LETTERS TO THE EDITORS

exercise or school-based exercise, calcium and vitamin D supplementation, and prophylactic factor replacement.

Acknowledgements

References

Wallny TA, Scholz DT, Oldenburg J et al.

Osteoporosis in haemophilia - an underestimated comorbidity? Haemophilia 2007; 13:
7984.
Abdelrazik N, Reda M, El-Ziny M, Rabea H.
Evaluation of bone mineral density in children
with hemophilia: Mansoura University chil-

editorial assistance and for improving the English language used in the
manuscript. We also thank Dr. Bazrafshan, Mrs. Ardeshiri and Ms. Zahedi
for helping in data collection.

Disclosures

This study was supported by the Shiraz Universities of Medical Sciences. We

thank Shirin Parand of the Hematology Research Center, Nemazee Hospital
in Shiraz, and K. Shashok (AuthorAID in the Eastern Mediterranean) for

553

The authors stated that they had no interests which might be perceived
as posing a conflict or bias.

dren hospital (MUCH) experience. Mansoura,

Egypt. Hematology 2007; 12: 4317.
Manco-Johnson MJ, Nuss R, Funk S, Murphy
J. Joint evaluation instruments for children
and adults with haemophilia. Haemophilia
2000; 6: 64957.
Khawaji M, Akesson K, Berntorp E. Longterm prophylaxis in severe haemophilia seems

to preserve bone mineral density. Haemophilia 2009; 15: 2616.

Baroncelli GI, Bertelloni S, Sodini F, Saggese
G. Osteoporosis in children and adolescents:
etiology and management. Paediatr Drugs
2005; 7: 295323.

Dengue virus infection in haemophilic patients: aggravation

of bleeding risk
A. CHUANSUMRIT,* K. TANGNARARATCHAKIT,* N. SIRACHAINAN,* A. KHOSITSETH,* T. KUPTANON,*
S . W A N I T K U N , * W . W I T H U R A W A N I T and D . S O N G D E J *
*Department of Pediatrics, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; and Surgery, Faculty of Medicine, Ramathibodi Hospital,
Mahidol University, Bangkok, Thailand

Dengue infection is one of the most common mosquito-borne viral

diseases of public health significance caused by any of the four dengue
serotypes (dengue 1 to 4) and is expanding globally [1]. Paediatric
patients and young adults including haemophiliacs in dengue virus
endemic areas are particularly at risk. The clinical manifestations of
dengue virus infection vary from the asymptomatic, mild degree of flulike symptoms of dengue fever (DF), to a more severe degree of dengue
haemorrhagic fever (DHF) and a serious condition characterized by
haemorrhage and shock, called dengue shock syndrome. The casefatality rate of patients with dengue infection was extremely high
(13.7%) in 1958 and gradually decreased to 0.17% in 2000 and has
remained unchanged (below 0.2%) during the last decade [2]. In cases
of massive uncontrolled bleeding manifestations, the case-fatality rate
would be higher than in those without serious complications.
The clinical diagnosis of DHF is based on four major characteristic
manifestations [3]: high continuous fever lasting for 27 days; haemorrhagic tendency such as positive tourniquet test, petechiae and
epistaxis; thrombocytopenia (platelet count 100 000 lL)1); and
evidence of plasma leakage due to increased vascular permeability
manifested by haemoconcentration (an increase in haematocrit >20%)
or pleural effusion. The three stages of DHF are, namely, febrile, toxic
and convalescent. The febrile stage lasts 27 days followed by an
abrupt fall to normal or subnormal levels of temperature; the toxic

Correspondence: Prof. Ampaiwan Chuansumrit, MD, Department of

Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University,
Rama VI Road, Bangkok 10400, Thailand.
Tel.: +662 2011748/9; fax: +662 2011748;
e-mail: raajs@mahidol.ac.th
Accepted after revision 14 August 2010
DOI: 10.1111/j.1365-2516.2010.02413.x

