Transfusion strategy for weak D type 4.0 based on RHD alleles and RH haplotypes in Tunisia

Mouna Ouchari; Kshitij Srivastava; Houda Romdhane; Saloua Jemni Yacoub; Willy Albert Flegel

doi:10.1111/trf.14411

. Author manuscript; available in PMC: 2018 Feb 8.

Published in final edited form as: Transfusion. 2017 Nov 29;58(2):306–312. doi: 10.1111/trf.14411

Transfusion strategy for weak D type 4.0 based on RHD alleles and RH haplotypes in Tunisia

Mouna Ouchari ¹, Kshitij Srivastava ¹, Houda Romdhane ², Saloua Jemni Yacoub ², Willy Albert Flegel ¹

PMCID: PMC5803429 NIHMSID: NIHMS928723 PMID: 29193104

Abstract

Background

With more than 460 RHD alleles, this gene is the most complex and polymorphic among all blood group systems. The Tunisian population has the largest known prevalence of weak D type 4.0 alleles, occurring in 1 of 105 RH haplotypes. We aimed to establish a rationale for the transfusion strategy of weak D type 4.0 in Tunisia.

Study design and methods

Donors were randomly screened for the serological weak D phenotype. The RHD coding sequence and parts of the introns were sequenced. To establish the RH haplotype, the RHCE gene was tested for characteristic single nucleotide positions.

Results

We determined all RHD alleles and the RH haplotypes coding for the serologic weak D phenotype among 13,431 Tunisian donations. A serologic weak D phenotype was found in 67 individuals (0.50%). Among them, 60 carried a weak D type 4 allele: 53 weak D type 4.0, 6 weak D type 4.2.2 (DAR), and 1 weak D type 4.1. Another 4 donors had 1 variant allele each: DVII, weak D type 1, weak D type 3, and weak D type 100, while 3 donors showed a normal RHD sequence. The weak D type 4.0 was most often linked to RHCE*ceVS.04.01, weak D type 4.2.2 to RHCE*ceAR, and weak D type 4.1 to RHCE*ceVS.02, while the other RHD alleles were linked to one of the common RHCE alleles.

Conclusions

Among the weak D phenotypes in Tunisia, no novel RHD allele was found and almost 90% were caused by alleles of the weak D type 4 cluster, of which 88% represented the weak D type 4.0 allele. Based on established RH haplotypes for variant RHD and RHCE alleles and the lack of adverse clinical reports, we recommend D positive transfusions for patients with weak D type 4.0 in Tunisia.

Introduction

Rh, encoded by the RHD and RHCE genes, is the most complex and polymorphic blood group system in humans. Apart from ABO,¹ the D antigen is the most immunogenic and clinically significant blood group antigen. Many alleles cause qualitative and quantitative changes in the expression of the D antigen on red blood cells. As a consequence, this diversity of D variants, such as weak D and partial D, causes variable serologic reactivity with monoclonal anti-Ds. The serologic weak D phenotype occurs in 0.2% to 1% Caucasians,¹ while DAR (weak D type 4.2) alone was found in 1.5% of the individuals in an African Black population.² The human RhesusBase³ lists more than 150 molecular weak D types, with weak D types 1 to 3 representing more than 90% of all weak D types in Caucasians.¹ In 2015, a Work Group determined that pregnant women with a weak D type 1, 2 or 3 are not at risk of forming alloanti-D and can safely be exposed to regular D positive red cells.⁴ However, the Work Group refrained from determining this risk in individuals with weak D types 4.0 or 4.1 until more data becomes available,⁴ because there is a known risk for anti-D alloimmunization in individuals with weak D type 4.2 (DAR). To obtain such data, clinical observations could be gathered in populations with a greater prevalence of such alleles than found in Caucasians.⁵

D antigen variants have been studied at the DNA level in any Arab population since 2009 only, notably in Gaza,⁶ Tunisia,^7–19 Egypt,^20–22 and Libya.²³ The molecular causes of the serologic D negative,^7,9,15,16 weak D^{7,10–13,15–18} and partial D phenotypes^7,10,17–19 have been evaluated in different sets of Tunisian samples ranging from 100 to 2,000 samples each. Similar to Caucasian populations,^24,25 the prevalence of individuals carrying the RHD gene approximated 2.5% among serologically D negative Tunisian individuals^7,15 and 25% among D negative with C+ or E+ antigens.¹⁶ Likewise, the RHD gene deletion (RHD*01N.01) was most common (97.5%), while RHD*Ψ (0.7%) and various RHD-CE-D hybrid alleles (1.1%) were rare, but some weak D types (0.7%), including 2 weak D type 4.0 (0.2%), were also found. However, the most striking difference to any previously studied population was the much greater prevalence of weak D type 4.0 among 1,000 random donors tested using molecular methods,¹² of whom 19 donors carried the weak D type 4.0 allele, all confirmed by RHD sequencing. Hence, the frequency of weak D type 4.0 was 1 in 105 RH haplotypes in Tunisia as compared to 1 in 6,060²⁶ or less in Europe.²⁷

