heme/onc Flashcards
What are the sites of erythropoiesis
embryo –> yolk sac fetus during first trimester through birth –> liver fetus during second trimester through adulthood –> bone marrow
Describe chronology of hemoglobin switching
Embryonic Hb during 1st trimester from yolk sac: includes HbGower 1 [z2e2], [a2e2], and Hb Portland [z2g2].
Fetal Hb (HbF) is a2g2, predominant Hb during fetal life and newborn (75% at birth). Doesn’t bind to 2,3 dbg which makes it have higher affinity for O2.
Adult Hb (HbA) is a2b2 and minor form HbA2 a2d2 increase after birth. Majority is HbA by 6m.
How are fetal RBCs different than adult RBCs
- larger MCV
- shorter life span 60-80d instead of 120
describe erythropoises in neonate
Epo production starts in liver initially and switches to kidney near birth. Erythropoeisis under control of neonate b/c epo doesn’t cross placenta. Higher production than adults because of relative hypoxia.
When does physiologic anemia of infancy happen and how is it different from anemia of prematurity
Anemia of infancy happens at about 8-12w in term infants, at an average of Hb 11.
Anemia of prematurity is multifactorial and usually at 6w with Hb 7-10.
Describe hemolytic disease of the newborn
HDN is usually due to maternal IgG against D Ag on RBC crossing placenta. This is clinically significant usually only after 2nd pregnancy. It can also be against C, E, anti-Kell and anti-Duffy antigents.
Anti-Kell also impacts reticulocytes.
In contrast, it is not usually severe with ABO incompatibility, although ABO hemolytic anemia can happen during first pregnancy and is not more severe with subsequent pregnancies.
how does RhoGAM work
RhoGAM is anti-D Ab. It is given to Rh- moms at 28w and 7w after delivery. It clears Rh+ fetal cells from maternal circulation before mother can make her own anti-D Ab.
Describe the different a thalassemias
There are four copies of a-globin gene on chr. 16.
more commonly in aa:
Deletion of 1 gene: silent carrier.
Deletion of 2 genes: a-thal trait. Mild anemia.
more commonly in asian:
Deletion of 3 genes: majority Hb B, and later in infancy HbH (b4)
Deletion of 4 genes: homozygous a-thal. mostly Hb Barts (g4)
HbH and HbBarts usually results in severe fetal anemia and hydrops.
Describe the types of B-Thallesemia
We have two copies of B-globin gene on Chr. 11. Gamma-globin in fetus prevents B-thal babies from being symptomatic as a fetus, usually mild symptoms at most in neonate.
Deletion of B-globin gene can results in silent carrier, B-thal trait, B- thal intermedia and B-thal major.
What is the genetic mutation that causes HbS
point mutation at position 6 in B chain replacing valine with glutamic acid
What is appropriate follow up for NBS for hemoglobinopathies?
Initial NBS is done using isoelectric focusing and high-performance liquid chromatography.
Anormal tests should be confirmed with Hb electrophoresis at 6 months.
HbS infants can benefit from PCN ppx, immunization against h. flu and s. pneumoniae.
What are two major intrinsic RBC defects that cause non-immune mediated hemolysis?
1) Glucose 6 Phosphate Dehydrogenase (G6PD) Deficiency: G6PD supplies NADPH to reduce glutathione in RBC via hexose monophospate shunt/pentose phosphate pathway. Without this, during oxidative stress hemolysis occurs. X-linked recessive. More common in AA and Medidterranean descent. Difficult to diagnose during crisis because immature RBCs have higher levels of G6PD.
2) Pyruvate Kinase (PK) deficiency: PK is enzyme in glycolysis, if deficient RBC cannot produce enough energy –> hemolysis. Autosomal recessive.
What are membrane protein defects causing non-immune hemolysis?
1) Spherocytosis: AD defect in ankyrin. Dx: Spherocytes on smear, osmotic fragility test.
