Heme

Question 1

Physiologic anemia definition

Answer 1

Physiologic anemia is the most common cause of anemia in young infants between 6 and 9 weeks of age. The cause of physiologic anemia is the decrease in erythropoiesis due to increased tissue oxygenation. In a healthy newborn, the hemoglobin level is elevated to greater than 14 g/dL. There is a rapid decline that reaches its lowest point, near 11 g/dL, at between 6 and 9 weeks.

Question 2

Iron Deficiency Anemia definition, sx, dx, tx

Answer 2

MC cause of anemia

Microcytic anemia w/ ↓ reticulocyte count & ↑ RDW due to a deficiency of iron

Etiologies:
*chronic blood loss (MC in US): excessive menstruation, GI blood loss (colon cancer)
*decreased absorption: diet (MC worldwide), celiac, bariatric surgery, H. pylori

PATHO: decreased RBC production due to lack of iron & decreased iron stores (decreased ferritin); normally, iron is stored in ferritin in bone marrow, liver, & spleen

sx
Classic sxs of anemia: fatigue, SOB, HA
CNS: irritability, difficulty sleeping

Pagophagia: craving for ice
Pica: craving for non-food substances

PE:
*koilonychia: spooning of the nails
*angular cheilitis: inflammation of one or both corners of the mouth
*tachycardia, glossitis (smooth tongue)
*signs of anemia (pallor)

*hx of drinking >24oz of cow’s milk a day or transition to cow’s milk <12mo old is common

dx
CBC:
*microcytic hypochromic anemia
*↑ RDW
*anisocytosis
*↓ reticulocytes
*may have thrombocytosis & poikilocytosis

Smear: hypochromic microcytic RBC w/ pencil forms

Iron studies:
↑ TIBC
↓ ferritin, transferrin saturation, serum iron

Bone marrow: absent iron stores

tx
Iron replacement: Ferrous sulfate – 4-6mg/kg/d divided in 2-3 doses

Take w/ vitamin C, w/ water or orange juice, & on an empty stomach for ↑ absorption
ADRs: GI (N/V/D/C, flatulence, dark stool)

*continue 8-12wks after Hgb has normalized (total of 3-4mo of replacement)
*limit milk to ≤8oz/d

Severe, life-threatening anemia: RBC transfusion

Question 3

Lead Poisoning Anemia definition, sx, dx, tx

Answer 3

PATHO: lead poisons enzymes, causing cell death; shortens life span of RBCs; inhibits multiple enzymes needed for heme synthesis, causing an acquired sideroblastic anemia

Risk Factors: MC in children

Sources: ingestion or inhalation of environmental lead (paint chips, lead dust)

sx
May be asymptomatic or nonspecific sxs

Neuro sxs: ataxia, fatigue, learning disabilities, difficulty concentrating, peripheral neuropathy (wrist or foot drop)
-Encephalopathy: AMS, vomiting, seizures, SIADH
GI: lead colic – intermittent abdominal pain, vomiting, loss of appetite, constipation
Anemia: pallor, shock, coma
Renal: glycosuria, proteinuria, chronic interstitial nephritis
Burton’s line: thin, blue-black line at the base of the gums near the teeth

dx
Serum lead levels: >10mcg/dL on venous sampling most accurate

Peripheral smear:
*microcytic hypochromic anemia w/ basophilic stippling
*ringed sideroblasts in the bone marrow

Normal/↑ serum iron, ↓ TIBC
↑ erythrocyte protoporphyrin

x-ray: “lead lines” – linear hyperdensities at the metaphyseal plates in children

tx
Removal of the source of lead most important
Mild (≤44mcg/dL): outpatient follow up & lifestyle modification

Moderate (45-69mcg/dL): succimer first line as inpatient
*calcium disodium (CaNa2EDTA) if PO not tolerated

Severe (≥70mcg/dL):
*w/o encephalopathy: succimer + CaNa2EDTA
*encephalopathy: dimercaprol (IM) followed by CaNa2EDTA (IM or IV)

Question 4

Alpha Thalassemia definition, sx, dx, tx

Answer 4

(-a/aa): silent carrier; clinically normal
Trans (-a/-a) or cis (–/aa): trait; trans common in pts of African descent
(-a/–): HbH disease; Heinz bodies
(–/–): hydrops fetalis; stillbirth or death shortly after
*Hgb Barts: gamma tetramers (γγγγ)

MC in SE Asians

sx
Trait: mild microcytic anemia, asymptomatic

HbH: moderate hemolytic anemia, jaundice, hepatosplenomegaly, gallstones, occasional need for transfusion during illness

dx
Trait: mild microcytic anemia
*normal levels of HbA, HbA2, & HbF
*+Hb Barts (gamma-chain tetramer) on newborn screen

HbH: moderate hypochromic, microcytic anemia (Hgb 7-10g/dL)
*variation in RBC shape/size on peripheral blood smear & other findings of chronic hemolysis
*reticulocytosis
*HbH on electrophoresis
*newborn screen >25% Hb Barts

tx
Trait: no intervention
HbH: folic acid supplementation
Stem cell transplant: curative

Question 5

Beta Thalassemia definition, sx, dx, tx

Answer 5

β,β – normal
β,βo or β,β+ – MC; minor; trait; heterozygous, mild reduction in beta-chain synthesis w/ a resultant mild microcytic anemia
β+,β+ or β0,β+ – intermedia (mild); homozygous, markedly reduced beta-chain synthesis & moderate anemia that will occasionally require transfusion
β+,β+ or β0,β0 – major (Cooley’s Anemia); homozygous, no detectable to severely reduced beta-chain production, severe microcytic hypochromic anemia that requires lifelong RBC transfusions

