Red Blood Cell Macrocytosis Research Articles

Variable Clinical Presentation in Individuals with Truncating Variants in DDX41

Background and AimsDefects in DDX41 have previously been associated with increased risk of myeloid neoplasms, lymphoid neoplasms, cytopenia, and red blood cell macrocytosis. DDX41-related phenotypes have a variable age of onset typically in the 60 s. A previous study analyzed a cohort of 1,385 individuals with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), identifying 33 individuals with a pathogenic variant in DDX41, 9 of whom had a familial history of MDS/AML. In our cohort of 6,103 participants with diverse clinical manifestations, we identified 7 individuals with truncating variants in DDX41. We sought to characterize age-related penetrance and the phenotypic spectrum of individuals with DDX41 truncating variants. MethodsWe performed exome or genome sequencing on DNA extracted from blood, saliva, fibroblasts, or EBV-transformed cell lines in individuals referred to the Centralized Sequencing Program at the NIH for immune-related, neurological, psychiatric, and other clinical indications. ResultsWe identified 7 subjects with truncating variants in DDX41, including 3 different frameshift variants in 5 subjects and 2 different nonsense variants in the other 2 subjects. The average age of subjects was 37 years old, ranging from 5 to 76 years old at time of enrollment. There were 3 males and 4 females. Family history of DDX41-related phenotypes was not reported in the families; furthermore, there were no familial cases, thought segregation data was incomplete. Clinical features were highly variable, ranging from a healthy volunteer to an individual with JAK2 p. Val617Phe-associated eosinophilic myeloid neoplasm. Previously associated DDX41-related phenotypes were not observed in the 7 subjects even include those above 60. ConclusionsHere, we report 7 subjects with truncating variants in DDX41. These individuals have variable immune phenotypes and further studies are necessary to delineate whether they are attributed to DDX41 truncating variants. Detection of DDX41-defects in younger individuals prior to symptom onset poses genetic counseling challenges given the long latency period and minimal evidence-based management guidelines at present. Nonetheless, current expert-based clinical recommendations for management and monitoring may provide clinical benefit upon further study. Additional studies of clinical and sub-clinical features in expanded cohorts are warranted to further delineate DDX41-related disease risk.

Iron accumulation in the choroid plexus, ependymal cells and CNS parenchyma in a rat strain with low-grade haemolysis of fragile macrocytic red blood cells.

Iron accumulation in the CNS is associated with many neurological diseases via amplification of inflammation and neurodegeneration. However, experimental studies on iron overload are challenging, since rodents hardly accumulate brain iron in contrast to humans. Here, we studied LEWzizi rats, which present with elevated CNS iron loads, aiming to characterise choroid plexus, ependymal, CSF and CNS parenchymal iron loads in conjunction with altered blood iron parameters and, thus, signifying non‐classical entry sites for iron into the CNS. Non‐haem iron in formalin‐fixed paraffin‐embedded tissue was detected via DAB‐enhanced Turnbull Blue stainings. CSF iron levels were determined via atomic absorption spectroscopy. Ferroportin and aquaporin‐1 expression was visualised using immunohistochemistry. The analysis of red blood cell indices and serum/plasma parameters was based on automated measurements; the fragility of red blood cells was manually determined by the osmotic challenge. Compared with wild‐type animals, LEWzizi rats showed strongly increased iron accumulation in choroid plexus epithelial cells as well as in ependymal cells of the ventricle lining. Concurrently, red blood cell macrocytosis, low‐grade haemolysis and significant haemoglobin liberation from red blood cells were apparent in the peripheral blood of LEWzizi rats. Interestingly, elevated iron accumulation was also evident in kidney proximal tubules, which share similarities with the blood–CSF barrier. Our data underscore the importance of iron gateways into the CNS other than the classical route across microvessels in the CNS parenchyma. Our findings of pronounced choroid plexus iron overload in conjunction with peripheral iron overload and increased RBC fragility in LEWzizi rats may be seminal for future studies of human diseases, in which similar constellations are found.

Biventricular diastolic dysfunction, thrombocytopenia, and red blood cell macrocytosis in experimental pulmonary arterial hypertension.