 2011 Blackwell Publishing Ltd

stage lasts 2448 h; and finally, rapid clinical recovery without

sequelae in the convalescent stage. The toxic stage is the most critical
period requiring intensive supportive care. Optimal fluid therapy is
essential to maintain vital organ function during the critical period.
The severity of DHF is categorized into four grades [3]: grade 1,
without overt bleeding but positive for the tourniquet test; grade 2,
with clinical bleeding diathesis such as epistaxis and ecchymosis; grade
3, circulatory failure manifested by a rapid, weak pulse and narrowing
pulse pressure (<20 mmHg) or hypotension, with the presence of cold,
clammy skin and restlessness; and grade 4, profound shock in which
pulse and blood pressure are not detected. The current WHO
guidelines do not consider congenital bleeding disorder as a high-risk
condition in patients with suspected dengue infection. Moreover,
virtually no data are available on the incidence and outcome of dengue
infection in people with haemophilia [4].
We report six moderate (n = 4) and severe (n = 2) haemophilic
patients (five haemophilia A, one haemophilia B) with dengue virus
infection. They reported to the physician after having fever for
25 days. Five patients were referred to Ramathibodi Hospital after
being admitted at their hometown hospitals for 36 days. Two patients
were in the febrile stage, while three patients were in the toxic stage.
Their ages ranged from 5 to 16 years. They presented with high fever
for 610 days with lethargy, loss of appetite and bleeding manifestations of petechiae, ecchymosis, epistaxis, and bleeding of the gums,
gastrointestinal tract and thorax as shown in Table 1. All patients were
serologically confirmed as having dengue virus infection by denguespecific IgM and IgG determined using ELISA. Secondary dengue
infection was found in all patients.
Haemoconcentration with increased haematocrit 20% for age was
evidenced in four of five patients with DHF, while the remaining
patient had a low haematocrit of 34% due to massive haemothorax.
Marked elevated alanine aminotransferase (122313 371 U L)1) and
aspartate aminotransferase (1714201 U L)1) indicating acute hepatic

Haemophilia (2011), 17, 538555

Haemophilia (2011), 17, 538555

FIX:C 2.6%

FVIII:C 1%

FVIII:C 1.3%

FVIII:C < 1%

28.0

18.0

16.5

36.0

58.3

D)3

D)5 (day 4 of fever)

D0 refer

D)3 Epistaxis, haemarthrosis at ankle (day 4 of fever)

D0 GI, epistaxis, oral cavity
D0 refer

D)4 Epistaxis

GI
petechiae, epistaxis,
gum & teeth, GI
GI
GI, ecchymosis,
haemothorax
CNS bleeding
D)8 ecchymosis
D)5 petechiae

D)1
D0
D0
D)2
D)1

D)5 (day 2 of fever)

D)4 refer
D)4
(day 2 of fever)
D+1 refer
D)5 (day 5 of fever)
D)1 refer

D)4 (day 2 of fever)

Replacement therapy

Dengue serotype 3

Dengue NS1 positive

Dengue serotype 1

2nd DF

Survived

Diagnosis Outcome

2nd DHF Dead

grade 4

2nd DHF Survived

grade 4

33 days at ward 2nd DHF Survived

grade 3

2nd DHF Survived

grade 1
10 days at ward 2nd DHF Survived
grade 2

8 days at ward

6 days at ward

Hospitalization
(days)

FFP 600 mL Cryoppt 3 units

1 day at ward
Factor VIII concentration
7 days at ICU
1750 units
Platelet concentration 40 units
8 days at ICU
Platelet SD 6 unit PRC 2400 mL
Cryoppt 55 units FFP 3600 mL
Factor VIII concentration 8000 units
rFVIIa 11.1 mg FEIBA 1500 units

Dengue NS1 negative Cryoppt 63 units

Dengue serotype 2
Dengue NS1 positive Factor VIII concentration
500 unit
Not done
Platelet concentration 4 units
PCC 3000 units
Platelet SD 1 units
Not done
PRC 510 mL, cryoppt 141 units
Factor VIII concentration
15 540 units FFP 1000 mL

Day of hospitalization* Dengue virus study

2nd, secondary; GI, gastrointestinal; SD, single donor pheresis; NS1, non-structural protein 1 antigen; Cryoppt, cryoprecipitate; PCC, prothrombin complex concentrate; PRC, packed red cells; FFP, fresh frozen
plasma; DF, dengue fever; DHF, dengue haemorrhagic fever.
*D0 was designated as day of defervescence, 1 or 2 days before defervescence were designated as D)1 and D)2, and 1 or 2 days after defervescence were designated as D+1, D+2, and so on.

5.5

4.8

6.3

10.2

16.1

FVIII:C 3%

D)4 haemarthrosis at
ankle & elbow
D)4 positive tourniquet test

12.8

FVIII:C < 1%

31.0

Age
(years) BW (kg) Onset of bleeding symptoms*

Patients FVIII/FIX

Table 1. Clinical manifestations, management and outcome of the studied patients.

