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
`
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
What is homocysteinuria ?
high homocysteine (secondary genetic mutations) causes homocystinuria – pred. to art and venous clots and arteriosclerosis
Liver Disease Bleeding manifestations
Manifestations:
- Severity of coagulation abnormalities correlates with extent of hepatocellular damage
- Typically have normal levels of VIII in plasma
- Reduction in Vit K dependant coagulation factors is common. Inability to correct coagulopathy with Vit K indicates that the coagulopathy may be caused by reduced levels of clotting factors that are not vitamin K dependant and/or by inadequate production of precursor vitamin K proteins
What is DIC?
Definition:
- a systemic thrombohemorrhagic d/o seen in association with well-defined clinical situations AND
- Laboratory evidence of:
o Procoagulant activation
o Fibrinolytic activation
o Inhibitor consumption
o Biochemical evidence of end-organ damage/failure
Thrombotic microangiopathy that results in consumption of clotting factors, platelets, and anticoagulant proteins.
Consequences:
o widespread intravascular deposition of fibrin, leading to tissue ischemia and necrosis,
o a generalized hemorrhagic state
o hemolytic anemia
Causes of Eosinophilia
The mnemonic device CHINA Connective tissue diseases Helminthic infections Idiopathic HES Neoplasia Allergies
What is B thalassemia?
- Two major features contribute to the pathogenesis of sequelae of β-thalassemia:
o inadequate β-globin gene production, leading to decreased levels of Hb
o imbalance in α- and β-globin chain production - In BM, leads to ineffective erythropoiesis (hyperactive marrow with few retics and severe anemia)
- there is an excess of α-globin chains relative to β- and γ-globin chains; α-globin tetramers (α4) are formed. These inclusions interact with the red cell membrane and shorten red cell survival, leading to anemia and increased erythroid production
Clinical Presentation of B thalassemia
- If un tx, usually become symptomatic as a result of progressive hemolytic anemia, with profound weakness and cardiac decompensation (around Hgb 40) during the 2nd 6 mo of life.
- Pallor, hemosiderosis, and jaundice may combine to produce a greenish brown complexion.
- The classic findings in children with severe thalassemia : typical facies, pathologic bone fractures, marked hepatosplenomegaly, and cachexia, are primarily seen in developing countries
- Features of ineffective erythropoiesis include expanded medullary spaces (where massive expansion of the marrow of the face and skull lead to maxillary hyperplasia, flat nasal bridge and frontal bossing), extramedullary hematopoiesis, and a huge caloric need
What is the main side effect of B thalassemia?
Iron toxicity:
o Anemia leads to an increase in iron absorption from the GI tract:
o Endocrine dysfunction may include hypothyroidism, gonadal failure, hypoparathyroidism, and diabetes mellitus. Congestive heart failure and cardiac arrhythmias are potentially lethal complications
Complications
- Mainly result from transfusional hemosiderosis
- Serum ferritin helps to assess iron trends, but doesn’t accurately predict stores. Liver biopsy is gold standard, but may not accurately predict changes in cardiac iron. Ferritometer and specialized MRI are alternatives.
o Prevention occurs by giving deferoxamine (iron chelator).
o Side effects: ototoxicity (high frequency hearing loss), retinal changes, bone dysplasia with truncal shortening
Diagnosis of B thalassemia
Investigations
- Infant is born with only Hb F. Eventually, develop severe anemia (Hgb 50 if untx), few reticulocytes, microcytosis
- Unconjugated bili increased
- Iron accumulation leads to increased ferritin and saturation of transferring
- Bone marrow hyperplasia on radiographs
- Dx confirmed by electrophoresis always abnormal
Treatment of B Thalassemia
- Obtain a red cell phenotype before initiating transfusions
- Blood products need to be leukoreduced and phenotypically matched for Rh and Kell antigens. If considering BMT, give CMV – and irradiated blood.
- Transfusions usually occur monthly – aim for Hgb 95-105
What is thalassemia trait (B)
- Frequently misdiagnosed as iron deficiency in children because the two are similar hematologically and iron deficiency is much more prevalent. A short course of iron and re-evaluation is all that is required to identify children who will need further evaluation.