Pulmonary arterial hypertension is a fatal disease, where death is associated with right heart failure and reduced cardiorespiratory reserve. The Sugen 5416, hypoxia and normoxia Fischer rat model mimics human pulmonary arterial hypertension, although the cause(s) of death remains incompletely understood. Here, we hypothesized that these animals develop biventricular diastolic dysfunction that contributes to tissue hypoperfusion coincident with severe pulmonary arterial hypertension. We performed comprehensive echocardiographic and hematologic assessments. Serial echocardiogram at 3–5 weeks was performed followed by blood sampling via aortic or cardiac puncture. Echocardiogram revealed pulmonary arterial hypertension in pulmonary artery Doppler waves, including notched wave envelopes, and decreased pulmonary artery acceleration time/pulmonary artery ejection time ratio and right ventricular outflow tract velocity time integral. Impaired right ventricular systolic function, assessed by decreased tricuspid annular plane systolic excursion and tricuspid tissue Doppler systolic positive wave velocity, was observed in pulmonary arterial hypertension. Tricuspid and mitral pulsed wave and tissue Doppler findings suggested biventricular diastolic dysfunction, with dynamic changes in early and late diastolic filling waves, their fusion patterns, and a decrease in e' velocity. Heart rate and ejection fraction did not change, but cardiac output, stroke volume, and end-diastolic volume were decreased, and inferior vena cava respiratory variation was decreased. Blood electrolyte values were suggestive of intravascular volume expansion early in the disease followed by volume contraction and tissue hypoperfusion in the latter stages of disease. Complete blood count showed thrombocytopenia and non-anemic macrocytosis with reticulocytosis and an increase in red blood cell distribution width. Thus, pulmonary, cardiac, and hematological findings in Fischer animals with pulmonary arterial hypertension are characteristic of humans and provide an insightful experimental platform to resolve mechanisms of disease progression.

Mean Corpuscular Volume to White Blood Cell Ratio for Thiopurine Monitoring in Pediatric Inflammatory Bowel Disease.

Thiopurines, commonly used to treat inflammatory bowel disease, cause lymphopenia and red blood cell macrocytosis, requiring therapeutic monitoring. Mean corpuscular volume/white blood cell (MCV/WBC) ratio has been proposed as a surrogate for therapeutic monitoring. Our aim was to investigate MCV/WBC ratio for assessing clinical response to thiopurines among pediatric patients with inflammatory bowel disease. We performed a retrospective cross-sectional study at a tertiary care center using laboratory results and standardized physician global assessments (PGA) among pediatric patients taking thiopurines. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fecal calprotectin, and 6-thioguanine nucleotides were assessed when available. The primary outcome was association between MCV/WBC ratio and clinical remission assessed by ESR, CRP, calprotectin, or PGA. We also used a composite outcome requiring all available data to be normal. Analyses were limited to 1 occurrence per patient, >60 days after starting thiopurine, and comparators were required to be within 14 days of one another. A total of 471 patients met inclusion criteria. MCV/WBC ratio poorly predicted quiescent disease as defined by PGA (area under receiver operating characteristic curve [AuROC] 0.55, 95% confidence interval [CI] 0.43-0.66). MCV/WBC ratio better predicted quiescent disease defined as normal CRP (AuROC 0.64, 95% CI 0.58-0.70) or normal ESR (AuROC 0.59, 95% CI 0.52-0.66). When the composite outcome measure was used, MCV/WBC ratio had an AuROC of 0.65 (95% CI 0.59-0.70), indicating it is reasonably accurate in discriminating between clinical remission and active disease. MCV/WBC ratio is a noninferior, easy, and low-cost alternative to thiopurine metabolite monitoring.

Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis.

Telomerase reverse transcriptase (TERT) or telomerase RNA (TERC) gene mutation is a major monogenic cause of pulmonary fibrosis. Sequencing of TERT/TERC genes is proposed to patients with familial pulmonary fibrosis. Little is known about the possible predictors of this mutation and its impact on prognosis.We retrospectively analysed all the genetic diagnoses made between 2007-2014 in patients with pulmonary fibrosis. We evaluated the prevalence of TERT/TERC disease-associated variant (DAV), factors associated with a DAV, and the impact of the DAV on survival.237 patients with pulmonary fibrosis (153 with familial pulmonary fibrosis, 84 with telomere syndrome features without familial pulmonary fibrosis) were tested for TERT/TERC DAV. DAV was diagnosed in 40 patients (16.8%), including five with non-idiopathic interstitial pneumonia. Prevalence of TERT/TERC DAV did not significantly differ between patients with familial pulmonary fibrosis or with only telomere syndrome features (18.2% versus 16.4%). Young age, red blood cell macrocytosis, and low platelet count were associated with the presence of DAV; the probability of DAV was increased for patients 40-60 years. Transplant-free survival was lower with than without TERT/TERC DAV (4.2 versus 7.2 years; p=0.046).TERT/TERC DAV were associated with specific clinical and biological features and reduced transplant-free survival.

