Congenital thrombotic thrombocytopenic purpura: a rare cause of severe neonatal jaundice and hypoxic respiratory failure – a case report

The concept of a relationship between severe neonatal hyperbilirubinemia and kernicterus evolved slowly. Jaundice was recognized in ancient as well as biblical times as a manifestation of disease. However, according to Louis K. Diamond (Fig. 1), who reviewed the history of neonatal jaundice, (1) the first record concerning jaundice of the newborn appears to be by Barthomomaeus Metlinger in 1473 in his book Ein Regiment der Jungen Kinder . The occurrence of jaundice shortly after birth as well as some suggestions for homeopathic treatment were mentioned by Michael Ettmuller in his 1708 treatise “De Infantum Morbis.” (1) An early description of icterus neonatorum was published in 1742 in London by John Burton in his treatise “A Full View of All the Diseases Incident to Children.” He suggested that “jaundice generally yields to any gentle purgative.” (1) This same approach was used by Condie in 1853 in Philadelphia. (2) At that time, he wrote that icterus neonatorum seemed to be “connected with the want of a free evacuation of meconium.” He suggested the use of castor oil or a small measure of calomel or rhubarb. It is interesting that he noted that the jaundice was known at times to be accompanied by a “good deal of drowsiness.” There were several publications in France concerning neonatal jaundice in the late eighteenth and early nineteenth centuries, the most significant of which, according to Thor Hansen, (3) was the thesis submitted by Jacques Francois Hervieux and defended by him for his M.D. degree at the University of Paris in 1847. The thesis was entitled “De l’ictere des nouveau-nes” (On the jaundice of newborns). Thor Hansen, to whom we are grateful for having reviewed the original French thesis, pointed out that the introductory section of the Hervieux thesis contains a valuable review of works by …

Severe neonatal unconjugated hyperbilirubinemia is associated with the risk of neurotoxicity and hence warrants prompt diagnostic and therapeutic interventions, including phototherapy and exchange transfusions. Although relatively rare, Hereditary spherocytosis (HS) is one of the common non-alloimmune hemolytic disorders associated with severe neonatal hyperbilirubinemia and hemolytic anemia during childhood. HS results from a mutation in genes encoding 1 or more proteins in the erythrocyte membrane, which leads to a loss of membrane structure and dysfunction of the cell. The clinical spectrum of HS varies widely, leading to under-diagnosis during the neonatal period, and management differs from alloimmune hemolytic disorders. In this case report of a neonate with severe unconjugated hyperbilirubinemia due to HS. Severe unconjugated hyperbilirubinemia due to HS. Phototherapy and exchange transfusion. Subsequent decrease in bilirubin levels and safe discharge of neonate with instructions to follow up with pediatrician, hematology, and genetics with outpatient appointments. In this case report, we emphasize the need for a high index of suspicion among neonatal caregivers and discuss management options. We also discuss the lack of response to intravenous immunoglobulin as a diagnostic clue and the feasibility of performing exchange transfusion using peripheral intravenous access.

