Cold Agglutinin Syndrome in Post-Liver Transplant Patients on Tacrolimus.

Abstract Following liver transplantation, patients require immunosuppressive medications to prevent graft rejection. However, these drugs can have significant side effects including severe anemia. Tacrolimus is now commonly used in pediatrics patients after liver transplantation. Case reports indicate that tacrolimus rarely can cause microangiopathic hemolytic anemia and also hemolytic anemia due to cold reactive IgM antibodies (cold agglutinin disease). We have seen 4 patients with symptomatic cold agglutinins thought to have been triggered by tacrolimus. Four patients, 6 to 26 months post-ABO-compatible liver transplant, presented with severe anemia (hemoglobin < 6g/dL), indirect hyperbilirubinemia, reticulocytosis and low serum haptoglobin (Table 1). Peripheral blood smear exhibited marked autoagglutination but no evidence of microangiopathic changes. The direct antiglobulin test (DAT) initially was strongly positive in all 4 patients (Table 2). After warm saline washes, the DAT remained positive for complements in 3 out of 4 patients. Cold agglutinin titers were low (1:4 – 1:16) but thermal amplitude studies were positive at 37°C in the two tested patients. Viral serologies significant for cold agglutinin syndrome were negative. None of the patients had clinical evidence of post-transplant lymphoproliferative disorder. All 4 patients had brisk hemolysis requiring multiple uncrossmatched packed red blood cells (PRBC) transfusions. Favorable resolution of the hemolytic anemia occurred following steroids, plasmapheresis and withdrawal of tacrolimus. Subsequently, patients were placed on cyclosporin and none exhibited liver rejection or recurrence of their hemolytic anemia. The above observation indicates that acute cold-agglutinin induced hemolysis occurs in patients following liver transplantation and these events appear to have temporally associated with tacrolimus administration. Patient Profiles Patient Age Diagnosis Months after transplant Presenting hemoglobin (g/dL) Reticulocyte (%/Abs k/μL Total/Direct Bilirubin Treatments (in addition to withdrawal of tacrolimus) ND=not done. MP=methylprednisolone 1 8 mos Neonatal iron storage disease 6 2.8 41%/469 4.2/0.6 MP 4mg/kg/d plus  30mg/kg/d x 3 days.  Plasmapheresis x 6. 2 13 mos Biliary atresia Idiopathic 6 5.3 8%/250 3.2/0.4 MP 4mg/kg/d.  Plasmapheresis x 15. 3 2 yrs 5 mos fulminant hepatic failure 14 4.6 19.5%/237 2.6/0.3 MP 10mg/kg/d.  Plasmapheresis x 10. 4 4 yrs Biliary atresia 26 5.3 5%/ND 8.8/0.5 MP 2mg/kg/d→ 4mg/kg/d.  Plasmapheresis x 10. Immunohematology Profiles Admission DAT Patient 1 Patient 2 Patient 3 Patient 4 Admission DAT Pre/post saline wash Pre/post saline wash Pre/post saline wash Pre/post saline wash DAT-Direct antiglobulin test, M-microscopically, NT-not tested, +-positive, 0-negative, Polyspecific 3+/0 1+/M+ 4+/4+ 3+/1+ Anti-IgG 2+/0 M+/0 4+/1+ 3+/1+ Anti-C3 2+/0 2+/1+ 4+/4+ 3+/1+ Saline Control 2+/0 1+/0 1+/0 1+/0 Eluate 0 NT Panreactive 1+ Panreactive 1+ Cold agglutinin titer at 4°C in saline NT 4 8 16 Thermal amplitude screen at 30°C NT NT Reactive Reactive Donath-Landsteiner Test NT NT Negative Negative Admission peripheral blood smear 4+ polychromatophilia. 4+ microcytosis 4+ autoagglutination. 3+ polychromatophilia. 3+ spherocytes. 3+ microcytes 3+ autoagglutination. 3+ polychromatophilia. 3+ spherocytes. 2+ macrocytes 4+ autoagglutination. 4+ spherocytes. 2+ polychromatophilia. 2+ macrocytes

