This document discusses managing anticoagulant and antiplatelet therapy in dengue patients with special medical conditions. It presents three clinical cases: 1) A woman on warfarin for a heart valve replacement who has dengue. 2) A man on dual antiplatelet therapy for stents who has dengue. 3) A pregnant woman at 32 weeks gestation who is admitted for sepsis and develops dengue. The document discusses balancing the risks of bleeding from continuing these medications against the risks of thrombosis if stopping them temporarily. It provides guidance on when it may be safe to withhold or adjust doses based on platelet counts and bleeding risk. Managing these complex cases requires a multidisciplinary

1. Dengue In Special Population
Speaker: Dr Ng Tiang Koi
Infectious Disease Physician
Hospital Tuanku Ja’afar, Seremban

2. Disclaimer
• This slide was prepared for the Webinar Series on COVID-19 session on
12th February 2022, by Dr Ng Tiang Koi, Infectious Disease physician at
Hospital Tuanku Ja’afar, Seremban, Malaysia.
• This is intended to share within healthcare professionals, not for public.
• This webinar is organised by Malaysian Society of Infection Control and
Infectious Diseases (MyICID) & Institute for Clinical Research, NIH in
conjunction of World NTD Day 2022.

3. Contents
1). Anticoagulant in dengue patients with valve replacement, VTE
2). Antiplatelet in dengue patients with cardiovascular diseases on long
term antiplatelet therapy.
3). Dengue patients with pregnancy.

4. Case 1
Ms CCY, 36 years old lady
• Mitral valve replacement for underlying severe mitral stenosis
• Taking warfarin 2mg od, compliant to medication.
• She is complaining of fever, arthralgia, myalgia for 2 days
• Still able to tolerate orally, and ambulate around. No bleeding
• Clinically well. Physical examination unremarkable finding.
• Dengue combo test: NS1 Ag positive, IgM and IgG negative
• FBC: WBC 6 x 103/L, Hb 11 g/dl, HCT 34%, Plt 108 x 109 /L
• INR 2.5 /APTT 42s

5. Case 2 - History
Mr ZA, 62 years old man
• Underlying T2DM, HTN, BPH and IHD (2 vessels disease)
• Stented with DES 3 months ago
• Taking DAPT (aspirin 100mg /glycine 45mg 1 tab od and clopidogrel
75mg od), metformin, insulin, atorvastatin, bisoprolol, telmisartan,
prazosin.
• Presented with 4 days of fever, dizziness and lethargy, associated with
sore throat and cough during first 2 days of fever.
• No signs and symptoms of bleeding.

6. Case 2 – Clinical finding and investigations
Conscious and alert
Tachypnoeic RR 22
BP 169/78 mmHg PR 106 bpm Temp 37.5 0C SpO2 96% @ Room air
Capillary glucose 16 mmol/L
Pulse volume good, warm peripheries, CRT <2s
Lungs reduce air entry right base
Abdomen soft, tender at epigastric region, no palpable organomegaly
FBC: wbc 3.1 x 103/L / Hb 15g/dl / HCT 46.6 % / Plt 68 x 109 /L
pH: 7.4/PCO2: 33 / PO2: 90/ HCO3-: 18.9/ Lac 2.5
Dengue combo test: NS1 Ag and IgG Positive , IgM Negative

7. Crossroad of clinical management
• When to bridge anticoagulant ?
• When to stop anticoagulant / antiplatelet ?
• When to re-initiate anticoagulant /antiplatelet if stopped ?

8. Anticoagulant /Antiplatelet in Dengue Patients
• There are limited available evidence and no guideline on how to manage
anticoagulant in dengue patients with prosthetic valves or venous
thromboembolism (VTE), and antiplatelet in dengue patients with
cardiovascular disease that required mono or dual antiplatelet therapy
(DAPT).
• The risks of bleeding need to be balanced against the risks of thrombosis from
temporary withhold anticoagulant or antiplatelet. Hence, the case
management is case to case basis, based on expert opinion from various
managing team with extrapolated evidence from non dengue patients.
• However, thrombocytopenia, platelet dysfunction and coagulopathies in
dengue fever are dynamics.

