Haematology Emergency in

Neonatal Critical Care

Why, What & How to Solve?

Muhammad Azharry R.

Neonatology Division - dr. Cipto Mangunkusumo Hospital-FMUI

 Outline

Hematology Emergency

Bleeding Thrombosis
• Anemia • Causes
• Coagulation disorders • Evaluation
• Transfusion and non- • Management
transfusion management
Bleeding

ANEMIA
in Neonates
 Formation Process of RBC
The formation process of RBC since intrauterine

Zivot A et al. Erythropoiesis: insights into pathophysiology and treatments in 2017. Mol Med. 2018;24:11
Bernard G Forget. Progress in understanding the hemoglobin switch. N Engl J Med. 2011;365:853-4
Zivot A et al. Erythropoiesis: insights into pathophysiology and treatments in 2017. Mol Med. 2018;24:11
The shorter lifespan of RBC, the easier it is to lyse (physiological) ->
higher dan faster risk of hyperbilirubinemia

Kuruvila et al. Estimation of adult and neonatal RBC lifespans in anemic neonates using RBCs labeled at several discrete biotin densities. Pediatr Res.2017;81:905-10.
Definition

Clinicians must look at the Hb/Ht trend

as well as the patient’s condition

Ann Rev Med. 1981;32:143–160.

Etiopathogenesis

Neoreviews. 2008 November 1; 9(11): e520

 Physiological
Non-Physiological

O’Brien RT, et al. J Pediatr. 1971;79(1):132-138.

Lopriore E.. Am J Perinatol. 2019;36:S37–S40.
Neoreviews. 2008 November 1; 9(11): e520
 Diagnosis
History (Anamnesis) Clinical Manifestation
Family history Main
• Pale (conjunctiva, skin, soles of feet)
• Chronic anemia is genetic
Advanced
Pregnancy • Shortness of breath
• Infection, medications, trauma/recurrent • Apnea
bleeding, intrauterine growth, gemelli, • Brady-tachycardia (cardiorespiratory
mother with anemia disorders, metabolic acidosis),
During birth • Shock (acute bleeding)
• Antepartum bleeding, labor method Other
Post-partum • Bleeding (skin, intracranial)
• Gestational age, birth weight, infection, • Icteric
• Failure to thrive (chronic)
respiratory assistance, medications,
• Lethargy
types of nutrient given, transfusion • Drinking intolerance
history • Hepatosplenomegaly

Aher S et al. Semin Fetal Neonatal Med. 2008;13(4):239-47.

Diagnostic Evaluation

Aher S et al. Semin Fetal Neonatal PediatrMed. 2008;13(4):239-47.

Lokeshwar MR,et al. Indian J. 2003;70(1):893-902.
NeoReviews 2000;1;e61
Bleeding

COAGULATION
DISORDERS
in Neonates
 Blood Clotting Process

A physiological cascade process Trauma in blood

to stop bleeding at the site of vessels
trauma and initiate the healing
process in blood vessels Vasoconstriction

Involving:
• Blood vessel Blood clots
(temporary)
• Platelets
• Coagulation factor and
fibrinolytic enzyme Blood clots
(permanent)
• Tissue
 Primary Hemostasis Secondary Hemostasis
1o 2o
Vasoconstriction, aggregation, and Activation of coagulation system →
platelet deposition fibrin plug which stabilizes the platelet
→ platelet plug plug
 PT & PTTValue
Normal Reference Value
of Platelets

Reference for Normal Value of Coagulation J Perinatol Off J Calif Perinat Assoc. 2009 Feb;29(2):130–6.
Factors in the First 6 Months of Term Babies Front Pediatr. 2021 Mar 2;9:627715.
Br J Haematol. 2002 Nov;119(2):295–309.
 BLEEDING BLEEDING

Mild Severe Mild Severe

Intervention
Intervention

Stops
Continues
Re-bleeding
Prolonged bleeding
(Delayed bleeding)
Platelet disorders
1o Coagulation factors
20
 Spontaneous Bleeding
(Without Trauma)

Superficial, Multiple Deep, solitary

Petechiae (dry/wet), purpura, Hematoma,

ecchymosis Hemarthrosis

Problem in Platelets Problem in Coagulation Factors

 Diagnosis Approach
Examinations forofNeonatal
BleedingBleeding
in Neonates

Who
Step 1 • Age,
Are gender,
there familyabnormalities?
any platelet history of bleeding, healthy/sick baby
DPL and peripheral blood
Thrombocytopenia or disfunction smear
Bleeding time
• Bleeding onset, bleeding clinical history, comorbidities, trauma history (at
When
Step 2 birth)
Are thereor surgery,
any medication
coagulation factorsusage in pregnancy
deficiency? PT,or infant period (giving
APTT
vitamin
Factor K atIX,
VII, VIII, birth?)
X, V, XI, Fibrinogen