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Congenital Malaria: A Rare Cause of Splenomegaly and Anemia in an American Infant

PEDIATRICS ◽

10.1542/peds.60.2.209 ◽

1977 ◽

Vol 60 (2) ◽

pp. 209-212

Author(s):

D. Thompson ◽

C. Pegelow ◽

A. Underman ◽

D. Powars

Keyword(s):

Plasmodium Vivax ◽

Hemolytic Anemia ◽

Peripheral Blood ◽

Endemic Area ◽

Blood Smear ◽

Clinical Manifestations ◽

Peripheral Blood Smear ◽

Pregnancy Malaria ◽

Congenital Malaria

A 38-day-old infant had fever, jaundice, hepatosplenomegaly, and a hemolytic anemia. A peripheral blood smear demonstrated intraerythrocytic malarial parasites identified as Plasmodium vivax. Maternal and infant sera contained antibodies to this species. A directed history revealed the mother had suffered several febrile illnesses in Mexico during her pregnancy. Malaria had not been diagnosed nor was it considered at the time of her delivery at this hospital. Review of this and six other cases of congenital malaria reported in this country since 1950 indicates clinical manifestations seldom appear before 3 weeks of age. Although these signs are more frequently associated with other transplacental infections, their occurrence in an infant whose mother is from or who has traveled in an endemic area should prompt consideration of the diagnosis of congenital malaria.

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Late Occuring Severe Autoimmune Hemolytic Anemia in a Liver Transplanted Child.

Blood ◽

10.1182/blood.v110.11.4025.4025 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4025-4025

Author(s):

Hulya Ozsahin ◽

Michela Schaeppi ◽

Thierry Peyrard ◽

Fabienne Gumy-Pause ◽

Klara Posfay-Barbe ◽

...

Keyword(s):

Case Report ◽

Liver Transplant ◽

Lymphoproliferative Disease ◽

Direct Antiglobulin Test ◽

Cold Agglutinin ◽

Reference Laboratory ◽

Solid Organ ◽

First Case ◽

Thermal Amplitude ◽

Antiglobulin Test

Abstract INTRODUCTION Autoimmune haemolytic anaemia (AIHA) can complicate solid organ as well as bone marrow transplantation both in children and adults. We describe the first case report of a child with AIHA due to mixed type warm-acting IgM and warm IgG auto-antibodies, 8 months after liver transplantation. CASE REPORT A sixteen-month old boy (A Rh D positive blood group,), 8 months after an orthotopic liver transplant (full cadaveric liver, male A Rh D negative) presented with fever and moderate hepatitis. Two weeks after this episode he developed severe anemia with a Hb level of 39 g/L. His red cells were A1 Rh(D) positive. Plasma testing could not be interpreted due to positive reactions with all test cells. Screening for irregular antibodies was positive. The direct antiglobulin test was repeatedly negative. Further analysis revealed a cold agglutinin with low titre (8 at 15°C) but high thermal amplitude (22–37°C) although of IgM nature, and the absence of any underlying alloantibodies. Only Rh null red blood cells were not agglutinated by the autoantibody. Therapy included keeping body temperature over 37° C, transfusions of A Rh(D) positive warmed crossmatched blood units, intravenous immunoglobulins (1g/kg/d x 5 days), and methylprednisolone (20 mg/kg/d). Tacrolimus was replaced by cyclosporin A. Further investigations revealed panagglutinating IgG autoantibodies in the plasma and on the erythrocytes and the monospecific direct antiglobulin test became positive for IgM, IgG, C3c and C3d. French National Reference Laboratory for Immuno-Hematology and Rare Blood Groups confirmed these findings and showed both the IgM and IgG autoantibodies to be directed against the Rh proteins (anti-RH29 antibody) and to be strongly active at 37°C. Crossmatched group O Rh(D) positive red blood cell (RBC) units were transfused, however with limited effect and progressive haemolysis. Hb level dropped to 33 g/L. One cryopreserved O Rh null RBC unit was obtained from the French National Rare Blood Bank. Rituximab® (375 mg/m2 once weekly) (anti-CD 20 monoclonal antibody) was also introduced. Immediately following this transfusion and 24 hours after the first dose of rituximab, Hb levels increased and were stable at 80 g/L. No further transfusions were needed and the haemolytic parameters normalized slowly. Total 4 doses of rituximab were administered.Ten weeks after admission, the child could be discharged. At 18 months’ follow-up, there is no recurrence of AIHA. DISCUSSION Only few cases of AIHA due to warm acting “cold” agglutinins have been described, generally resulting in death. AIHA in patients with liver transplant has been previously reported, mainly due to warm autoantibodies or to classical cold agglutinin disease associated with viral infections, lymphoproliferative disease or autoimmune disorders. Our case is interesting in that this unusual AIHA occurred not only in a liver transplanted child, but also late after transplantation. Although extensive investigations revealed no aetiology, the hypothesis of a viral infection-triggered AIHA with first an IgM, then a mixture of IgM and IgG autoantibodies directed against the same epitope is plausible. This case illustrates the efficacy of rituximab in AIHA not responding to first-line therapy and the importance of international collaboration to provide extremely rare compatible blood units.