554
LETTERS TO THE EDITORS

 2011 Blackwell Publishing Ltd

LETTERS TO THE EDITORS

involvement were found in three patients, while the remaining patients
had normalized liver profiles. Additional renal failure was found in one
patient with DHF grade 4 exhibiting massive bleeding.
The management included adequate fluid therapy to maintain
effective circulation. Close monitoring of clinical manifestations and
laboratory investigations in the ward or intensive care unit, especially
for patients with DHF grades 3 and 4, was essential for obtaining
favourable outcomes [5]. Treatment included adequate blood component transfusion of fresh frozen plasma, cryoprecipitate and platelet
concentrate to maintain haemostasis and platelet counts of
100 000 lL)1. In addition, factor concentrate infusion was provided
to achieve factor VIII or IX clotting activity at 80100% and
maintained at 4060%. Other medications such as H2 blocker, proton
pump inhibitor, lactulose or local intervention of anterior nasal
packing for those with epistaxis were given, accordingly. Another
constraint was the indicated invasive procedures such as central line
placement. Although it was performed carefully by skilled personnel,
the risk of bleeding was higher than among non-haemophiliacs.
Appropriate blood components were given immediately before the
procedure. In cases where platelet concentrates were not immediately
available, recombinant activated FVII at a dose of 100 lg kg)1 was
alternatively given to one patient with effective response.
The median hospitalization in haemophiliacs of 8 days (interquartile range 7.515.8) was significantly longer than that of 811 nonhaemophiliacs (median 4 days, interquartile range 35) admitted to the
Department of Pediatrics during the same period between 2000 and
2010 (P = 0.0001). One haemophilic patient complicated with haemothorax required pleural tapping to obtain haemolysed blood 7 mL
on D+8 and 30 mL on D+11 (D0 was designated as day of
defervescence, 1 or 2 days before defervescence were designated as
D)1 and D)2 and 1 or 2 days after defervescence were designated as
D+1, D+2, and so on). Due to persistent pleural effusion, intercostal
drainage was performed on D+16 to obtain haemolysed blood of
460 mL and 30 mL on the following day and the intercostal drainage
was off on the third day without reoccurrence of pleural effusion. The
fatal case succumbed to multiorgan failure caused by massive
uncontrolled plasma leakage. He had high haematocrit levels
approaching 51% to 55%, even though he exhibited massive bleeding
from the gastrointestinal tract and nose. He developed acute hepatic
and renal failure, although he received intensive supportive treatment
combined with continuous veno-venous haemofiltration. The case-

References
1

Rigau-Perez JG, Clark GG, Gubler DJ, Reiter

P, Sanders EJ, Vorndam AV. Dengue and
dengue hemorrhagic fever. Lancet 1998; 352:
9717.
Bureau of Epidemiology, Department of Disease Control, Ministry of Public Health. Annual report cases and deaths of suspected
dengue fever and dengue hemorrhagic fever in

 2011 Blackwell Publishing Ltd

555

fatality rate of 16.7% (1/6) tended to be higher than that of nonhaemophiliacs (7/811 = 0.86%) admitted to the Department of Pediatrics during the same period between 2000 and 2010 (P = 0.058). The
case-fatality rate of non-haemophiliacs in our hospital is higher than
that of Thailand Ministry of Public Health as our university hospital is
a referral centre.
In dengue virus endemic areas, people with bleeding disorders such
as haemophilia are also at risk of dengue virus infection. It is essential
to emphasize that people with haemophilia exhibited bleeding manifestations since the early febrile stage. It might be caused by the lack of
factor VIII or IX itself or aggravation of bleeding risk to the
vasculopathy. Moreover, serious bleeding manifestations continued
during the late febrile and toxic stages, where an additional low
platelet counts existed. Adequate fluid therapy and blood component
transfusion combined with factor concentrate to maintain haemostasis,
platelet counts of 100 000 lL)1 and factor VIII or IX clotting activity
of 40100% are the key issues involved in treatment management.
Invasive procedures should be performed by skilled personnel. If the
patients conditions allow, the procedures should be postponed until
the convalescent stage when the platelet counts are normalized.
In conclusion, factors leading to favourable outcomes of dengue
virus infection in haemophiliacs include early recognition of dengue
virus infection, prompt and adequate fluid therapy, effective bleeding
control and close monitoring by the attending physician and medical
personnel. Further study including more data on the incidence
and outcome of haemophiliacs with dengue infection is warranted.
An international registry through the haemophilia network is
needed.

Acknowledgement
This work was supported by the Thailand Research Fund-Senior Research
Scholar 2006 (A.C.) and Mahidol University Grant 2007.

Disclosures
The authors stated that they had no interests which might be perceived as
posing a conflict or bias.

Thailand. Retrieved July, 2010, http://

www.dhf.ddc. moph.go.th/status.htm
World Health Organization. Dengue Hemorrhagic Fever: Guidelines for Diagnosis,
Treatment, Prevention and Control, Geneva:
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tion and Control, 2nd edition. Geneva: WHO,

1997; pp. 1247.
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Haemophilia (2011), 17, 538555