A systematic study was missing for samples with the serologic weak D phenotype routinely found in blood donor and patient testing in Tunisia. We tested a cohort of 13,431 Tunisian blood donations, identified all samples with a serologic weak D phenotype, and sequenced their RHD genes. Characteristic single nucleotide polymorphisms (SNP) were also determined to ascertain the RHCE allele linked to the known RHD allele, thus constituting RH haplotypes.

Materials and Methods

Study subjects

EDTA-anticoagulated whole blood samples from 13,431 random blood donations were collected at the Regional Blood Transfusion Center of Sousse (CRTS) which serves the 4 Gouvernorates Sousse, Monastir, Mahdia and Kairouan of eastern Tunisia between December 2015 and August 2016. Some donors may have donated repeatedly, which is common in previous similar large studies and known to not affect the statistics and conclusions. The study was approved by the Institutional Review Board of the University Hospital Farhat Hached, Sousse, Tunisia (IRB00008931).

Immunohematology

For the D antigen (RH1), we used a monoclonal anti-D reagent (clones P3×61 [IgM], P3×21223B10 [IgM], P3×290 [IgG] and P3×35 [IgG], lot no. AC-125; Biomaghreb, Tunis, Tunisia) and another monoclonal IgG/IgM mixture (lot no. DD1401-y13; Fortress Diagnostics, Antrim, UK). An indirect antiglobulin test was performed in case of negative reactions. For the CEce antigens, we used 1 monoclonal reagent each (all IgM; Bio-Rad, Marnes-la Coquette, France): anti-C (RH2, clone MS24), anti-E (RH3, MS260), anti-c (RH4, MS33) and anti-e (RH5, MS16, MS21, and MS63).

Rh phenotyping was performed in all samples by hemagglutination in 3 techniques (opaline plate, tube, and microtiter plate)²⁸ according to the regulation for blood donor testing in Tunisia (Circular no. 49). A serologic weak D phenotype⁴ was defined by a 2+ or less agglutination strength in any of the 3 methods routinely used (Table S1). A panel of 6 monoclonal anti-D clones LHM76/55 (IgG), LHM77/64 (IgG), LHM70/45 (IgG), LHM59/19 (IgG), LHM169/80 (IgG), and LDM1 (IgM) was used in antiglobulin technique (rabbit polyspecific anti-IgG and monoclonal anti-C3d, clone C139-9) with gel cards (ID-Partial RhD-Typing Set, Bio-Rad).

Red cell genotyping

The RHD gene was sequenced in all samples with serologic weak D phenotype and the RHCE gene in select samples as described previously.^27,29 The nucleotide sequences of all 10 exons as well as the adjacent intronic regions including the 5′ and 3′ untranslated regions (UTR) were determined. Zygosity testing for the RHD gene was done by quantitative fluorescence polymerase chain reaction (QF-PCR) using RHD intron 4²⁴ and RHCE exon 7 (two-copy internal control) as described previously.³⁰ For screening of the RHCE gene, characteristic SNPs were determined (RHCE BeadChip Kit, BioArray Solutions),³¹ which cannot detect RHCE*ceAG recently described in African Americans.³² Nucleotide sequences were aligned and compared to reference sequences as described previously.³³

When sequencing of RHD exons 5 or 6 or both failed in 5 samples – there was no amplification because of presumably low DNA quality – we were, however, able to confirm the positions 602 (T201R) and 667 (F223V) by PCR-SSP^12,18 and assigned weak D type 4.0: No possible alternative RHD allele was known for 2 samples; while weak D type 4.3, weak D type 4.0.1, and RHD(T201R,F223V,G307R)³ could not be ruled out in 3 samples, such alleles that are rare in Caucasian have never been observed in Tunisia.