Are there any

ofspecific blood clotting (mucocutaneous),
disorders? PT, APTT
Step 3 • Location bleeding: superficial internal organs or
Where Vitamin K Deficiency,
muscles, joints liver disease, warfarin Clotting factor content
• Gastrointestinal bleeding (upper/lower), ETT bleeding, hematuria, etc.
Are there any circulating anticoagulants? APTT, TT, Reptilase time
Step 4 Heparin, factor VII/IX antibody, lupus anti-coagulant
• Emergency conditions: shock, shortness of breath, decrease of
consciousness
What
Step 5 Consumption
• Bleeding
Sepsis, trauma,
coagulopathy?
characteristics (prolonged/delayed),
vasculitis, hemolytic uremic
DIC screening: platelet count,
bleeding
blood film,types (petechiae,
PT, APTT, TT,
ecchymosis
syndrome, or hematoma)
liver disease Fibrinogen, anti-thrombin III,
2-anti-trypsin, D-dimer

Hillman et al. Hematology in clinical practice. 4th ed. 2005. p. 326-33.

Causes of Bleeding (Primary Hemostasis Problems)
Thrombocytopenia:
Increased destruction and/or decreased production

Pediatr Ann. 2015 July ; 44(7): e175–e180

Causes of Bleeding (Secondary Hemostasis Problems)
VKDB (vitamin K deficiency bleeding)
APCD (acquired prothrombin complex
deficiency)
• Causes of intracranial hemorrhage <1 year:
• High pitch cry
• Decrease of consciousness
• Bulging fontanel
• Pale without any other source of bleeding

Davenport P and Sola-Visner M. Hemostatic Challenges in Neonates. Front. Pediatr. 2021;9:627715

 Neonatal Hemofilia

• Rarely noticed in neonatal period

• Baby boy, extensive delayed
bleeding and difficult to resolve
due to trauma at birth (atypical)
• Community: hematoma on vitamin
K injection and/or hepatitis B
vaccine
• Identify family factors (create
pedigree chart)
Comparison of Bleeding Diseases in Neonates
based on Laboratory Examinations

Davenport P and Sola-Visner M. Hemostatic Challenges in Neonates. Front. Pediatr. 2021;9:627715

Bleeding

TRANSFUSION &
NON-TRANSFUSION
MANAGEMENT
 Management of Anemia

Principles of
Management
• Adequate oxygenation
(according to cardiorespiratory
clinical manifestation)
• Adequate nutrition and fluid
• Selective RBC transfusion
(top-up)
• Supplementation (if indicated)
 Blood Transfusion
The process of administering blood or blood components from one person to another

Benefit
• life saving
• Improve oxygenation & homeostasis
• return blood volume

Risk
• Infection transmission
• Acute/delayed reaction

Sahu S, Hemlata, Verma A. Adverse events related to blood transfusion. Indian J Anaesth. 2014;58(5):543–51.
Blood Product Transfusion
Whole
blood

Platelet Packed red

concentrate cell

Transfusion

Fresh
Cryoprecipit
Frozen
ate
Plasma
RBC Transfusion
RBC Transfusion Indications
Clinical symptoms of anemia

• Looks pale, desaturated, bradycardia/tachycardia

Clinical symptoms of severe anemia

• Apnea, hypotension, acidosis

Evident clinical bleeding

Other clinical symptoms

• Lethargy, inadequate weight gain, increased episodes of apnea

Von Lindern et al. BMC Pediatrics 2021, 11:4

 RBC Transfusion

• Generic risks (transfusion of incorrect

• increasing circulatory hemoglobin
blood due to errors, or transfusion-
• improving tissue oxygenation
related reactions)
• reducing the cardiac output to maintain
• Increasing concern regarding
the same level of oxygenation
associations with IVH, BPD, ROP, NEC

• Dose of 10-15 mL/kg BW/day if Hb ≥6 g/dL

• Dose of 5 mL/kg BW/day if Hb ≤5 g/dL in the first hour, followed by the rest of the
blood transfusion in the next 2-3 hours
• The formula for calculating PRC needs: (Hb target – current Hb) x Body weight x 4

Clarke G, Charge S. Clinical guide to transfusion medicine. Canadian Blood Services; 2019
 RBC Transfusion

Liberal Restrictive
• Transfusion is carried out if • Transfusion is carried out
Hemoglobin is ≤10 g/dL if Hemoglobin is ≤6 g/dL
• Hemoglobin target is ≥11 • Hemoglobin target is ≥8-
g/dL 10 g/dL

• Until now, there are no restrictions on the use of liberal or restrictive

transfusion criteria
• Consideration to do RBC transfusion based on clinical symptoms and
clinician’s consideration

