HEMOGLOBIN

Vol. 28, No. 4, pp. 343–346, 2004

SHORT COMMUNICATION

Prenatal Diagnosis in a Family at Risk for b-Thalassemiaand Hemophilia A: An Uncommon Association

Roshan B. Colah,1,* Shrimati D. Shetty,1 Reema R. Surve,1

Supriya P. Phanasgaonkar,1 Anita H. Nadkarni,1 Ajit C. Gorakshakar,1

Kanjaksha Ghosh,1 Sunil J. Parekh,2 and Dipika Mohanty1

1Institute of Immunohaematology, Indian Council of Medical Research (ICMR),

Mumbai, India2Haematology Laboratory, Parekh House, Mumbai, India

ABSTRACT

b-Thalassemia (thal) is an autosomal recessive disorder with a prevalence of 2–3% in

Indians, while hemophilia A is X-linked with a prevalence of 1 in 5,000–10,000 male

births. The chances of both these disorders being present together is extremely rare (1 in

250,000). We report an interesting consanguineous family from Western India with a

combination of these two disorders, which was referred to us for prenatal diagnosis.

Key Words: Prenatal diagnosis; b-Thalassemia; Hemophilia A

b-Thalassemia is an autosomal recessive disorder with a prevalence of 2–3% in

Indians (1), while hemophilia A is X-linked with a prevalence of 1 in 5,000–10,000

male births (2). The chances of both these disorders being present together is extremely

rare (1 in 250,000).

*Correspondence: Dr. Roshan B. Colah, Assistant Director, Institute of Immunohaematology,

Indian Council of Medical Research (ICMR), 13th Floor, New Building, King Edward Memorial

(KEM) Hospital Campus, Parel, Mumbai 400 012, India; Fax: +91-22-24138521; E-mail:

mohanty@bom5.vsnl.net.in.

343

DOI: 10.1081/HEM-200037719 0363-0269 (Print); 1532-432X (Online)

Copyright D 2004 by Marcel Dekker, Inc. www.dekker.com

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We report an interesting consanguineous family from Western India with a

combination of these two disorders referred to us for prenatal diagnosis. Their first

child (a male) was diagnosed with b-thalassemia (thal) major at 8 months of age and

was subsequently transfused every month. At age 2, his gums bled for 5 days after a

fall. Investigations done at that time showed the following data: hemoglobin (Hb)

5.7 g/dL, RBC 2.25 � 1012/L, MCV 78.0 fL, MCH 25.0 pg, MCHC 33.0 g/dL, Hb F

55.9%, Hb A2 3.5%, normoblasts 12/100 WBCs. The coagulation data are shown in

Table 1. He was thus diagnosed as suffering from severe hemophilia A with b-thal

major. Subsequently, he had only one episode of bleeding in the knee, elbow and

gums and was given fresh frozen plasma only once at the age of 2.5 years. This child

died at the age of 6 years. During this long interval he never had any other episode of

bleeding. Their second child (a female) had b-thal trait and was a carrier of hemophilia

A. None of the family members had a history of bleeding.

The index case was also analyzed for the common thrombophilia markers to

evaluate whether any co-inherited thrombotic marker had resulted in the mild

manifestation. The results were as follows: protein C 73% (normal range 70–140%);

protein S 82% (normal range 70–140%); antithrombin III 102% (70–140%); Factor V

Leiden normal.

During a third pregnancy 4 years ago, the couple came to us for prenatal diagnosis.

Chorionic villus sampling (CVS) was done trans abdominally under ultrasound

guidance, and reverse dot-blot hybridization (3) was used to diagnose the b-thal

anomaly. Both parents had the IVS-I-5 (G!C) mutation and the fetus was homozygous

for IVS-I-5 (G!C). Screening for intron 22 inversions of the factor VIII gene (4) was

positive in the index case, the mother, daughter and the CVS sample. Restriction

fragment length polymorphism (RFLP) analysis for hemophilia A (5) was also done,

and showed that the mother was not informative for DXS52 St14 and IVS 19 HindIII

Table 1. Coagulation parameters in the index case and other family members.

Subject Index case Sister Father Mother Normal range

Prothrombin time (sec.) 10.5 11.0 12.0 11.6 10.0–12.0

Activated partial

thromboplastin time (sec.)

110.3 39.5 35.4 38.6 35.0–40.0

Thrombin time (sec.) 14.4 13.4 13.0 13.2 14.0–16.0

Factor XII (%) normal ND ND ND 50.0–150.0

Plasma fibrinogen (mg/dL) 280.0 320.0 300.0 296.0 150.0–450.0

Factor VIII:

coagulant activity (%)

<1.0 53.0 58.0 57.0 50.0–150.0

Factor IX:

coagulant activity (%)

50.0 62.0 76.0 96.0 50.0–150.0

von Willibrand factor

antigen (%)

95.0 102.0 75.0 99.0 50.0–150.0

Ristocetin induced platelet

aggregation (%)

normal normal normal normal 50.0–100.0

Inhibitor screen negative NA NA NA –

ND = not done; NA = not applicable because the APTT of these subjects is within normal limits.

344 Colah et al.

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markers. However, she was informative for the IVS 18 Bcl 1 marker, which also

confirmed these findings. The parents decided to terminate the pregnancy as the male

fetus had b-thal major and hemophilia A.

The couple came back for prenatal diagnosis this year. Chorionic villus sampling

and DNA analysis showed that the fetus had b-thal major [homozygous IVS-I-5

(G!C)]; however, it was a female fetus and unaffected by hemophilia A. The couple

again opted for termination of pregnancy as the fetus was affected with b-thal major.

Co-inheritance of b-thal and hemophilia A is an uncommon association. We only

found two reports in the literature where there was a co-inheritance of thalassemia with

other bleeding disorders. In one study, there was a report of two sisters with multiple

sclerosis, lamellar ichthyosis, b-thal minor and a quantitative deficit of factor VIII-von

Willebrand complex (6), whereas the second was the report of a female presenting with

Wilsons disease with concomitant b-thal and factor V deficiency (7).

There are several reports of mild bleeding diathesis in severe hemophilia patients

due to the co-inheritance of prothrombotic factors, i.e., protein C, protein S,

antithrombin III, factor V Leiden mutation, prothrombin gene polymorphism, etc.

(8–10). There is also strong evidence for the presence of a hypercoagulable state in

both thalassemia and sickle cell anemia due to platelet activation and intravascular

thrombi generation. Biological markers for this could be found, and in particular, a

decreased level of coagulation inhibitors (protein C and protein S) (11–13). There are

also reports of experiments conducted in animal models of congenital hemolytic

anemias, showing that even abnormal RBCs lead to a thrombotic tendency (14). In this

case, several evidences support the hypothesis that b-thal hypercoagulable state may

have balanced the severe hemophilia, resulting in a thrombohemorrhagic balance. Level

of coagulation inhibitors protein C and protein S are in the normal range, whereas they

are decreased in b-thal, and the index case did not require replacement therapy until the

age of 6 except during one episode. In a severe hemophilia patient, the bleeding

complications are likely to be more severe than those reported for this case. In the

absence of other common thrombotic markers such as protein C, protein S,

antithrombin III and factor V Leiden mutation, we feel that co-inheritance of b-thal

major might have contributed to the amelioration, resulting in a thrombohemorrhagic

balance. The rarity of this situation, and the implication of missing a severe hemophilia

diagnosis during prenatal diagnosis of thalassemia in such a family, prompted us to

report this case.

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Prenatal Diagnosis of b-Thal and Hemophilia A 345

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Received April 5, 2004Accepted June 4, 2004

346 Colah et al.

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