Statistics

The 95% confidence interval (CI) for allele frequencies was calculated based on the Poisson distribution using a web resource. The DVII allele frequency in Southwestern Germany was calculated from the observed phenotype frequency.³⁴ RH haplotype frequencies are known for Tunisia³⁵ and Germany.³⁶ A 2-sided Chi-Square test was performed to compare the DVII allele frequency distributions between 2 populations.^19,34

Nomenclature

The RHCE*ce(48C, 105T, 733G, 744C, 1025T), as observed in Tunisia¹² and France,³⁷ differs by 2 silent SNPs from the ceTI type 2.^38,39 Per ISBT Working Group on Red Cell Immunogenetics and Blood Group Terminology, alternative names for this RHCE allele are ceTI type 2.01, RHCE*01.20.04.01, RHCE*ce.20.04.01, and RHCE*ceVS.04.01.

Results

Using blood center routine methods, we screened 13,431 blood donations in Tunisia for the D antigen, 11,974 of whom were found D positive (89.15%) and 1,390 D negative (10.35%). The serologic weak D phenotype was observed in 67 distinct donors (0.50%). They were sorted based on the anti-D agglutination strength in the 3 routine techniques, and 47 of them were also tested with a panel of 6 monoclonal anti-D reagents (Table S1). Despite multiple serologic routine methods were applied, a discrimination of D variant was impossible by serology alone.

RHD alleles

We determined the full length RHD coding sequence in all 67 samples (Table 1). Among them, 60 carried an allele of the weak D type 4 cluster (89.6%), of which 53 samples (88.3%) showed the weak D type 4.0 allele. We deposited 3 representative alleles (GenBank accession no. KY075647 to KY075649) including 106 nucleotides of the 5′ UTR and at least 126 nucleotides of the 3′ UTR for a total of at least 5,019 nucleotides of RHD gene (Table 1). Only 1 sample each was found for the weak D types 1, 3 and 100 and the DVII, while 3 samples showed the consensus RHD sequence, all compatible with published GenBank data (Table 1).

Table 1.

RHD alleles found among donors with a serologic weak D phenotype

RHD allele	Donors observed			RHD allele frequency in the population corrected for RH haplotype frequency ^*		Comment

	n	Rh phenotype	RH haplotype	Estimate	95% CI	ISBT terminology	GenBank
Weak D type 4 cluster	60
weak D type 4.0	53	ccDee ^†	cDe	1:193 ^‡	n.a. ^‡	RHD^*09.03.01	KY075648
weak D type 4.2.2	6	ccDee ^†	cDe	1:1,710 ^‡	n.a. ^‡	RHD^*09.01.02	KY075647
weak D type 4.1	1	ccDee	cDe	1:10,260 ^‡	n.a. ^‡	RHD^*09.04	KY075649
Other weak D types	3
weak D type 1	1	CcDee	CDe	1:12,838	1:3,718 – 1:43,417	RHD^*01W.1	AJ428455
weak D type 3	1	CcDee	CDe	1:12,838	1:3,718 – 1:43,417	RHD^*01W.3	KF680198
weak D type 100	1	ccDee	cDe	1:10,260	1:3,718 – 1:43,417	RHD^*01W.100	LC053443
Other RHD alleles	4
DVII	1	CcDee	CDe	1:12,838 ^‡	n.a. ^‡	RHD^*07.01	KC515380
RHD consensus	3	CcDee ^†	n/a	n.a.	n.a.	RHD^*01	NG_007494.1
Total	67

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Corrected for the RH haplotype frequency and RHD allele variants masked by normal D positive RHD alleles in trans.

^†

2 of the 53 donors were CcDee, 1 of the 6 donors was compound heterozygous for weak D type 4.2.2/RHD*Ψ, and 2 of the 3 donors CCDee.

^‡

The DVII frequency is known to be much greater (see Table S2), as most carriers of DVII occur among D positive donors and do not present a serologic weak D phenotype. To a smaller extent, this caveat also applies to alleles of the weak D type 4 cluster. For instance, the frequency of weak D type 4.0 is actually 1:105, as determined by PCR in random donors.¹²

n.a. – applicable

Comparing allele frequencies with previous Tunisian cohorts

The weak D type 4.0 was the most prevalent molecular weak D type in Tunisians, confirming our previously published data.¹² Comparing our current data (Table 2), we concluded that only approximately 69% of all Tunisian donors expressing the weak D type 4.0 phenotype (53 out of a calculated 77) were actually typed as having a serologic weak D phenotype. Also, many weak D type 4.0, even if recognized among the serologic weak D phenotypes, were considered D positive for transfusion purposes according to the current routine serology standards in Tunisia (Table S1). Without molecular data, at least 1 weak D type 4.2 carrier would have been assigned as D positive for transfusions (Table S1).

