Lack of Efficacy of Prophylactic Platelet Transfusion for Severe Thrombocytopenia in Adults with Acute Uncomplicated Dengue Infection

Abstract

Thrombocytopenia in dengue infection raises concerns about bleeding risk. Of 256 patients with dengue infection who developed
thrombocytopenia (platelet count, <20×103 platelets/µL) without prior bleeding, 188 were given platelet transfusion. Subsequent bleeding, platelet increment, and platelet
recovery were similar between patients given transfusion and patients not given transfusion. Prophylactic platelet transfusion
was ineffective in preventing bleeding in adult patients with dengue infection.

Full text

1262 •CID 2009:48 (1 May) •BRIEF REPORT
BRIEF REPORT
Lack of Efficacy of Prophylactic
Platelet Transfusion for Severe
Thrombocytopenia in Adults
with Acute Uncomplicated
Dengue Infection
David C. Lye,
1
Vernon J. Lee,
2,3
Yan Sun,
4
and Yee Sin Leo
1
Departments of
1
Infectious Disease and
2
Clinical Epidemiology, Tan Tock Seng
Hospital,
3
Biodefence Center, Ministry of Defence, and
4
Clinical Project
Management and Planning, National Healthcare Group, Singapore
Thrombocytopenia in dengue infection raises concerns about
bleeding risk. Of 256 patients with dengue infection who
developed thrombocytopenia (platelet count, !
3
20 ⫻10
platelets/mL) without prior bleeding, 188 were given platelet
transfusion. Subsequent bleeding, platelet increment, and
platelet recovery were similar between patients given trans-
fusion and patients not given transfusion. Prophylactic plate-
let transfusion was ineffective in preventing bleeding in adult
patients with dengue infection.
Acute dengue infection is endemic to many tropical countries,
and its incidence is increasing globally [1]. Thrombocytopenia
is common in acute dengue infection [2], and many experi-
mental therapies, including corticosteroid treatment [3] and
intravenous immunoglobulin treatment [4], have been used to
treat severe thrombocytopenia in dengue hemorrhagic fever,
because of the fear of potential bleeding.
Although severe bleeding and coagulopathy occur in dengue
shock syndrome (DSS) [5], the cause is multifactorial [6, 7]
and is not caused by thrombocytopenia alone. Thrombocyto-
penia was not an independent predictor of severe bleeding in
pediatric DSS [8]. Prophylactic transfusion with platelets and
fresh frozen plasma was also not beneficial in pediatric DSS
[9]. Despite this, platelet transfusion was frequently given for
severe thrombocytopenia to adults with acute dengue infection
Received 7 October 2008; accepted 5 January 2009; electronically published 17 March
2009.
D.C.L. and V.J.L. contributed equally to this article.
Reprints or correspondence: Dr. Vernon J. Lee, 42 How Sun Dr., Singapore 538611, Republic
of Singapore (vernonljm@hotmail.com).
Clinical Infectious Diseases 2009; 48:1262–5
2009 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2009/4809-0018$15.00
DOI: 10.1086/597773
in Singapore and Taiwan [2, 10]. We studied the impact of
prophylactic platelet transfusion for severe thrombocytopenia
in a large retrospective cohort of adults with acute dengue.
Methods. We studied all patients with acute dengue in 2004
who were admitted to the Department of Infectious Diseases,
Tan Tock Seng Hospital, Singapore [2]. Only patients who ful-
filled the World Health Organization criteria for acute dengue
(fever and ⭓2 of the following symptoms: headache, eye pain,
myalgia, arthralgia, leukopenia, rash, and bleeding) and who
had results of laboratory diagnostic tests positive for dengue
were included. All cases were classified as dengue fever, dengue
hemorrhagic fever (all 4 criteria present: fever, thrombocyto-
penia [platelet count, !platelets/mL], bleeding man-
3
100 ⫻10
ifestation, and plasma leakage), or DSS [5]. Patients with prob-
able cases had acute dengue with positive results of serological
analysis (Dengue Duo IgM & IgG Rapid Strip Test; Panbio),
and those with confirmed cases had positive results of PCR.
Medical chart review was performed to extract demographic
characteristics, serial clinical and laboratory data, and treatment
and outcome data.