2) Elliptocytosis: AD mutation in a/b spectrin. Dx: ovalocytes. Milder anemia than spherocytosis.
3) Pyropoikilcytosis: mutations of a or b spectrin.
What is Diamond - Blackfan Anemia
DBA is an AD bone marrow syndrome causing impaired erythropoises –> paucity of erythrocyte precursors, non-megaloblastic (vs b12/folate def) macrocytic anemia, reticulocytopenia, and assc with short stature, abnormal facies, abnormal (triphalangeal) thumbs and skeletal abnormalities. Mutations in genes that code ribosomal units.
pneumonics: diamond ring (finger — tri phalyngeal thumb), ‘black’fan - bone marrow is dark without any rbcs, ‘non-mega’loblastic –> congenital
What is Fanconis Anemia
Bone marrow syndrome, anemia +/- thrombocytopenia/leukopenia. Usually presents in late childhood. Due to BRCA2 mutation –> defect in DNA repair enzymes. Higher incidence of cancer. Inherited aplastic anemia, AR. Hypoplastic or absent thumb, radius bone abnormalities.
pneumonic: ‘fan’ –> brrr –> BRCA mutation / fan cuts off your thumb
What is Shwachman-Bodian-Diamond Syndrome?
Bone marrow failure syndrome. Neutropenia +/- anemia/thrombocytopenia. Assc with exocrine pancreatic insufficiency and skeletal abnormalities. Due to SBDS gene mutation on chr. 7.
What is Pearson Syndrome?
Mitochondrial disease with anemia, exocrine pancreatic insufficicency, renal and hepatic failure.
What is appropriate iron supplemenation to avoid iron deficiency anemia.
Term infants : On formula, no additional Fe needed. If >50% breast milk, 1mg/kg Fe starting at 4 months.
Preterm infants: 2mg/kg Fe starting at 1m.
Wait to give cow’s milk until 1 y/o –> not enough Fe.
what are symptoms of chronic kernicterus
dental dysplasia, hearing loss, choreoatheosis
what are sypmtoms of acute bilirubin encephalopathy
hypertonia (opisthotonis/retrocollis), high pitched cry, fever, poor feeding. Preterm infants will have abornmal BAER.
In hematopoiseis, what do lymphoid progenitors and myeloid progenitors become?
lymphoid: all lymphocytes including B cells, T cells and NK cells
myeloid: RBCs, platelets, and other WBCs including granulocytes, monocytes and macrophages
In NAIT, what is the most common platelet antigen involved
HPA-a1 (75%)
how low do platelets get in NAIT and what is the typical course and treatment?
Can have severe thrombocytopenia (<50k), usually recovers after 3d b/c Ab wear off. 10% can have intercranial bleed.
Treat with anti-antigen platelets, or maternal washed platelets. Normal pooled platelets are fine too. Steroids and IVIG are optional.
There is a high recurrence rate in moms, treating prenatally with IVIG and steroids can help.
What are characteristic features of TAR?
Thrombocytopenia that resolves in a year, due to maturation defect in megakaryocyte progenitors. Unlike fanconis, thumbs are normal. Radii are absent. High risk of ICH.
Which factors are affected in Hemophilia?
What marker will be elevated?
What are the patients at risk for?
F VIII (A) and F IX (B/christmas). Both are X linked recessive.
Prolonged PTT. Factor levels will be decreased, that is definitive diagnostic test.
1/3 can have clinically significant bleeding in neonatal period including ICH.
What is the most common inherited bleeding disorder?
VW disease is rarely diagnosed in neonatal period b/c VW levels are elevated in neonate.
Treat with VW containing F VIII concentrate. DDAVP contraindicated in neonates due to risk of hyponatremia.
How does Vit K deficiency present and how is it diagnosed?
Can be early (24h), classic (upto 1w) or late (most commonly presents as ICH.
PT is prolonged. Vit K needed to make F II, VII, IX, and X.
