Approach to bleeding neonate siddarth mahajan

1. APPROACH TO BLEEDING NEONATE
Dr. Siddharth Mahajan
Moderator: Dr. Pradeep Pazare/ Dr. Girish Nanoti

2. Introduction
• The normal range for the new-born prothrombin (PT)and
partial thromboplastin time (PTTK) extend above than those
for a healthy adult.
• But there is NO increased risk of bleeding in a healthy
newborn.
• Platelet counts is the same as the normal range for the adult
(150,000–400,000/mm3).
• Bleeding disorders may present during the neonatal period but
several factors make it difficult to establish a diagnosis.
• Therefore evaluation of the neonatal haemostasis system, with
the intention of identifying bleeding diathesis, should be
performed similarly to any other clinical problem in the
neonatal period.
Manno CS. Management of bleeding disorders in children. Hematology Am Soc Hematol Educ Program. 2005:416-
22.

3. Neonatal haemostatic system- how is
it different?
• At birth, concentrations of the vitamin K dependent (FII,
FVII, FIX, FX) and factors (FXI, FXII) are reduced to about
50% of normal adult values and are further reduced in
preterm infants (Hemorrhagic Disease of Newborn).
• Concentrations of the naturally occurring
anticoagulants, antithrombin, protein C, and protein S,
are low at birth and as a consequence, both thrombin
generation and thrombin inhibition are reduced in the
newborn period.
• Plasminogen is also low in neonatal period resulting in a
relatively hypofibrinolytic state.
Andrew M et al. Development of the haemostatic system in the neonate and young infant. J
Pediatr Hematol Oncol1990;12:95–104.

4. • Despite this there seems to be relatively few clinical
bleeding problems for the healthy term infant.
• The haemostatic system matures after birth reaching
adult values by 6 months of age.
• Platelet count is within the normal adult range in both
term and preterm infants but are hyporeactive
compared with adult platelets.
• Despite this bleeding time is shortened in neonates
owing to increased concentrations of von Willebrand
factor (vWF) and high neonatal packed cell volume.

5. Causes of Bleeding
• Coagulation defects
• Platelet Quantitative/ Qualitative defects
• Fibrinolytic dysfunction
• Vascular causes
• Miscellaneous

6. Clinical approach to the bleeding neonate:
1. Was the baby sick or well at the onset of
bleeding?
2. Was Vit K given to the baby?
3. Is the bleeding generalized or localized?
4. Is there a family history of bleeding/ coagulation
defects?
5. Is there a h/o maternal thrombocytopenia,
connective tissue disease, PIH or intake of
barbiturates, phenytoin, aspirin, rifampin, INH
or warfarin?

7. Cont..
6. What was the age of onset of bleeding?
7. Is the bleeding petechial with small mucosal
hemorrhages or are the bleeds deep/ large?
8. Are the coexisting signs like conjugated
hyperbilirubinemia, organomegaly, signs of
sepsis?

8. Fibrin polymer
Negatively charged activator
IX
IXa
XI XIa
X Xa
XII XIIa
Tissue Injury
Tissue Factor
Thromboplastin
VIIa VII
X
Prothrombin Thrombin
Fibrinogen Fribrin monomer
XIIIa
Intrinsic Pathway [PTTK] Extrinsic Pathway [PT]
Factors affected
By Heparin
Vit. K dependent Factors
Affected by Oral Anticoagulants
IX
HMWK
HMWK- High Molecular
Weight Kininogen
Ca++ Ca++
Ca++
VIIIaVIII

9. Normal Coagulation parameters in
Healthy Term and Preterm Infants
Coagulation Test Full term infant Premature infant Older child
Platelets 150,000 – 400,000 150,000 – 400,000 150,000 – 400,000
PT 10.1 – 15.9 10.6 – 16.2 10.6 – 11.4
PTTK 31.3 – 54.5 27.5 – 79.4 24 – 36
TT 19 – 28.3 19.2 – 30.4 19.8 – 31.2
Fibrinogen 167 – 399 150 – 373 170 – 405
Fibrin degradation
products
<10 <10 <10
Factor VIII 0.50 – 1.78 0.50 – 2.13 0.59 – 1.42
Factor IX 0.15 – 0.91 0.19 – 0.65 0.47 – 1.04
vW factor 0.50 – 2.87 0.78 – 2.10 0.60 1.20
Klaus & Fanoroff’s - Care of the High Risk Neonate