Severe thrombocytopenia was defined as platelet count
!platelets/mL, on the basis of local clinical practice.
3
20 ⫻10
Prophylactic platelet transfusion was defined as platelet trans-
fusion without clinical bleeding, in contrast to therapeutic
platelet transfusion with clinical bleeding. Clinical bleeding ex-
cluded petechiae. We excluded all patients with clinical bleeding
before and on the day that their platelet count decreased to
!platelets/mL. Patients whose platelet count decreased
3
20 ⫻10
to !platelets/mL without clinical bleeding and who
3
20 ⫻10
were given prophylactic platelet transfusion were compared
with those who were not given prophylactic platelet transfusion.
Prophylactic platelet transfusion was given on the basis of a
clinician’s assessment. Outcome measures consisted of clinical
bleeding after prophylactic platelet transfusion, platelet count
increment the day after transfusion, time to platelet count
1platelets/mL, length of hospitalization, and death.
3
50 ⫻10
The x
2
test and Fisher’s exact test were used to compare
categorical variables, and Student’s ttest and the Mann-Whit-
ney Utest were used to compare continuous variables. All
statistical analyses were performed using Stata, version 9.0
(Stata Corp), and tests were conducted with the significance
level at 5%. Corresponding percentages, 5th and 95th percen-
tiles, ORs, and 95% CIs are reported.
Results. In 2004, 1973 patients were admitted to our de-
partment at Tan Tock Seng Hospital who fulfilled the World
Health Organization criteria for acute dengue and who had
Downloaded from https://academic.oup.com/cid/article-abstract/48/9/1262/409226 by guest on 17 September 2019

BRIEF REPORT •CID 2009:48 (1 May) •1263
positive results of laboratory diagnostic tests. Of the cases, 54%
were probable, and 46% were confirmed. There were 1855 pa-
tients with dengue fever and 118 patients with dengue hem-
orrhagic fever; 10 of the patients with dengue hemorrhagic fever
had DSS. Seven patients required admission to the intensive
care unit, and 1 patient died; all 8 of these patients had dengue
hemorrhagic fever.
The median age was 32 years (5th–95th percentiles, 17–57
years), and 64% of patients were male. The median duration
of illness at presentation was 5 days (5th–95th percentiles, 3–
7 days), and the median length of hospital stay was 4 days (5th–
95th percentiles, 2–7 days). At presentation, clinical bleeding
occurred in 220 patients (85% had gum bleeding, 16% had
epistaxis, 5% had menstrual bleeding, and 1% had gastroin-
testinal bleeding). The median platelet count nadir for patients
with dengue fever was platelets/mL (5th–95th percen-
3
51 ⫻10
tiles, platelets/mL), compared with a median of
3
11–97 ⫻10
platelets/mL (5th–95th percentiles, plate-
33
49 ⫻10 9–90 ⫻10
lets/mL) for patients with dengue hemorrhagic fever ( ).
P1.05
Platelet transfusion was given to 249 patients (12.6%) during
hospitalization (either prophylactic or therapeutic platelet trans-
fusion); 61 of these patients received therapeutic transfusion.
Of the 1973 patients, 1666 had a platelet count nadir
1platelets/mL, and 51 patients had bleeding and/or
3
20 ⫻10
received platelet transfusion when the platelet count was
1platelets/mL; these patients were excluded from fur-
3
20 ⫻10
ther analysis. The remaining 256 patients without bleeding
whose platelet count decreased to !platelets/mL were
3
20 ⫻10
included in subsequent analysis, and 188 received prophylactic
platelet transfusion.