Patients who are exclusively breastfed and who do not get Vit K IM are at risk.
How and why does neonatal purpura fulminans present?
It is due to deficiency of protein C and protein S (anticoagulation factors that are vitamin K dependent and produced by the liver). Assc with GBS bacteremia.
Presents as purpura.
Treat with FFP.
Wilms Tumor/nephroblastoma:
benign/malignant
clinical features
diagnosis
treatment/outcome
Malignant (Congenital mesoblastic nephroma is most common renal tumor in neonates, benign)
Renal Mass. hematuria, htn,
resection/nephrectomy, 80% of patients are diagnosed between 1 and 5 years of age. On ultrasonography, the tumor appears as a smooth, well-delineated mass of uniform texture. Assc with Beckwith-Wiedmann
excellent prognosis
most common intra-abdominal tumor of childhood
genes on the 11th and 16th chromosomes.
Cardiac rhabdomyomas:
benign/malignant
clinical features
diagnosis
treatment/outcome
benign
cardiac masses (mc in ventricles or septum), association with TS, arise in utero from cardiac striated muscle
natural course is regression. If very large, surgical resection, brain MRI and genetic testing for TS
observation, regression, f/u for TS
neuroblastoma:
benign/malignant
clinical features
diagnosis
treatment/outcome
malignant (mc malignant neonatal tumor, 2nd most common neonatal tumor after teratoma)
adrenal mass, hepatomegaly, blue skin nodules, stage IV-S (s = special, spontaneous regression) common in neonates
biopsy to stage, urine hva/vma, MIBG scan to evaluate for mets. N-MYC amplification in unfavorable.
observation, good prognosis, spontaneous resolution
from neural crest cells. most commonly in adrenal glands or along sympathetic chain. abdomen. spread to liver and skin, also bone marrow, bone, lung, cns.
hemangiomas:
benign/malignant
clinical features
diagnosis
treatment/outcome
benign
varied, associateions with internal hemangiomas
if large > 5cm or > 5# perform additional imaging including liver. Assc w/ PHACES syndrome: posterior fossa malformation/hemangioma/arterial-aortic abnormalities/cardiac defects/eye abnormalities/sternal cleft-supraumbilical raphe syndrome
normally regresses, proponalol is 1st line, sirolimus (rapamycin) is an mTOR inhibitor, also promising against massive hemangiomas
teratoma:
benign/malignant
clinical features
diagnosis
treatment/outcome
90% benign
midline mass, usually sacrococcygeal>mediatstinum. Most common neonatal tumor.
afb and b-hcg in immature termatomas or with germ cell components
surgical resection, good outcome
langerhans cell histiocytosis (macrophages):
benign/malignant
clinical features
diagnosis
treatment/outcome
malignant
scaly ezcematous rash, lytic bone lesions, birbreck granules (tennis racket shaped organelles)
biopsy, cell stain positive for cd1a or cd207, may get DI
if multisystem disease, need chemo (steroids, vinblastine), otherwise obs/ressection, BRAF inhibitor therapy
transient abnormal myelopoises (TAM)
benign/malignant
clinical features
diagnosis
treatment/outcome
formerly known as TMD (transient myeloproliferative disorder)
malignant but transient
symptoms similar to leukemia but only see in tri 21
elevated wbc, leukemia cutis (skin nodules with leukemia cells)
observer, increased 25% lifetime risk of AML
leukemia
benign/malignant
clinical features
diagnosis
treatment/outcome
aml > all
malignant
skin nodules, hsm, bruising/bleeding
elevated wbc, anemia, thromboctopenia
chemo. very poor prognosis.
is unconjungated bilirubin hydrophobic or hydrophilic?
Unconjugated bili is hydrophobic. It binds to albumin in plasma. It can cross the placenta.
Which enzyme converts heme into biliverdin?
Heme oxygenase
Which enzyme converts biliverdin into bilirubin?
