune-Hemolytic Anemia Associated with Montelukast and Zafirlukast Therapy in a Patient with Hepatitis C

Objective To report a case of autoimmune-hemolytic anemia (AIHA) associated with montelukast and, subsequently, zafirlukast in a patient with hepatitis C. Case Summary A 57-year-old white man with known hepatitis C presented with jaundice, bilateral lower-extremity edema, fatigue, and exertion for 3 weeks. He started using montelukast a week prior to experiencing these symptoms. After consultation with his primary care provider, montelukast was replaced with zafirlukast, which improved edema but other symptoms persisted. The patient was admitted to the hospital with symptoms, physical findings, and laboratory tests suggestive of AIHA. Leukotriene receptor antagonist therapy was discontinued and the patient received treatment with red blood cell transfusions and corticosteroids. The patient's hemoglobin stabilized within 9 days. Discussion AIHA may occur idiopathically or secondarily in association with drug or chemical exposures, lymphoproliferative disorders, collagen vascular diseases, or malignancies. Several mechanisms for drug-induced AIHA have been elucidated; however, direct laboratory testing is difficult. Therefore, diagnosis of drug-induced AIHA should be made when other causes have been ruled out, when temporal relation can be made, and when improvement of symptoms occurs upon discontinuation of the suspected agent. Conclusion Over 100 drugs have been implicated in the formation of warm antibody hemolytic anemia; however, there are currently no reports of leukotriene receptor antagonists associated with AIHA. Even though, in this case report, the patient had coexisting hepatitis C, which can cause AIHA alone, an objective causality assessment revealed that the AIHA was possibly due to montelukast and zafirlukast.

Anti-CD20 Therapy for Chronic Lymphocytic Leukemia-associated Autoimmune Diseases

Rituximab is active in chronic lymphocytic leukemia (CLL) and may interfere with autoantibodies production in some immune diseases. We report the results of rituximab treatment in 7 patients with CLL-associated symptomatic autoimmune diseases refractory to standard immunosuppressive therapies: warm antibody hemolytic anemia (AHA) 4 patients, cold agglutinin disease (CAD) 1, immune thrombocytopenia (IT) I , axonal degenerating neuropathy (ADN) 1. Rituximab was given at the dose of 375mg/m2 per week for 4 weeks. One patient with AHA and one with CAD achieved complete normalization of hemoglobin levels and laboratory signs of haemolysis, with response duration (RD) of 8+ and 38+ months, respectively. In the patient with IT, complete remission was reached after the first week of treatment and RD was 6 months. The patient with ADN achieved a marked neurological improvement after rituximab therapy, with RD of 12 months. Retreatment of both patients with IT and ADN was effective. Rituximab may be an alternative agent for the treatment CLL-associated autoimmune diseases.

Autoimmune hemolytic anemia with hemoglobinemia and hemoglobinuria in the absence of a demonstrable hemolysin or complement-binding antibody.

Summary. The present report describes the occurrence of hemoglobinemia and hemoglobinuria in a patient with warm antibody hemolytic anemia in whom extensive studies failed to demonstrate the presence of a hemolysin or complementfixing antibody. Studies of the patient's red cells revealed only gamma globulin coating. Studies of the patient's serum revealed the presence of a γG globulin antibody capable of coating normal cells with gamma globulin but not with complement. No hemolysin could be demonstrated even with the use of special techniques known to enhance detection of hemolytic antibodies. Based on these negative findings and on previous experimental and clinical observations concerning the iso‐antibody, anti D, the possibility is raised that the hemoglobinuria observed in this patient resulted from extravascular red cell destruction of such magnitude that the capacity of the reticuloendothelial system to metabolize the products of red cell breakdown was exceeded.

Warm antibody hemolytic anemia; prolonged remission despite persistent positive Coombs test.

Warm antibody hemolytic anemia; prolonged remission despite persistent positive Coombs test.