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Case Rep Pediatr 2022 22;2022:3267189. Epub 2022 Apr 22.

Carilion Children's Pediatric Hematology/Oncology, Carilion Clinic, Roanoke, VA, USA.

We describe the case of a 4-year-old female who presented with sepsis and disseminated intravascular coagulation (DIC), developed ongoing intravascular hemolysis with acute renal failure from suspected pigment-induced acute tubular necrosis necessitating continuous renal replacement therapy (CRRT) for five days followed by four episodes of intermittent hemodialysis (iHD), and was subsequently diagnosed with paroxysmal cold hemoglobinuria (PCH). She was successfully treated with plasma exchange and eculizumab, a humanized monoclonal antibody targeting complement protein C5, and demonstrated significant improvement of hemolysis and recovery of renal function. Read More

J Pediatr Hematol Oncol 2022 Apr;44(3):71-78

Department of Pediatrics, St. Louis University School of Medicine, St. Louis, MO.

Autoimmune hemolytic anemia is a relatively uncommon pediatric clinical condition. As such, the evaluation and management of these cases can be challenging for even the most seasoned pediatrician. In this review, the 3 major forms of autoimmune hemolytic anemia in children will be discussed: warm autoimmune hemolytic anemia, cold agglutinin disease, and paroxysmal cold hemoglobinuria. Read More

J Pediatr Hematol Oncol 2022 03;44(2):60-61

Department of Pediatrics, Monash Children's Hospital.

Phagocytosis of red cells by neutrophils, referred to as neutrophil erythrophagocytosis, on the blood smear as a helpful diagnostic sign of paroxysmal cold hemoglobinuria is underrecognized. We present a child with paroxysmal cold hemoglobinuria and prominent neutrophil erythrophagocytosis to highlight the importance of this finding in the diagnosis of paroxysmal cold hemoglobinuria. Read More

Front Immunol 2021 25;12:791429. Epub 2021 Nov 25.

Hematology Unit, King's College Hospital, London, United Kingdom.

The complex pathophysiologic interplay between SARS-CoV-2 infection and complement activation is the subject of active investigation. It is clinically mirrored by the occurrence of exacerbations of complement mediated diseases during COVID-19 infection. These include complement-mediated hemolytic anemias such as paroxysmal nocturnal hemoglobinuria (PNH), autoimmune hemolytic anemia (AIHA), particularly cold agglutinin disease (CAD), and hemolytic uremic syndrome (HUS). Read More

Am J Case Rep 2021 Nov 25;22:e933102. Epub 2021 Nov 25.

Faculty of Nutrition, Kobe Gakuin University, Kobe, Hyogo, Japan.

BACKGROUND Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic disease caused by the Donath-Landsteiner (DL) antibody. Paroxysmal nocturnal hemoglobinuria (PNH) is a non-autoimmune hemolytic disease that is caused by a dysfunction in the synthesis of the glycosyl phosphatidylinositol anchor protein, resulting in the deregulation of the complement cascade and hypersensitivity for a hemolytic attack against erythrocytes. The mechanisms of these 2 hemolytic diseases are distinct. Read More

Blood 2022 Jun;139(25):3571-3582

Severe Aplastic Anemia Working Party, European Group for Bone Marrow Transplantation.

Complement is an elaborate system of innate immunity. Genetic variants and autoantibodies leading to excessive complement activation are implicated in a variety of human diseases. Among them, the hematologic disease paroxysmal nocturnal hemoglobinuria (PNH) remains the prototypic model of complement activation and inhibition. Read More

Arch Dis Child Educ Pract Ed 2022 06 25;107(3):199-206. Epub 2021 Aug 25.

Paediatrics, University Hospitals Dorset NHS Foundation Trust, Poole, Dorset, UK

Paroxysmal cold haemoglobinuria (PCH) accounts for around a third of cases of autoimmune haemolytic anaemia in children. PCH is caused by an autoantibody that fixes complement to red cells at low temperatures and dissociates at warmer temperatures (a biphasic haemolysin), triggering complement-mediated intravascular haemolysis. Named the Donath-Landsteiner (D-L) antibody after its discoverers, it is usually formed in response to infection and demonstrates specificity for the ubiquitous red cell P-antigen. Read More

Indian J Pathol Microbiol 2021 Jul-Sep;64(3):613-614

Department of Pediatrics, Bharati Vidyapeeth University Medical College Hospital and Research Centre, Pune, Maharashtra, India.

Blood 2021 03;137(10):1432

Shaare Zedek Medical Center.

Indian Pediatr 2021 Aug 25;58(8):737-740. Epub 2021 Feb 25.