- Children who have β-thalassemia trait have a persistent RDW, and on hemoglobin analysis, they have Hb F and diagnostically increased Hb A2. , profound microcytosis , high RBC
- There are “silent” forms of thalassemia trait, and if the family history is suggestive, further studies may be indicated.
When does Alpha Thalassemia become present?
- Prenatally, may become sx because Hb F requires sufficient α-globin gene production, whereas postnatally, infants with β-thalassemia become symptomatic because Hb A requires adequate production of β-globin genes
Describe the clinical manifestation of a silent alpha thalassemia
α silent trait 1 α globin gene affected Normal MCV, Hgb Barts H < 3% Common in African Americans No treatment required
Describe the clinical manifestation of a alpha thalassemia trait
2 α globin genes
Microcytic anemia, Hgb analysis n, except in NN period,
Bart H < 8% but > 3%, high RBC
Looks like iron deficiency anemia
Treatment: iron trial. If no improvement, conduct α-globin gene deletion analysis (if known alpha trait, no iron)
Describe the clinical manifestation of Hb H disease
Hb H dz
3 α globin genes
Barts H > 25% (with 1 parent with trait).
Later on, excess β = Hb H.
MCV 51-73, Hgb 70-110 Marked microcytosis, anemia, splenomegaly, occ, sceral icterus or cholelithiasis
May need transfusion
Describe the clinical manifestation of alpha thalassemia major
4 α globin genes
No normal Hgb at birth (all Barts, with Gower 1,2 and Portland)
Hydrops fetalis (ζ-globin gene essential for fetal survival) If fetus survives, imm exchange transfusion
Transfusion dependant. BMT only cure
Overall treatment for alpha thalassemia
Overall, consists of folate supplementation, possible splenectomy, intermittent transfusion during severe anemia. Should not be exposed to oxidant medications
Differentiating between thalassemia minor and iron deficiency
Differentiating α thal minor from iron deficiency
- Both have hypochromia and microcytosis. But microcytosis is much more profound, and the anemia much milder, than that seen in iron deficiency anemia.
- Patients with beta thalassemia minor/trait also tend to have total red blood cell counts higher than normal, often into the “polycythemic” range. Patients with beta thalassemia trait almost always have a hematocrit >30 percent, and a mean corpuscular volume of the red cells (MCV) <75 fL. In contrast, patients with iron deficiency rarely become microcytic (MCV <80 fL) until the hematocrit has dropped below 30. Another potentially useful indicator is the red cell distribution width (RDW). The RDW in patients with thalassemia trait tends to be normal, since virtually all cells are hypochromic and microcytic. In contrast, there is considerable heterogeneity in cell size in the early and intermediate stages of iron deficiency, producing an increased RDW.
Inheritance if hereditary spherocytosis
Etiology
- 1/5,000 in people of Northern European descent. AD, but also sometimes AR.
~ 25% individuals have no FHx
- It is the most common inherited abnormality of the red blood cell (RBC) membrane.
Pathophysiology of HS
- Affected individuals may be asymptomatic, without anemia and with minimal hemolysis, or may have severe hemolytic anemia
- The decreased deformability of the spherocytic RBCs impairs cell passage from the splenic cords to the splenic sinuses, and the spherocytic RBCs are destroyed prematurely in the spleen. Splenectomy markedly improves RBC life span and cures the anemia
Clinical presentation of HS
Clinically
- hemolytic disease in the newborn and may present as anemia and hyperbilirubinemia sufficiently severe to require phototherapy or exchange transfusions
- Severity of sx’s is variable – some are asymptomatic and others may have severe anemia, with pallor, jaundice, fatigue, and exercise intolerance
- Severe cases may be marked by expansion of the diploë of the skull and the medullary region of other bones, but to a lesser extent than in thalassemia major.
- After infancy, the spleen is usually enlarged, and pigmentary (bilirubin) gallstones may form as early as age 4–5 yr. At least 50% of unsplenectomized patients ultimately form gallstones, although they may be asymptomatic.
