Hemoglobinopathies

Question 1

Hb regulation
- allosteric
- cooperative
- alkaline Bohr effect
- 2,3 DPG

Answer 1

• allosteric: low affinity (tense) –> high affinity (relaxed) when oxygen binds
• cooperative: O2 binding to one site increases affinity of remaining sites
• alkaline bohr: H+ from tissue CO2 production reduces Hb O2 affinity (increasing tissue oxygenation)
• 2,3DPG: glycolysis byproduct reduces Hb O2 affinity

Question 2

Hb composition: embryonic, A1, A2, F, Barts, H

Answer 2

embryonic: Gower (z2e2, a2e2) and Portland (z2g2, z2b2)
A1: a2b2
A2: a2d2
F: a2g2
Barts: g4
H: b4

Question 3

Hb mutations: HbS, HbC

Answer 3

HbS: B6 Glu-Val
HbC B6 Glu-Lys

Question 4

Which Hb is thalassemia phenotype vs SCD phenotype? Which Hb run together on gel?

Answer 4

Thalassemia: HbEb+/0, HbDb+/0, Hb Lepore, HbCS
SCD: HbS, HbC, HbSE, HbSD, HbSO

Run together
- C, E, OArab, A2
- D, G, S, Lepore

Question 5

high oxygen affinity Hb

Answer 5

Montefiore, Chesapeake

Question 6

What are Hb electrophoresis vs HPLC

Answer 6

Hb electrophoresis: separates by size; lower sensitivity

HPLC: separates by electric charge; higher sens/spec, quantitative

Question 7

Outline general pathophys of thalassemia

Answer 7

decreased synthesis of 1+ globin chain –> a/b imbalance –> precipitation –> cell damage

Question 8

HbE epi

Answer 8

30% in Laos, Cambodia, Thailand

Question 9

Chronic transfusions toxicity

Answer 9

iron overload –> cardiac/endo dysfunction
alloimmunization
transfusion reactions
Infection

Question 10

Thalassemia systemic complications (non-transfusion related)

Answer 10

HSM
medullary overgrowth - thal facies, square vertebrae, rib widening
osteoporosis
bilirubin gallstones
thrombosis

Question 11

hydrops pathophys and mgt

Answer 11

severe anemia and Hb Barts (g4) with high O2 affinity –> CHF –> edema

IUT –> chronic transfusions –> HSCT
consider pregnancy options
stillborn usually 3rd trimester if no treatment

Question 12

Thalassemia Lucarelli RF and OS

Answer 12

HSCT related toxicity
- hepatomegaly >2cm
- liver fibrosis
- poor iron chelation

0 is 95% OS, 1-2 is 85%, 3 is 75-80%

Question 13

Iron chelators - names, routes, tox

Answer 13

Deferoxamine = Desferal = DFO (SC infusion)
- neurotox (eye/ear), abdo pain, NVD, local skin reaction

Deferasirox = DFX (Exjade and Jadenu)
- renal injury, NVD/abdo pain, rash

Deferiprone = DFP
- risk agranulocytosis, neutropenia, NVD, arthralgias

Question 14

Metzner index

Answer 14

MCV/RBC
<13 Thal
>13 IDA

Question 15

Methemoglobinemia pathophys, etiol, mgt

Answer 15

heme pocket mutation prefers Fe3+ over Fe2+ –> increased O2 affinity –> tissue hypoxia (art sats normal)

Inherited: CYB5R3 or CRB5A gene mutations (aut rec), HbM (aut dom)
Acquired: drugs (lidocaine, nitrite, dapsone, chloroquine)

tx >30% or symptomatic
Methylene blue (contraind G6PD), Vitamin C, exchange transfusion

Question 16

Sickle Cell trait complications

Answer 16

hyposthenuria (dilute urine)
hematuria
VTE/PE
glaucoma after hyphema
exertional heat illness, rhabdo
high altitude splenic infarcts
renal medullary carcinoma

Question 17

SCD Screening

Answer 17

TCD annual after 2yo
BP each visit
urine protein and albumin annual after 10yo
dilated eye exam q1-2y after 10yo
PFT annual
Head MRI once w/o sedation

Question 18

SCD acute anemia DDx

Answer 18

hemolysis
splenic/hepatic sequestration
aplastic crisis
AHTR/DHTR/hyperhemolysis

Question 19

SCD exchange transfusion indications

Answer 19

stroke
ACS
MOFS
rapid clinical deterioration

chronic: 1o/2o stroke prevention, recurrent ACS, frequent pain

Question 20

HbSC presentation differences from HbSS

Answer 20

milder (less VOC, ACS)
more retinopathy
more AVN (femoral head)
renal papillary necrosis
delayed splenic involution (~4yo)

Question 21

SCD immunizations

Answer 21

Pneumococcus: Prevnar-13, Pneumovax (23 valent)
Meningococcus: MCV4
Hib
Influenza yearly

Question 22

SCD ASH HSCT indications

Answer 22

stroke/abnormal TCD if MSD
frequent pain
recurrent ACS

Question 23

ACS definition and mgt

Answer 23

new CXR infiltrate AND 1 of:
fever, tachypnea, cough, new hypoxia, WOB, chest pain

CTX + macrolide (azithro)
PRBC: simple or exchange
resp: O2, incentive spirometry
limit overhydration
analgesia

Question 24

TCD values and stroke risk

Answer 24

Normal <170 (cm/s)2 - <1%
Conditional 170-200 - 2-7%
Abnormal >200 - 10% over 3y

Question 25

SCD stroke 1o prevention trials

Answer 25

SOC: chronic transfusion x1y -> HU

STOP I/II - chronic transfusions reduced stroke risk 90%
TWiTCH - switch to HU after 1y (noninferiority, excluded severe vasculopathy)

Question 26

SCD stroke 2o prevention trials

Answer 26

SWiTCH - chronic transfusion > HU
SIT (silent infarct) - chronic transfusions (stroke, observation 14% vs transfusion 6%)

Question 27

compare AHTR and DHTR

Answer 27

AHTR: <7d, DAT neg, no new Ab identified
DHTR: >7d, DAT +, often new Ab

Question 28

alpha thal a0 vs a+ mutations

Answer 28

a0 (both genes on single chrom deleted)
-a20.5, SEA, FIL, MED, THAI

a+
-a3.7, -a4.2

Question 29

Thal iron targets

Answer 29

Liver: normal <1.8, target 2-5 mg/g
Heart: normal and target >20 ms
ferritin: target ~1000