9. Safe platelet cut off for anticoagulant ?
Tufano et al. Seminars in Thrombosis and hemostasis 2011. Apr;37(3):267-74
Mild/moderate thrombocytopenia (> 50,000/mL) should not interfere
with VTE prevention decisions. In severe thrombocytopenia,
prophylaxis should be considered on an individual basis.

10. Safe platelet cut off for anticoagulant ?
• In acute and non acute VTE, the panel suggests safe anticoagulation with
LMWH at therapeutic doses for PLT between ≥50 and < 100×109 /L and
at 50% dose reduction for PLT ≥30 <50 ×109 /L.
Blood Transfus 2019; 17: 171-80 DOI 10.2450/2018.0143-18

11. • Retrospective cohort study of adult dengue patients on antiplatelet therapy for
ischaemic heart disease or stroke. Decision on continuation or discontinuation
of antiplatelet therapy was made on clinical grounds, in discussion with the
patients, by the attending physician
• Primary outcome: composite outcome of major adverse cardiac and
cerebrovascular events (MACCE), and all-cause mortality in-hospital and for 1-
year post discharge.
• Secondary outcomes: platelet and blood transfusion, and occurrence of dengue
haemorrhagic fever (DHF), dengue shock syndrome, dengue with warning signs
and severe dengue according to WHO criteria.

12. Result
• 66 patients (15 were continued antiplatelet therapy)
• 40 patients (61%) were on antiplatelet therapy for ischemic heart disease, 25
patients (38%) for ischemic stroke and 1 patient for both conditions. (*11
patients had PCI with coronary stent)
• Patients who were continued on antiplatelet therapy had a higher median
Charlson’s comorbidity index at 6 (IQR: 3-7) vs 4 (IQR: 2-5), higher median
platelet nadir at 60 000/µL (IQR: 23 000-131 000/µL) vs 27 000/µL (IQR: 13
000-47 000/µL) for those whose antiplatelet therapy were discontinued.
• 5 patients developed non-fatal ischemic stroke (among 2/15 who continued,
3/51 who discontinued antiplatelet. No patient had coronary artery stent
thrombosis or major cardiac events.
• Discontinuation of antiplatelet therapy did not result in higher composite
outcome (p=0.192). Continuation of antiplatelet therapy did not result in
more platelet or blood transfusion (p=0.489 and p=0.567 respectively), DHF
(p=0.923).
• Author suggested that discontinuation or continuation of antiplatelet therapy
based on clinical judgement in dengue with thrombocytopenia, is largely safe
but further studies are needed.

13. Safety Evidence Of Antiplatelet Interruption
Cochrane Database of Systematic Reviews 2018, Issue 7. Art. No.: CD012584.
DOI: 10.1002/14651858.CD012584.pub2.

14. All Cause Mortality (Up to 30 days)

15. All Cause Mortality (Up to 6 months)

16. Risk Of Ischaemic Events (within 30 days)

17. Safety Of Antiplatelet Interruption
• Plasma half-life of aspirin is only 20 minutes.
• However, the effects of aspirin may last up to ≈10 days (life span of platelet),
because platelets cannot generate new COX. After a single dose of aspirin,
platelet COX activity recovers by ≈10% per day as a function of platelet
turnover. Although it may takes 10 days to restore normal COX activity when
total platelet population is renewed, it has been shown that if as little as 20%
of platelets have normal COX activity, hemostasis may be normal*.
• Marrow suppression +/- peripheral destruction of platelet causing
thrombocytopenia in dengue fever and platelet dysfunction may prolonged
the effect of aspirin.
*Eric H. Awtry and Joseph Loscalzo. Circulation. 2000;101:1206–1218

18. Situations to consider :
• Significant bleeding
• Phase of dengue fever
• Presence of warning signs /severe dengue
• Platelet trend
• Risk of thrombosis
• Risk of bleeding
Multi-disciplinary team approach, always discuss and make decision
together with patient and/or family.
Approach To Anticoagulant / Antiplatelet In DF

19. With Significant Bleeding
• Stop the anticoagulant or antiplatelet
• Antidote if available ( Vit K for warfarin, Idarucizumab for Dabigatrand)
• Fresh Frozen Plasma (FFP) or Prothrombin Complex Concentrate (PCC)
• Platelet Concentrate and/or Packed cell or Whole Blood transfusion
• Stabilise the haemodynamic