The baseline demographic and clinical variables on the day
that the platelet count decreased to !platelets/mL for
3
20 ⫻10
the 256 patients who either were or were not given prophylactic
platelet transfusion are shown in table 1. The median platelet
count for both patients given transfusion and patientsnot given
transfusion was platelets/mL (OR, 1.02; 95% CI, 0.94–
3
15 ⫻10
1.09; ). Patients given transfusion were more likely to
Pp.87
have fever (temperature, 138C), compared with patients not
given transfusion (33% vs. 18%; OR, 2.30; 95% CI, 1.15–4.59;
), and had significantly higher systolic blood pressurePp.02
(OR, 1.03; 95% CI, 1.01–1.06; ) and pulse pressure (OR,Pp.01
1.02; 95% CI, 1.00–1.05; ). The median time from dis-Pp.03
ease onset to hospital admission was 3 days (5th–95th percen-
tiles, 2–6 days) for patients given transfusion, compared with
3 days (5th–95th percentiles, 1–6 days) for patients not given
transfusion ( ). The median time from disease onset toPp.38
platelet count !platelets/mL and platelet transfusion
3
20 ⫻10
was 5 days (5th–95th percentiles, 3–7 days) for patients given
transfusion, compared with 4.5 days (5th–95th percentiles, 3–
8 days) for patients not given transfusion ( ). TherewerePp.94
no other significant demographic or clinical differences between
the 2 groups.
The incidence of clinical bleeding was 6% among pa-
tients with platelet count 1platelets/mL, 12%
3
150 ⫻10
among patients with platelet count of plate-
3
100 –149 ⫻10
lets/mL, 11% among patients with platelet count of
platelets/mL, 10% among patients with platelet
3
80–99 ⫻10
count of platelets/mL, 11% among patients with
3
50–79 ⫻10
platelet count of platelets/mL, 13% among patients
3
20–49 ⫻10
with platelet count of platelets/mL, and 0% among
3
10–19 ⫻10
patients with platelet count !platelets/mL( ,by
3
10 ⫻10 Pp.22
test for trend).
Among patients whose platelet count decreased to
!platelets/mL, prophylactic transfusion was given to
3
20 ⫻10
188 patients at a median of 4 units of platelets (range, 1–12
units). Clinical bleeding subsequently occurred in 1 (0.5%) of
188 patients given prophylactic transfusion (severe gastroin-
testinal bleeding in a patient with known peptic ulcer disease
who died due to disseminated intravascular coagulation and
acute renal failure), compared with 2 (2.9%) of 68 patients not
given transfusion ( ) (both instances of bleeding were
Pp.17
mild and did not require additional intervention). The median
platelet increment on the day after platelet transfusion in pa-
tients given transfusion ( platelets/mL) was lower than
3
7⫻10
the median platelet increment on the day after platelet count
first decreased to !platelets/mL in patients not given
3
20 ⫻10
transfusion ( platelets/mL; OR, 1.00; 95% CI, 0.98–1.01;
3
11 ⫻10
). The median time to platelet count 1plate-
3
Pp.26 50 ⫻10
lets/mL was similar for patients given transfusion and patients
not given transfusion (3 days; OR, 1.05; 95% CI, 0.79–1.39;
). The median length of hospital stay was 6 days for
Pp.59
patients given transfusion, compared with 5 days for patients
not given transfusion ( ). One patient died in the group
Pp.09
given transfusion, compared with none in group not given
transfusion ( ).
Pp1.00
Discussion. Prophylactic platelet transfusion is given be-
cause of the fear of severe bleeding in patients with acute dengue
and thrombocytopenia. Experimental use of corticosteroid
treatment and intravenous immunoglobulin treatment [3, 4]
and the overuse of platelet transfusion [2, 10] have been re-
ported. Platelet transfusion was given to 50.3% of hospitalized
patients with dengue in Taiwan [10] and 12.6% in Singapore
[2]. Only 7 patients in our study had severe bleeding—1 was
in the group given transfusion, and the other 6 had a mean
platelet count of platelets/mL (range,
33
78 ⫻10 23–111 ⫻10
platelets/mL) during the bleeding episode without ever reaching
the platelet count nadir of !platelets/mL. Notably, a
3
20 ⫻10
randomized study showed that intravenous immunoglobulin
treatment did not hasten recovery from thrombocytopenia
among patients with secondary dengue infection [4].
Our study further strengthens the evidence that thrombo-
Downloaded from https://academic.oup.com/cid/article-abstract/48/9/1262/409226 by guest on 17 September 2019

Table 1. Baseline demographic characteristics, clinical and laboratory data on the day the platelet count decreased
to !platelets/mL, and clinical outcomes for patients with acute dengue infection who did or did not receive
3
20 ⫻10
prophylactic platelet transfusion.