Article1 April 1941ACQUIRED HEMOLYTIC ICTERUSWILLIS M. FOWLER, M.D.WILLIS M. FOWLER, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-14-10-1838 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptHemolytic icterus, in its literal sense, is a term so broad and inclusive that it may embrace a wide variety of conditions in which there is hemolysis of the erythrocytes and anemia. By common usage the term is applied to a more specific entity characterized not only by increased hemolysis and anemia, but by splenomegaly, increased fragility of the erythrocytes and evidences of bone marrow stimulation. This disease has been subdivided into the familial or congenital (Chauffard-Minkowski) type and the acquired (Hayem-Widal) type. The former represents a definite, clear-cut, clinical entity, whereas there is a diversity of opinion as to...Bibliography1. CHENEYCHENEY WFG: Chronic hereditary hemolytic jaundice, Am. Jr. Med. Sci., 1934, clxxxvii, 191-213. CrossrefGoogle Scholar2. DAWSON L OF PENN.: Hemolytic icterus, Brit. Med. Jr., 1931, l, 963-966. Google Scholar3. THOMPSON WP: Hemolytic jaundice, Jr. Am. Med. Assoc., 1936, cvii, 1776-1781. CrossrefGoogle Scholar4. WATSON CJ: Hemolytic jaundice and macrocytic hemolytic anemia: certain observations in a series of 35 cases, ANN. INT. MED., 1939, xii, 1782-1796. Google Scholar5. KRUMBHAAR EB: A classification and analysis of clinical types of splenomegaly accompanied by anemia, Am. Jr. Med. Sci., 1915, cl, 227-245. CrossrefGoogle Scholar6. LYNCH JH: Acquired hemolytic icterus, Nebr. State Med. Jr., 1932, xvii, 71-75. Google Scholar7. WITTS LJ: The pathology and treatment of anemia. III. The hemolytic anemias, Lancet, 1932, i, 601-605. CrossrefGoogle Scholar8. TILESTON W: Hemolytic jaundice, Medicine, 1922, i, 355-388. CrossrefGoogle Scholar9. GALLIEJANES WERM: Hemolytic jaundice associated with splenomegaly, Canad. Med. Assoc. Jr., 1926, xvi, 379-383. Google Scholar10. MURDOCK TP: Hemolytic anemia of pregnancy with reports of cases, ANN. INT. MED., 1927, i, 133-136. LinkGoogle Scholar11. MINOT GR: Two curable cases of anemia. I. Chronic hemolytic anemia, Med. Clin. N. Am., 1921, iv, 1733-1750. Google Scholar12. ALLAN W: Hemolytic anemia in pregnancy, Surg., Gynec. and Obst., 1928, xlvii, 669-672. Google Scholar13. DAWSON L OF PENN.: Indications for, and results of, removal of the spleen, Brit. Med. Jr., 1932, ii, 699-700. Google Scholar14. WISE WD: Hemolytic jaundice, Am. Jr. Surg., 1933, xx, 722-736. CrossrefGoogle Scholar15. DOANWISEMANERF CABKLA: Studies in hemolytic jaundice, Ohio State Med. Jr., 1934, xxx, 493-504. Google Scholar16. DUTHIE ES: Acquired hemolytic jaundice, Lancet, 1937, i, 1167-1169. CrossrefGoogle Scholar17. SHARPEDAVIS JCHH: Severe reactions following transfusion in hemolytic jaundice, Jr. Am. Med. Assoc., 1938, cx, 2053-2056. CrossrefGoogle Scholar18. WITTS LJ: A note on blood transfusion, Lancet, 1929, i, 1297-1299. CrossrefGoogle Scholar19. LEDERER M: A form of acute hemolytic anemia probably of infectious origin, Am. Jr. Med. Sci., 1925, clxx, 500-510. CrossrefGoogle Scholar20. LEDERER M: Three additional cases of acute hemolytic (infectious) anemia, Am. Jr. Med. Sci., 1930, clxxix, 228-236. CrossrefGoogle Scholar21. BRILL IC: Acute febrile anemia; a new disease?, Arch. Int. Med., 1926, xxxvii, 244-247. CrossrefGoogle Scholar22. MURRAY-LYON RM: Familial acholuric jaundice simulating Lederer's anemia, Brit. Med. Jr., 1935, i, 50-52. CrossrefGoogle Scholar23. PAYNE RV: Acute hemolytic anemia; death after transfusion, Guy's Hosp. Rep., 1934, lxxxiv, 65-71. Google Scholar24. DAMESHEKSCHWARTZ WSO: Hemolysins as the cause of clinical and experimental hemolytic anemias, Am. Jr. Med. Sci., 1938, clxxxxvi, 768-792. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Iowa City, Iowa*Received for publication December 22, 1939.From the Department of Internal Medicine, State University of Iowa, College of Medicine, Iowa City, Iowa. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byIs there a Primary, Acquired Hemolytic Jaundice? 1 April 1941Volume 14, Issue 10Page: 1838-1848KeywordsAnemiaBone marrowHemolytic anemiaSplenomegaly Issue Published: 1 April 1941 PDF downloadLoading ...