Department of Pediatric Hematology Oncology and BMT, Institute of Child Health, Sir Ganga Ram Hospital, New Delhi.  Correspondence to: Dr Anupam Sachdeva, Director Pediatric Hematology Oncology and BMT, Institute for Child Health, Sir Ganga Ram Hospital, New Delhi.

Objective: To analyze clinical and laboratory parameters, and treatment outcomes of children with autoimmune hemolytic anemia (AIHA).

Methods: Retrospective analysis of 50 children aged 0-18 years. Monospecific direct antiglobulin test (DAT) and investigations for secondary causes were performed. Read More

J Clin Med 2021 Jan 9;10(2). Epub 2021 Jan 9.

Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

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. Read More

Cureus 2020 Nov 22;12(11):e11622. Epub 2020 Nov 22.

Internal Medicine, Government Medical College Kottayam, Kottayam, IND.

Paroxysmal cold hemoglobinuria (PCH) is a rare form of autoimmune hemolytic anemia (AIHA). PCH occurs in acute and chronic forms. The main risk factors for PCH include viral infections, vaccination, and syphilis. Read More

Immun Ageing 2020 Nov 20;17(1):38. Epub 2020 Nov 20.

Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznań, Poland.

Autoimmune hemolytic anemia (AIHA) is an acquired, heterogeneous group of diseases which includes warm AIHA, cold agglutinin disease (CAD), mixed AIHA, paroxysmal cold hemoglobinuria and atypical AIHA. Currently CAD is defined as a chronic, clonal lymphoproliferative disorder, while the presence of cold agglutinins underlying other diseases is known as cold agglutinin syndrome. AIHA is mediated by autoantibodies directed against red blood cells (RBCs) causing premature erythrocyte destruction. Read More

Indian J Hematol Blood Transfus 2020 Nov 22:1-6. Epub 2020 Nov 22.

Department of Obstetrics & Gynaecology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Manohar Lohia Hospital Delhi, New Delhi, India.

Paroxysmal cold haemoglobinuria (PCH) is an acquired cause of haemolytic anaemia. It is caused by the biphasic IgG antibodies that sensitize and attach the red cells at lower temperature; detach and rebind on rewarming. Donath-Landsteiner antibody test is the diagnostic test for PCH. Read More

Asian J Transfus Sci 2020 Jan-Jun;14(1):57-59. Epub 2020 Jul 24.

Department of Transfusion Medicine, Medanta-The Medicity, Gurgaon, Haryana, India.

61-year old male patient was admitted to the hospital with clinical picture of hemolytic anemia with hemoglobinuria. Patient was suspected to have Infectious Mononucleosis (IM) with Auto Immune Hemolytic Anemia (AIHA). DAT was positive with anti-C3d specificity. Read More

Front Immunol 2020 4;11:1006. Epub 2020 Jun 4.

UO Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Autoimmune hemolytic anemia (AIHA) is characterized by immune mediated erythrocytes destruction by autoantibodies with or without complement activation. Additional pathologic mechanisms include cellular cytotoxicity, cytokline dysregulation, and inadequate bone marrow compensation with fibrosis/dyserythropoiesis. The latter resembles that of bone marrow failures, namely aplastic anemia and myelodysplastic syndromes. Read More

Clin Epidemiol 2020 22;12:497-508. Epub 2020 May 22.

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

Background: Acquired hemolytic disorders-autoimmune hemolytic anemia (AIHA), cold agglutinin disease (CAD), paroxysmal nocturnal hemoglobinuria (PNH), drug-induced hemolysis (DIHA), and acquired hemolysis not otherwise specified (AHNOS)-are considered rare. Despite their potentially major health implications, data regarding their incidence and prevalence are scarce.

Methods: To fill this gap we collected data regarding all patients with acquired hemolytic disorder diagnoses in 1977-2016 from the Danish National Patient Register. Read More

J Clin Invest 2020 05;130(5):2152-2163

Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Read More

Transfus Clin Biol 2020 Apr 18;27(2):83-86. Epub 2020 Mar 18.

Department of pretransfusion testing and hemovigilance, Institute for Blood Transfusion of Serbia, Svetog Save 39, 11000 Belgrade, Serbia. Electronic address:

Paroxysmal cold hemoglobinuria is a rare form of autoimmune hemolytic anemia caused by the Donath-Landsteiner autoantibody. The condition is characterized by the presence of an IgG biphasic hemolysin with specificity to the P blood group antigen. The antibody biphasic action may be demonstrated in the Donath-Landsteiner test. Read More

Blood 2020 01;135(5):393

Johns Hopkins University.

Blood Adv 2019 11;3(22):3575-3578

Department of Pediatrics, University of California, San Francisco, San Francisco, CA; and.