MC in Mediterranean

sx
Trait: mild microcytic anemia, asymptomatic

Intermedia (β+,β+ or β0,β+): moderate hemolytic anemia (Hgb >7g/dL)
*splenomegaly, intermittent transfusion requirement

Major (β+,β+ or β0,β0):
*massive hepatosplenomegaly, growth retardation
*bony deformities – frontal bossing, maxillary prominence from extramedullary hematopoiesis (all preventable w/ aggressive transfusion therapy)

*if iron overload from chronic transfusions is not adequately treated w/ chelation therapy, pts can develop cirrhosis, endocrine abnormalities, cardiac dysfunction, & skin hyperpigmentation

dx
Trait: mild microcytic anemia
*HbA2 level 3.5-8%
*HbF level 1-5%
*significant variability depending on type of mutation; may not be detected on newborn screen

Intermedia: clinical designation based on having a moderate microcytic anemia (Hgb >7g/dL) – only necessitates transfusion w/ normal growth

Major (Cooley’s): clinical designation w/ a resultant severe anemia (Hgb 3-7g/dL)
*reticulocytosis
*HbF 30-100%, HbA2 2-7%
*MCV 50-60fL
*NB screen will demonstrate only HbF in pts w/o any beta-chain production

tx
Trait: no intervention

Major: chronic transfusion therapy may be required as early as 2mo, but necessary by 2y
*10-15mL/kg of PRBCs required q3-4wks
*goal pretransfusion Hgb 9-10g/dL
Chelation therapy for chronically transfused pts w/ iron overload – PO/SC/IV chelators available & necessary 5-7d/wk

In pts receiving chronic transfusion, ferritin levels should be monitored to screen for iron overload, but annual MRI should be used to more accurately assess cardiac/liver iron concentrations & guide chelation therapy

Stem cell transplant: curative

Question 6

B12 Deficiency definiton, sx, dx, tx

Answer 6

Sources: meats, eggs, dairy
Absorption: combines w/ intrinsic factor, absorbed mainly in distal ileum

PATHO: deficiency causes abnormal DNA synthesis

Etiologies:
*decreased absorption: pernicious anemia, Crohn disease, chronic ETOH use, H2 blockers/PPIs, metformin
*decreased intake: vegans

sx
Hematologic: fatigue, exercise intolerance, pallor

Epithelial: glossitis, diarrhea, malabsorption

Neuro sxs:
*symmetric paresthesias MC initial symptom
*lateral & posterior spinal cord demyelination & degeneration: ataxia, weakness, vibratory, sensory, & proprioception deficits, ↓ DTRs

dx
CBC w/ peripheral smear:
*megaloblastic anemia: hypersegmented neutrophils, macro-ovalocytes, mild leukopenia &/or thrombocytopenia
*low reticulocytes

↓ B12, ↑ LDH, ↑ homocysteine

↑ methylmalonic acid (distinguishes from folate deficiency)

tx
IM B12 – IM cyanocobalamin
- weekly until corrected 🡪 monthly
- can switch to PO once resolution of sxs
- pts w/ pernicious anemia need lifelong monthly injections

Question 7

Folate Deficiency definition, sx, dx, tx

Answer 7

PATHO: deficiency causes abnormal DNA synthesis

Etiologies:
*inadequate intake (MC): alcoholics, unbalanced diet
*increased requirements: pregnancy
*impaired absorption
*impaired metabolism: methotrexate, trimethoprim
*loss: dialysis

sx
NO NEURO SXS!

Hematologic: fatigue, exercise intolerance, pallor, chlorosis (pale, faintly green complexion – extremely rare)

Epithelial: glossitis, aphthous ulcers, diarrhea, malabsorption

dx
CBC w/ peripheral smear:
*megaloblastic anemia (hypersegmented neutrophils, macro-ovalocytes)
*low reticulocytes

↓ B12, ↑ LDH, ↑ homocysteine

NORMAL methylmalonic acid (distinguishes from B12 deficiency)

tx: PO folic acid

Question 8

Anemia of Chronic Disease definition, sx, dx tx

Answer 8

Anemia due to decreased RBC production in the setting of chronic disease

Etiologies: chronic inflammatory conditions – chronic infection, inflammation, autoimmune disorders, malignancy

sx
PATHO: 3 main factors decrease serum iron
*↑ hepcidin: blocks release of iron from macrophages & reduces GI absorption
*↑ ferritin: sequesters iron into storage
*erythropoietin inhibition

dx
CBC:
*mild normocytic normochromic anemia
*↓ reticulocytes, normal/↑ RDW

Iron studies:
*normal/↑ ferritin
*↓ TIBC, ↓ serum iron

tx
Treat the underlying disease
Erythropoietin-alpha if renal disease or low EPO levels

Question 9

Hemolytic Anemias definition and dx

Answer 9

Hemolytic Anemia: anemia caused by ↑ RBC destruction when the rate of destruction exceeds the bone marrow’s ability to replace the destroyed cells

dx
Diagnostics:
*peripheral smear: ↑ reticulocytes; schistocytes (bite cells) if intravascular hemolysis
*↓ haptoglobin
*↑ INDIRECT bilirubin, reticulocyte count, LDH

Question 10

Sickle Cell Anemia definition

Answer 10

SCD – group of inherited hemoglobinopathies secondary to the production of abnormal Hgb complicated w/ an associated hemolytic anemia & vaso-occlusion

Genetic mutation in both beta-globulin genes, w/ at least 1 mutation resulting in HbS – homozygous SS MC form & most severe (MC in AA)