To study the masking effect of folic acid on Vitamin B12deficiency anemia

Background and Aim: A deficiency of either Vitamin B 12 or folate can lead to megaloblastic anemia. Folate and Vitamin B 12 metabolism is linked in transfer of a methyl group from N5-methyltetrahydrofolate to cobalamin. Methods: This was an observational study carried out among healthy adults (students and staff) of a medical college in rural Northwest India. Results: Despite the occurrence of suboptimal serum Vitamin B 12 in more than half of our healthy study population on one hand, we observed normal hematological variables such as hemoglobin or lack red blood cell macrocytosis (mean corpuscular volume > 100 fL) among participants as a rule. Folic acid deficiency usually coexists with that of Vitamin B 12 , and this has been reported by many studies in past. Strikingly, our study population had 16.98 ± 5.44 ng/ml as mean serum folic acid which was toward higher side of normal range. This sufficiency of folic acid in the group having suboptimal Vitamin B 12 might have masked the manifestations of Vitamin B 12 deficiency. Conclusion: The sufficiency of folic acid in the study group might have masked the overt manifestations of Vitamin B 12 deficiency.

Folate deficiency in an unselected population in Calgary, Alberta and its relationship with red blood cell macrocytosis.

BackgroundFolate deficiency is rare in western countries and therefore blood tests for folate level have limited indications. One such indication is red cell macrocytosis, however it is unclear if the association of macrocytosis with folate deficiency is robust enough to serve as a risk marker. Our objective is to determine whether macrocytosis is a useful marker for folate deficiency.FindingsPaired data from the Calgary Laboratory Services Information System was analyzed using receiver operating characteristic (ROC) curves to determine strength of association between mean corpuscular volume and serum folate. Strength of association was analyzed for serum folate cut-off values of 12, 10, 8, and 6 nmol/L. Overall, 0.2% of individuals were folate deficient (<6 nmol/L serum folate). Based on ROC curves, at each cut-off level, mean corpuscular volume was a poor predictive marker for serum folate level.ConclusionsFolate deficiency is rare in Calgary, Alberta. Macrocytosis is not a strong predictor for folate deficiency.

Clinical complications in pregnant women with sickle cell disease: prospective study of factors predicting maternal death or near miss.

ObjectiveTo evaluate complications in pregnant women with sickle cell disease, especially those leading to maternal death or near miss (severe obstetric complications).MethodsA prospective cohort of 104 pregnant women registered in the Blood Center of Belo Horizonte (Hemominas Foundation) was followed up at high-risk prenatal units. They belonged to Group I (51 hemoglobin SS and three hemoglobin S/β0-thalassemia) or Group II (49 hemoglobin SC and one hemoglobin S/β+-thalassemia). Both groups had similar median ages. Predictive factors for ‘near miss’ or maternal death with p-value ≤ 0.25 in the univariate analysis were included in a multivariate logistic model (significance set for p-value ≤ 0.05).ResultsGroup I had more frequent episodes of vaso-occlusive crises, more transfusions in the antepartum and postpartum, and higher percentage of preterm deliveries than Group II. Infections and painful crises during the postpartum period were similar in both the groups. The mortality rate was 4.8%: three deaths in Group I and two in Group II. One-third of the women in both the groups experienced near miss. The most frequent event was pneumonia/acute chest syndrome. Alpha-thalassemia co-inheritance and β-gene haplotypes were not associated with near miss or maternal death. In multivariate analysis predictors of near miss or death were parity above one and baseline red blood cell macrocytosis. In Group I, baseline hypoxemia (saturation < 94%) was also predictive of near miss or death.ConclusionOne-third of pregnant women had near miss and 4.8% died. Both hemoglobin SS and SC pregnant women shared the same risk of death or of severe complications, especially pulmonary events.