- Aplastic crisis:
o Because of the increased RBC turnover and heightened erythroid marrow activity, kids are susceptible to aplastic crisis, (Parvo B19 infection) and to hypoplastic crises associated with various other infections.
o The erythroid marrow failure may result rapidly in profound anemia (hematocrit <10%), high-output heart failure, hypoxia, cardiovascular collapse, and death. White blood cell and platelet counts may also fall.
Lab findings for HS
- hemolysis (hgb 60-100, but can be normal, can show increased haptoglobin and gallstones on u/s) and indirect hyperbilirubinemia.
Retics increased 6-20% (mean 10%). MCV n - spherocytes are smaller and hyperchromic
- Erythroid hyperplasia is evident on BM
- Dx is made on blood film, FHx and on seeing splenomegaly
- Presence of spherocytes can be confirmed with an osmotic fragility test
Treatment for HS
Treatment
- Splenectomy (esp if hgb > 100 and retic < 10%)
- Folic acid 1mg daily (to prevent deficiency and resultant decreased in erythorpoiesis)
- For patients with more severe anemia and reticulocytosis or those with hypoplastic or aplastic crises, poor growth, or cardiomegaly, splenectomy is recommended after age 5–6 yr to avoid the heightened risk of postsplenectomy sepsis in younger children
Inheritance of G6PD
Epi/etiology
- induced by infections, certain drugs or, rarely, fava beens
- X-linked
- 13% of male African-Americans have a mutant enzyme (G6PDA-) with an RBC G6PD activity ≤5–15%.
- 5-40% of Italians, Greeks, and other Mediterranean, Middle Eastern, African, and Asian ethnic have G6PDB- (G6PD Mediterranean) with RBC G6PD activity <5% of normal.
Clinical Presentation of G6PD
Clinically
- sxs develop 24-48 hrs after a pt has ingested a substance that has oxidant properties
- The degree of hemolysis varies with the inciting agent, the amount ingested, and the severity of the enzyme deficiency. In severe cases, hemoglobinuria and jaundice result, and hgb may drop - can be life-threatening.
- Associated reticulocytosis may produce a compensated hemolytic process.
- In A-G6PD deficiency, spontaneous hemolysis may occur in premature infants, but not in term infants.
- When a pregnant woman ingests oxidant drugs, they may be transmitted to her G6PD-deficient fetus, and hemolytic anemia and jaundice may be apparent at birth.
What can incite an event with G6PD?
aspirin in high doses, sulfonamides, chloramphenicol, nitrofurontoin, antimalarials, phenacetin, vit K analogs, methylene blue, probenacid, acetylsalicylic acid, phenazopyridine, benze, naphthalene, DKA, hepatitis, sepsis
Diagnosis of G6PD
o Heinz bodies being seen on the smear in the first 3-4 days of illness
- Dx depnds on direct (<10%) or indirect demonstration of decreased G6PD activity in RBCs
- Also diagnosed if G6PD activity is within low-normal range in the presence of a high retic count
- Screening tests are based on decoloration of methylene blue, reduction of methemoglobin, or fluorescence of NADPH
Hemophilia Inheritance
- 1:5000 males. 85% VIII, 10-15% IX. Hemostatic level FVIII: > 30-40%, FIX: > 25-30%
- Most common severe inherited bleeding disorders. High rate of spontaneous mutation.
- Genese are carried on the long arm of X chromosome. Can be detected in amniotic fluid
- Affects all racial groups
Labs found in Hemophilia
- PTT usually 2-3x normal. Platelets, BT, INR, TT are normal.
- In newborns, they may have an abnormally high factor VIII level (acute phase response to birth process). On the other hand, factor IX levels are naturally low in the newborn period.
- Because factor VIII is carried in plasma by von Willebrand factor, the ratio of factor VIII to von Willebrand factor is sometimes used to diagnose carriers of hemophilia.