10. Screening Tests
• Complete blood count
• Peripheral smear: Platelet size/morphology
• PT and aPTT
Thrombocytopenia?
Yes No
Prolonged PT and aPTT?
1. DIC
2. Sepsis
1. ITP
2. Bone marrow
hypoplasia
3. Occult infection
4. Thrombosis
PT and aPTT?
1. Giant Platelet-
ITP & bernard soulier
2. Microthrombocytes-
Wiscott Aldrich Syn.
Hb for underlying
bleed
Yes No

11. No Thrombocytopenia
With PT& aPTT?
Abnormal Normal
1. Factor XIII deficiency
2. Von Willebrand disease
(except Type 2b)
3. Platelet function disorder
4. Vascular disorders
1. Early liver disease
2. Factor VII deficiency
3. Warfarin
Abnormal PT and normal aPTT
Normal PT and abnormal aPTT
1. Factor VIII, IX, XI deficiency
2. Moderate to severe VWD Abnormal PT and aPTT
Liver disease Vitamin K deficiency
DIC Deficiency of fact or II, X or V

12. Likely diagnosisPTTKPTPlatelets
Clinical
Evaluation
DICSick
Sepsis, NECNN
Liver diseaseN
Stress bleedNNN
IT, occult infection, thrombosis, B.M.
hypoplasia or infilterationNNHealthy
Hemorrhagic disease of newborn ( vit. K
deficiency )N
Hereditary clotting factor deficiencies
(Hemoplilia A/B, VWD)
NN
Bleeding due to local factor ( trauma,
anatomic anomalies); Factor XIII
deficiency
NNN
PT = prothrombin time; PTT = partial thromboplastin time; = decreased; = increased; DIC =
disseminated intravascular coagulation; N= normal .

13. DIFFERENCES IN BLEEDING PATTERN
PLATELET DISORDER COAGULATION DISORDER
SITE OF BLEEDING Skin, mucous membrane Deep in soft tissue, joints,
muscles
PETECHIAE yes no
ECCHYMOSES Small, superficial Large, deep
HEMARHTROSIS/ MUSCLE
BLEEDING
Extremely rare common
BLEEDING AFTER SURGERY Immediately, mild Delayed(12 days), severe
EXAMPLES vWD
ITP
Hemophilia A, B

14. COMMON COAGULATION DISORDER
• Haemophilia A and B
• Von- willebrand disease
• Factor VII, X, XII deficiency
• AfibrinogenesisInherited
• Liver disease
• Vit k deficiency/ Hemorrhagic
disease of newborn.
• Warfarin overdose
• DIC
Acquired

15. CLASSIFICATION OF PLATELET DYSFUNCTION
• Bernaud- soulier syndrome
• Glanzmann’s thrombasthenia
• Platelet type VWD
• Mother’s use of antiplatelet agents
Qualitative
• Immune thrombocytopenia
• Neonatal alloimmune thrombocytopenia [NAIT]
• DIC due to infection or asphyxia
• Inherited marrow failure syndromes
• Congenital leukemia
• Heparin induced thrombocytopenia [HIT]
Quantitative

17. Vascular causes of bleeding
• Pulmonary hemorrhage
• CNS hemorrhage
• A-V malformations
• Hemangioma.

18. Miscellaneous problems:
• Trauma:
– rupture of spleen or liver with breech delivery.
– Retroperitoneal or intraperitoneal bleeding may
present as scrotal ecchymosis.
– Subdural hematoma, cephalhematoma, or
subgaleal hemorrhage (maybe asso. with vaccum
extraction)
• Liver dysfunction

19. Presentations in newborn are unique:
EXCESSIVE BLEEDING can appear as
• Expanded cephalhematoma.
• Prolonged bleeding after circumcision.
• Oozing from venipuncture site and line placement site.
• Bleeding from umbilicus .
Sick neonate may present as
• Bleed from bladder –hematuria
• Mucous membrane bleed
• IC bleed
• Pulmonary hemorrhage