Table 2.

Prevalence of Tunisian individuals expressing the weak D type 4.0 phenotype ^*

Parameter	Number of donors	Frequency as published		References and calculations

		Rate	Fraction
Donors (all)	13,431	n/a	n/a	This study
RhD antigen negative RH haplotypes	n/a	0.3021	1 : 3.31	cde = 0.284, Cde = 0.018, cdE = 0.0001 ³⁶
Weak D type 4.0 positive RH haplotypes	n/a	0.0095	1 : 105.26	2,000/19 = 105.26 ^†¹²
Donors with weak D type 4.0 phenotype ^*
Expected (calculated)	77	n/a	n/a	13,431 × (0.3021 × 0.0095) × 2 = 77.25 ^‡
Observed (RHD sequence confirmed)	53	n/a	n/a	This study

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These individuals must be hemizygous for an RH haplotype with a functional RHD allele on 1 chromosome (i.e., no functional RHD allele on the other chromosome).

^†

Among 1,000 random donors, including RhD negative donors and representing 2,000 RH haplotypes, a total of 19 donors were found carrying a weak D type 4.0 allele.¹²

^‡

The frequency of an RhD antigen negative RH haplotype paired with the weak D type 4.0 positive RH haplotype must be multiplied by 2, because this haplotype combination can occur in 2 ways for the pair of chromosomes in a given donor.

RHCE alleles

All 67 samples were tested for characteristic SNPs by a DNA bead platform. The RHCE exons 1, 5 and 7, harboring diagnostic SNPs, were sequenced in all 53 weak D type 4.0 samples and included in the GenBank submissions (KY075647 to KY075649), indicating the RH haplotypes. We tabulated the concordance between distinct RHD alleles and distinct RHCE alleles along with the frequency of RH haplotypes formed by such RHD-RHCE linkage disequilibrium in the population (Table 3). All Rh phenotypes (CcDEe) observed were compatible with the prediction derived from red cell genotyping of the involved RHCE alleles.

Table 3.

RHCE alleles linked to RHD alleles (in cis on 1 chromosome)

RHD alleles	Donors observed (n)	RHCE allele linkage		RHCE allele probable or proven in cis to RHD

		RHCE alleles observed	n
Weak D type 4 cluster	60
weak D type 4.0	53	RHCEce + RHCEceVS.04.01	43	RHCEceVS.04.01*
		RHCEce.01 + RHCEceVS.04.01	2	RHCEceVS.04.01*
		RHCECe* + RHCEceVS.04.01*	2	RHCEceVS.04.01*
		RHCEceVS.02 + RHCEceVS.04.01	2	RHCEceVS.04.01*
		RHCEceVS.04.01* + RHCEceVS.04.01*	2	RHCEceVS.04.01*
		RHCEce* + RHCEceVS.02* or RHCEce.01* + RHCEceVS.01*	1	RHCEce*
		RHCEce + RHCEce	1	RHCEce*
weak D type 4.1	1	RHCEce* + RHCEceVS.02*	1	RHCEceVS.02*
weak D type 4.2.2	5	RHCEce + RHCEceAR	5	RHCEceAR*
weak D type 4.2.2/RHDΨ*	1	RHCEce.01 + RHCEceAR	1	RHCEceAR*
Other weak D types	3
weak D type 1	1	RHCECe + RHCEce	1	RHCECe*
weak D type 3	1	RHCECe + RHCEce	1	RHCECe*
weak D type 100	1	RHCEce + RHCEce	1	RHCEce*
Other RHD alleles	4
RHD consensus	3	RHCECe + RHCECe	2	RHCECe*
		RHCECe + RHCEce	1	RHCECe*
DVII	1	RHCECe + RHCEce	1	RHCECe*
Total	67		67

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DVII alleles

The greatest prevalance of DVII alleles had been reported in the German population. Comparing published data (Table S2),^19,34,36 we found that the DVII allele may be more common in the Tunisian (0.4%) than the German population (0.13%). This difference was statistically significant (p<0.001, χ²=19.94, 2-sided).

