The role of antithrombin III in

neonatal sepsis
Dr. dr. Novie Amelia Chozie Sp.A (K)
Dr. dr. Pustika Amalia Wahidiyat Sp.A (K)

Division of Hematology-Oncology
Department of Child Health
Cipto Mangunkusumo Hospital
Faculty of Medicine Universitas Indonesia
The proportional cause distribution of neonatal death
(WHO, 2000-2013, data from 194 countries)
: early period (0-6 days)

: late period (7-27 days)

https://www.who.int/bulletin/volumes/93/1/14-139790/en/
 Coagulation activation in sepsis

Iba T, Gando S, Thachil J. Anticoagulant therapy for sepsis-associated disseminated intravascular coagulation: the view from Japan. J Thromb Haemost 2014; 12:
DIC

Rajagopal R, et al. Arch Dis Child 2016;0:1–7

 Diagnosis of DIC in neonates
Typical haemorrhagic features of DIC
▸ Bleeding venepuncture sites
▸ Oozing of blood from indwelling catheters
▸ Spontaneous or minimal trauma-related
generalised ecchymoses
▸ Development of large, bullous haemorrhagic
skin lesions on previous viral exanthematous
sites
▸ Mucosal bleeding from gingiva, gastrointestinal
or renal tracts
▸ Unexpected and major bleeding around drain
sites or surgical wounds postsurgery in
postoperative states
Typical thrombotic features of DIC
▸ Thrombophlebitis at unusual sites
▸ Renal impairment in the absence of other
explanations
▸ Fluctuating central nervous system disturbances
like confusion, and seizures—consistent with
the microcirculatory ischaemia
▸ Respiratory distress syndrome with no obvious
explanation
▸ Dermal infarcts and skin necrosis
▸ Greyish discolouration of finger tips, toes or ear
lobes, which has been termed ‘acral cyanosis’;
usually seen in extreme cases
Rajagopal R, et al. Arch Dis Child 2016;0:1–7.
 Diagnosis of DIC in neonates
• Laboratory results
Indicators Abnormalities Problems in children
Platelet ↓ Difficult phlebotomy  platelet
count aggregation  platelet ↓
PT/aPTT ↑ Depend on the citrate anticoagulant
concentration, Hct concentration
INR ↑ Normal value for neonates is not
available
Fibrinogen ↓ Acute phase reactant

D-dimer ↑ Acute phase reactant

Rajagopal R, et al. Arch Dis Child. 2017;102(2):187-93.

DIC score to predict significant bleeding and thrombosis events
International Society of Thrombosis and Haemostasis (ISTH)
Step 1: Risk assessment Does the patient have underlying diseases that cause Yes  use this scoring
DIC? No do not use this scoring

Step 2: Order lab Platelet, PT, fibrinogen, D-dimer or fibrin degradation products (FDP)

Step 3: Count the total score Platelet

>100.000 /µL 0
50.000 – 100.000 /µL 1
<50.000 /µL 2
An increase of d-dimer or other FDPs
No increase (< 2 times up of upper limit of normal level/ULN) 0
Mild increase (2-4 times ULN) 2
High increase (>4 times ULN) 3

PT prolongation
<3 seconds 0
3-6 seconds 1
> 6 seconds 2
Fibrinogen
≥1 g/L 0
<1 g/L 1
Total score ≥ 5 – Overt DIC Repeat the lab every day
<5 – DIC diagnosis is doubtful Repeat the lab every 1-2 days
Kutny MA, Rajpurkar M, Alonzo TA, et al. Evaluation of ISTH DIC score to predict significant bleeding and thrombosis events in pediatric acute promyelocytic leukemia: a report from the
Children’s Oncology Group AAML0631 Trial. Blood. 2014.
The main principle of treating DIC in neonatal sepsis
• Eliminate the underlying causes of sepsis
• Identify the microorganism (culture, PCR, other tools)
• Antimicrobe sensitivity test
• Use broad spectrum antimicrobe while waiting for the result of microorganism
identification
• Give appropriate treatment based on the clinical condition

Thrombosis Bleeding
Anticoagulant that directly Coagulation factors
act on sepsis mediator and platelet
Developmental hemostasis

(Jaffray et al, Pediatr Clin N Am 2013, 60, 1407-1417)

The balance between thrombogenic and antithrombogenic
Thrombogenic Antithrombogenic

Vascular:
• Disrupted endothelial layer Vascular:
• TF • Heparin
• Collagen • Thrombomodulin
Circulation: • Tissue plasminogen activator
• Platelet
• Fibrinogen Circulation:
The levels
• Prothrombin • Antithrombin
decrease in • Plasminogen
• Coagulation factor
sepsis • Protein C dan protein S
• vWF

Thrombosis Bleeding
Antithrombin
• A small glycoprotein
produced by the liver
• α-Antithrombin & β-
antithrombin.
• Antithrombin activity is
increased by heparin,
(enhances binding of
to F II & F X)

https://diapharma.com/antithrombin/
 The role of antithrombin III in neonatal sepsis

• Antithrombin is a vitamin K-
independent glycoprotein
• Anticoagulation properties
• Anti-inflammatory properties

Iba T, Saitoh D. Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation. J Intensive Care. 2014;2(1):66
 Antithrombin deficiency in sepsis
: severe sepsis : septic shock
• Multiple mechanism(s) probably
responsible for this deficiency, one
of which:
• Cytokines production (IL-6 and IL-1β)
suppress the AT III synthesis
• The AT III activity has decreased at
the onset of fever

White B, et al. Acquired antithrombin deficiency in sepsis. Br J Haematol. 2001;112: 25-31.