20. ON EXAMINATION
• Sick infant – DIC, sepsis, liver diseases
• Well infant – Vit K deficiency ,Clotting factor
deficiency.
• Petechiae, small ecchymosis –platelet disorder
• Deep bruises – clotting factors deficiency, DIC,
liver disorders ,or vit k deficiency
• Splenomegaly – congenital
Infection/erythroblastosis.
• Jaundice – TORCH infections or LIVER disease
• Abnormal retinal finding- TORCH infection

21. Vitamin K Deficiency Bleeding
Type Age Typical site of bleed Cause
Early <24 hrs Intracranial,
gastrointestinal,
intra-abdomenal
Maternal drugs,
inherited
coagulopathy
Classic 2-7 days GIT, mucosal,
umbilical stump,
injection sites
Missing the dose of
Vit K at birth
Late 1-3 months Intracranial, GIT,
skin
Cholestasis,
diarrhea, idiopathic

22. Prevention of Bleeding:
• Give 1 mg Vit K IM at birth to all babies >1.5
kg and 0.5 mg to all babies < 1.5 kg.
• Give 1 mg Vit K weekly to babies on TPN,
broad spectrum antibiotics and sick neonates.
• Give 10 mg Vit K IM/IV to mothers 24 hours
before delivery, who are on drugs like
phenobarbitone, phenytoin, anti-tubercular
drugs or coumarins.

23. Swallowed blood syndrome
• Blood or bloody stools are passed during the 2nd or 3rd day of
life due to swallowing of maternal blood during delivery or
from a fissure in the mother’s nipple .
• It may be confused with hemorrhage from GIT of the newborn .
• The Apt test is used to rule out maternal blood, based on the
fact that the infant’s blood containing hemoglobin mostly HbF
is alkali-resistant where as the maternal blood (Hb A) forms
alkaline hematin on addition of alkali .

24. APT Test:
• Used to rule out maternal blood.
• If the child is well and only GI bleeding is
noted, it is performed on gastric aspirate or
stool to rule out presence of maternal blood
swallowed during labour.
– Mix 1 part bloody stool/ vomitus + 5 parts of
water. Centrifuge and separate clear pink
supernatant. Add 1 ml 1% Na hydroxide to 4 ml
supernatant.
– HbA changes from pink to yellow brown
(maternal); HbF stays pink (fetal).

25. Laboratory tests
TEST FOR PLATELET DISORDER.
• BLEEDING TIME: assesses the function of platelets &
their interaction with vascular wall. (Normal range:4-
8 minutes)
• PLATELET COUNT: normal (150,000-400,000)
• PLATELET FUNCTION ANALYSIS (PFA-100)
• PLATELET AGGREGATION STUDY: with ADP,
Epinephrine, collagen , thromboplastin and
Ristocetin is done.

26. TEST FOR COAGULATION FACTOR
• PTTK: measure the initiation of clotting at level of
intrinsic factor VII,IX,XI (normal 25-40s.)
• PT: measures the extrinsic clotting time i.e.
II,V,VII,X. (12-14s)
• THROMBIN TIME:- measures final step of clotting
cascade. (Normal 11-15 s) prolonged in
fibrinogen deficiency.
• Fibrinogen.
• D-dimer assays.

27. PERIPHERAL BLOOD SMEAR
• Assess the number, size and granulation of
platelets and the presence of fragmented
RBCs’ as seen in DIC.

28. Likely diagnosisPTTKPTPlatelets
Clinical
Evaluation
DICSick
Sepsis, NECNN
Liver diseaseN
Stress bleedNNN
ITP, occult infection, thrombosis, B.M.
hypoplasia or infilterationNNHealthy
Hemorrhagic disease of newborn ( vit. K
deficiency )N
Hereditary clotting factor deficiencies
(Hemoplilia A/B, VWD)
NN
Bleeding due to local factor ( trauma,
anatomic anomalies); Factor XIII
deficiency
NNN
PT = prothrombin time; PTT = partial thromboplastin time; = decreased; = increased; DIC =
disseminated intravascular coagulation; N= normal .

29. Q.
• You are called to evaluate a 2 day old full term
male infant who was noted to have continued
oozing from the circumcision site. The nurse
provides results for CBC and coagulation
studies, which reveals normal platelet count
of 2.2 lac, PT of 12.9 sec (normal for age), and
PTTK of 72 sec (prolonged).

