Hemolytic Disease of the Newborn

¶ … History of Pediatric Hemolytic Monitoring

Retrospect to the career of physician, Dr. James A. Wolff I and his early progress in treatment of Rh hemolytic disease as described in Pochedly (1984), looks at the development of interest in hematology in European field hospitals during World War II. After the war period, the transformation of Wolff's research in this area was advanced by research conducted during a pediatric residency at the Boston Children's Hospital, between 1945 and 1947. During his tenure at Children's he was engaged with Dr. Louis Diamond in his seminal investigation on treatment of erythroblastosis fetalis by exchange transfusion.

Collaborative efforts with Drs. Diamond and Farber focused on preliminary clinical trials of aminopterin for the treatment of acute leukemia, of which Wolff was in observation. Instrumental to the development of the concept of treating erythroblastosis fetalis by exchange transfusion; collaborative in the area of pathophysiology of disease where hemolytic conditions are found in the publication of work by colleagues, Drs. Philip Levine and Alexander Wiener. In those early studies, three techniques of exchange transfusion were implemented with Diamond's umbilical catheter technique succeeding in tests because of the ready insertion and multiple exchange facilitation made possible in what became the accepted method for treating infants diagnosed with erythroblastosis fetalis.

In Feldman and Tauber (1997), Sickle Cell Anemia: Reexamining the First "Molecular Disease" recount of the developments in molecular paradigms between 1910 and the 1950s, looks at the baseline research leading to medical classification of the pathophysiology of sickling, and definition of the term "sickle cell anemia;" used to designate two conditions: 1) hereditary predisposition to anemia occurring only in the 'negro race' characterized by crescentic distortion of the red corpuscles, and (2) chronic, severe anemia affecting only 'negroes' with this predisposition. Linus Pauling's (1949) seminal clinical study, offered foundation to molecular research on hemolytic disorders, showing that sickle cell anemia was due to an abnormal hemoglobin molecule.

Within subsequent studies, it was discovered that of a large group of the population that inherited the sickle cell trait, "an undetermined number, due to factors unknown, develop varying degrees" of sickle cell anemia "a hemolytic type of blood dyscrasia with characteristic clinical and pathological features" (Feldman and Tauber). Characterized by hemolytic jaundice, episodes of abdominal pain, and remissions and exacerbations including joint pains without inflammation and a tendency to ulcer in limbs, the persistence of the disorder found in predisposition where those affected by hemolytic anemia showed signs that the mechanism of sickle cell formation occurred in vitro.

Searching for a point of early intervention, attempts to distinguish between fetal and adult hemoglobin, Andersch, Wilson, and Menten (1944) conducted a clinical trial using a new electrophoretic technique. Although the two distinct hemoglobins had been identified through observation, according to the different rate of denaturation by alkali, the study sought information on how electrophoretic differences correlated to varying structure in the hemoglobin molecule. Using what was called a modified Tiselius apparatus, Andersch et al. tested the carbonylhemoglobin in infants ranging up to 90 days old, finding that hemoglobin types were present in varying degrees according to developmental stage, based on the hypothesis that "fetal hemoglobin is normally replaced gradually by adult hemoglobin in the first seven months of life" (Feldman and Trauber). Noting significant difference in the mobilities and in the sedimentation constants of adult and fetal hemoglobin the study confirmed the existence of two molecular species of hemoglobin in fetal and adult subjects, each differing in molecular protein constitution.

Since the studies of the mid-twentieth century, much has been done regarding diagnosis and treatment of fetal contraction of erythroblastosis, and attendant general hemolytic uremic syndrome (HUS) in infant and child patients. If the developments in molecular medicine have supported the definition and treatment of sickle cell anemia, the history of those developments has contributed greatly to knowledge on hemolytic pediatric medicine and to the History of Global Medicine more generally.

While quite a bit of the early research conducted on hemolytic related disorders is attributed to medical science in the United States and Western Europe, an important number of investigations outside the 'West' in recent decades has furthered pediatric knowledge of fetal molecular contraction and prevalence of hemolytic type of blood dyscrasia and attendant complications as patient populations in Africa, Asia, Eastern Europe, Latin America and the Middle East exhibit signs of associated autoimmune disorder or immunoregulatory abnormalities (serum imunoglobulins).

In Al Eisa and Al-Hajeri (2001) HUS was observed in twenty five, Kuwaiti Arab children in a longitudinal study from 1985 to 2000 in the P. Pediatric Nephrology Unit at Mubarak Al-Kabeer Hospital. Of the twenty five participants to the study, 14 patients (56%) exhibited typical (D+) HUS whereas 11 (44%) exhibited atypical (D-) HUS. Secondary symptoms were relatively absent, which is often not the case where HUS is diagnosed as part of spectrum of disorders, even where it is first called to the attention of physicians by way of a secondary diagnosis. In the Kuwait study, no bacterial or viral pathogens could be isolated in the majority of the cases.

