Hematology Flashcards
What are the compensatory mechanisms for anemia?
- expanded cardiac output
- increased production of 2,3-DPG in RBC
- higher levels of erythropoietin (EPO)
- increased reticulocyte production by the BM
Examples of acquired decreased production of RBCs
Viral (parvo B19)
Iron
TEC
Examples of congenital decreased production of RBCs
Diamond- Blackfan Anemia
When are most diamond blackface anemias diagnosed?
Etiology
- > 90% cases recognized in 1st yr of life. Average age of dx: 3yrs.
What is the pathophys of DBA?
- Intrinsic defect in erythroid progenitor cells that results in increased apoptosis.
- Consists of macrocytic anemia, reticulocytopenia and deficiency or absence of RBC precursors in an otherwise normally cellular bone marrow
- Most cases are sporadic (familial cases occur in ~15% pts)
What is the clinical presentation of DBA?
Clinically
- some infants appear pale at birth or in the 1st days after birth. Rarely, hydrops occurs.
- Profound anemia develops by 2-6 m of age.
- > 50% have congenital abn :short stature, craniofacial dysmorphism (snub nose, wide-set eyes, thick upper lip), or defects of the upper extremities (weak radial pulse, flattening of thenar eminence), including triphalangeal thumbs
What investigations do you do for DBA?
Investigations
- Macrocytic RBCs, but no neutrophil hypersegmentation or other characteristics of megaloblastic anemia. Folic acid and B12 levels are normal. Decreased reticulocyte count.
- Erythrocyte ADA activity is elevated (helps to distinguish from transient erythroblastopenia of childhood)
- Thrombocytopenia and neutropenia can present initially
- RBC precursors are markedly decreased in BM, Serum iron levels are increased
Management of DBA?
Management
- Steroids works in 75% of pts. Results in an increase in RBC precursors.
- 20% go into remission spontaneously, usually within the 1st decade
- Otherwise, transfusions q 4-8 wks are necessary to sustain normal growth and activities. Chelation therapy is then required (deferoxamine) for ferritin levels > 1500 mg/dL.
- Stem cell transplantation is considered for children who don’t respond to corticosteroids and have shown several-year need for pRBCs
Complications of DBA?
- Mean survival > 40 yrs. May be a premalignant syndrome (AML and myelodysplaisa occur in 5% pts).
- Complications are related to iron overload, stem cell transplantation and steroids
What is TEC?
Transient Erythroblastopenia of childhood
- The most common red cell aplasia occurring in childhood.
- Severe, transient hypoplastic anemia that occurs in previously healthy children between 6m-3yr (usually > 12 m at onset)
- Cause is a transient immunologic suppression of erythropoiesis, often following a viral illness (NOT parvoB19)
Investigations for TEC
- Reticulocytes and bone marrow erythroid precursors are decreased. (examination of the BM rarely is needed to make the diagnosis). Some degree of neutropenia may occur in up to 20% of cases while platelet numbers are normal or increased (due to secondary increase in EPO, which also stimulates platelets)
- MCV normal (which differentiates from iron deficiency anemia), Hb F normal in recovery phase. RBC ADA levels are normal
Tx of TEC
Prognosis and tx
- virtually all children recover within 1-2m. Transfusions may be necessary in absence of signs of early recovery.
- Steroids are NOT needed
What is anemia of Chronic Disease
Etiology
- Multifactorial
o Mild decrease in RBC life span
o Relative failure of BM to respond adequately to the anemia with a blunted response to EPO (despite the fact that EPO levels are usually mod. elevated)
o decreased serum iron (due to retention of iron in macrophages as well as decreased iron absorption, thought to be secondary to increased hepcidin)
Labs seen in anemia of chronic disease
Labs
- Hgb 60-90, normochromic, normocytic
- Retic count normal or low, leukocytosis is common.
- Serum iron decreased, but without the increase in TIBC (serum transferring) seen in IDA. Ferritin may be increased.
- In pts with inflammatory dz, measurement of the TfR/ferritin ratio is helpful (increased in iron deficiency)
Treatment of Anemia of Chronic Disease
Treatment
- don’t respond to iron therapy (unless there is a combined deficiency). If underlying dz can be controlled, anemia resolves.
- EPO can increase Hgb and improve QOL in pts with cancer or those with anemia of chronic inflammation. Tx with iron is usually needed for optimal EPO effect
- If strictly secondary to renal dz, then EPO is definitely useful as the primary issue is decreased EPO production
Vitamin B12 Absorption…how?