Discussion

The prevalences of the common weak D types 1, 2, 3, 4, 5 and 11 alleles had been tested moleculary among 2,000 random blood donors in Tunisia including D positive and D negative individuals.¹⁸ Here we identified all samples with a serologic weak D phenotype in a cohort of 13,431 Tunisian blood donations, sequenced their RHD genes and established the RH haplotypes. The study was designed to obtain data on weak D type 4.0 in a population known to harbor the greatest prevalence of such allele worldwide.^12,18 Recently, a Work Group⁴ identified the need for more data for weak D types 4.0 or 4.1,⁴ the topic of this research.

Only 2 samples found by our screen for the serologic weak D phenotype represented weak D types 1 and 3 (Table 1), which are much more common in Caucasians. Because we performed molecular genotyping only in cases with serologic weak D phenotype, the true prevalence of D variants in the Tunisian population certainly exceeds 0.50%. An estimated 24 out of 77 Tunisian individuals (31%, Table 2) expressing the weak D type 4.0 phenotype have routinely been typed as D positive, and would eventually be transfused with D positive blood and not receive RhIG in case of pregnancies. No adverse clinical effect has been documented in Tunisia, except 1 observation of an auto-anti-D.¹³

Alloanti-D immunizations have not been observed in weak D types 1, 2, and 3; therefore, carriers of these alleles may safely be transfused with D positive blood.^4,40,41 There is a consensus that pregnant women and recipients of blood transfusions expressing the weak D type 4.2 (DAR phenotype) should be managed as D negative and require anti-D prophylaxis.^2,40 A recent Work Group refrained from a recommendation of how to manage weak D type 4.0 in the US,⁴ although a D positive strategy was recommended in Europe⁴¹ and has been recently adopted for Tunisia.¹⁸ The weak D type 4.0 has been associated with low-titer anti-D, often difficult to distinguish between auto- and allo-anti-D. In a recent summary, only 1 of 16 observations was confirmed as allo-anti-D⁴ in France,⁴² and no additional examples have been published since.

Based on our previous studies¹² and the current data (Table 2), along with the lack of any observed substantial adverse clinical effect,¹³ we conclude that patients and pregnant women in Tunisia expressing weak D type 4.0 phenotype should be treated as D positive and should not be exposed to RhIG, from which these women or their babies cannot be expected to benefit clinically. We propose this strategy as a pragmatic clinical decision in the light of current evidence. If eventually a rare allo-anti-D immunization should occur, a revised strategy may be considered in Tunisia, depending on the frequency, the clinical relevance and the cost to detect and manage weak D type 4.0 with D negative transfusions. Molecular matching studies may determine in the future a clinical significance of some seemingly innocuous protein mismatches even if no allo- or auto-antibody formation would ever occur. Cellular mechanisms might also be involved, and dry matching would forestall such potential, currently hypothetical, clinical issues. There remains a need to monitor, wherever possible, whether patients expressing the weak D type 4.0 phenotype would incur allo-anti-D or other detrimental clinical effects, because our current strategy is based on today’s absence of evidence.

The molecular analysis of the RHCE gene showed that 59 out of 67 samples with serologic weak D phenotype (88.06%) had a variant RHCE allele and the most common associations were: weak D type 4.0 linked to RHCE*ceVS.04.01; and weak D type 4.2.2 with ceAR (Table 3). A previous study conducted in Tunisian¹² and French populations,³⁷ showed that weak D type 4.0 is predominantly cis-associated with RHCE*ceVS.04.01 with rates of 100% and 87%, respectively. Although we frequently found weak D type 4.0 associated with RHCE*ceVS.04.01, the combination of weak D type 4.0 with RHCE*ceVS.02 was more prevalent in the Brazilian study (63.4%).⁴³ Hence, the associated RHCE alleles differed to some extent depending on the population studied.

There is a possibility that the RHCE*ceVS.04.01 allele, typically associated in Tunisian individuals (Table 3), may protect from allo-anti-D immunization, while other RHCE alleles, such as the RHCE*ce more often associated in individuals of other ethnic groups, may not. This conjecture, supported by not much evidence, would need corroboration by experimental and clinical data before it could be used to guide clinical recommendations.

