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:
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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Received April 5, 2004Accepted June 4, 2004
346 Colah et al.
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