Other forms: compound heterozygous states where HbS is combined w/ another abnormal Hgb or a beta-thalassemia mutation – HbC, HbE, beta-plus thalassemia, beta-zero thalassemia

Question 11

Sickle Cell Anemia sx

Answer 11

Painful episodes: vaso-occlusive event resulting in acute onset of severe pain commonly in back, check, & extremities
*swelling of hands/feet in infants (dactylitis)

Fever (>38.5C): more susceptible to bacterial infections because of functional asplenia; highest risk for sepsis from encapsulated organisms such as S. penumoniae, N. meningitidis, & Salmonella

Splenic sequestration: intrasplenic trapping of RBCs & platelets – decrease in Hgb & often platelets w/ an acute enlargement of spleen that can lead to life-threatening anemia (often associated w/ acute viral/bacterial illnesses)

Acute chest syndrome: fever, respiratory sxs, new pulmonary infiltrate on CXR
*causes: bacterial (M. pneumoniae, C. pneumoniae, S. aureus, S. pneumoniae, H. flu), viral, fat emboli, in situ vaso-occlusion, pulmonary edema, thromboembolism

Aplastic crisis: marked anemia w/ reticulocytopenia, frequently secondary to parvovirus infection that causes a maturation arrest of RBC production in bone marrow for 1-2wks
*increased fatigue, pallor, fever
*reticulocytopenia begins ~5d after exposure & lasts 7-10d

Stroke: SCD-SS & Sβ0-thalassemia have 10% risk of stroke by 20yo; predominant etiology is large-vessel vasculopathy w/ proliferative intimal hyperplasia
*hemiparesis, facial droop, aphasia, generalized sxs (AMS, stupor, seizures)

Question 12

Sickle Cell Anemia dx

Answer 12

Peripheral smear:
*target cells, sickled erythrocytes, ↓ H/H

*Howell-jolly bodies indicates functional asplenia

Hgb electrophoresis: 90% HbS, 8% HbF

Fever: all pts w/ SCD + fever need urgent evaluation w/ PE, blood culture, CBC w/ diff, reticulocyte count; consider urine culture, CXR

Stroke: head MRI, CBC w/ reticulocyte count, Hgb electrophoresis for HbS %, type & screen
*prevention: routine transcranial Doppler

Question 13

Sickle Cell Anemia tx

Answer 13

Painful episodes:
*outpatient: PO meds (anti-inflammatories w/ or w/o opioid) & hydration
*inpatient: combo of ibuprofen or ketorolac w/ an opioid & IV hydration

Fever: ceftriaxone or high-dose ampicillin + observation

Splenic sequestration: follow Hgb & spleen size closely; fluid admin in stable pts w/ mild decrease in Hgb
*hypoxia, tachypnea, tachycardia: transfuse 5-10mL/kg RBCs, then reassess

Acute chest syndrome: ampicillin or 3rd gen cephalosporin (cefotaxime, ceftriaxone) + macrolide (erythromycin, azithromycin, clarithromycin) + oxygen if hypoxic; pain control; incentive spirometry
*respiratory/hemodynamic instability requires RBC transfusion

Aplastic crisis: PRBC transfusion if pt is symptomatic

Stroke: exchange transfusion to decrease HbS %; long-term – placed on chronic RBC transfusion protocol to minimize risk for further strokes

Preventative Management:
*Penicillin prophylaxis, folic acid supplementation, hydroxyurea for pts >9mo

Question 14

G6PD Deficiency definition, sx, dx, tx

Answer 14

x-linked recessive enzymatic disorder of RBCs that may cause episodic hemolytic anemia

Risk Factors: males, AA males
PATHO: decreased G6PD activity during oxidative stress results in an oxidative form of Hb (methemoglobin); the denatured hemoglobin precipitates as Heinz bodies

Exacerbating factors:
*infection MC cause, fava beans
*dapsone, methylene blue, primaquine, nitrofurantoin, phenazopyridine

sx
*neonatal jaundice

For milder forms pts are clinically & hematologically normal until they have an “oxidative challenge”

Severe forms can have a baseline hemolytic anemia

6-24h after exposure to oxidative agent: dark urine, jaundice, pallor, tachycardia, nausea, abdominal pain

24-48h: low-grade fever, irritability, listlessness, splenomegaly, hepatomegaly

dx
Peripheral smear:
*normocytic hemolytic anemia only during crises
*schistocytes (“bite” cells), anisocytosis, blister cells
*(+) Heinz bodies hallmark

Hemolytic anemia:
↑ reticulocytes, indirect bilirubin
↓ haptoglobin

DAT (-)

Enzyme assay for G6PD: fluorescent spot test; DNA testing; usually performed after episodes

tx
Usually self-limited; avoid offending foods & drugs
*Hgb returns to normal within 3-6wks

Hgb >7mg/dL + clinically stable + no hemoglobinuria: observe for 24-48h

Hgb <7mg/dL or Hgb 7-9mg/dL w/ continued brisk hemolysis (persistent hemoglobinuria): consider PRBC transfusion

Neonatal jaundice: phototherapy

Question 15

Hereditary Spherocytosis definition, sx, dx, tx

Answer 15

Autosomal dominant hereditary intrinsic hemolytic anemia

PATHO: deficiency in RBC membrane & cytoskeleton (spectrin), leading to increased RBC fragility & sphere-shaped RBCs

sx
Anemia: mild to severe; pts may have hyperhemolytic periods & are susceptible to an aplastic crisis from parvovirus infection
*jaundice, splenomegaly, gallstones