Findings to the research reported that the atypical HUS group showed more severe anemia (P=0.03), significantly more prolonged in comparison with the typical HUS group (P=0.0028). However, there was no distinct indicators present between the two groups in terms of "mean maximum serum creatinine (P=0.1); blood urea nitrogen values (P=0.8) and severity of leukocytosis (P=0.4)" (Al Eisa and Al-Hajeri). Treatment factors such as anuria and the need for dialysis were not significant in outcome between the two groups, expressed as: P=0.1 and 0.05, respectively.

The incidence of mortality was significantly higher in the D- HUS patients (P

Recurrence of HUS where there is combined immune thrombocytopenia (ITP) and autoimmune haemolytic anemia (AIHA) with absence of any known underlying etiology is known as Evans' Syndrome (ES), which is the focus of much of the pediatric research on hemolytic disorders. In a French study, Blouin, P. et al. (2005), a retrospective discussion on research conducted at SHIP french centres (Societe d'hematologie et d'immunologie pediatrique) between 1990 and 2002, looks at a homogeneously-studied and prospectively-analysed cohort of childhood ES patients; controlled from those patients with ES from specific immune deficiency (especially fas gene mutations) is known.

Of consideration to the project was generalized autoimmune and/or inflammatory disorders and genetic diseases; as well as identification of known classificatory ES subsets with establish prognostic factors from which optimal treatment could be prescribed or was already underway. Consistent to the hypothesis to the research, pathophysiology, epidemiology and outcomes were not defined as dependent or independent factors to the dataset.

Of the study population comprised of thirty-six children, twenty of whom were male, and sixteen female, median age at diagnosis was four years. In twenty one of the children, ES occurred were consanguine family history of autoimmune/inflammatory disease was present, and "associated autoimmune disorder or immunoregulatory abnormalities (serum imunoglobulins, peripheral blood lymphocytes subsets, low level of the C3-C4 complement components, nuclear antibodies)" (Blouin, P. et al.).

The research was conducted with a series of several successive treatments, with a median of three treatments, on a continuum of 0 to 10. The treatments included: "corticosteroid therapy (35/36), intravenous immunoglobulins (32/36), immunosuppressive agents (14/36), splenectomy (9/36) and anti-CD 20 monoclonal antibodies (6/36)" (Blouin, P. et al.). Participants with low level of serum immunoglobulins exhibited no response to corticosteroidtherapy/intravenous immunoglobulins; requiring accelerated frequency in therapy (P=0.03). Mortality of three patients in response to intracranial bleeding was expressed as significant to the hypothesis, where ES is often chronic, severe life-threatening disease, where aggressive immunosuppressive therapy supports approximately half the patients.

A similar study by Friedmann et al. (1998) in the United States, advanced the hypothesis that autoimmune hemolytic anemia (AIHA) is due to warm-reactive immunoglobulin M (IgM) antibodies. According to composite of prior research, the condition is rare in adults and at the time had never been described in children in the U.S. Findings to this pediatric study of a nine years old Evan's symdrome patient with warm AIHA due to high-titer complete IgM antibody revealed that this rare form of AIHA where severe anemia, fatigue, and skin mottling were symptomatic to "high-titer, high thermal amplitude (37 degrees C) complete IgM autoantibody" according to serologic examination (Friedmann et al.).

While morbidity and mortality resulted when a secondary impact to the patient's system from disseminated Aspergillosis infection contracted during the course of the study due to cardiovascular collapse "caused by agglutinated red blood cells in the right ventricle with outflow obstruction, cerebrovascular infarcts, hepatic failure, and infarction of her extremities" the investigation is informative, once again, to the limits that clinical intervention in the form of aggressive dosages corticosteroids, intravenous immune globulin, cyclophosphamide, mycophenolate mofetil, and even whole blood exchange transfusions, and cyclosporine A (Friedman et al.).

While still under physician care, the patient expressed obvious symptoms of anemic and developed multiorgan system failure from diffuse in vivo hemagglutination. Another such study advances interpretation of AIHA treatment with lesser used Rituximab; anti-CD20 (B-cell) monoclonal antibody typically employed for the treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin's lymphoma (Gottardo, Baker and Willis (2003). Long-term remission is mentioned here.

Mechanism Rh Hemolytic Disease in studies of embryonic and fetal transmission and complications as a result of in utero exposures constitutes related component of the research on hemolytic disorders in the field of pediatric medicine. For instance, Zeltzer et al. (1983) further insights into the presence of acute lymphoblastic leukemia in their study of a child whose mother was exposed to diethylstilbestrol (DES) in utero sometime during the first and second trimesters of pregnancy. While family disposition to cancer was present in the report, potential that the susceptible host mother may have had a DES-induced abnormal changes in germ cells would have affected embryonic tendency to develop premalignant or malignant genetic outcomes. Other indicators point to possible early somatic change during embryogenesis or a later prenatal or postnatal event (Zeltzer et al.).