30. Q.
• You are called to evaluate a 12 hour old infant
weighing 3.45 kg born by NVD who was noted
to have petechial rash soon after delivery.
Baby appears well except for scattered
petechie and bruising heel stick and
venepuncture sites. A complete blood count is
obtained, which reveal a platelet count of
80000.

31. Q
• A 12 day old newborn baby
presented with profuse
bleeding from umbilical stump.
No other active bleeding from
any site. Complete blood count:
Hb – 15.2 gm/dl; TLC – 11000;
Platelets – 2.33 lac; PCV – 45;
RBC – 5.1 m/cmm. Coagulation
profile: PT – 12.1 sec; PTTK –
41.6 sec. Probable diagnosis is -

32. • 3 day old male neonate delivered at home to a primi
mother with CGA of 37 weeks, CIAB, Bt.wt 2.8 kg was
brought to OPD with complaints of multiple bruises
over body and 1 episode of vomiting after feeds. On
examination vitals: HR – 132/ min, RR – 42/ min, SpO2
– 96% RA. Most likely positive investigation:
a) Prolonged prothrombin time
b) Defective platelet count
c) Prolonged bleeding time
d) Prolonged thrombin time

33. • Late onset hemorrhagic disease of newborn is
characterized by all of the following features
except –
a) Usually occurs in cow milk fed babies
b) Onset occurs at 4 to 12 weeks
c) Intracranial hemorrhage can occur
d) i.m. Vit K prophylaxis at birth has a protective
role.

34. • Von Willebrands disease all are true except –
a) Factor VIII deficiency
b) BT prolonged
c) Normal Ristocetin test
d) Defective aggregation

35. REFERENCES
• Avery’s neonatology 6th edition, pg no. 1190-
1195.
• Care of the High-Risk Neonate, Klaus & Fanaroff,
6th edition pg no. 432-475
• Manual of neonatal care, john p cloherty
7th edition pg no. 538-545
• Care of newborn ,Meherban Singh
7THEdition pg no. 355-365.
• PGI Handbook of protocols. 4th edition pg no.
176-182.

36. THANK YOU

37. Treatment of Bleeding
• Vitamin K1
– IV/IM dose of 1 mg is given if infant not received Vit K
at birth.
– Infants receiving TPN and infants receiving antibiotics
for > 2 weeks should be given atleast 0.5-1 mg Vit K1
weekly to prevent Vit K depletion.
– Ideally Vit K should be given for long PT and PTTK due
to Vit K deficiency with minimal bleeding, while FFP
should be reserved for significant bleeding or
emergencies because correction with Vit K can take 12
to 48 hours.

38. • FFP
– 10ml/kg is given intravenously for active bleeding
and is repeated every 8 to 12 hours as needed.
– FFP replaces clotting factors immediately.

39. • Platelets
– If there is no increased platelet destruction, 1 unit
(10-15ml/kg) of platelets given to 3 kg infant will
raise platelet count by 50,000 to 1 lac/ mm3.
– if no new platelets are made or transfused,
platelet count will drop slowly over 3 to 5 days.
– The blood of the donor should be matched for Rh
factor and type and washed, because RBCs’ will be
mixed in platelet concentrates.

40. • Clotting factor concentrates:
– When there is a known deficiency of factor VIII or
IX, the plasma concentration should be raised to
normal adult levels to stop serious bleeding.
– Recombinant DNA- derived factors VIII and IX
should be used if diagnosis is clear.
– If severe VWD is considered, a VWF- containing
plasma derived factor VIII concentrate should be
used.
– Cryoprecipitate is the most practical source of
fibrinogen or factor XIII for neonates untill specific
diagnosis is made.

41. (Hereditary Clotting Factor Deficiency)
HEMOPHILIA A OR B
• X-linked recessive disorders; therefore, they affect males
almost exclusively. Reports of affected females are rare.
• Most common inherited clotting disease.
• Hemophilia A and B are inherited bleeding disorders caused by
deficiencies of clotting factor VIII (FVIII) and factor IX (FIX),
respectively.
• They account for 90-95% of severe congenital coagulation
deficiencies.
• Affect all racial groups.