- When possible, specific genetic mutations should be identified in the propositus and used to test other family members who are at risk for either having hemophilia or being carriers
- Unless inhibitors have developed, mixing of normal plasma with pt plasma corrects the PTT
o Inhibitors (antibodies) develop in 25-35% of pts – Bethesda assays are used to measure titers. - Perform Factor VIII or IX assay to make dx of hemophilia
Clinical Presentation of Hemophilia
Clinical manifestations
- VIII and IX don’t cross the placenta – bleeding may occur from birth or in the fetus
o 2% of neonates get ICH, 30% males bleed with circumcision
- Clinical severity proportional to # of factor ( < 1: severe, 1-5: mod, mild 5-40%)
- Easy bruising, intramuscular hematomas, and hemarthroses. Bleeding from minor traumatic lacerations of the mouth (a torn frenulum) may persist for hr or days and may cause the parents to seek medical evaluation.
- Hallmark of hemophilia is hemarthrosis induced by minor trauma; many hemarthroses are spontaneous.
o The earliest joint hemorrhages appear most commonly in the ankle.
o In the older child and adolescent, hemarthroses of the knees and elbows are common.
o After repeated bleeding episodes into the same jt, they may develop a “target” joint. Recurrent bleeding may then become spontaneous because of the underlying pathologic changes in the joint
- Iliopsoas bleeds: pts may loose large amounts of blood, present in shock and hold their hip in flexed, internally rotated position due to irritation of iliopsoas. Dx is made clinically (unable to extend hip) – confirm with CT.
Treatment of Hemophilia
Treatment
- Mild to moderate bleeding: levels of factor VIII or factor IX must be raised to hemostatic levels : 35–50%
- Life-threatening or major hemorrhages: dose should aim to achieve levels of 100% activity
- Do a DDAVP challenge (von willebrand’s carries factor VIII: if he reacts well, this could replace VIII for minor bleeding episodes)
What does DDAVP do?
Desmopressin (DDAVP®) is used to help stop bleeding in patients with von Willebrand’s disease or mild hemophilia A. DDAVP causes the release of von Willebrand’s antigen from the platelets and the cells that line the blood vessels where it is stored. Von Willebrand’s antigen is the protein that carries factor VIII.
Who gets prophylaxis in hemophilia
- Lifelong prophylaxis is given at onset of first joint hemorrhage (in severe pts, usually not in mild-mod) to prevent spontaneous joint bleeding.
- Treatment is usually provided every 2–3 days to maintain a measurable plasma level of clotting factor (1–2%) when assayed just before the next infusion (trough level)
- If moderate arthropathy develops, prevention of future bleeding will require higher plasma levels of clotting factors.
- In the older child who is not given primary prophylaxis, secondary prophylaxis is frequently initiated if a target joint develops
What are the degrees of Hemophilia
Severe hemophilia: <1 percent factor activity
Moderate hemophilia: factor activity level ≥1 percent of normal and ≤5 percent of normal
Mild hemophilia: factor activity level >5 percent of normal and <40 percent of normal
List some chronic complications of hemophilia
- Chronic hemophilic arthropathy with risk of developing articular fusion.
- the development of an inhibitor to either factor VIII or factor IX
- risk of transfusion-transmitted infectious diseases.
How do you diagnose a factor XI deficiency
Factor XI Deficiency (Hemophilia C)
Epi and Dx
- autosomal deficiency
- mild to moderate bleeding symptoms.
- It is frequently encountered in Ashkenazi Jews
- The deficiency of factor XI can be confirmed by specific factor XI assays.
- The bleeding tendency is not as severe as in factor VIII or factor IX deficiency
- Chronic joint bleeding is rarely a problem, and for most patients, factor XI deficiency is a concern only at the time of major surgery unless there is a second underlying hemostatic defect (e.g., von Willebrand disease).
Treatment of Hemophilia C
Treatment:
- Unless the patient previously had surgery without bleeding, replacement therapy should be considered and given preoperatively.
- There is no approved concentrate of factor XI available in the United States; therefore, use FFP
- Bleeding during minor surgery can be controlled with local pressure; patients undergoing dental extractions can be monitored closely and treated only if hemorrhage occurs.
What is the most common hereditary bleeding disorder.