20. Without Significant Bleeding
• Withhold anticoagulant /antiplatelet in DF with any of following:
A). Severe Dengue
B). Platelet < 50 x 109/L
• Consider withhold anticoagulant / antiplatelet in DF in febrile phase with warning
signs or platelet reducing trend to between 50 -100 x 109/L, especially in those with
high risk of bleeding, but relatively lower thrombosis risk.
• If anticoagulant needed for dengue patients with high risk of thrombosis but
relatively low risk of bleeding, switch DOAC/ Warfarin (VKA) to LMWH/
Conventional heparin infusion when INR subtherapeutic if platelet 50 -100 x 109/L
or even earlier with platelet > 100 x 109/L in febrile phase.
• Multi-disciplinary team management with cardiologist, haematologist,
intensivist/anaesthetist, patient and patient’s family for decision making.

21. Clinical Course Of Dengue Fever
Muhammad Zaman Khan Assir 2011

22. Re-initiate Anticoagulant/ Antiplatelet
• Generally, anticoagulant or antiplatelet can be resumed once dengue
patient in recovery phase and platelet improving trend to ≥ 50 x 109/L,
unless any specific contra-indication.

23. Case 3
28-year-old G1P0 at 32w 6d
• Referred from private for sepsis.
• Presented with only high grade fever for 1 day, without other
specific symptoms.
• BP on arrival 90/60mmHg , pulse 106 bpm T 370C (taken PCM)
• FBC: Hb 12.9/hct 38.3/plt 250/wbc 13.9
• Given 2 pints NS bolus in Casualty à Repeated BP 100/66mmHg
• Followed by drip I pint NS / 2 hours (~3mls/kg/hr)

24. 22/2
0132 0856
23/2
0628 1800 2240
24/2
0356
Hb (g/dl) 12 11.1 10.8 10.2 11.0 11.5
HCT (%) 34.5 31.5 28.9 30.0 30.8 32.6
Plt (x109 /L) 229 182 182 127 75 65
Wcc (103 /L) 12.08 9.10 8.89 7.4 7.09 6.91
AST/ALT 95/56
HCO3- 18 16 16 15 14 14
Lactate 1.0 0.8 0.9 1.2 1.6 1.6
peripheries warm Warm warm warm warm warm
CRT <2s <2s <2s <2s <2s <2s
Temp ( 0C) 37 37 38 38 38 37.5
BP (mmHg) 90/60 100/66 98/64 100/60 96/58 98/60
Pulse/
volume
106/
good
104/
good
118/
good
120/
good
126/
good
120/
good
symptoms nil nil nil dyspnoe dyspnoe
IO 6122/1120 6752/2260
*Dengue NS1 +ve

25. Progress of patient
24/2
0517 0815
Fluid was stopped and
pt was transferred to ICU
for NIPPV
Hb 11.6 11.9
HCt 32.5 34.5
Plt 53 55
Wcc 7.44 7.97
Ast/alt 106/62
HCO3 14
Lactate 1.4
peripheries Warm warm
CRT <2s <2s
BP 100/58 102/64
Pulse/volume 110/good 106/good
IO +9L

26. Physiological changes in pregnancy
Dilutional anaemia
}Expansion of blood volume (~1.5L) with relatively lesser
increment of red blood cell from the maternal
erythropoietin drive, cause Hb and Hct levels drop during
pregnancy.
Thrombocytopenia
}Hemodilution, increase consumption and aggregation
cause thrombocytopenia in 7-8% of all pregnancies,
occur usually during 2nd half of pregnancy.

27. Physiological changes in pregnancy (Cardio)
Variable Change
Cardiac output (CO) Increased by 30–50%
Stroke volume (SV) Increases to a maximum of 85 mL at
20 weeks of gestation
Heart rate (HR) Increased (~90–100 bpm at rest during
3rd trimester)
Systemic vascular resistances Decrease 21% (nadir at 20–24 weeks)
Pulmonary vascular resistances Decrease by 34%
Pulmonary capillary wedge
pressure
No significant change
Colloid osmotic pressure Decreased by 14%
Hemoglobin concentration Decreased
CPG Management of Dengue Infection in Adults (3rd Edition)