- B12 comes mainly from cobalamin found in : meats, eggs and dairy products.
- The cobalamins are released by the acidity of the stomach
- They combine with R proteins and intrinsic factor (IF)
- They then traverse the duodenum, where pancreatic proteases break down the R proteins
- Then they are absorbed in the distal ileum via specific receptors for IF-cobalamin.
- In the plasma, cobalamin binds to a transport protein, transcobalamin II (TC-II), which carries the vitamin B12 to the liver, bone marrow, and other tissue storage sites
- Older children and adults have stores to last 3-5yrs. - However, breast fed infants of vegan mothers may develop vit B12 deficiency if the maternal stores are low (by 6-18 months of life)
Etiology of Vit B12 deficiency
Etiology:
Vitamin B12 dieficiency results from inadequate dietary intake of vitamin, lack of IF secretion by the stomach, impaired intestinal absorption of IF-cobalamin, or absence of vitamin B12 transport protein.
What is congenital pernicious Anemia?
Congenital pernicious anemia
- AR disorder
- inability to secrete gastric IF or secretion of functionally abnormal IF.
- sx’s present by 1 yr of age (exhaustion of stores acquired in utero)
- As the anemia becomes severe, weakness, irritability, anorexia, and listlessness occur. The tongue is smooth, red, and painful. Neurologic manifestations include ataxia, paresthesias, hyporeflexia, Babinski responses, and clonus
What is juvenile pernicious Anemia?
Juvenile pernicious anemia
- immunologic disorder
- atrophy of the gastric mucosa, achlorhydria, and antibodies in serum against IF and parietal cells.
These children may have additional immunologic abnormalities, cutaneous candidiasis, hypoparathyroidism, and other endocrine deficiencies. An abnormal Schilling result is corrected by addition of exogenous IF.
How does folate Deficiency Happen?
- EBM, pasteurized cow’s milk, and infant formulas provide adequate amounts of folic acid. Goat’s milk is deficient, so folic acid supplementation must be given when it is the child’s main food. Unless supplemented, powdered milk also may be a poor source of folic acid.
- Pregnancy:
decrease in serum and RBC folate levels occur in as many as 25% of pregnant women at term and may be aggravated by infection. Folate supplementation of at least 400μg/day is recommended from the start of pregnancy to prevent neural tube defects and to meet growth needs of the developing fetus.
- Pregnancy:
- Secondary to malabsorption due to chronic diarrheal states, diffuse inflammatory disease, post intestinal surgery, certain anticonvulsants (phenytoin, primidone, phenobarb) or in association with enteroenteric fistulas.
Congenital abn in folate metabolism
- results from congenital dihydrofolate reductase deficiency. Very rare disorder that is due to an inability to form biologically active tetrahydrofolate. Affected individuals have developed severe megaloblastic anemia in early infancy. These patients were treated successfully with large doses of folic acid or folinic acid.
- Deficiency of methylene tetrahydrofolate reductase has been described in some patients with homocystinuria without hematologic abnormalities
Drug induced abnormalities
- Lots of drugs have anti-folic activity as their primary pharmacological effect
o Ex: Methotrexate, pyrimethamine (for toxoplasmosis), trimethoprim. Ie, tx with folinic acid
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Clinical Manifestations of folate deficiency
Manifestations
- peak incidence at 4–7 mo of age
- usual clinical features of anemia, affected infants with folate deficiency are irritable, have inadequate weight gain, and have chronic diarrhea. Hemorrhages from thrombocytopenia occur in advanced cases.
- May accompany kwashiorkor, marasmus or sprue
Osteosarcoma Age
- highest risk period is during adolescent growth spurt (assoc b/w rapid bone growth and malignant transformation)
- pts are taller than peers of similar age
What syndromes is osteosarcoma associated with
- ↑ risk with hereditary retinoblastoma, Li-Fraumeni syndrome, Rothmund-Thomson syndrome (rare, short stature, skin telangiectasia, small hands and feet, hypoplastic or absent thumbs, and ↑ risk of osteosarcoma), Paget disease
Where do osteosarcomas occur?
- usually in metaphyses of long bones, high grade in diaphyses and invades medullary cavity
What are the two variants of osteosarcoma?