50% of HS pts present in NB period w/ jaundice

dx
Peripheral smear:
*hyperchromic microcytosis, 80% spherocytes
*↑ MCHC, reticulocyte count, RDW

*EMA binding assay: flow cytometry assay
*(+) osmotic fragility, Coombs NEGATIVE

tx
- folic acid daily
- splenectomy
*delayed until at least 5yo
*pneumococcal vaccine prior
- transfusion support if needed

Question 16

Autoimmune Hemolytic Anemia (AIHA) definition, sx, dx, tx

Answer 16

Acquired hemolytic anemia due to autoantibody production against RBCs; peak incidence in first 4y of life (warm MC)

PATHO:
*warm: IgG antibodies
*cold: IgM antibodies

Etiologies:
*warm: penicillin, cephalosporins, SLE
*cold: M. pneumoniae, EBV

sx
Anemia: pallor, fatigue, weakness, dyspnea
Hemolysis: hemoglobinuria, jaundice, splenomegaly

PE: hepatosplenomegaly, tachycardia, systolic flow murmur, orthostasis

Cold-induced vascular phenomenon:
*acrocyanosis: numbness or mottling of the fingers, toes, nose, ears that resolves w/ warming up of the body parts

dx
CBC + peripheral smear:
*microspherocytosis (esp. warm)
*polychromasia

Hemolysis:
*↓ haptoglobin
*↑ reticulocyte count, indirect bilirubin, LDH

Coombs POSITIVE (+ DAT)
*Warm: IgG detected on RBC surface +/- C3
*Cold: C3 detected on RBC surface

UA: large blood, but few RBCs, indicated hemoglobinuria

tx
RBC transfusion: pts w/ life-threatening anemia or rapid hemolysis

Immunosuppression: corticosteroids
Alt: rituximab, mycophenolate, mofetil, sirolimus, splenectomy

Question 17

Paroxysmal Nocturnal Hemoglobinuria definition, sx, dx, tx

Answer 17

Rare, acquired stem cell mutation – RBCs become deficient in GPI anchor surface proteins

PATHO: deficiency in CD55 & CD59 lead to increased complement activation & intravascular RBC destruction

sx
Triad: hemolytic anemia (hemoglobinuria) + pancytopenia + unexplained thrombosis in atypical veins
*dark, cola-colored urine during the night or early morning

dx
Hemolysis:
*↓ haptoglobin
*↑ reticulocyte count
*↑ indirect bilirubin
*↑ LDH

Flow cytometry test: CD55/CD59-deficienct RBCs

tx
Complement inhibitors:
- eculizumab

• folic acid
• allogenic hematopoietic cell transplant only potential for cure

Question 18

Immune Thrombocytopenic Purpura (ITP) definition, sx, dx, tx

Answer 18

PATHO: autoimmune-antibody reactions vs. platelets w/ splenic platelet destruction 🡪 consumptive thrombocytopenia; <100,000/uL platelets >12mo

Incidence:
*young children 2-4yrs; often 1-3wks following acute viral infection (often self-limited)
*adults: young women <40; idiopathic, often recurrent

sx
Sudden onset widespread bruising, petechiae, &/or purpura; typically days to weeks after a viral illness

Mucosal bleeding sxs: epistaxis, wet purpura, GI bleeding
*no splenomegaly

dx
Isolated thrombocytopenia
Normal coagulation tests

tx
No to mild bleeding (skin only):
*observation only, regardless of platelet count

Consider tx in pts w/ significant bleeding sxs (mucosal, GI, menstrual):
*IVIG x1-2d; premedicate w/ Tylenol & Benadryl to decrease side effects
*anti-D (WinRho): should not be given to pts w/ anemia, evidence of bleeding, AIH, or s/sxs of infection
*corticosteroids: prednisone x2-4wks then taper

Second-line: splenectomy, rituximab, TPO-Ras (eltrombopag, romiplostim)

Question 19

Thrombotic Thrombocytopenic Purpura (TTP) definition, sx, dx, tx

Answer 19

PATHO: auto-ab vs. ADAMTS13 (vWF-cleaving protease) 🡪 unusual large vWF multimers 🡪 micro thrombosis of small vessels 🡪 thrombocytopenia (consumptive) & hemolytic anemia

Incidence:
*young adults 20-50yrs
*MC women

sx
PENTAD: “FAT RN”
*fever
*anemia: microangiopathic hemolytic anemia
*jaundice
*thrombocytopenia: bruising, purpura, bleeding
*renal failure/uremia
*neuro sxs: HA, CVA, AMS

dx
Thrombocytopenia

Hemolytic anemia:
*peripheral smear: ↑ reticulocytes, schistocytes (bite or fragmented cells)
*LFTs: ↑ indirect bilirubin, ↓ haptoglobin

Normal coagulation tests

tx
- plasmapheresis: removes Ab & adds ADAMTS13

• immunosuppression: steroids, cyclophosphamides

Question 20

Hemolytic Uremic Syndrome (HUS) definition, sx, dx, tx

Answer 20

PATHO: exotoxins (shiga-like & shiga toxins) damages vascular endothelium, activating platelets 🡪 microthrombosis of small vessels 🡪 consumptive thrombocytopenia & hemolytic anemia
*ADAMTS13 normal

Incidence:
*predominantly seen in children w/ diarrhea prodrome: Enterohem. E coli O157:H7 (80%), Shigella, Salmonella
*adults: seen w/ HIV, SLE, & antiphospholipid syndrome

sx
TRIAD: “RAT”
*renal failure/uremia (predominant symptom)
*anemia: microangiopathic hemolytic anemia
*jaundice
*thrombocytopenia: bruising, purpura, bleeding

dx
Thrombocytopenia

Hemolytic anemia:
*peripheral smear: ↑ reticulocytes, schistocytes (bite or fragmented cells)
*LFTs: ↑ indirect bilirubin, ↓ haptoglobin