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Neutrophil aggregation on the peripheral blood smear in a patient with cold agglutinin disease

Annals of Hematology ◽

10.1007/s00277-017-3077-8 ◽

2017 ◽

Vol 96 (10) ◽

pp. 1767-1768 ◽

Cited By ~ 1

Author(s):

Sigbjørn Berentsen

Keyword(s):

Peripheral Blood ◽

Blood Smear ◽

Peripheral Blood Smear ◽

Cold Agglutinin ◽

Cold Agglutinin Disease ◽

Neutrophil Aggregation

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Dehydrated Hereditary Stomatocytosis: A Rare Inherited Hemolytic Anemia

Blood ◽

10.1182/blood-2021-150968 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4148-4148

Author(s):

Farah Shaukat ◽

Zeba Singh ◽

Hira Latif

Keyword(s):

Iron Overload ◽

Red Blood Cells ◽

Hemolytic Anemia ◽

Peripheral Blood ◽

Blood Cells ◽

Blood Smear ◽

Peripheral Blood Smear ◽

Blood Transfusions ◽

Erythroid Progenitor ◽

Distribution Width

Abstract Background: Dehydrated hereditary stomatocytosis (DHSt), also known as hereditary xerocytosis, is a rare congenital hemolytic anemia with an autosomal dominant inheritance. It is often misdiagnosed for other hemolytic conditions, such as hereditary spherocytosis. Herein, we present the case of a young female presenting with hemolytic anemia, who was found to have a mutation in PIEZO1 gene and was subsequently diagnosed with DHSt. Case Presentation: A 39-year-old woman of Asian origin presented to the hematology clinic for evaluation of anemia diagnosed on blood work performed by primary care physician for symptoms of fatigue. She was adopted and had no information about her family history. A complete blood count revealed: hemoglobin 8.2 g/dL, mean corpuscular volume (MCV) 121.6 fL, absolute retic counts 0.08 M/mcL, lactate dehydrogenase 851 units/L and a negative coombs test. Iron profile revealed iron saturation 85% and ferritin 1961.4 ng/mL (see table 1 for laboratory work up). The peripheral blood smear showed anisopoikilocytosis, macrocytes, spherocytes and several stomatocytes along with polychromatophils. An ultrasound of the abdomen was subsequently performed, and which revealed hepatomegaly and biliary stones. Enzyme assay for glucose-6-phosphate dehydrogenase and flow cytometry for paroxysmal nocturnal hemoglobinuria were also sent and were negative. Red blood cells osmotic fragility was decreased. The bone marrow biopsy showed full spectrum trilineage hematopoiesis with no mutations on molecular testing. Based on the blood smear and clinical presentation, a diagnosis of DHSt was suspected. Genetic testing was performed and which revealed Sc.2842C>T; p.Arg948Cys mutation in the PIEZO1 gene by massively parallel sequencing and confirmation by Sanger sequencing. This confirmed the diagnosis of DHSt. Patient was started on high dose folic acid with improvement in her hemoglobin in one month. She did not require any blood transfusions. MRI liver T2* scan measured quantitative liver iron of 31 mM/g, which was at the high normal range. Discussion: DHSt is caused by gain of function mutation in PIEZO1 gene or KCCN4 gene which encode the transmembrane cation ion channel and Gardo's channel respectively on red blood cell membrane. This results in delayed inactivation of the channel. The disease presents as a spectrum from asymptomatic anemia to massive hemolysis, and many patients present later in life. Patients may manifest clinical signs of jaundice, pallor, fatigue, splenomegaly, gallstones and iron overload. Labs are typically significant for elevation in mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW) and MCV, with classic slit cells red blood cells seen on peripheral blood smear (see image 1). PIEZO1 is expressed early in erythroid progenitor cells and may delay erythroid differentiation and reticulocyte maturation, which may be the cause of low reticulocyte count such as in our patient. While treatment is supportive with blood transfusions, only a minority of DHSt patients ever require regular transfusions. Interestingly, hyperferritinemia, high transferrin saturation or clinical iron overload are quite frequent in DHSt and iron chelation is recommended. Splenectomy is contraindicated due to increased risk of thrombosis. Conclusions: DHSt as a rare inherited hemolytic anemia and its diagnosis warrants maintaining a high index of clinical suspicion based on supportive laboratory findings. Diagnosis involves thorough testing earlier in the disease as patients may be asymptomatic until adulthood. Delaying the diagnosis may lead to severe iron overload and consequent organ damage. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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A family with red cell pyrimidine 5'-nucleotidase deficiency