Von Willebrand Dz
What is the chromosome responsible for vWF
Epi: Most common hereditary bleeding d/o. Present in up to 1-2% of the population. F>M. Chromosome 12 contains gene for WVF.
What are the classifications of vWF
Classification:
Type 1: (85%) protein is quantitatively reduced, but not absent
Type 2: qualitatively abnormal
Type 3: (1/250 000) absent (with normal levels VIII) – intracranial bleed, major epistaxis and menorrhagia
Mutations in different loci that code for different functional domains of the VWF protein cause the variants of VWD
What are the clinical manifestations of vWD?
- mucocutaneous hemorrhage (including excessive bruising, epistaxis, menorrhagia, post op bleeding (esp after mucosal surgery – tonsillectomy or wisdom tooth extraction). Bleeding is much more profound in type 3 or homozygous VWD.
- VWF is an acute-phase protein – stress increases its level. Pts may not bleed with procedures that incur major stress (appendectomy and child birth). Levels increase 2-3x in pregnancy
- Can have GI telangiectaisa
- Pts with severe type 3 can have joint hemorrhages and spontaneous CNS bleeding.
What investigations should you do to look for vWD
- Because there is no single assay that has demonstrated the ability to rule out VWD, if the history is suggestive of a mucocutaneous bleeding disorder, VWD testing should be undertaken, including:
o quantitative assay for VWF antigen and testing for:
o VWF activity (ristocetin cofactor activity)
o plasma factor VIII activity
o determination of VWF structure (VWF multimers)
o platelet count (may be normal except in type 2B) - Levels may vary with blood type ( O < A < B < AB)
- ** Consider it in adolescent females that present with menorrhagia and anemia
Treatment of vWD
Type 1 VWD.
- Bleeding symptoms include epistaxis, bruising, and menorrhagia. If bleeding is excessive:
o desmopressin (DDAVP). Intranasal DDAVP (Stimate) is particularly helpful for the outpatient treatment of bleeding episodes.
Type 2 VWD
- Intermittent response to DDAVP
- Some pts will require infusion of VWF
Type 3 VWD
- is the homozygous or compound heterozygous inheritance of VWF deficiency. These patients will have major hemorrhage, but only rarely have joint hemorrhages. Bleeding episodes require treatment with:
o VWF-containing concentrates. VWF is both a plasma and a platelet protein.
DDAVP is not effective in type 3 VWD
- Overall :
Aimed at increasing the plasma level of VWF and factor VIII.
Dental extractions and sometimes nosebleeds can be managed with both DDAVP and an antifibrinolytic agent, such as ε-aminocaproic acid (Amicar)
Classic Clinical Presentation of Hemorrhagic disease of the newborn
2–7 days of age
Sites fo Hemorrhage: Gastrointestinal Ear-nose-throat–mucosal Intracranial Circumcision Cutaneous Injection sites
Etiology: Vitamin K deficiency
Breast-feeding
Prevented by parenteral vitamin K at birth. Oral vitamin K regimens require repeated dosing over time
Incidence ≈2% if not given vitamin K
Clinical presentation of Early onset hemorrhagic disease of the newborn.
EARLY ONSET
0–24 hr
Sites of Hemorrhage: Cephalohematoma Subgaleal Intracranial Gastrointestinal Umbilicus Intra-abdominal
Etiology: Maternal drugs (phenobarbital, phenytoin, warfarin, rifampin, isoniazid) that interfere with vitamin K
Inherited coagulopathy
Prevention: Possible vitamin K at birth or to mother (20 mg) before birth
Avoid high-risk medications
Very rare
What is the clinical presentation of late onset hemorrhagic disease of the newborn.
1–6 mo
Sites of Hemorrhage Intracranial Gastrointestinal Cutaneous Ear-nose-throat–mucosal Injection sites Thoracic
Etiology: Cholestasis—malabsorption of vitamin K (biliary atresia, cystic fibrosis, hepatitis) Abetalipoprotein deficiency Idiopathic in Asian BF infants Warfarin ingestion
Prevented by parenteral and high-dose oral vitamin K during periods of malabsorption or cholestasis
Etiology of late hemorrhage disease of the newborn.