Bilrubin reductase
What does glucuronyl transferase do?
UDPGT catalyzes binding of glucuronic acid to bilirubin, making it water soluble so it can be excreted in bili and making it harder to get absorbed intestinally.
What does beta glucuronidase do
Deconjugates bilirubin –> then gets reabsorbed in intestine. AKA enterohepatic circulation.
which form of bilirubin crosses over the placenta
Unconjugated bilirubin (hydrophobic). Conjugated bili and biliverdin do not cross.
1 g of Hgb gives how much bilirubin?
35 mg of bilirubin
What are sources of bilirubin?
~80% RBC, the rest is from myoglobin, cytochromes, catalase, peroxidase, free heme, early RBC in marrow
What is a direct measurement of hemolysis?
ETCO (carbon monoxide) - 1:1 for Heme break down
What does tin mesoporphyrin do?
inhibit heme oxygenase
what does bilirubin get converted into by natural gut flora?
urobilinogen to be excreted
What MCHC and MCHC:MCV is indicative of hereditary spherocytosis
MCVC >/= 36, MCHC:MCV >/= 0.36
What are two factors in hyperbilirubinemia that are associated with lower iq?
positive DAT and length of exposure to high levels (matter of days)
What is ligandin?
ligandin is a carrier protein that helps transport bilirubin-albumin complex into hepatocyte for conjugation.
what is a risk factor of exchange transfusion?
hypocalcemia from the citrate in PRBC
In kernicterus, how is IQ effected?
usually normal IQ. Can have renal tubular necrosis, pancreatic necrosis and SNHL, dental dysplasia, abnormal upward gaze and intestinal necrosis.
what is the normal blue light range for phototherapy
420-290 Um
what is the configuration of lumirubin
converted from 4z-15z to E configuration
when does breast milk jaundice vs breast feeding jaundice happen?
BM jaundice is after 7 days of life, due to extra b glucuroindase. Breast feeding jaundice is in first 3-5 days due to dehydration.
Kinds of common Liver tumor
the most common neonatal liver tumor is infantile hemangioma, accounting for approximately 60% of cases. Mildly elevated afp, endothelial glut 1+. usually regress.
Mesenchymal hamartoma is second in prevalence, accounting for approximately 23% of cases. usually has cysts lined with bile duct epithelium.
primary hepatoblastoma is third, accounting for approximately 17% of cases. Most commonly presents in childhood. assc with BWS, aicardi, familial adenomatous polyposis coli, tri 18
Describe G6PD: impacted population, presentation, pathopysiology
Disproportionately impacts african american babies. Presents as hemolytic jaundice, may jaundice may be due to poor conjugation. Can be induced by nitrofurantoin, fava beans. X linked.
What is Gilbert Syndrome
Gilbert syndrome is associated with impaired bilirubin uptake and impaired UDP-glucuronosyl transferase conjugation of bilirubin. Elevated uncojugated hyperbilirubinemia.
What is pyruvate kinase deficiency?
the second most common enzymatic cause of neonatal hyperbilirubinemia and hemolytic anemia
Pyruvate kinase is a glycolytic enzyme responsible for conversion of 2-phosphoenolpyruvate to pyruvate and production of ATP. If activity is reduced because of insufficient protein or inadequate functioning, energy is not available to maintain water and potassium content; the red blood cells become rigid and lyse as they travel through the spleen and reticuloendothelial organs.
what is hgb M
in methemoglobinemia, Fe 2+ (ferrous) is oxidized to Ferric 3+ and unable to reversibly bind oxygen –> when methemoglobin leves > 10%. HbM –> doesn’t bind o2 well. remaining Hb bind tightly to o2 and dont release o2 well.
Methemoglobinemia I: cyctochrome b5 reductase (methemoglobin reductase) absent in RBC
Meth. II: meth reductase absent in all cells, most severe. No ability to reduce Fe3+