Blood ◽

10.1182/blood.v47.6.919.bloodjournal476919 ◽

1976 ◽

Vol 47 (6) ◽

pp. 919-922

Author(s):

I Ben-Bassat ◽

F Brok-Simoni ◽

G Kende ◽

F Holtzmann ◽

B Ramot

Keyword(s):

Hemolytic Anemia ◽

Peripheral Blood ◽

Blood Smear ◽

Peripheral Blood Smear ◽

Early Infancy ◽

Red Cell ◽

Chronic Hemolytic Anemia ◽

Congenital Hemolytic Anemia

Congenital hemolytic anemia associated with pyrimidine 5′-nucleotidase deficiency is reported in two siblings. Both have had moderate chronic hemolytic anemia, splenomegaly, and jaundice since early infancy. The peripheral blood smear is characterized by striking red cell basophilic stippling. As this feature has been found in all previously reported cases, it should be the clue to the diagnosis.

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A Case of Congenital Red Cell Pyruvate Kinase Deficiency Associated with Hereditary Spherocytosis

Blood ◽

10.1182/blood.v118.21.5272.5272 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5272-5272

Author(s):

Cristina Vercellati ◽

Anna Paola Maria Luisa Marcello ◽

Elisa Fermo ◽

Paola Bianchi ◽

Carla Boschetti ◽

...

Keyword(s):