Peripheral blood cell counts in infants with Down's syndrome.

The current literature indicates that several abnormalities have been observed in the three hematopoietic cell lines of infants with Down's syndrome. This prospective, longitudinal study was designed to clarify the physiological variation in peripheral blood cell values of children with Down's syndrome by following 25 such infants during their first year of life. Apart from polycythemia in the first week of life, the hemoglobin concentration was, in general, the same as in normal term infants. At 9-12 months of age values for mean corpuscular hemoglobin and mean corpuscular volume tended to be elevated. Serum erythropoietin concentrations were low to normal. White blood cell counts were slightly lower in children with Down's syndrome than in normal children. The study infants had profound thrombocytosis from the age of 6 weeks to the end of follow-up at 1 year. This study, the first longitudinal follow-up of such subjects, indicates that infants with Down's syndrome often have evidence of polycythemia soon after birth and red blood cell macrocytosis and thrombocytosis later in infancy. In conclusion, we carried out peripheral blood cell counts in 25 infants with Down's syndrome, but with no actual hematological disturbance, during their first year of life, and compared them with values for normal term infants.

Etiology of Red Blood Cell Macrocytosis During Childhood: Impact of New Diseases and Therapies

Although an elevated erythrocyte mean corpuscular volume has been noted in many conditions, the relative frequency of various causes of macrocytosis in the pediatric population has not been defined. Therefore, the different medical conditions associated with red cell macrocytosis were retrospectively reviewed. One hundred forty-six children between 6 months and 12 years of age with a mean corpuscular volume greater than or equal to 90 fL were identified during a 13-month period. The most common association with macrocytosis was drug ingestion (anticonvulsants, zidovudine, immunosuppressive agents), observed in 51 (35%) of the cases. Other conditions associated with macrocytosis were congenital heart disease (20), Down syndrome (12), reticulocytosis (11), and marrow failure/myelodysplasia (6). Miscellaneous diseases were identified in 21 children. Twenty-four cases had no apparent cause of their macrocytosis; 21 of them had just a slight elevation of the mean corpuscular volume (91 or 92 fL), suggesting that these values probably represent the upper limit of normal. No cases of vitamin B12 or folate deficiency were observed. The use of relatively new drugs such as valproate, zidovudine, and immunosuppressants (for the treatment of diverse medical conditions) accounted for more than half of the cases of drug administration and 24% of the children with macrocytosis. Three children with bone marrow failure had macrocytosis and pancytopenia, suggesting that this finding might be the first manifestation of serious but treatable disorders such as aplastic anemia.

On reducing the frequency of severe abruptio placentae

At Parkland Memorial Hospital the frequency of abruptio placentae so severe as to kill the fetus has decreased from 1 in 420 deliveries during 1956 through 1969 to 1 in 830 during 1974 through 1989. Major factors in this reduction were elimination of very high parity and a marked increase in the percentage of Latin American women, in whom the risk was 1 in 1473 deliveries compared with 1 in 595 for black women and 1 in 876 for white women. Abdominal trauma was encountered rarely, as was fetoplacental-to-maternal hemorrhage sufficient to impair fetal perfusion seriously. Abnormal development of Müllerian ducts and uterine myomas were encountered rarely. Neither red blood cell macrocytosis characteristic of folate deficiency nor iron deficiency could be implicated in the genesis of severe abruptio placentae. Abruptio placentae recurred in 12% of subsequent pregnancies and proved fatal to the fetus in 7%, unchanged from our earlier experience.