Although “late” hemorrhagic disease
- reported in BF infants, but vitamin K deficiency occurring after the neonatal period is usually secondary to lack of oral intake of vitamin K
- alterations in the gut flora due to the long-term use of broad-spectrum antibiotics
- malabsorption of vitamin K
- Intestinal malabsorption of fats may accompany cystic fibrosis or biliary atresia and result in a deficiency of fat-soluble dietary vitamin, with reduced synthesis of vitamin K–dependent clotting factors (factors II, VII, IX, and X, and protein C and protein S).
Serum marker for hepatoblastoma.
Increased AFP
Age of ALL diagnosis
- peak incidence between 2–6 yrs, boys > girls
Genetic Conditions associated with ALL
Down syndrome Fanconi syndrome Bloom syndrome Diamond-Blackfan anemia Schwachman syndrome Klinefelter syndrome Turner syndrome Neurofibromatosis type 1 Ataxia-telangiectasia Severe combined immune deficiency Paroxysmal nocturnal hemoglobinuria Li-Fraumeni syndrome
Clinical Manifestations of ALL
- Usually non-specific and relatively brief history
- Anorexia, fatigue, irritability, low grade intermittent fever
- Bone or jt pain exp in lower extremities, may be severe and wake pt at night
- With disease progression, show S&S of BM failure including pallor, fatigue, bruising, epistaxis, fever
- PE findings: pallor, listlessness, purpuric and petechial skin lesions, MM hemorrhage, lyphadenopathy, splenomegaly, hepatomegaly, bony tenderness
o May have signs of ↑ ICP if leukemic involvement of CNS (papilledema, retinal hemorrhages, CN palsies) [CNS involvement in 5%]
o Resp distress secondary to anemia or airway obstruction d/t large anterior medistinal mass (usually with T cell ALL) - Early pre–B-cell ALL is the most common, onset b/w 1–10 yrs, high leuks (median 33), HSM in 30-40%
- Testicular (20%) and ovarian (30%) involvement also occurs
What factors make ALL high risk?
Risk factors
- CNS, testicular +
- Age < 1, > 10
- WBC > 50
- Also based on minimum residual disease and response to induction
Diagnosis of ALL
Diagnosis
- anemia and thrombocytopenia see in most pts
- leukemic cells in peripheral blood
- can present with leuks < 10, so a high leuk count is not necessary for dx
- if smear suggests possibility of leukemia, then need bone marrow (aspiration usually sufficient, bx may be needed to exclude other causes of BM failure)
- ALL dx’d if BM shows >25% homogeneous population of lymphoblasts
- Need a CSF examination at dx (if lymphoblasts found and ↑ leks, then have CNS/meningeal leukemia – worse stage, need additional CNS and systemic tx)
Stages of Chemo for ALL
- Remission induction – 4 wks of tx: vincristine, steroids, L-asperaginase; intrathecal cytarabine or MTX
- Intensification/Consolidation
- Delayed Intensification, Interim Maintenance
What chemo is fatal if given IT?
Vincristine
Prognosis of ALL
Prognosis
- most children can expect long-term survival, with survival rate >80% at 5 yr
- poorer outcome with hypodiploidy, Philadelphia chromosome, and MLL gene rearrangements and translocations [t(1:19) or t(4;11)]
- favorable characteristics: rapid response to tx, hyperdiploidy, trisomies of specific chromosomes, and rearrangements of the TEL/AML1 genes
Clinical Manifestations of AML
- Features that can present with and are different from ALL include subcutaneous nodules or “blueberry muffin” lesions, infiltration of gingiva, S&S of DIC (M3, acute promyelocytic leukemia), and discrete masses known as chloromas or granulocytic sarcomas [more likely to have coagulation problems than ALL]
o Masses may occur in absence of apparent BM involvement, assoc with M2 and t(8;21) translocation - CNS symptoms more common in AML than ALL
What is different in kids with T21 and AML/ALL?