Cell Membrane ◽

Pyruvate Kinase ◽

Hemolytic Anemia ◽

Peripheral Blood ◽

Blood Smear ◽

Hereditary Spherocytosis ◽

Osmotic Fragility ◽

Peripheral Blood Smear ◽

Red Cell ◽

Red Cell Membrane

Abstract Abstract 5272 Pyruvate kinase (PK) deficiency, transmitted as an autosomal recessive trait, is the most common erythroenzymopathy of glycolytic pathway (prevalence of 1:20,000) associated with chronic non spherocytic hemolytic anemia from mild to severe. More than 180 mutations in the PK-LR gene have been so far reported, and genotype-phenotype correlation has been established for some of them. Hereditary Spherocytosis (HS) is the most common congenital hemolytic anemia in Caucasians, with an estimated prevalence ranging from 1:2000 to 1:5000. The main clinical features are hemolytic anemia from compensated to severe, variable jaundice, splenomegaly and cholelythiasis. The molecular defect is highly heterogeneous, caused by proteins involved in the attachment of cytoskeleton to the membrane integral domain (spectrin, ankyrin, band 3 and protein 4.2). We describe a case of PK deficiency associated with HS. The propositus was a 13 years-old Italian male with neonatal jaundice and need of blood transfusion (Hb 5.8 g/dL) during an infectious episode. At the time of the study Hb was 13.9 g/dL, MCV 81.8 fL, reticulocytes 207×109/L, unconjugated bilirubin 2.16 mg/dL, LDH 605 U/L, haptoglobin <20 mg/dL. The peripheral blood smear examination showed the presence of spherocytes (16%) and some ovalocytes (2%). The study of the most important red cell enzymes revealed reduced PK activity (59% of normal). Direct sequencing of PK-LR gene showed compound heterozygosity for the 994A mutation (Gly332Ser) and the −148T variant localized the erythroid specific promoter region. The presence of spherocytes in peripheral blood smear prompted us to investigate for the coexistence of HS. Erythrocyte osmotic fragility was decreased and SDS–PAGE analysis of red cell membrane proteins revealed a 30% spectrin reduction. Family study demonstrated a heterozygous condition for the 994A mutation in the father, who also displayed comparable enzyme deficiency, whereas promoter variant −148T was detected in the mother and in the brother. No red cell membrane abnormalities were present in the family members, although positive EMA binding test and increased osmotic fragility were found in the father and brother. The co-existence of HS and PK deficiency is very rare event, only few cases are described to date. Clinical, family and molecular studies allowed the determination of the interrelationship between the two RBC abnormalities in the patient and his relatives. The reduced PK activity in the propositus and his father is justified by heterozygous 994A mutation. The more severe clinical picture in the propositus could be caused by the coexistence of HS and by the presence of −148T mutation, that although it seems not to have effects on PK-LR mRNA expression, is often detected in PK deficient subjects with heterozygous PK mutations. Disclosures: No relevant conflicts of interest to declare.

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A family with red cell pyrimidine 5'-nucleotidase deficiency

Blood ◽

10.1182/blood.v47.6.919.919 ◽

1976 ◽

Vol 47 (6) ◽

pp. 919-922 ◽

Cited By ~ 27

Author(s):

I Ben-Bassat ◽

F Brok-Simoni ◽

G Kende ◽

F Holtzmann ◽

B Ramot

Keyword(s):

Hemolytic Anemia ◽

Peripheral Blood ◽

Blood Smear ◽

Peripheral Blood Smear ◽

Early Infancy ◽

Red Cell ◽

Chronic Hemolytic Anemia ◽

Congenital Hemolytic Anemia

Abstract Congenital hemolytic anemia associated with pyrimidine 5′-nucleotidase deficiency is reported in two siblings. Both have had moderate chronic hemolytic anemia, splenomegaly, and jaundice since early infancy. The peripheral blood smear is characterized by striking red cell basophilic stippling. As this feature has been found in all previously reported cases, it should be the clue to the diagnosis.

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Heinz-Body Hemolytic Anemia Associated with Phenazopyridine and Sulfonamide

DICP ◽

10.1177/106002808902300207 ◽

1989 ◽

Vol 23 (2) ◽

pp. 140-142 ◽

Cited By ~ 4

Author(s):

Charles D. Ponte ◽

Michael J. Lewis ◽

John S. Rogers

Keyword(s):

Hemolytic Anemia ◽

Clinical Features ◽

Peripheral Blood ◽

White Woman ◽

Blood Smear ◽

Peripheral Blood Smear ◽

Drug Induced ◽

Oxidative Hemolysis ◽

Abnormal Laboratory ◽

Heinz Body

A 27–year-old white woman developed Heinz-body hemolytic anemia following multiple courses of oral phenazopyridine and trimethoprim-sulfamethoxazole. Her diagnosis was supported by the finding of bite cells on peripheral blood smear. The patient's rapid recovery and reversal of abnormal laboratory parameters were consistent with an acquired hemolytic disorder. This case should sensitize the clinician to the development of drug-induced oxidative hemolysis, its clinical features, and its reversibility. It is also important that the clinician recognize those drugs capable of causing this disorder and appreciate the methods available to establish the diagnosis.

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