The weak D type 100 observed in our study was associated with an RHCE*ce allele (Table 3) while it had previously been reported with an RHCE*Ce allele.⁴⁴ The serologic weak D phenotype in 3 samples (Table 1) without any RHD coding exon mutation may be explained by the suppressive effect of the RHCE*Ce allele in trans. We observed only 1 donor with a DVII allele among the serologic weak D phenotypes, while the DVII allele was shown to be more common (Table S2) in the Tunisian (0.4%)¹⁹ than even the German population (0.13%).³⁴ Similar to weak D type 4.0, most DVII were likely typed as normal D, not having a serologic weak D phenotype. We regularly and unknowingly transfuse most patients carrying the DVII, a partial D, with D positive blood.⁴⁵ No precautions to detect DVII have ever been mandated, although D negative transfusions would be recommended in any patient, especially women of childbearing age, known to express DVII, as carriers of this partial D can make anti-D. The study exemplified that D variants cannot reliably be discriminated with serologic methods (Table S1)^46–48 using samples from the Arab population, which has been characterized by serology and molecular techniques before (see Supplement).^49–53

No novel RHD allele was found in our study among 67 donors with the serologic weak D phenotype. We conclude that the molecular description of RHD alleles may have become rather complete, even for complex and variable alleles, such as represented by the RHD alleles constituting the weak D type 4 cluster.⁵⁴ While weak D type 4.0 is the most prevalent weak D type in Tunisia (Table 1),¹² data from Egypt documented weak D type 4.2 as most prevalent.^20,21 Hence, exploring the distribution of RHD alleles remains incomplete for many populations and may yield interesting clinical clues for current questions,⁴ as demonstrated by weak D type 4.0 in this study.

Supplementary Material

Table S1-S2

Table S1. Serologic results for 67 samples with a Serologic weak D phenotype among 13.431 Tunisian blood donor sauries*

Table S2. DVII allele frequency in Tunisian and German blood donors

NIHMS928723-supplement-Table_S1-S2.pdf^{(374.7KB, pdf)}

Acknowledgments

We are grateful to the Tunisian blood donors who contributed their blood samples for this study. We thank Harvey Gordon Klein and Franz Friedrich Wagner for critical review of the manuscript. The authors acknowledge Batoul Houissa, Saida Abdelkefi and Taher Chakroun for expert technical assistance; Sharon Dolores Adams for sample coordination; the staff of the HLA laboratory for DNA extraction; and Elizabeth Jane Furlong for English edits.

This work was supported by the Intramural Research Program (project ID Z99 CL999999) of the NIH Clinical Center, the Centre Regional de Transfusion Sanguine Sousse (CRTS grant UR12SP26) and a Fulbright Visiting Scholar Program (grant no. 68150490) to M.O. since October 2015.

Footnotes

Conflict of interest disclosure: WAF is inventor of patents for RHD genotyping owned by German Red Cross Blood Service Baden-Württemberg – Hessen. The remaining authors declared having no competing financial interest relevant to this article.

Statement of Disclaimer: The views expressed do not necessarily represent the view of the National Institutes of Health, the Department of Health and Human Services, or the U.S. Federal Government.

Authorship contribution: SJY collected the samples and coordinated the blood donor study; MO and HR performed the serologic testing; and MO, HR and SJY analysed the serologic data. MO and KS performed the molecular testing; and MO, KS and WAF analyzed the molecular data. SJY and WAF contributed tools, methods and essential reagents. MO wrote drafts and WAF the manuscript.

Web Resource

Pezzullo, J.C., Merser, S., Miller, B., Weiner, K: StatPages.Org. Exact Binomial and Poisson Confidence Intervals. (statpages.info/confint.html)Hassine, M et al. Manuel Des Procedures De Gestion Du Sang Etde Ses Derives. 2010, Tunis, Tunisia. (www.santetunisie.rns.tn/fr/images/articles/manuels/Manuel_procedures_sang_V2.pdf)Kacem, M PhD Thesis, 2013 (www.theses.fr/2013AIXM5093/abes)²⁸

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1-S2

Table S1. Serologic results for 67 samples with a Serologic weak D phenotype among 13.431 Tunisian blood donor sauries*

Table S2. DVII allele frequency in Tunisian and German blood donors

NIHMS928723-supplement-Table_S1-S2.pdf^{(374.7KB, pdf)}

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[R16] 16.Moussa H, Tsochandaridis M, Kacem N, Chakroun T, Abdelkefi S, Gabert J, Levy A, Jemni Yacoub S. RHD positive among C/E+ and D-negative blood donors in Tunisia. Transfus Clin Biol. 2014;21:320–3. doi: 10.1016/j.tracli.2014.10.004. [DOI] [PubMed] [Google Scholar]