- 14x risk, ratio of ALL to AML in pts with T21 is same as in general population
- If develop ALL, expected outcome of tx is same as for non-T21 kids, have ↑ sensitivity to MTX and substantial toxicity if standard doses given
- In AML, T21 pts have much better outcomes (>80% long-term survival), need less intensive therapy
What is Transient Leukemia or myeloproliferative syndrome in kids with T21?
- 10% of neonates with DS get transient leukemia or myeloproliferative syndrome
o characterized by high leukocyte counts, blast cells in peripheral blood, and associated anemia, thrombocytopenia, and hepatosplenomegaly
o usually resolve in days to weeks, may need temporary transfusion support but NOT chemo
o need close F/U as 20–30% will develop leukemia (often M7 - acute megakaryocytic leukemia) by 3 yrs - note: transient myeloproliferative dz may occur in pts w/o phenotypic features of T21, blasts may be T21 suggesting mosaic state
What translocation is associated with CML?
- CML 2–3% of all cases of childhood leukemia
- 99% characterized by a specific translocation, t(9;22)(q34;q11), known as the Philadelphia chromosome
Clinical Presentation of CML
- assoc with exposure to ionizing radiation, but very few children with CML have such a hx
- clinically, have an initial chronic phase
- spleen often greatly enlarged (can give LUQ pain), can also have mild anemia and thrombocytosis
- chronic phase terminates 3–4 yr after onset, then CML moves into accelerated or “blast crisis” phase
o blood counts rise dramatically, cannot control with drugs such as hydroxyurea
o can also have hyperuricemia and neuro symptoms, related to ↑blood viscosity with ↓CNS perfusion - nonspecific presenting symptoms; include fever, fatigue, wt loss, and anorexia; splenomegaly also present
What is infant leukemia and what is the prognosis?
Infant Leukemia
- 2% of cases of leukemia occur <1 yr, ratio of ALL to AML is 2 : 1
- unique biologic features (rearrangement MLL gene), particularly poor prognosis, very high relapse rate
- present with hyperleukocytosis and tissue infiltration giving organomegaly and CNS disease
- subcut, known as leukemia cutis, and tachypnea d/t diffuse pulmonary infiltration by leukemic cells observed
- very intensive chemo including SCT stem cell transplantation
Frequency and age of onset for non Hodgkins lymphoma
- 60% of all lymphomas in children/ado. Represents 8–10% of all malignancies in children between 5–19 yr of age.
- Although >70% of patients present with advanced dz at dx, the px has improved dramatically, with survival rates of 90–95% for localized disease and 60–90% with advanced dz
How does Burkitt’s Lymphoma typically present?
o BL : with abd (sporadic type) or head & neck (endemic type) dz with involvement of bone marrow or CNS.
How does Lymphoblastic lymphoma typically present?
o LL : with an intrathoracic or mediastinal supradiaphragmatic mass, and also has a predilection for spreading to the bone marrow and CNS.
How does Diffuse Large B cell Lymphoma Present?
DLBCL : with either an abdominal or mediastinal primary and, rarely, dissemination to bone marrow/CNS.
How does Anaplastic Large Cell Lymphoma present?
o ALCL : either with a primary cutaneous manifestation (10%) or with systemic disease (fever, weight loss) with dissemination to liver, spleen, lung, mediastinum, or skin; spread to the bone marrow or CNS is rare
Investigations when suspicious of Lymphoma
Investigations
- CBC, lytes, UA, Ca, Phos, BUN, creat, ALT, AST, bone marrow aspiration & Bx, LP with CSF cytology, cell count and protein;
- CXR, neck, chest, abdominal, and pelvic CT scans,
- PET scan and bone scan (optional), and head CT scan (optional)
- The tumor tissue (i.e., biopsy, bone marrow, CSF, or pleural/paracentesis fluid) should be tested by flow cytometry for immunophenotypic origin (T, B, or null) and cytogenetics (karyotype).
- Additional tests might include fluorescent in situ hybridization (FISH) or quantitative RT-PCR for specific genetic translocations, T and B cell gene rearrangement studies, and molecular profiling by oligonucleotide microarray