28. Physiological changes in pregnancy (Resp)
Antonella LoMauro et al. Breathe 2015 11: 297-301 Hegewald et al. clinic in chest meds 32.1 (2011): 1-13
Blood gases
Resp alkalosis with compensated metabolic acidosis in third trimester
pH: 7.4-7.45, PaCO2: 28-31mmHg, PaO2: 101-105mmHg, HCO3-: 18-21

29. Maternal Outcome
CPG Management of Dengue Infection in Adults (3rd Edition)
} Higher percentage of severe dengue infection occurred among pregnant
women compared to non-pregnant
} Significant bleeding due to thrombocytopenia is not common.
} Increased risk for haemorrhage in the presence of dengue shock
syndrome (DSS).
•Machado CR, Machado ES, Denis Rohloff R, et al. Is Pregnancy Associated with Severe Dengue? A Review of Data from the Rio de Janeiro
Surveillance Information System. PLoS Negl Trop Dis. 2013;7(5):5–8.
•Adam I, Jumaa AM, Elbashir HM, et al. Maternal and perinatal outcomes of dengue in PortSudan, Eastern Sudan. Virol J. 2010;7:153.
•Pouliot SH, Xiong X, Harville E, et al. Maternal dengue and pregnancy outcomes: a systematic review. Obstet Gynecol Surv. 2010;65(2):107–18.

30. • 6071 pregnant women, 292 were exposed to dengue during pregnancy.
• Miscarriage OR 3·51 (95% CI 1·15–10·77, I²=0·0%, p=0·765)
• Stillbirth crude relative 6·7 (95% CI 2·1–21·3)
• Preterm birth OR 1·71 (95% CI 1·06–2·76, I²=56·1%, p=0·058)
• Low birth weight OR 1·41 (95% CI 0·90–2·21, I²=0·0%, p=0·543)
Pregnancy Outcome
Lancet Infect Dis. July 2016.

31. • 14 from 1048 studies that identified were included.
• Risk of adverse fetal outcomes from maternal DENV infection with a pooled RR of
0.96 (95% CI: 0.85–1.09, I2 = 49.6%) for premature birth, RR of 0.99 (95%CI: 0.87–
1.12, I2 = 35.1%) for low birth weight, OR of 1.77 (95% CI: 0.99–3.15, I2 = 17.5%) for
miscarriage and RR of 3.42 (95% CI: 0.76–15.49, I2= 54.8%) for stillbirth.
• Subgroup analysis of studies in symptomatic participants still did not indicate DENV
infection appeared to be a risk factor for premature birth, low birth weight and
miscarriage as well.
Pregnancy Outcome

32. Delivery
CPG Management of Dengue Infection in Adults (3rd Edition)
} Dengue infection is not an indication for elective delivery.
} Majority of patients can be allowed to progress to spontaneous vaginal delivery.
} Premature labour occurs during the acute infection. It is advisable to delay the delivery until
acute infection resolve with tocolytic (nifedipine, atosiban) if indicated and appropriate by
Obstetrician.
•Chitra TV, Panicker S. Maternal and fetal outcome of dengue fever in pregnancy. J Vector Borne Dis. 2011;48(4):210–3.
•Kariyawasam S, Senanayake H. Dengue infections during pregnancy: Case series from a tertiary care hospital in Sri Lanka. J Infect Dev Ctries. 2010;4(11):767–75.
• Close fetal monitoring is required in this group of patients to detect fetal distress and decision for
delivery can be made
• All pregnant mothers with dengue should be co-managed in hospitals by physician, anaesthetist
and obstetrician.

33. Delivery
CPG Management of Dengue Infection in Adults (3rd Edition)

34. Summary (Anticoagulant/ Antiplatelet in DF)
• No clear guideline available on the management of anticoagulant and
antiplatelet in patients with dengue fever.
• Risks of bleeding need to be balanced against the risks of thrombosis.
• Multi-discipline approach is required.

35. Summary (Dengue in pregnancy)
• HCT value in pregnant women is usually lower compared to normal adult due to
physiological haemodilution.
• Dengue infection in pregnancy has a higher risk of developing severe dengue and
mortality.
• Dengue infection in pregnancy has a higher adverse fetal outcome.
• Routine platelet transfusion is not indicated unless there is presence of bleeding
manifestation or patient is planned for operative or instrumental delivery.
• Intramuscular injection must be avoided in pregnant patients with
thrombocytopaenia.

36. Thank you