Using a Next Generation Sequencing Panel to Discover the Obscure Causes of Hereditary Hemolytic Anemias

Intravascular Hemolysis and Acute Renal Failure After Mitral and Aortic Valve Repair

Severe neonatal unconjugated hyperbilirubinemia, with the risk of bilirubin encephalopathy or kernicterus in severe, untreated cases, occurs when bilirubin production exceeds the body's ability to eliminate it. The causes of neonatal hyperbilirubinemia are multifactorial and comprise increased hemolysis on the one hand, and diminished bilirubin conjugation on the other. In recent years, many of these etiologies have been found to have a genetic origin. Sometimes hereditary factors act independently, but in other circumstances, single mutations which ordinarily do not produce disease in and of themselves, may result in severe hyperbilirubinemia as a result of interaction with other mutated genes. Of cardinal importance to this discussion is the concept of the human genome, whereby the thousands of genes of which it is comprised may interact one with the other, or with the environment, exacerbating the severity of jaundice in certain individuals, and protecting against hyperbilirubinemia in others. Genetic interactions have been demonstrated combining increased bilirubin production with diminished bilirubin conjugation, resulting in severe hyperbilirubinemia. Appreciation of the multiplicity of genetic interactions is of importance in our evaluation of the neonate with severe hyperbilirubinemia, in our attempts to prevent future cases of kernicterus, and in genetic counseling of families who have had an infant with severe neonatal hyperbilirubinemia. Gene therapy for the most severe of these inherited defects of bilirubin conjugation, Crigler-Najjar syndrome type 1, might become a reality in future years.

After completing this article, readers should be able to: 1. Explain methods of preventing the hyperbilirubinemia caused by glucose-6-phosphate dehydrogenase (G6PD) deficiency. 2. Compare and contrast the correlation between hemolysis and serum bilirubin levels in healthy infants and those who are G6PD-deficient. 3. Describe the role of deficient bilirubin conjugation in the pathogenesis of G6PD deficiency-associated neonatal hyperbilirubinemia. 4. Define the risk for neonatal hyperbilirubinemia in female G6PD-deficient heterozygotes, G6PD-deficient homozygotes, and hemizygote males. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a commonly occurring X-linked genetic enzyme defect, is notorious for its association with acute hemolytic crises occurring in response to a frequently identifiable trigger (favism). Another potentially devastating danger of this condition is severe neonatal hyperbilirubinemia with its accompanying bilirubin encephalopathy, kernicterus, and death. Far from being a condition limited to historical time epochs and developing countries, G6PD deficiency-associated kernicterus still is seen in modern times. Indeed, among 80 infants from 21 states in the United States documented in a pilot Kernicterus Registry between 1984 and 1998, 18 (22.5%) were reported to have G6PD deficiency. Furthermore, Maisels recently listed G6PD deficiency among the 10 factors that are associated most commonly with an increased risk of nonhemolytic jaundice. Because of the association with favism, G6PD-associated hyperbilirubinemia traditionally has been regarded as hemolytic in origin. However, recent research has shown that although acute hemolysis does play a role, its contribution in many cases may be smaller than previously thought. The emphasis now has been placed on decreased bilirubin conjugation, with promoter polymorphism for the gene for the bilirubin conjugating enzyme, UDP glucuronoslytransferase 1A1 (UGT1A1), being a major factor in production of the icterus. In this review we highlight key aspects of the pathogenesis of this type of hyperbilirubinemia, explain the relevance of the condition, and describe a particularly problematic group that has a recently recognized high incidence of …

Background: Many cases of severe neonatal hyperbilirubinemia never have the underlying cause of the jaundice clearly identified. Thus they are said to have ‘idiopathic' severe neonatal jaundice. However, finding the exact cause, if it is a genetic condition, can enable informed anticipatory guidance regarding future episodes of hemolysis, anemia, or bilirubin cholelithiasis. Objective: ‘Next generation' gene sequencing can often reveal the mutations responsible for severe neonatal hyperbilirubinemia, but wisely using this new technology involves selective application, employing this testing only if inexpensive technology fails to reveal the diagnosis. Methods: In this review, we display and discuss five types of red blood cell morphological abnormalities that have helped us categorize cases of neonatal hemolytic jaundice. Results: As an aid to applying inexpensive technology, we review morphological abnormalities of erythrocytes that are easily identified on a blood film. When found, these abnormalities can be important clues to the underlying hemolytic condition giving rise to neonatal jaundice. Conclusions: Applying these simple and inexpensive methods can assist neonatologists in caring for neonates who have hemolytic jaundice. We predict that by using these principles the term ‘idiopathic' neonatal jaundice will become less common as the underlying causes are identified.

