Duffy Null Phenotype + Sickle Cell Disease + G6PD DeficiencyNiki LeeSt. Vincent’s Hospital Melbourne

2017 NICE, Brisbane

Duffy Blood Group System (ISBT 008)

• Chromosome 1 – FY or DARC gene

• Multipass glycoprotein – passes red cell membrane 7 times

• Fya and Fyb

• Products of FY*A and FY*B allele• FY*X similar to Fyb but weak

• 3 phenotypes: Fy(a+b-), Fy(a+b+), Fy(a-b+)

• Polymorphic in most populations

• Other Fy antigens • Fy3/Fy5/Fy6 are high incidence

Duffy Null

• 2 types of Duffy null – Fy(a-b-)• Those common in Africa (~100% certain regions)

• Fy*Null is identical to Fy*B - mutation in the promoter region• Alteration in GATA-1 sequence• Disrupts binding of the erythroid specific transcription factor, preventingthe expression in erythroid cells• Phenotypically null but not genotypically• Fyb antigens are expressed in lung, spleen, colon• Therefore will not be alloimmunized

• Other parts of the world – very rare• Total absence in the Fy gene• Resulting from deletion (frame shift) or nonsense mutation

• introduction of stop codon

• Protection against p. vivax and p. knowlesi

GATA-1

Normal Haemoglobinhttps://allaboutblood.com/category/blood-cells/erythrocytes/haemoglobin/

HbA: α2β2 >96%

HbA2: α2δ2 2.2 – 3-2%

HbF: α2Υ2 <1%

Adult haemoglobin

Haemoglobin Variants

• Due to point mutation in the haemoglobin gene• Haemoglobinopathies

• Hb S, C, DPunjab, E, Oarab

• Detected by electrophoresis and chromatography techniques

• Hb S• Relatively common• High significance due to sickling• Result from glutamic acid – valine replacement in pos.6 in the β globin gene• Poor solubility in deoxygenated blood and can polymerize within the red cells

Sickle Cell Disease

• Collective name for a group of conditions• Common in Africans but can be seen in Indians, Arabics and Greeks

• Homozygous sickle cell anaemia (SS)• Moderate to severe haemolytic anaemia• Sickle cells• Vascular occlusion leading to organ damage• Clinical severity may be variable

• Sickle cell trait (AS)• Heterozygous state is very common• No clinical abnormalities• Sickle cells only at high altitude and low O2 pressure

Interactions

Hb Genotype Name Clinical symptoms

S βA/βS

βS/βSSickle cell traitSickle cell anaemia

NoneSevere haemolytic anaemia, vaso-occlusive episodes

Compound Hb βS/βC

βS/βD Punjab

βS/βO Arab

βO thal/βS

Β+ thal/βS

SC disease

SD diseaseSO diseaseSickle-β0 thal

Sickle-β+ thal

Mild anaemia, some vaso-occlusive episodes

Sickle cell anaemia

Mild sickle cell disease

G6PD Deficiency

• Sex linked in the X chromosome• Many variants, 2 most common types

•Mediterranean type – very low enzyme activity, may lead to favism •A- type – In West Africans and US, sensitive to primaquine

• Susceptible to haemolysis - oxidative drugs• Hemizygous in males readily detectable (XY)• Heterozygous in females, harder to detect (XX)

• rarely homozygous

• Clinical syndromes:• intravascular haemolysis

Case

•30 y.o female

•RAN 18/40

•HE performed as per MHW Thal programme

FBE

31/4018/40 33/40 36/40

CE electropherogram

• Likely βS/βS or β0/βS

No Hb A Not typical SS,

lower Hb S%

Normal CE

Day/Month/Year Footnote to go here Page 14

Homozygous α 3.7 deletion

Homozygous S

G6PD Assay

18/40 33/40

RETIC = 184 x 109/LG6PD = 0.75 IU/g Hb[5.2-13.4 IU/g Hb]

R1r K-k+Kpa-, Jk(a+b+)

Conclusion

• Delivered a healthy baby

• Mother required minimal blood transfusion Hydroxyurea Ok to transfuse Fy(a-b+)

• Child’s phenotype, thalassaemia and G6PD status

References

Day/Month/Year Footnote to go here Page 19

Human Blood Groups 3rd Edition, Geoff Daniels

The global prevalence of glucose-6-phosphate dehydrogenase deficiency: A systematic review and meta-analysis, Ella T. Nkhmo et. All, Blood Cells, Molecules and Diseases; Vol 42, Issue 3 May–June 2009, Pages 267-278

Sickle Cell Disease in sub-Saharan Africa, Michael DeBaun et. All; https://www.uptodate.com/contents/sickle-cell-disease-in-sub-saharan-africa

Introduction

• Background theory

Duffy blood group system and the null phenotype

Sickle cell disease

G6PD deficiency

• Case

• Questions

Red Cell Structure

Embden-Meyerhof Pathway/Krebs Cycle

No oxidative protection

Sickle Trait + α Thal Expected Values

Haemoglobinopathy Diagnosis, Barbara Bain