- two variants of osteosarcoma: parosteal and periosteal osteosarcoma; have characteristic clinical features
o parosteal is a low-grade and well-differentiated, does not invade medullary cavity, commonly in posterior aspect of distal femur; surgical resection alone often curative as low propensity for metastatic spread
o periosteal osteosarcoma is rare, arises on surface of bone, ↑rate of metastases, intermediate prognosis
Diagnosis of osteosarcoma
Diagnosis
- suspect if deep bone pain, nighttime awakening, palpable mass, and radiographic lesion
- classic radiographic appearance: sunburst pattern
- need MRI of primary lesion and entire bone for evaluating proximity to nerves and blood vessels, soft tissue and joint extension, and skip lesions
o
- need a tissue bx to determine the dx
- metastatic work-up done pre-bx: chest CT and radionuclide bone scan (for mets)
o go to lungs first !!
- ddx of lytic bone lesion: histiocytosis, Ewing sarcoma, lymphoma, bone cyst
Treatment for osteosarcoma
Treatment
- need chemo and surgery, 5-yr dz-free survival with nonmetastatic extremity osteosarcoma is 65–75%
- need complete surgical resection for cure
- prognostic factors: histologic response to chemotherapy (very impt)
- pre-surgery, if tumors on weight-bearing bones, should use crutches to avoid pathologic fractures
Where do Ewing sarcomas occur?
- Extremely rare among African-American children
- Is an undifferentiated sarcoma of bone, also may arise from soft tissue
- anatomic sites of bone bone tumors: distributed evenly b/w extremities and central axis (pelvis, spine, chest wall)
- usually in the diaphysis of bones and flat bones
Diagnosis of Ewings Sarcoma
- classic radiography: onion-skinning ; see large associated soft tissue mass on MRI or CT
- metastatic evaluation: chest CT, radionuclide bone scan, and BM aspirate and bx
- MRI of tumor and entire length of involved bone to determine extension of soft tissue and bony mass, proximity to neurovascular structures
- Impt to obtain adequate tissue
What is prognosis for Ewing sarcoma?
- best prognosis if small, nonmetastatic, distally located extremity tumors (cure rate up to 75%)
- type of chromosomal translocation may be related to prognosis
- with metastatic dz at dx (esp bone or BM mets) have a poor prognosis (<30%)
- need long-term f/u for late effects of tx (anthracycline cardiotoxicity); 2nd malignancies (esp in radiation field); and late relapsess
Most common childhood tumours
Medulloblastoma/primitive neuroectodermal tumor Juvenile pilocytic astrocytoma Low-grade astrocytoma High-grade astrocytoma Ependymoma Craniopharyngioma
Late Effects of radiotherapy
Late effects from radiotherapy:
- hypopituitarism
- second malignant neoplasm
- somnolence syndrome (not a late effect) – can sleep for 22 hrs / day
- memory problems
Hemoglobin pathophysiology
- During fetal life and early childhood, the rates of synthesis of γ and β chains and the amounts of Hb A and Hb F are inversely related.
- The average life span for a neonatal RBC is 60–90 days, approximately ½ to⅔ that of an adult RBC.
- With increasing degrees of prematurity, remarkably shorter red cell life spans (35–50 days) are found
most common solid tumors
CNS tumours
most common neoplasm
leukemia
What is the most commonest inherited bleeding d/o?
VWD
How does DDAVP work?
DDAVP: releases subendothelial stores of VIII, V and platelet aggregation (can’t give > 2 doses in 24 hr period?
A PTT measures what?
Intrinsic pathway: Factors 12, 11, 9 (kind of 8)
INR measures what?
Extrinsic pathway: Factors 7, 5, 10
PT = INR. Not prolonged with deficiencies in VIII, IX, XI or XII
Umbilical stump bleeding…think of what?
. XIII: umbilical stump bleeding (can make clot, but can’t stabilize it)
How to determine what the etiology is for acute bleeding?
Actively bleeding pt, looking for etiology:
- CBC (for plt), PT, PTT
- VIII (only one not produced in liver), IX (hemophilia), VII (extrinsic pathway), V (sensitive in early DIC)
What is in FFP and cryo
- FFP: gives all factors – give to someone who is vit K deficient until factors kick in
- Cryo: (plasma that’s been spun): fibrinogen and VIII (and VWF and XIII) – for DIC
What are some anticoagulants in the body?
Protein C/S, Antithrombin III and tissue factor pathway inhibitor (TFPI)
What is factor V Leiden deficiency?
Factor V Leiden :
Common mutation in factor V that is associated with significant risk of thrombosis.
The mutation in factor V prevents inactivation of factor Va by activated protein C, hence, persistence of factor Va.
Dx is established by DNA testing