Severe neonatal thrombocytopenia due to fetomaternal anti-A alloimmunization: A case report

Although severe neonatal hyperbilirubinemia in the term neonate and bilrubin encephalopathy is rare, it is associated with significant morbidity. A number of reports have been published in recent years of bilirubin encephalopathy in term neonates who appeared to be healthy and breast-fed with no evidence of hemolytic disease (Maisels 1995, Ebbesen 2000). Some risk factors are known to be associated with severe hyperbilirubinemia in the newborn and include: jaundice in the first 24 hours of life, previous sibling with jaundice, and gestational age of 35 to 38 weeks (Dennery et al 2001). Additional risk factors include Rh and ABO incompatibility and Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency. Attempts to better quantify the frequency, etiologies and risk factors for neonatal hyperbilirubinemia would be of value prior to identifying strategies for risk reduction. Our objective was to obtain epidemiological data about severe neonatal hyperbilirubinemia in order to develop prevention strategies for this condition. Data on term infants 60 days of age or less with unconjugated hyperbilirubinemia was collected from July 2002 to present through the Canadian Pediatric Surveillance Program. Criteria for inclusion in this study included: 1) peak serum total bilirubin >425 μmol/L or 2) neonatal exchange transfusion. Infants who had exchange transfusions for well-documented Rh isoimmunization disease or were less than 36 weeks of gestational age were excluded. After 16 months of surveillance 220 cases of severe neonatal hyperbilirubinemia were reported. Of these, 148 were confirmed, 33 were duplicates or discarded, and 39 are still under review. In only 47 cases was the cause of the hyperbilirubinemia identified. The etiologies included ABO incompatibility (n=28), G6PD deficiency (n=13), other antibodies (n=4), and unstable hemoglobin (n=2). The range of bilirubin reported was from 156 to 731 μmol/L. 37 of the neonates required exchange transfusion, while all neonates were treated with phototherapy. 6 neonates had documented hearing loss and 3 had seizures prior to discharge from hospital. This study shows that severe neonatal hyperbilirubinemia continues to occur in term neonates with significant morbidity. In the majority of cases the underlying etiology could not be identified, which could partly be attributed to incomplete evaluation at the time of presentation. This finding highlights the importance of a complete hematological workup for such children prior to discharge such as a screen for blood group, Coomb's testing, peripheral smear, and a screen for G6PD. Further testing including a hearing assessment and close pediatric follow-up is also likely to be beneficial.

Neonatal unconjugated hyperbilirubinaemia may have a multifactorial aetiology, and different conditions may act together to increase the risk of severe hyperbilirubinaemia and bilirubin-induced neurological dysfunction.We report a novel case of severe neonatal unconjugated hyperbilirubinaemia requiring treatment with exchange transfusions in two premature twins with a similar clinical presentation. The aetiological investigation revealed glucose-6-phosphate dehydrogenase (G6PD) deficiency combined with heterozygosity for two variants in the UGT1A1 gene. These two conditions alone are common genetic causes of neonatal hyperbilirubinaemia, but the co-occurrence of both in the same patient is unusual.This case highlights a rare synergistic interaction between preterm birth, G6PD deficiency and UGT1A1 variants in the development of a severe case of neonatal unconjugated hyperbilirubinaemia in the absence of identifiable haemolysis.

Neonatal hyperbilirubinemia is frequent and severe in Japanese infants. Although the G71R mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene is associated with severe neonatal hyperbilirubinemia in this population, it accounts for only half of the neonates with severe hyperbilirubinemia. It was suggested that increased bilirubin production would also be associated with severe neonatal hyperbilirubinemia in Japanese infants. To elucidate the genetic factors causing severe hyperbilirubinemia in these patients, we studied two notable factors associated with bilirubin production: heme oxygenase-1, a key enzyme of heme metabolism, and fetal Hb composition, a factor possibly associated with heme load in neonates. We first determined the sequences of promoter and all coding regions of the heme oxygenase-1 gene in Japanese neonates who had undergone phototherapy, but found no mutation except for the polymorphic (GT)n repeats in the promoter region. These repeats modulate the transcription of the heme oxygenase-1 gene, and the longer repeat sequences are known to reduce the transcription. We detected a significant difference in the allele frequencies of each number of (GT)n repeats between Japanese and German populations. However, we could not find a relation between those polymorphisms and neonatal hyperbilirubinemia. We next analyzed the state of Hb switching of the gamma- to beta-globin chain and the phenotype of gamma-globin chain isoforms in cord blood. We found no relation between fetal Hb composition and neonatal hyperbilirubinemia. Further studies are required to elucidate genetic or environmental factors in neonatal hyperbilirubinemia in Japanese infants.