42. • Hemophilias may be undiagnosed in the newborn. It’s
noticed when a child begin to crawl & walk because
mobility causes the initiation of easy bruising,
intramuscular hematoma & hemoarthrosis.
• In the newborn factor VIII level may be artificially elevated
because of acute phase response elicited by the birth
process. In contrast, factor IX level is physiologically low in
the new born.
LABORATORY FINDINGS:
• Reduced level of factor VIII or factor XI.
• Prolonged Clotting time & aPTT.
• Normal Platelet count , BT, PT & thrombin time.
• Prolonged thromboplastin generation time.

43. Von Willebrand disease
• VWD is the commonest inherited bleeding disorder, with an
estimated prevalence of 0.8–1.3%
• Inherited as an Autosomal Dominant disorder.
• Both superficial bleeding problems and ICH have been reported in
affected neonates.
• Type IIb vWD can also be recognized at this time due to the presence
of thrombocytopenia
• Most other forms of vWD are masked by physiologically elevated levels
of vWF and cannot be diagnosed in neonates other than by molecular
analysis
DIAGNOSIS:
• Type III vWD: low levels of both FVIII and vWF.
• Some cases of type II vWD may also be diagnosed in the neonate
where there is reduced vWF activity.

44. Management of DIC
• DIC is a secondary phenomenon ,management is reversal of the
underlying disease process.
• Supportive therapy with FFP, cryoprecipitate and platelets to
maintain adequate hemostasis.
 The platelet count should be maintained above
50000/mm3.
 FFP (10 –15 mL/kg) can be used to replace hemostatic
proteins, including the coagulation inhibitors AT III,
protein C & S.
 Cryoprecipitate (5 –10 ml/kg) is a better source of
fibrinogen, which should be maintained above 1 g/L.
 Red cell concentrates are also frequently required.
• Exchange transfusion may be undertaken in sepsis induced DIC.

45. Disseminated Intravascular Coagulation
• DIC is a clinicopathologic syndrome resulting into widespread
intravascular coagulation induced by procoagulants that are
introduced into or produced in the blood circulation and
overcome the natural anticoagulant mechanisms.
• Baby appears sick and may have petechiae, GI hemorrhage,
oozing from venipunctures, infection, asphyxia, hypoxia.
• Platelet count is decreased, and PT and PTTK are increased.
• Fragmented RBCs’ are seen on PS.
• Fibrinogen decreased and D-dimers are increased.
• Spectrum of DIC includes:
 Thrombosis
 Bleeding
 Progressive organ dysfunction
• The end result is usually hemorrhage.

46. Primary Haemostasis
INJURY
Collagen Exposure
Platelet Adhesion and release
reaction
Platelet aggregation
VASOCONSTRICTION
Serotonin
Thromboxane A2
ADP
Primary haemostatic plug
Bleeding
Time
Primary Haemostasis

47. Secondary Haemostasis
INJURY
Collagen Exposure
Platelet Adhesion and release
reaction
Platelet aggregation
VASOCONSTRICTION
Serotonin Platelet
Phospolipid
Thromboxane A2
ADP
Primary haemostatic plug
Stable haemostatic plug
Tissue Factor
Coagulation
Thrombin
Fibrin
Fibrinolysis
Extrinsic
pathway

48. Clotting factors defects
1) Transitory deficiencies :
Procoagulant Vit K dependent factors 2 ,7, 9, 10 and
anticoagulant protein C and S and may be attenuated by
• Administration of total parenteral nutrition or antibiotics or
lack of administration of Vit K to premature infants.
• Term infant may develop Vit K deficiency by day 2 or 3 if
they are not supplemented Vit K.
• Mother might have received certain drug during pregnancy
that can cause bleeding in first 24hr of infant life like
phenytoin, phenobarb, salicylates, warfarin.

49. 2) Disturbance of clotting :
- may be related to associated disease such as DIC
due to infection, shock ,anoxia, NEC, renal vein
thrombosis, vascular catheter, liver disease.