Clarke G, Charge S. Clinical guide to transfusion medicine. Canadian Blood Services; 2019
 Hemoglobin
Hemoglobin ConcentrationLimits
HematocritConcentration
Concentration Limitsfor
Limits
for Giving
Giving
forPRC PRC Transfusion
Transfusion
Giving PRC (Term)
(Premature)
Transfusion
Condition Hb (g/dL)

Infant respiratory distress syndrome - severe <13

Infant respiratory distress syndrome - moderate <10

Congenital heart disease <13

Operation <10

Symptomatic anemia <8

➢ Infusion rate of 2 mL/kg/hour in neonates with cardiac abnormalities

➢ Infusion rate of 10 mL/kg/hour in neonates without cardiac abnormalities

Neonatology 2021;114:7–16
KirpalaniH, Whyte RK, J Pediatr2020; 149: 301-7.
 Whole Blood vs PRC Transfusion

• Advantages:
• Suitable for acute bleeding conditions BW (kg) x Hb
Whole • Easy to prepare increase target
Blood • Disadvantages: (g/dL) x 6
• Risk of overload because the volume is greater than PRC

• Advantages:
• Smaller volume BW (kg) x Hb
PRC • Contains less plasma increase target
• Disadvantages: (g/dL) x 4
• Contains much less coagulation factors than WB

Clarke G, Charge S. Clinical guide to transfusion medicine. Canadian Blood Services; 2019
Platelet Transfusion
Platelet Transfusion Indications
• Thrombocytopenia with or without clinical symptoms of
bleeding
• Prophylaxis
Transfusion of platelet concentrate as prophylaxis of
bleeding is not recommended

Dose of 5-10 mL/kg BW

Dose of 10-20 mL/kg BW in severe thrombocytopenia

Every administration of 5 mL/kg BW platelets will

increase platelets by 20.000-60.000/mm3

New HV. Guidelines on transfusion for fetuses, neonates and older children. British Committee for Standards in Hematology; 2019.
 Limits for Platelet Transfusion
Administration
Conditions Platelets (mm3)
Term neonates, without bleeding <30.000
Preterm neonates, without bleeding <25.000
• With bleeding, clinically unstable 30.000-50.000
• BW <1000 g
• IVH grade III/IV
• Coagulopathy
• Surgery (<72 hours)

Surgical procedures with active bleeding 50.000-99.000

Curley A, Stanworth SJ, Willoughby K. RCT Platelet-Transfusion Thresholds in Neonates. N Engl J Med. 2021.
Coagulation Factors Transfusion
Limit Values for Coagulation Factors
Transfusion

Joint United Kingdom (UK) Blood Transfusion (2021). Neonatal Transfusion guidelines.
 Fresh Frozen Plasma (FFP)
• Each unit (200-250 mL)
• All coagulation factors, include
• FVIII (0.6 IU/mL)
• FIX (0.9 IU/mL)
• Fibrinogen 250-300 mg
• Albumin, globulin, protein C, & protein S

Indication
1. APCD
2. DIC with active bleeding
3. Hepatic dysfunction with active bleeding

Dose: 10-15 mL/kg/day

Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee (2019). Neonatal Transfusion guidelines. [online] Transfusionguidelines.org.
 Cryoprecipitate

• Each unit (30-40 mL):

• F VIII (75-80 unit)
• Fibrinogen (150-300 mg)
• vWF (110 unit)

Indication:
• von Willebrand disease, F VIII Def (hemofilia
A) or F XIII Def
• fibrinogen def. with active bleeding, invasife
procedure, trauma, DIC

Doses: 5-10 mL/kg/12 hours

Rch.org.au. (2019). Blood Transfusion : Neonatal Transfusion Recommendations at RCH

 Major bleeding and live threatening

Massive transfusion
• Blood loss of >40% of the total blood
volume (i.e. >30ml/kg) is immediately
life-threatening.

• Serious cardiovascular and neurological

effects
Transfusion Reactions

Delayed
reaction
Acute reaction >24 hours – 30
days
Occurs
immediately or
<24 hours
Reactions that
occur due to
transfusion
administration and
its components

Josephson CD. Neonatal and pediatric transfusion practice. In: Roback JD, Combs MR, Grossman BJ. 2022.
 Transfusion-Related Adverse
Reactions

• Medication error:
• Blood product type error
• Recipient identity error
• Immunological reaction
• Non-immunological
reaction

J Pediatr 2011;158:403–409.
Basavarajegowda A, Plakkal N. Transfusion reactions in neonates and pediatrics: How and why are they different? Asian J Transfus Sci 2023;17:97-102
 Transfusion-Related Adverse
Reactions in Neonates
Because the immunity is still immature, reactions like fever or allergy occur
less frequently
Transfusion-Related Adverse
Reactions in Neonates
Impaired BS stability due to low glycogen and mucosal G-6-
phosphatase reserves
Transfusion Reaction Management