Levi M. Antithrombin in sepsis revisited. Crit Care. 2005;9(6): 624-5.
Use of AT III in sepsis
• AT concentrate has been evaluated in several small clinical
trials in adults showed some beneficial effects :
• improvement of a DIC score
• shortening of the duration of DIC
• improvement in organ function

Intensive Care Med 1998;24(7):663–672

 Kybersept Trial
• RCT high dose AT III in severe sepsis
• n = 2314 patients with severe sepsis
• High-dose AT over 4 days
• No significant effect on mortality at
28 days
• Patients who do not receive any
concomitant heparin in the first 4
days of study have a better response
than patients who receive heparin
• 90-day mortality : 25.4% in non-
heparin group versus 40.0% in
heparin group; p = 0.02
Warren BL, Eid A, Singer P. High-dose antithrombin III in severe sepsis: a randomized controlled trial.
JAMA 2001;286(15):1869-78.
 Time of treatment
• AT III is beneficial for severe sepsis patients only if the diagnosis of DIC
has been confirmed (using ISTH criteria)

Kienast J, Juers M, Wiedermann CJ, et al. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without
disseminated intravascular coagulation. J Thromb Haemost. 2006;4(1):90-7.
 J Thromb Haemost 2016; 14: 518–30.

• Meta-analyses of RCT for anticoagulant therapy in 3 different populations:

(i) overall population with sepsis
(ii) population with sepsis-induced coagulopathy
(iii) population with sepsis-induced DIC

• Survival benefit was observed only in septic DIC population

• Further RCT should focus on specific population with specific DIC

All cause mortality
All study population
mortality

Study population
with DIC
mortality
Bleeding complication
Bleeding risk
• Antithrombin treatment increase the
risk of bleeding 1.52 times greater than
control

• One study in pediatric revealed that

29% of patients who were given AT
treatment had a new or increased
bleeding manifestation

Afshari A, Wettersley J, Brok J, Moller A. Antithrombin III in critically ill

patients: systematic review with meta-analysis and trial sequential
analysis. BMJ. 2007;335(7632):1248-51.
Stockton WM, Padilla-Tolentino E, Ragsdale CE. Antithrombin III doses
R=rounded to available vial sizes in critically Ill pediatric patients. J Pediatr
Pharmacol Ther. 2017;22(1):15-21. Forest plot for bleeding risk
Current recommendations
• The British & Italian versus Japanese guidelines :
opposite recommendations for antithrombin use in septic DIC

• The Scientific Standardization Committee on DIC of the International

Society on Thrombosis Haemostasis (ISTH). Guidance for diagnosis and
treatment of DIC from harmonization of the recommendations from
three guidelines :
antithrombin is ‘potentially recommended, but needs further evidence’.

Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, et al. J Thromb Haemost 2013; 11: 761–7.
AT III in pediatric population
• Safety and efficacy in the pediatric population have not been
well established
• Lack of RCTs antithrombin use in neonatal sepsis
• Remember: plasma level of AT III is lower in neonates than
adults, approximately 60% in normal term infants and much
lower in preterm infants
• Always check the AT III levels/activity (%) before administer
AT therapy
Dose of AT III for pediatric
• Dosage forms and strengths • For venous-occlusive disease,
• 1 vial contains 500 IU / 1000 IU
some centers give AT III with
dose of 30-100 IU/kg for 2-16
• Dosage and administration days, depending on the clinical
• Intravenous infusion over 10-20 minutes improvement
• Loading dose: • Some centers also give the AT III
as a continuous infusion, not a
bolus

• Maintenance dose :60% of initial dose (every 24 hours)

• Monitoring AT III levels
• Pre-infusion, 20 minutes post infusion (peak level), and after 12 hours
• Repeated this for each infusion
• Target https://hemonc.org/w/images/4/43/Antithrombiniii.pdf
• AT III level between 80% - 120% Salas CM, Miyares MA. Antithrombin III utilization in a large teaching hospital.
PT. 2013;38(12):764-7.
• Maintain target level for 2-8 days Todd TDR, Myers J, Wells T, Stewart D, Fanning JJ, Sullivan JE. The use of recombinant
antithrombin III in pediatric and neonatal ECMO patients. ASAIO K. 2017;63(1):93-8.
Take home message
• Activation in coagulation during sepsis is an important part of the
host defense mechanisms
• DIC diagnosis must be supported by clinical manifestation and
laboratory results. Use the scoring criteria if you are unsure. Do not
depend only on one parameter.
• The main principle for treating DIC in neonatal sepsis is eliminate the
source of sepsis.
• Antithrombin III is deficient in sepsis; therefore, it increases the risk of
DIC.
• Beneficial effects of antithrombin have to be confirmed in further
prospective RCT, including the right timing and the adequate dose.
Thank you