[R17] 17.Kacem N, Jemni-Yacoub S, Chiaroni J, Bailly P, Silvy M. Paternal RHD zygosity determination in Tunisians: evaluation of three molecular tests. Blood Transfus. 2015;13:59–65. doi: 10.2450/2014.0308-13. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R18] 18.Ouchari M, Romdhane H, Chakroun T, Abdelkefi S, Houissa B, Hmida S, Yacoub SJ. Weak D in the Tunisian population. Blood Transfus. 2015;13:295–301. doi: 10.2450/2014.0073-14. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R19] 19.Ouchari M, Romdhane H, Abdelkefi S, Houissa B, Chakroun T, Hmida S, Jemni Yacoub S. Occurrence of partial RhD alleles in the Tunisian population. Transfus Med. 2015;25:426–7. doi: 10.1111/tme.12254. [DOI] [PubMed] [Google Scholar]

[R20] 20.Hussein E, Teruya J. Weak D types in the Egyptian population. Am J Clin Pathol. 2013;139:806–11. doi: 10.1309/AJCP1T9FGZBHIQET. [DOI] [PubMed] [Google Scholar]

[R21] 21.Abdelrazik AM, Elshafie SM, Ezzat Ahmed GM, Abdelaziz HM. Combining serology and molecular typing of weak D role in improving D typing strategy in Egypt. Transfusion. 2013;53:2940–4. doi: 10.1111/trf.12100. [DOI] [PubMed] [Google Scholar]

[R22] 22.Hussein E, Teruya J. Serologic findings of RhD alleles in Egyptians and their clinical implications. Transfus Apher Sci. 2014;51:184–7. doi: 10.1016/j.transci.2014.08.014. [DOI] [PubMed] [Google Scholar]

[R23] 23.Silvy M, Beley S, Peyrard T, Ouchari M, Abdelkefi S, Jemni Yacoub S, Chiaroni J, Bailly P. Short duplication within the RHCE gene associated with an in cis deleted RHD causing a Rhnull amorph phenotype in an immunized pregnant woman with anti-Rh29. Transfusion. 2015;55:1407–10. doi: 10.1111/trf.12937. [DOI] [PubMed] [Google Scholar]

[R24] 24.Wagner FF, Frohmajer A, Flegel WA. RHD positive haplotypes in D negative Europeans. BMC Genet. 2001;2:10. doi: 10.1186/1471-2156-2-10. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R25] 25.Gassner C, Doescher A, Drnovsek TD, Rozman P, Eicher NI, Legler TJ, Lukin S, Garritsen H, Kleinrath T, Egger B, Ehling R, Körmöczi GF, Kilga-Nogler S, Schoenitzer D, Petershofen EK. Presence of RHD in serologically D-, C/E+ individuals: a European multicenter study. Transfusion. 2005;45:527–38. doi: 10.1111/j.0041-1132.2004.04211.x. [DOI] [PubMed] [Google Scholar]

[R26] 26.Yu X, Wagner FF, Witter B, Flegel WA. Outliers in RhD membrane integration are explained by variant RH haplotypes. Transfusion. 2006;46:1343–51. doi: 10.1111/j.1537-2995.2006.00902.x. [DOI] [PubMed] [Google Scholar]

[R27] 27.Wagner FF, Gassner C, Müller TH, Schönitzer D, Schunter F, Flegel WA. Molecular basis of weak D phenotypes. Blood. 1999;93:385–93. [PubMed] [Google Scholar]

[R28] 28.Kacem N. Détermination de la zygotie du gène RHD dans la population tunisienne: impacts des polymorphismes des “boîtes Rhésus” dans la pertinence des analyses moléculaires. Monastir, Tunisia: Aix-Marseille Université-France and Université de Monastir-Tunisie; 2013. pp. 50–1. [Google Scholar]

[R29] 29.Fasano RM, Monaco A, Meier ER, Pary P, Lee-Stroka AH, Otridge J, Klein HG, Marincola FM, Kamani NR, Luban NL, Stroncek D, Flegel WA. RH genotyping in a sickle cell disease patient contributing to hematopoietic stem cell transplantation donor selection and management. Blood. 2010;116:2836–8. doi: 10.1182/blood-2010-04-279372. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R30] 30.Pirelli KJ, Pietz BC, Johnson ST, Pinder HL, Bellissimo DB. Molecular determination of RHD zygosity: predicting risk of hemolytic disease of the fetus and newborn related to anti-D. Prenat Diagn. 2010;30:1207–12. doi: 10.1002/pd.2652. [DOI] [PubMed] [Google Scholar]