↑ BUN/creatinine
Normal coagulation tests

tx
- observation in most children (usually self-limited)

• plasmapheresis
• +/- FFP if severe
  *NO ABX – may worsen the disease

Question 21

Disseminated Intravascular Coagulation (DIC) definition, sx, dx, tx

Answer 21

PATHO: pathologic clotting cascade activation 🡪 widespread thrombi 🡪 consumption of platelets 🡪 diffuse bleeding

Incidence:
*MC in young or elderly
*MC gram negative species
*OB emergencies, malignancy, massive tissue trauma

sx
Diffuse hemorrhage: venipuncture sites, mouth, nose; extensive bruising

Thrombosis: renal failure, gangrene (as clots block circulation)
Pts usually acutely ill

dx
Hemolytic anemia:
*peripheral smear: ↑ reticulocytes, schistocytes (bite or fragmented cells)
*LFTs: ↑ indirect bilirubin, ↓ haptoglobin

*abnormal coagulation tests
↓ fibrinogen
↑ D-dimer, PT, & PTT
Severe thrombocytopenia

tx
Reversal of the underlying cause mainstay of tx
- +/- platelet transfusion (if <20,000)
- +/- FFP
- +/- heparin in select cases

Question 22

Heparin Induced Thrombocytopenia (HIT) definition, sx, dx, tx

Answer 22

Acquired thrombocytopenia esp. within the first 5-10d of the initiation of heparin

Risk Factors:
*UFH > LMWF
*surgical > medical
*F > M

PATHO: autoantibody formation to the hapten of heparin + platelet factor 4 causes platelet activation & consumption, leading to thrombocytopenia & thrombosis

sx
Thrombocytopenia – bleeding
Thrombosis – venous thrombosis, gangrene, organ infarction, skin necrosis

dx
*thrombocytopenia
*timing of platelet drop (>50%)
*thrombosis
Gold standard: 14-C-serotonin release assay

tx
Immediate D/C of all heparin + initiation of non-heparin anticoagulants
- direct thrombin inhibitors (argatroban, lepirudin)
- fondaparinux
- DOAC (apixaban, edoxaban, rivaroxaban)

Question 23

Hemophilia definition, sx, dx, tx

Answer 23

x-linked recessive disorder occurring almost exclusively in males

*A = factor VIII deficiency (MC)
*B = factor IX deficiency *Christmas disease
*C = factor XI deficiency *Ashkenazi jews

sx
3 classifications (bleeding related to amount of residual factor clotting activity present): <1% = severe, 1-5% = moderate, >5-40% = mild

Hemarthrosis: delayed bleeding or swelling in weight-bearing joints (knees, elbows, shoulders, ankles, hips)

Excessive hemorrhage due to trauma & surgery or incisional bleeding
*epistaxis, bruising, GI or urinary tract hemorrhage

dx
*prolonged aPTT, normal PT, normal bleeding time

Mixing studies: PTT corrects w/ mixing studies

A = low factor VIII
B = low factor IX
C = low factor XI

tx
A: factor VIII infusion; desmopressin (DDVAP)
B: factor IX infusion
C: factor XI infusion

Pts w/ inhibitors: recombinant factor VIIa, emicizumab

Aminocaproic or tranexamic acid:
*antifibrinolytics; useful for mucosal bleeding

Question 24

Von Willebrand Disease definition, sx, dx, tx

Answer 24

Autosomal dominant disorder associated w/ ineffective platelet adhesion due to deficient or defective vWF

MC hereditary bleeding disorder

sx
Mucocutaneous bleeding: epistaxis, bleeding gums, petechiae, purpura, easy bruising, menorrhagia, prolonged bleeding time after minor cuts

dx
*prolonged PTT & bleeding time (worse w/ aspirin)

Ristocetin-induced platelet aggregation (gold standard)

tx
DDVAP
plasma-derived vWF concentrates (Humate P, Alphanate)

Question 25

Vitamin K Deficiency definition, dx, tx

Answer 25

Required for factors II, VII, X, & proteins C & S

PATHO: infants not supplemented w/ vitamin K after delivery may develop hemorrhagic disease of the newborn (peak incidence @2-5d); increased risk if mother taking anticonvulsants, phenobarbital, phenytoin

dx
Prolonged PT & PTT
Low vitamin K-dependent factors (II, VII, IX, X, proteins C & S)

tx
SC/IM/IV vitamin K – infants should be treated shortly after birth

Question 26

Factor V Leiden Mutation definition, sx, dx, tx

Answer 26

MC inherited cause of hypercoagulability (thrombophilia)

PATHO: mutated factor V is resistant to breakdown by activated protein C, leading to increased hypercoagulability

sx
Increased incidence of DVT, PE, hepatic vein, or cerebral vein thrombosis
Increased risk of miscarriages during pregnancy

dx
*activated protein C resistance assay
(+) 🡪 confirm w/ DNA testing

*DNA testing: mutation analysis

tx: indefinite anticoagulation

Question 27

Protein C or S Deficiency definition, sx, dx, tx

Answer 27

Proteins C & S are vitamin K-dependent anticoagulant proteins produced by the liver that stimulate fibrinolysis & inactivate factors V & VIII
*decreased protein C or S leads to hypercoagulability