Delaney M et al. Transfusion reactions: prevention, diagnosis, and treatment. The Lancet. 2016;388:2825–36.
 Management of Bleeding
• If the bleeding is active, apply a splint
• In case of 2o hemostasis, consider doing RICE
→Rest-Ice (cold)-Compress-Elevation

• Transfusion according to hemostasis problems

• In special cases
• Vitamin K administration
• Prothrombin complex consentrate

Journal of Perinatology (2016) 36, S29–S34

Cochrane Database of Systematic Reviews 2018, Issue 2. Art. No.: CD008342.
 Vitamin K

• The procedure for administering vitamin K is prophylactic in:

• IM for every newborn baby:
Oral Vs IM ? What about premature babies?
There haven’t been many valid IM Vitamin K can be given:
studies on the use of 2mg • >1000 gram: 0.5 mg
vitamin K tablets given single or • <1000 gram: 0,3 mg/kg BW
multidose in preventing VKDB with the lowest dose of 0,2 mg

• Patients with TPN and long-term use of antibiotics (>2 weeks)

• Cholestasis (2,5-5 mg with minimum of 2x per week)
• Active bleeding with suspected DIC (combination with
transfusion)
 Prothrombin Complex Concentrates
(PCC) for Bleeding?

Doses (based on INR):

• 25 IU/kg (max 2500 IU) -> INR 2-4
• 35 IU/kg (max 3500 IU) -> INR 4-6
• 50 IU/kg (max 5000 IU) -> INR >6

Munlemwo DM, et.al. Prothrombin Complex Concentrates to Treat Coagulation Disturbances: An Overview With a Focus on Use n Infants and Children. Cardiol Res. 2022;13(1):18-26.
 Tranexamic acid

• Consider if bleeding continues after emergency blood

products have been given
• Tranexamic acid is contraindicated if: renal tract bleeding (risk
of obstruction from clots) & intravascular thrombosis in DIC.
• Intravenous tranexamic acid can be given by continuous
infusion or by bolus doses.
• Bolus dosing is 10-15 mg/kg, 8 hourly.
• Oral tranexamic acid doses are 15-20mg/kg 8 hourly.
• For continuous infusion give 15mg/kg tranexamic acid loading dose
(max 1g) over 10 minutes followed by 2mg/kg per hour infusion for 8
hours or until bleeding stops.
Thrombosis

THROMBOSIS
in Neonates
 Causes
Developing coagulation system, need for intensive care (including catheterization),
and comorbid conditions are responsible for the high risk of thrombosis in neonates
compared to older children

Risk factors of neonatal thrombosis:

• Central arterial/venous catheterization (CAVC) -> higher risk if the duration of usage
are longer (≥14 days)
• Sepsis
• Major surgery
• Comorbid conditions (excluding congenital heart disease & congenital nephrotic
syndrome)
• Elevated hematocrit
• Thrombophilia
• Male sex
• Being outborn
• Femoral location

Bhatt MD, Chan AKC. Venous thrombosis in neonates. Faculty Reviews. 2021;10:(20).
 Management
Unfraction
ated
heparin
(UFH)

Anti-
coagulant
drugs
Oral Low-
molecular-
vitamin K
weight
antagonis heparin
ts (VKA) (LMWH)

Monagle P, Newall F. Management of thrombosis in children and neonates: practical use of anticoagulants in children. American Society of Hematology. 2018;1:399-404.
 Unfractionated Heparin (UFH)
Advantages:
• Short half-life
• Rapid onset and offset of action
• Ideal for cardiopulmonary bypass, circuit prophylaxis, procedural prophylaxis (ex. Cardiac
catheterization), and maintaining vascular access patency

Monagle P, Newall F. Management of thrombosis in children and neonates: practical use of anticoagulants in children. American Society of Hematology. 2018;1:399-404.
 Unfractionated Heparin (UFH)
Maintenance UFH doses are age dependent
• Infants (up to 2 months) → 28 U/kg/hour
• Older than 1 year old → 20 U/kg/hour
• Older children → 18 U/kg/hour
Potential side effects:
• Bleeding
• Anaphylaxis
• Osteoporosis

Avoid long-term use (weeks to

months) of UFH

Monagle P, Newall F. Management of thrombosis in children and neonates: practical use of anticoagulants in children. American Society of Hematology. 2018;1:399-404.
Case thrombosis post central line insertion

Clinical and Applied Thrombosis/Hemostasis. 2018;25: 1-7

 Heparinization
protocol in CMH
“We already move to NICU KIARA Building”

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