Variable
Patients given
platelet transfusion
()np188
Patients not given
platelet transfusion
()np68 P
Demographic characteristics
Age, years 40 (22–64) 39 (22–58) .54
Male sex 144 (77) 45 (66) .11
Dengue diagnosis
Dengue hemorrhagic fever 4 (2) 2 (3) .66
Positive results of PCR 124 (66) 46 (68) .88
Test results positive for IgG 60/86 (70) 24/32 (75) .65
Preexisting medical conditions
Diabetes mellitus 11 (6) 2 (3) .52
Hypertension 18 (10) 5 (7) .80
Hyperlipidemia 9 (5) 1 (1) .30
Ischemic heart disease 0 (0) 0 (0) 1.00
Clinical features
Fever 46 (24) 22 (32) .26
Headache 13 (7) 3 (4) .57
Myalgia/arthralgia 27 (14) 12 (18) .56
Eye pain 1 (1) 0 (0) 1.00
Anorexia 17 (9) 4 (6) .61
Nausea 21 (11) 6 (9) .82
Vomiting 17 (9) 5 (7) .80
Diarrhea 14 (7) 3 (4) .57
Rash 27 (14) 8 (12) .68
Temperature, C 37.5 (36.6–39) 37.2 (36.5–39.4) .09
Temperature ⭓38C 62 (33) 12 (18) .02
Systolic blood pressure, mm Hg 115 (95–140) 110 (95–130) .01
Diastolic blood pressure, mm Hg 70 (50–87) 70 (50–85) .12
Systolic blood pressure !90 mm Hg 0 (0) 1 (1) .27
Pulse pressure, mm Hg 45 (30–70) 40 (30–60) .03
Pulse, beats/min 70 (55–93) 70 (60–94) .84
Pulse !60 beats/min 18 (10) 2 (3) .11
Abdominal tenderness 3 (2) 0 (0) .57
Pleural effusion or ascites 0 (0) 0 (0) 1.00
Laboratory results
Hematocrit, % 45.7 (36.7–52.1) 44.9 (35.4–50.3) .24
Hematocrit ⭓50% 23 (12) 4 (6) .17
Leukocyte count, ⫻10
3
leukocytes/mL 3.4 (1.7–7.2) 3.6 (1.7–8.2) .46
Leukocyte count !leukocytes/mL
3
3.3 ⫻10 86 (46) 26 (38) .32
Platelet count, ⫻10
3
platelets/mL 15 (7–19) 15 (8–19) .87
Clinical outcomes
Any bleeding 1 (1) 2 (3) .17
Platelet increment the next day, ⫻10
3
platelets/mL7(⫺7 to 50) 11 (⫺4 to 41) .26
Time to platelet count ⭓platelets/mL, days
3
50 ⫻10 3 (1–4) 3 (1–5) .59
Length of hospital stay, days 6 (4–8) 5 (4–7) .09
Death 1 (1) 0 (0) 1.00
NOTE. For dichotomous variables, data are no. (%) of patients; for continuous variables, data are median (5th–95th percentiles).
Downloaded from https://academic.oup.com/cid/article-abstract/48/9/1262/409226 by guest on 17 September 2019

BRIEF REPORT •CID 2009:48 (1 May) •1265
cytopenia in acute dengue infection does not correlate with
bleeding risk. In pediatric DSS, thrombocytopenia did not pre-
dict severe bleeding in univariate analysis; the only 2 indepen-
dent predictors of severe bleeding were shock and low hemat-
ocrit [8]. Another prospective pediatric study found that
bleeding score did not correlate with platelet count [11]. Our
large cohort of adults with acute dengue revealed that the in-
cidence of clinical bleeding at hospital admission was inde-
pendent of platelet count.
The efficacy of prophylactic platelet transfusion and the
threshold for transfusion is questionable. In a prospective study
of acute myeloid leukemia, lowering the platelet threshold for
prophylactic platelet transfusion from platelets/mLto
3
20 ⫻10
platelets/mL did not increase the incidence of bleeding
3
10 ⫻10
but significantly reduced the number of patients who received
platelet transfusion [12]. In pediatric DSS, prophylactic trans-
fusion of platelets and fresh frozen plasma did not reduce bleed-
ing or expedite platelet recovery; instead, it caused fluid over-
load and prolonged hospitalization [9]. In addition, the
improvement in platelet count was transient, lasting !5 h [9].