Etiologies:
*inherited: autosomal dominant (C MC)
*acquired: ESLD, severe liver disease w/ synthetic dysfunction, early warfarin admin.

sx
Increased incidence of DVT/PE
Warfarin-induced skin necrosis

Newborns: purpura fulminans: red purpuric lesions at pressure points, progresses to painful black eschars

dx
*protein C & S functional assay, plasma protein C & S antigen levels

tx
Thrombosis:
- protein C concentrate
- indefinite anticoagulation

Warfarin-induced necrosis:
- immediate D/C warfarin
- admin. IV vitamin K, heparin, protein C concentrate, or FFP

Question 28

Antithrombin III Deficiency definition, sx, dx, tx

Answer 28

PATHO: antithrombin normally inhibits coagulation by neutralizing the activity of thrombin (factors IIa, IXa, & Xa); decreased levels lead to increased risk of clotting

Etiologies:
*inherited: autosomal dominant
*acquired: liver disease, nephrotic syndrome, DIC, chemo

sx: Increased incidence of DVT, PE

dx: antithrombin III assays

tx
Asymptomatic:
- anticoagulation only before surgical procedures

Thrombosis:
- high-dose IV heparin
- PO anticoagulation indefinitely

Question 29

Astrocytoma definition, sx, dx, tx

Answer 29

*Derived from astrocytes
*Can appear in any part of the brain
*MC infratentorial in children

Pilocytic Astrocytoma (Grade I): Juvenile Astrocytoma – typically localized; considered “most benign” astrocytoma; MC primary childhood CNS tumor

sx
Focal deficits: MC – depends on location
*Cerebellum: weakness, tremor, ataxia
*Visual pathway: visual loss, proptosis, nystagmus
*Spinal cord: pain, weakness, gait disturbance

General sxs: HA (may be worse in the morning, awaken pt at night, or positional), cranial nerve deficits, AMS changes, neurologic deficits, ataxia, vision changes, weakness

↑ ICP: due to mass effect 🡪 HA, N/V, papilledema, ataxia, drowsiness, stupor

dx
*CT/MRI w/ contrast: grade I non-enhancing

BX: generally form sacs of fluid (cystic), or may be enclosed within a cyst; Rosenthal fibers (eosinophilic corkscrew fibers)

tx
*surgical excision
*post-op radiation if tumor cannot be completely removed; 90% 5y survival rate

Question 30

Medulloblastoma definition, sx, dx, tx

Answer 30

*Most common MALIGNANT posterior fossa tumor in children and represents about 20% of all pediatric CNS cancers
*METS through CSF

Bimodal peak age: 3-4yrs, 8-10yrs

sx
*vomiting, HA, nausea, visual changes (double vision), unsteady walking or clumsiness

DX: MRI, bx

tx
*surgery, radiation, chemo
Long-term survival w/ treatment is 70%

Question 31

Ependymoma definition, sx, dx, tx

Answer 31

*Ependymal cells line the ventricles & parts of the spinal column; 3rd MC pediatric CNS tumor (10%)
*MC in children (mean age @ dx is 6yrs, 30% occur <3y)
*MC seen in 4th ventricle, spinal cord, & medulla

sx
Infants:
*increased in head size, irritability, developmental delay
*sleeplessness, vomiting

Older children/adults: N/V, HA, changes in mood, personality, or concentration; seizures, balance/gait disturbances, spinal cord compression sxs (back pain, loss of bladder/bowel control)

dx
*CT/MRI w/ contrast: hypointense T1, hyperintense T2

BX: perivascular pseudo rosettes (tumor cells surrounding a blood vessel)

tx: surgical resection 🡪 adjuvant radiation

Question 32

Retinoblastoma definition, sx, dx, tx

Answer 32

*MC primary intraocular malignancy in childhood
*Most diagnosed before 3yo

Types:
*Non-Heritable: due to somatic mutations in the RB1 gene in the tumor (RB1 is a tumor suppressor gene on chromosome 13)
*Heritable: due to germline mutations in the RB1 gene
*may develop bilateral retinoblastoma

sx
*leukocoria (presence of abnormal white reflex instead of the normal red reflex)
*may develop strabismus or nystagmus

dx
*dilated ophthalmologic exam
*ocular U/S: intraocular calcified mass
*MRI/CT

tx
*radiation, chemo, &/or enucleation
F/U: retinoblastoma can be associated w/ bone neoplasms (Osteosarcoma)

Question 33

Neutropenia definition, sx, dx, tx

Answer 33

ANC <1000

sx
FEVER – earliest & only sign
Hx of chemo

dx
CBC, CMP, blood culture, UA
CXR, CT, U/S, LP

tx
Outpatient: cipro + Augmentin; moxifloxacin
Monotherapy *pseudomonas: cefepime, imipenem, Augmentin
Dual therapy *unstable: monotherapy + Vanc or flagyl (abd)

Question 34

Hodgkin Lymphoma (HL) definition, sx, dx, tx

Answer 34

HL: malignant lymphoma typically of B-cell origin ▪︎⊕Hodgkin/Reed-Sternberg (HRS) cells: classic RS cells
Classical Hodgkin Lymphoma (cHL)
* Nodular sclerosis * Mixed cellularity * Lymphocyte rich/depleted
o Nodular lymphocyte predominant

A 3x ↑ risk in young adults with prior history of serologically
confirmed infectious mononucleosis

sx
“B” symptoms present in approx. 30% of cases.
o Fever > 38°C (100.4°F)
o Drenching night sweats
o Weight loss (>10% of body weight) * Generalized pruritus * Single LN group and spreads to contiguous areas
* Late disseminated * Pain in involved lymph nodes immediately after the ingestion of
alcohol