Objective To explore the necessity of conventional calcium supplement in peripheral arteriovenous synchronous blood exchange transfusion on neonatal severe hyperbilirubinemia. Methods A total of 171 cases of infants with neonatal severe hyperbilirubinemia who needed to receive blood exchange transfusion were selected as research subjects from December 1, 2014 to November 30, 2015 in West China Second University Hospital, Sichuan University. And 86 cases of infants with neonatal severe hyperbilirubinemia who received conventional calcium supplement in peripheral arteriovenous synchronous blood exchange transfusion from December 1, 2014 to April 30, 2015 were enrolled into study group (n=86), while 85 cases of infants who did not received any calcium supplement in peripheral arteriovenous synchronous blood exchange transfusion from May 1, 2015 to November 30, 2015 were enrolled into control group (n=85). The total serum calcium concentrations before and after blood exchange, the incidence rates of hypocalcemia, hypercalcemia and abnormal serum calcium concentration of two groups were statistically compared. Adverse reactions related with calcium in study group were analyzed. The study protocol was approved by the Ethical Review Board of Investigation in Human Beings of West China Second University Hospital, Sichuan University. Informed consents were signed with the guardians of each child. Results ①There were no statistical differences between two groups in the gender ratio, constituent ratio of premature infants and term infants, gestational age, birth weight, age of infants, serum total calcium concentrations before blood exchange transfusion and so on (P>0.05). ②For study group, the serum total calcium concentrations before and after blood exchange transfusion were (2.27±0.26) mmol/L and (2.51±0.33) mmol/L, respectively, and the difference was statistically significant (t=-8.518, P<0.001). For control group, the serum total calcium concentrations before and after blood exchange transfusion were (2.33±0.35) mmol/L and (2.09±0.37) mmol/L, respectively, and the difference also was statistically significant (t=5.268, P<0.001). After blood exchange transfusion, the serum total calcium concentration in study group was higher than that in control group, and the difference was statistically significant (t=-7.894, P<0.001). ③There was no statistical difference between two groups in the incidence rates of abnormal serum calcium concentration (11.8% vs 11.6%, χ2=0.001, P=0.975). The incidence rate of hypocalcemia in study group was 2.3% (2/86), which was lower than that of 11.8% (10/85) in control group, and the difference was statistically significant (χ2=5.837, P=0.016). The incidence rate of hypercalcemia in study group was 9.3% (8/86), which was higher than that of 0 in control group, and the difference was statistically significant (χ2=6.340, P=0.012). ④In study group, 8 cases (9.3%, 8/86) of infants had bradycardia during intravenous injection of calcium supplementation in peripheral arteriovenous blood exchange transfusion therapy, and the symptom recovered when injection was stopped; after intravenous injection of calcium supplementation, 3 cases (3.5%, 3/86) had local skin redness, 1 case (1.2%, 1/86) had localized skin swelling. There was no hypercalcemic crisis occured in study group. Conclusions The calcium supplement cannot completely prevent the occurrence of hypocalcemia in peripheral arteriovenous synchronous blood exchange transfusion for infants with severe neonatal hyperbilirubinemia, but increases the risks of calcium leakage and hypercalcemia. Therefore, the necessity of conventional calcium supplement during the process of blood exchange transfusion therapy needs to be further confirmed by more studies in the future. Key words: Hyperbilirubinemia, neonatal; Peripheral arteriovenous synchronous blood exchange transfusion; Serum calcium; Hypocalcemia; Hypercalcemia; Infant, newborn

Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity

See article on page 1381–1390, in this issue