Indian Pediatr 2019 10;56(10):879-880

Department of Transfusion Medicine, Max Superspeciality Hospital, Saket, New Delhi, India.

Paroxysmal Cold Hemoglobinuria is a rare cause of intravascular hemolysis presenting in children following an acute viral illness. It is usually self-limiting in nature. We present the details of a 4-year-old boy who presented with rapid onset intravascular hemolysis. Read More

Ther Adv Hematol 2019 9;10:2040620719873321. Epub 2019 Sep 9.

Department of Medicine, Henri Mondor Hospital, Université Paris-Est, Assistance Publique Hôpitaux de Paris Creteil, Creteil, France.

Complement-mediated hemolytic anemias can either be caused by deficiencies in regulatory complement components or by autoimmune pathogenesis that triggers inappropriate complement activation. In paroxysmal nocturnal hemoglobinuria (PNH) hemolysis is entirely complement-driven. Hemolysis is also thought to be complement-dependent in cold agglutinin disease (CAD) and in paroxysmal cold hemoglobinuria (PCH), whereas warm antibody autoimmune hemolytic anemia (wAIHA) is a partially complement-mediated disorder, depending on the subtype of wAIHA and the extent of complement activation. Read More

Blood Adv 2019 06;3(12):1897-1906

Department of Research and Innovation, Haugesund Hospital, Haugesund, Norway.

The terminology applied to autoimmune hemolytic anemia (AIHA) seems inconsistent. We aimed to evaluate the consistency of definitions used for diagnosis and treatment. In this systematic review of literature from January 2006 to December 2015, we assessed heterogeneity in the definition of AIHA and its subtypes, refractory disease, disease phase, severity, criteria for treatment response, and response durability. Read More

Tidsskr Nor Laegeforen 2019 Mar 18;139(6). Epub 2019 Mar 18.

Immunohematology 2019 Jan;35(1):3-6

Medical Director of Donor Services, Associate Medical Director of Transfusion Medicine, Houston Methodist Hospital, Department of Pathology and Genomic Medicine, 6565 Fannin Street, MS 205, Houston, TX.

Conclusions: The Donath-Landsteiner (DL) test is a serologic test used to detect the presence of a biphasic hemolysin. This autoantibody is seen in patients with paroxysmal cold hemoglobinuria. The test relies on the characteristic cold binding of an IgG autoantibody with specificity to the P blood group antigen. Read More

Case Rep Hematol 2018 13;2018:7586719. Epub 2018 Nov 13.

Division of Hematology and Medical Oncology, Department of Medicine, Mount Sinai Beth Israel, Mount Sinai Hospital, New York, NY, USA.

Paroxysmal cold hemoglobinuria (PCH) is a rare form of cold autoimmune hemolytic anemia first discovered in the early 20th century in adults with tertiary syphilis. Today, it is more commonly seen in children as a life-threatening anemia during a viral upper respiratory tract infection (URI). Although respiratory syncytial virus (RSV) has previously been reported to cause PCH in a child, herein we present the first documented case in an adult. Read More

BMJ Case Rep 2018 Nov 8;2018. Epub 2018 Nov 8.

Medicine, Nassau University Medical Center, East Meadow, New York, USA.

Donath-Landsteiner haemolytic anaemia (DLHA), also known as paroxysmal cold haemoglobinuria, is a very rare and difficult condition to diagnose as well as treat. Here, we present a case of a 55-year-old Hispanic woman who presented with severe intravascular haemolytic anaemia in the setting of a viral illness 2 weeks prior to presentation. Direct antiglobulin testing revealed mixed results: positive for either complement, IgG or both on various occasions which led to a battery of tests including the Donath-Landsteiner antibody testing which turned out positive establishing the diagnosis of DLHA. Read More

Vnitr Lek Summer 2018;64(5):514-519

Autoimmune hemolytic anemia (AIHA) is caused by auto-antibodies directed against self red blood cell (RBC) surface antigens. A consequence may be an intravascular hemolysis mediated by activated complement or extravascular hemolysis caused by destruction of complex of RBC with autoantibody in spleen and liver. The basic classification subdivides AIHA in primary/idiopathic and secondary with known underlying disease. Read More

Semin Hematol 2018 07 10;55(3):141-149. Epub 2018 Apr 10.

Department of Research and Innovation, Haugesund Hospital, Helse Fonna HF, Haugesund, Norway. Electronic address:

The classical complement pathway and, to some extent, the terminal pathway, are involved in the immune pathogenesis of autoimmune hemolytic anemia (AIHA). In primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, the hemolytic process is entirely complement dependent. Complement activation also plays an important pathogenetic role in some warm-antibody AIHAs, especially when immunoglobulin M is involved. Read More