We have shown that prophylactic platelet transfusion did not
improve relevant outcome measures, such as clinical bleeding,
platelet increment, and platelet recovery.
Our study has several limitations. Its retrospective cohort
design does not allow for increased recruitment, and the overall
number of episodes of clinical bleeding was small (3 [1%] of
256 patients). The lack of randomization may have resulted in
treatment bias, although both the transfusion and the non-
transfusion groups had similar baseline features. Our cohort of
patients with platelet count !platelets/mL was limited
3
20 ⫻10
to adult patients and included only 6 patients with dengue
hemorrhagic fever, limiting the generalizability of our findings.
Additional research on the role of prophylactic platelet trans-
fusion in a randomized study with a larger cohort is needed.
Because our results revealed that there were no significant
benefits of prophylactic platelet transfusion among adult pa-
tients with dengue, which are similar to results of other studies
involving different cohorts, we no longer advocate prophylactic
platelet transfusion given on the basis of platelet count for
adults with acute uncomplicated dengue infection. This ap-
proach will save precious blood products and will reduce un-
necessary patient exposure to transfusion risks.
Acknowledgments
Financial support. National Healthcare Group (small innovative grant
SIG/05048); National Medical Research Council (individual research grant
NMRC/1006/2005).
Potential conflicts of interest. All authors: no conflicts.
References
1. World Health Organization. Impact of dengue. Available at: http://
www.who.int/csr/disease/dengue/impact/en/index.html. Accessed 29
September 2008.
2. Lee VJ, Lye DCB, Sun Y, Fernandez G, Ong AK, Leo YS. Predictive
value of simple clinical and laboratory variables for dengue hemor-
rhagic fever in adults. J Clin Virol 2008; 42:34–9.
3. Leong KW, Srinivas P. Corticosteroid-responsive prolonged throm-
bocytopenia following dengue haemorrhagic fever. Med J Malaysia
1993; 48:369–72.
4. Dimaano EM, Saito M, Honda S, et al. Lack of efficacy of high-dose
intravenous immunoglobulin treatment of severe thrombocytopenia
in patients with secondary dengue virus infection. Am J Trop Med
Hyg 2007; 77:1135–8.
5. Dengue haemorrhagic fever: diagnosis, treatment, prevention and con-
trol. 2nd ed. Geneva: World Health Organization, 1997.
6. Hathirat P, Isarangkura P, Srichaikul T, Suvatte V, Mitrakul C. Ab-
normal hemostasis in dengue hemorrhagic fever. Southeast Asian J
Trop Med Public Health 1993;24(Suppl 1):80–5.
7. Wills BA, Oragui EE, Stephens AC, et al. Coagulation abnormalities
in dengue hemorrhagic fever: serial investigations in 167 Vietnamese
children with dengue shock syndrome. Clin Infect Dis 2002;35:277–85.
8. Lum LC, Goh AY, Chan PW, Abdel-Latif ME, Lam SK. Risk factors
for severe hemorrhage in severe dengue infections. J Pediatr 2002; 140:
629–31.
9. Lum LC, Abdel-Latif ME, Goh AY, Chan PW, Lam SK. Preventive
transfusion in dengue shock syndrome—is it necessary? J Pediatr
2003; 143:682–4.
10. Lee MS, Hwang KP, Chen TC, Lu PL, Chen TP. Clinical characteristics
of dengue and dengue hemorrhagic fever in a medical center of south-
ern Taiwan during the 2002 epidemic. J Microbiol Immunol Infect
2006; 39:121–9.
11. Krishnamurti C, Kalayanarooj S, Cutting MA, et al. Mechanisms of
hemorrhage in dengue without circulatory collapse. Am J Trop Med
Hyg 2001; 65:840–7.
12. Wandt H, Frank M, Ehninger G, et al. Safety and cost effectiveness of
a10⫻10
9
/L trigger for prophylactic platelet transfusions compared with
the traditional 20⫻10
9
/L trigger: a prospective comparative trial in 105
patients with acute myeloid leukemia. Blood 1998; 91:3601–6.
Downloaded from https://academic.oup.com/cid/article-abstract/48/9/1262/409226 by guest on 17 September 2019