Diffuse/puffy swelling rather than a discrete mass may be apparent in the
supraclavicular, infraclavicular, or anterior chest wall regions
* ~70% cervical node involvement

dx
LABS: CBC, kidney/liver function (CMP), albumin, electrolytes, ESR, HIV testing

Imaging: CXR, PET-CT (staging)

Confirmatory ⇢ tissue BX: excisional/incisional peripheral lymph node biopsy preferred
» ⊕HRS cells (classic RS/variants)

Classic Reed-Sternberg cell:
▪︎at least 2 nucleoli in separate nuclear lobes
▪︎characteristic “owl’s eye” appearance

tx
Limited Stage (I & II): chemo + RT
▪︎MC used chemotherapy ⇢ ABVD
» Adriamycin (doxorubicin)
» bleomycin
» vinblastine
» dacarbazine

Advanced Stage (III & IV):
▪︎3 possible treatment options
➀ ABVD
➁ Stanford V
➂ BEACOPP (bleomycin, etoposide,
Adriamycin, cyclophosphamide,
oncovin, procarbazine, prednisone)

Refractory/relapse: high-dose chemo, autologous stem cell transplant

Question 35

Non-Hodgkin Lymphoma types

Answer 35

▪︎B-cell lymphomas MC (85%)

Indolent (slow growing)
➀ Follicular Lymphoma ⇢ MC low-grade lymphoma in adults
PATHO: t(14;18) ⇢ IGH/BCL2 fusion gene ⇢ overexpression of BCL2 (blocks apoptosis) causes prolonged cell survival

➁ Hairy Cell Leukemia (HCL) ⇢ MC in middle-aged men
PATHO: late, activated memory B-cell w/ a BRAF V600E mutation

➂ Small lymphocytic Lymphoma (SLL): identical to CLL
▪︎CLL ⇢ disease manifests primarily in the blood

➃ Marginal Zone Lymphomas (MZLs)
▪︎post-germinal center memory B cells w/ capacity to differentiate into marginal zone cells & plasma

Aggressive
➀ Diffuse Large B-cell (DLBCL) ⇢ MC NHL overall**
▪︎mutations: BCL6 (MC), TP53, BCL2; MYC overexpression
▪︎AIDS-defining malignancy, associated w/ EBV

➁ Mantle Cell Lymphoma (MCL) ⇢ nodal & non-nodal MCL
▪︎express cyclin D1, BCL2, & CD5⊕; CD23⊖
PATHO: t(11;14) ⇢ translocation of CCND1 w/ Ig genes

➂ Burkitt Lymphoma (BL) ⇢ MC in children
PATHO: translocation/deregulation of MYC gene

Question 36

Non-Hodgkin Lymphoma sx, dx, tx

Answer 36

sx
S/SXS: MC ⇢ painless lymphadenopathy +/- noncontiguous LNs
▪︎Indolent: insidious, slowly growing or waxing/waning LAD, obstruction

▪︎Aggressive: rapidly growing mass, ⊕B SXS

dx
LABS: anemia MC +/- lymphocytosis, ⇡ LDH
Imaging: CXR, PET-CT (staging)

Confirmatory ⇢ tissue BX: excisional/incisional peripheral lymph node biopsy of unfixed tissue
▪︎B-cell lymphomas CD19⊕, CD20⊕, CD79a⊕
▪︎T-cell lymphomas CD3⊕

Microscopy ⇢ Burkitt lymphoma: “starry sky”
▪︎benign histiocytes (“stars”) w/ abundant clear
cytoplasm dispersed throughout neoplastic tumor
cells (“sky”

tx
Indolent: highly treatable, but not reliably curable
▪︎asymptomatic ⇢ monitor
▪︎regional radiation therapy

Aggressive: responsive to chemo & often curable ⇢ R-CHOP
» rituximab
» cyclophosphamide
» hydroxydaunorubicin (doxorubicin)
» oncovin (vincristine)
» prednisone
CNS prophylaxis ⇢ MTX

Hairy Cell Leukemia:
▪︎cladribine or pentostatin

Question 37

Acute Leukemias (AML & ALL)

Answer 37

S/SXS ⇢ sudden symptom onset & rapid progression
▪︎anemia: fatigue, pallor, weakness
▪︎thrombocytopenia: epistaxis, bleeding

types
Acute Myelogenous Leukemia (AML): ▪︎MC acute leukemia in adults, peak incidence 65yo AML S/SXS:
AML w/ minimal granulocyte maturation
▪︎skin infiltration ⇢ leukemia cutis (most often involves the face)
M2 AML w/ granulocyte maturation » papules/nodules, may be erythematous, violaceous, gray-blue
M3 Acute promyelocytic leukemia (APL)
▪︎M5 (monocytic): gingival infiltration ⇢ gingival hyperplasia
» t(15;17), ⊕Auer rods, MPO⊕ ▪︎bone pain & CNS involvement uncommon*

Acute Lymphocytic Leukemia (ALL): ▪︎MC childhood malignancy, peak incidence 2-5yo, ♂︎ > ♀︎
B-ALL B-lymphoblastic leukemia (MC, 80-85%) ALL S/SXS:
» CD19⊕, CD22⊕, CD79a⊕ ▪︎fever, night sweats, unexplained weight loss, painless LAD
T-ALL T-lymphoblastic leukemia (CD3⊕)
▪︎bone pain (limping/refusal to bear weight), hepatosplenomegaly
» mediastinal/thymic infiltration
▪︎CNS/meningeal infiltration (common): cranial nerve palsies, HA,