[R31] 31.Sippert E, Fujita CR, Machado D, Guelsin G, Gaspardi AC, Pellegrino J, Jr, Gilli S, Saad SS, Castilho L. Variant RH alleles and Rh immunisation in patients with sickle cell disease. Blood Transfus. 2015;13:72–7. doi: 10.2450/2014.0324-13. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R32] 32.Westhoff CM, Vege S, Hipsky CH, Horn T, Hue-Roye K, Keller J, Velliquette R, Lomas-Francis C, Chou ST, Reid ME. RHCE*ceAG (254C>G, Ala85Gly) is prevalent in blacks, encodes a partial ce-phenotype, and is associated with discordant RHD zygosity. Transfusion. 2015;55:2624–32. doi: 10.1111/trf.13225. [DOI] [PubMed] [Google Scholar]

[R33] 33.Srivastava K, Polin H, Sheldon SL, Wagner FF, Grabmer C, Gabriel C, Denomme GA, Flegel WA. The DAU cluster: a comparative analysis of 18 RHD alleles, some forming partial D antigens. Transfusion. 2016;56:2520–31. doi: 10.1111/trf.13739. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R34] 34.von Zabern I, Wagner FF, Moulds JM, Moulds JJ, Flegel WA. D category IV: a group of clinically relevant and phylogenetically diverse partial D. Transfusion. 2013;53:2960–73. doi: 10.1111/trf.12145. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R35] 35.Hmida S, Karrat F, Mojaat N, Dahri R, Boukef K. Rhesus system polymorphism in the Tunisian population. Rev Fr Transfus Hemobiol. 1993;36:191–6. doi: 10.1016/s1140-4639(05)80233-3. [DOI] [PubMed] [Google Scholar]

[R36] 36.Wagner FF, Kasulke D, Kerowgan M, Flegel WA. Frequencies of the blood groups ABO, Rhesus, D category VI, Kell, and of clinically relevant high-frequency antigens in South-Western Germany. Infusionsther Transfusionsmed. 1995;22:285–90. doi: 10.1159/000223144. [DOI] [PubMed] [Google Scholar]

[R37] 37.Fichou Y, Marechal CL, Ferec C. The RHD*weak D type 4.0 allele is predominantly but not exclusively cis-associated with the altered RHCE*ce(c.48C, c.105T, c.733G, c.744C, c. 1025T) allele in the French population. Transfus Med. 2014;24:120–2. doi: 10.1111/tme.12100. [DOI] [PubMed] [Google Scholar]

[R38] 38.Ba A, Beley S, Chiaroni J, Bailly P, Silvy M. RH diversity in Mali: characterization of a new haplotype RHD*DIVa/RHCE*ceTI(D2) Transfusion. 2015;55:1423–31. doi: 10.1111/trf.13109. [DOI] [PubMed] [Google Scholar]

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PERMALINK

Transfusion strategy for weak D type 4.0 based on RHD alleles and RH haplotypes in Tunisia

Mouna Ouchari

Kshitij Srivastava

Houda Romdhane

Saloua Jemni Yacoub

Willy Albert Flegel

Abstract

Background

Study design and methods

Results

Conclusions

Introduction

Materials and Methods

Study subjects

Immunohematology

Red cell genotyping

Statistics

Nomenclature

Results

RHD alleles

Table 1.

Comparing allele frequencies with previous Tunisian cohorts

Table 2.

RHCE alleles

Table 3.

DVII alleles

Discussion

Supplementary Material

Acknowledgments

Footnotes

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Transfusion strategy for weak D type 4.0 based on RHD alleles and RH haplotypes in Tunisia

Mouna Ouchari

Kshitij Srivastava

Houda Romdhane

Saloua Jemni Yacoub

Willy Albert Flegel

Abstract

Background

Study design and methods

Results

Conclusions

Introduction

Materials and Methods

Study subjects

Immunohematology

Red cell genotyping

Statistics

Nomenclature

Results

RHD alleles

Table 1.

Comparing allele frequencies with previous Tunisian cohorts

Table 2.

RHCE alleles

Table 3.

DVII alleles

Discussion

Supplementary Material

Acknowledgments

Footnotes

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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