50. 3) Inherited abnormalities of Clotting Factors
X linked recessive (present in male, affected is
female)
a)Factor 8 levels are decreased in newborn with
hemophilia A (1 in 5000).
b) Heamophilia B or christmas disease is due to
deficiency of factor 9 (1 in 25000)

51. • Autosomal dominant: (expressed in boys and
girl with one parent affected)
– Von willebrand disease is due to decreased levels
or functional activity of VW factor.It is the most
common inherited coagulation defect.
– Dysfibrinogenemia is due to fibrinogen structural
mutation.

52. • Autosomal recessive: (occur in both boys and
girls born to carrier parents)
– Deficiency of factor 11, 7 , 5, 10, 2, fibrinogen and
13 are all encoded by autosomal gene.

53. Extrinsic Pathway
Prothrombin time (PT)
factors VII, X, II, V, and fibrinogen
adding phospholipids and tissue
factor +
citrated plasma (sodium
citrate chelates calcium and prevents
spontaneous clotting)
calcium
Normal~11 to 13 seconds
Because factor VII is the vitamin K
dependent coagulation factor with the
shortest half-life (roughly 7 hours), the
PT is used to guide treatment of patients
with vitamin K antagonists (e.g.,
coumadin).
Intrinsic Pathway
Partial thromboplastin time (PTT)
Factors XII, XI, IX, VIII, X, V, II, and
fibrinogen
Adding a negatively charged
activator of factor XII (e.g., ground
glass) and phospholipids
+
citrated plasma
Calcium
Normal~28 to 35 seconds
Heparin increase aPTT

54. Hematologic consequences to the fetus due to
maternal disease
• Diabetes : polycythemia and thrombosis
• Hypertension : neutropenia, thrombocytopenia
• SLE : thrombocytopenia or thrombosis
• Smoking : polycythemia
• Medications : aspirin  effects on hemostasis
• Chemotherapy  thrombocytopenia
• Intrauterine infection : anemia (hemolytic), thrombocytopenia,
consumptive coagulopathy.

55. • Moderate transient deficiencies of vitamin K dependent factors 2, 7, 9,10
1. Reduced body store of Vit K of the newborn due to lack of free vitamin K in
the mother (more common among the preterm infants).
2. No vitamin K administration after birth. (Breast milk is a poor source of
vitamin K) more common in breast-fed infants than formula-fed ones.
3. Liver immaturity or disease.
4. Malabsorpation disease (biliary atresia, cystic fibrosis, hepatitis).
5. Absence of bacterial intestinal flora (that form vitamin K): Total parenteral
alimentation , Broad spectrum antibiotics.
6. Maternal medication : phenytoin, phenobarbital, salicylates, rifampcin and
isoniazid

56. EARLY HDN
• Least common form.
• The onset: within the first 24 hours of life.
• Bleeding pattern is variable but can be serious,
ICH does occur.
• Typically (not exclusively), associated with the drug ingestion
during pregnancy.
• Warfarin, anticonvulsants and the anti-tuberculous drugs
rifampicin and isoniazid have all been implicated.
MANAGEMENT
• At risk mothers should be given about 10 to 20 mg/day of
vitamin K orally for 15 to 30 days before delivery.
• When Warfarin is to be prescribed it is advised that it is
avoided between wks 6 &12 of gestation(Teratogenic) and
close to term (neonatal bleeding.)

57. CLASSICAL HDN
• Estimates of the frequency of classical VKDB in the absence
of vitamin K prophylaxis vary considerably (0.25 –1.7%) and
depend particularly on the method of feeding employed.
• They are almost exclusively breast-fed.
• Typically presents between days 2 and 5 in infants who
appear otherwise well.
• Bruising, purpura and gastrointestinal hemorrhage are
typical presentation.
• Bleeding from the umbilicus and mucous membranes is also
common, but ICH appears to be relatively infrequent.
MANAGEMENT:-
 I/V or S/C Vit K 1mg
 Transfusion therapy
 Supportive treatment

58. LATE HDN
• Breast-feeding and failure to receive vitamin K
at birth are frequently documented risk
factors.
• Can occur at 4 to 12 weeks of age.
• Infants who are undergoing treatment with
broad spectrum antibiotics or with
malabsorption (Liver disease, Cystic Fibrosis)
• Vit K 1mg/ week for first three months of life
may prevent late HDN.