Question 38

Acute Leukemias (AML & ALL) dx and tx

Answer 38

LABS: thrombocytopenia, anemia
Tumor lysis syndrome: ⇡ phosphate, ⇡ K, ⇣ calcium,
⇡ uric acid, ⇡ LDH

DX: bone marrow aspiration/BX, peripheral smear
AML DX: >20% myeloblasts, ⊕Auer rods
▪︎cytogenetic abnormalities:
» t(8;21), inv(16), t(16;16), trisomy 8
▪︎immunophenotype:
» MPO⊕, TdT⊖, PAS⊖
» CD13⊕, CD33⊕, CD34⊕, CD117⊕
▪︎Acute promyelocytic leukemia (APL)
» t(15;17)/PML-RARA

ALL DX: >20% lymphoblasts, ⊘Auer rods
▪︎cytogenetic abnormalities:
» childhood ⇢ t(12;21), high hyperdiploidy
» adults ⇢ t(9;22)/BCR-ABL1 (Philadelphia
chromosome, Ph⊕)
▪︎immunophenotype: MPO⊖, TdT⊕, PAS⊕

tx
Remission:
▪︎<5% blast cells in bone marrow
▪︎ANC >1000/mcL

AML TX:
▪︎cytarabine + idarubicin
▪︎APL ⇢ all-trans retinoic acid (ATRA)
» matures blasts cells

ALL TX:
▪︎doxorubicin, cyclophosphamide
▪︎vincristine, MTX, prednisone
▪︎Ph⊕ ⇢ add TKI (e.g., imatinib)
CNS prophylaxis: intrathecal MTX, cytarabine, & hydrocortisone

Question 39

Chronic Myelogenous Leukemia (CML) definition, sx, dx, tx

Answer 39

CML: proliferation of mature myeloid cells ▪︎peak incidence 50-60yo, ♂︎ > ♀︎

PATHO: t(9;22) causes fusion between ABL1 gene (chromosome 9) & BCR gene (chromosome 22) & gives rise to the Philadelphia chromosome (Ph) which inhibits apoptosis & ⇡ miotic rate, resulting in uncontrolled proliferation of mature myeloid cells

S/SXS ⇢ 3 phases
➀ Chronic Phase (<10% blasts): MC clinical presentation at diagnosis (85% of patients)
▪︎often asymptomatic early on w/ insidious onset of nonspecific symptoms
▪︎fatigue, weight loss, excessive sweating, bleeding episodes d/t platelet dysfunction
▪︎abdominal fullness, splenomegaly w/ LUQ pain, gouty arthritis (overproduction of uric acid)
➁ Accelerated Phase (10-19% blasts):
▪︎ worsening splenomegaly, worsening cytopenias (anemia, infection/fever)
▪︎genetic instability (e.g., additional chromosomal abnormalities)
➂ Blast Phase/Crisis (≥20% blasts):
▪︎manifests as an acute leukemia, resembles AML (e.g., night sweats, weight loss, bone pain, bleeding)
▪︎leukostasis (hyperleukocytosis): dyspnea, visual changes, HA, tinnitus, priapism, fever

dx
Peripheral smear:
▪︎leukocytosis, median white count ~100,000/µL
▪︎differentiation ⇢ all cells of neutrophilic series
» myeloblasts, myelocytes, mature neutrophils
▪︎LOW leukocyte alkaline phosphatase (LAP)
» excludes leukemoid reaction
▪︎basophilia, eosinophilia
▪︎thrombocytosis (platelet count >600,000/µL)

Bone marrow BX: granulocytic hyperplasia

Confirmatory ⇢ cytogenetic testing:
» ⊕Ph chromosome &/or BCR-ABL1 fusion gene

TX: tyrosine kinase inhibitors (TKIs)
▪︎imatinib, dasatinib, nilotinib

Leukocytosis ⇢ hydroxyurea

Allogenic stem cell transplant
▪︎TKI-resistant CML, advanced phases

Question 40

Chronic Lymphocytic Leukemia (CLL) definition, sx, dx, tx

Answer 40

CLL: proliferative mature B-cell malignancy
S/SXS: asymptomatic lymphocytosis MC (B SXS in 5-10%), fatigue
▪︎MC leukemia in adults, median onset 70-72yo
▪︎painless LAD (MC) ⇢ cervical, supraclavicular, axillary
▪︎RF: men, ⇡ age ▪︎splenomegaly (2nd MC), usually painless & nontender to palpation
▪︎leukemia cutis (rare), neutropenia, anemia, thrombocytopenia

LABS:
▪︎lymphocytosis >5,000/µL (threshold)
» often as high as 100,000/µL
▪︎hypogammaglobulinemia common

dx
Peripheral smear:
▪︎lymphocytosis (small mature lymphocytes)
▪︎⊕smudge cells ⇢ lymphocytes are mechanically
disrupted & smear out when being spread on slide

Immunophenotype:
▪︎CD5⊕, CD19⊕, CD20⊕ (dim), CD23⊕, CD10⊖

Markers of good prognosis:
▪︎CD38⊖, ZAP-70⊖
Markers of poor prognosis:
▪︎CD38⊕, ZAP-70⊕, del(11q)⊕, del(17p)⊕

tx
Low-risk (Rai 0, Binet A):
▪︎observation w/ regular f/u

Intermediate/high-risk, symptomatic or progressive ⇢ chemotherapy
▪︎ibrutinib, rituximab, alemtuzumab
▪︎fludarabine, cyclophosphamide

Curative ⇢ allogenic stem cell transplant (not routinely performed)