On reducing the frequency of severe abruptio placentae

At Parkland Memorial Hospital the frequency of abruptio placentae so severe as to kill the fetus has decreased from 1 in 420 deliveries during 1956 through 1969 to 1 in 830 during 1974 through 1989. Major factors in this reduction were elimination of very high parity and a marked increase in the percentage of Latin American women, in whom the risk was 1 in 1473 deliveries compared with 1 in 595 for black women and 1 in 876 for white women. Abdominal trauma was encountered rarely, as was fetoplacental-to-maternal hemorrhage sufficient to impair fetal perfusion seriously. Abnormal development of Mullerian ducts and uterine myomas were encountered rarely. Neither red blood cell macrocytosis characteristic of folate deficiency nor iron deficiency could be implicated in the genesis of severe abruptio placentae. Abruptio placentae recurred in 12% of subsequent pregnancies and proved fatal to the fetus in 7%, unchanged from our earlier experience. At Parkland Memorial Hospital the frequency of abruptio placentae so severe as to kill the fetus has decreased from 1 in 420 deliveries during 1956 through 1969 to 1 in 830 during 1974 through 1989. Major factors in this reduction were elimination of very high parity and a marked increase in the percentage of Latin American women, in whom the risk was 1 in 1473 deliveries compared with 1 in 595 for black women and 1 in 876 for white women. Abdominal trauma was encountered rarely, as was fetoplacental-to-maternal hemorrhage sufficient to impair fetal perfusion seriously. Abnormal development of Mullerian ducts and uterine myomas were encountered rarely. Neither red blood cell macrocytosis characteristic of folate deficiency nor iron deficiency could be implicated in the genesis of severe abruptio placentae. Abruptio placentae recurred in 12% of subsequent pregnancies and proved fatal to the fetus in 7%, unchanged from our earlier experience.

Recognition and evaluation of red blood cell macrocytosis in the primary care setting

To investigate primary care physicians' recognition and evaluation of red blood cell (RBC) macrocytosis in adults. Retrospective chart review. Utilizing a computerized laboratory result system, all complete blood counts (CBCs) with RBC indices performed between May 1986 and May 1987 were retrieved. Patients having mean corpuscular volumes (MCVs) more than three standard deviations from the mean (greater than 98.5 fL) were selected for evaluation. The primary care clinics of a public university hospital. 138 (3.7%) of 3,805 adult outpatients had MCVs greater than 98.5 fL, and of these, 128 (93.4%) had medical charts available for review. 55 patients with elevated MCVs were not evaluated for this finding, and their mean MCV (100.6 fL) was significantly lower than that of the 73 patients who were evaluated (102.5 fL; p = 0.003). The investigation of macrocytosis included vitamin B12 and folate levels consistently, and the reticulocyte count and peripheral smear were examined infrequently. Five patients had vitamin B12 deficiency, and two had hypothyroidism. Macrocytosis was ascribed to alcohol abuse in 47 patients, six of whom had no laboratory evaluation. Nine alcoholic patients with macrocytosis had other causes for this finding. Among the 55 patients whose macrocytosis was not evaluated, 12 were anemic and one had a peripheral neuropathy. Clinically significant and treatable disease was often associated with macrocytosis in our study. Macrocytosis was common, and its recognition and evaluation were variable in this primary care outpatient setting.

Multiple symmetric lipomatosis: an updated clinical report.

A systematic survey of 19 male patients with multiple symmetric lipomatosis (MSL) gives evidence for newly delineated and clinically relevant features of the disease. Signs and symptoms of a hitherto unrecognized severe peripheral and autonomic neuropathy were observed in all patients. A mediastinal location of lipomatous tissue was identified by computed tomography in five patients, with clinical evidence of a space-occupying syndrome in four of them. A further deep location of lipomatous tissue below the trapezius muscle, independent of the involvement of the overlying subcutaneous adipose tissue, was demonstrated in seven patients. Alcohol-related abnormalities in liver function tests were present in 10 of 19 patients. The disease is characterized by peculiar metabolic abnormalities, such as marked increase in adipose tissue lipoprotein lipase activity, a plasma hyperalphalipoproteinemia and a specific defect of the adrenergic-stimulated lipolysis in lipomatous tissue. Finally, a red blood cell macrocytosis or overt macrocytic anemia and abnormalities in liver function tests were found in MSL patients, related to elevated alcohol intake. An 8-year follow-up of nine MSL patients demonstrated that peripheral neuropathies and space-occupying mediastinal syndromes represent the most incapacitating, sometimes rapidly progressive, complication of MSL.

Foetal blood abnormality associated with hypodactyly in the hd strain of rat.

The homozygous foetuses of hypodactyl rats (hd strain) present an obvious red blood cell macrocytosis (day 14 of gestation). This blood abnormality could give rise to thrombosis leading to early necrosis of the extremities.