This document discusses neonatal thrombophilia and procoagulant disorders. It begins by defining thrombophilia as a clinical tendency to thrombosis or molecular abnormalities that predispose to thromboembolic disease. It then discusses various inherited and acquired hypercoagulable states including factor V Leiden mutation, prothrombin gene mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency. It notes that thrombophilia in neonates is a significant problem often associated with predisposing disorders and triggers like sepsis.

1. ‫الرحيم‬ ‫الرحمن‬ ‫ا‬ ‫بسم‬‫الرحيم‬ ‫الرحمن‬ ‫ا‬ ‫بسم‬
Neonatal thrombophiliaNeonatal thrombophilia
Alexandria University ChildrenAlexandria University Children
HospitalHospital

2. An acute ischaemic
limb in a noenate
secondary to a
catheter related
thrombosis.

3. Neonatal procoagulantNeonatal procoagulant
disordersdisorders
Dr Tai Al AkawyDr Tai Al Akawy
Neonatologist & PediatricianNeonatologist & Pediatrician
Alexandria University Children HospitalAlexandria University Children Hospital

4. ThrombophiliaThrombophilia
Is aIs a clinical tendency to thrombosisclinical tendency to thrombosis
OrOr
MolecularMolecular abnomalities of hemostasis thatabnomalities of hemostasis that
predisposes to thromboembolicpredisposes to thromboembolic disease.disease.
A multicausal disease, with an interplay ofA multicausal disease, with an interplay of
acquiredacquired andand geneticgenetic thrombotic riskthrombotic risk
factorsfactors

5. Hypercoagulable statesHypercoagulable states
a group of inherited or acquireda group of inherited or acquired
conditions associated with aconditions associated with a
predisposition to venous thrombosis,predisposition to venous thrombosis,
arterial thrombosis or both.arterial thrombosis or both.

6. 66
ThrombophiliaThrombophilia
ThrombophiliaThrombophilia
iis a technical term fors a technical term for hypercoagulablehypercoagulable statestate
ThrombosisThrombosis
is produced by a shift in the balanceis produced by a shift in the balance
betweenbetween procoagulantprocoagulant andand
profibrynolyticprofibrynolytic systemsystem

7. Profibrynolytic Prothrombotic
Vessel injury
)Favors fluid blood( )Favors clotting(

8. In neonatesIn neonates
ThrombosisThrombosis is a significant problemis a significant problem
affecting both term and preterm infantsaffecting both term and preterm infants
Most neonates that develop thrombosisMost neonates that develop thrombosis
havehave predisposing disorders and triggerspredisposing disorders and triggers
SepsisSepsis is a powerful promoter ofis a powerful promoter of
prothrombotic hemostatic alterationsprothrombotic hemostatic alterations
Genetic thrombophiliaGenetic thrombophilia contributes tocontributes to
thrombotic tendency of newbornthrombotic tendency of newborn

9. Normal hemostasis

13. PhysiologyPhysiology

14. Role of thRombin

15. Abnormal hemostatic mechanismsAbnormal hemostatic mechanisms

17. The concept of a state ofThe concept of a state of
hypercoagulabilityhypercoagulability
dates back todates back to
18541854, when, when
GermanGerman
pathologistpathologist
Rudolph VirchowRudolph Virchow
postulated thatpostulated that
thrombosisthrombosis
resulted fromresulted from threethree
interrelated factorsinterrelated factors

18. Virchow Triad in ThrombosisVirchow Triad in Thrombosis

19. Hemostatic system of neonatesHemostatic system of neonates
HemorrhageHemorrhage > thrombosis> thrombosis
Levels ofLevels of vitamin K dependent clottingvitamin K dependent clotting
factors arefactors are lowlow
Antithrombin, protein C, protein SAntithrombin, protein C, protein S levels arelevels are
lowlow
Decreased fibrinolytic potentialDecreased fibrinolytic potential

20. EpidemiologyEpidemiology
ThrombosisThrombosis occursoccurs more frequentlymore frequently inin
the neonatal periodthe neonatal period than at any otherthan at any other
age in childhood.age in childhood.
2.4 per 1,000 admissions to the2.4 per 1,000 admissions to the
NICU inNICU in CanadaCanada
5.1 per 100,000 live births in5.1 per 100,000 live births in
GermanyGermany
Male and femaleMale and female equalequal
<10% is idiopathic<10% is idiopathic

22. Hemostatic balance

25. 2525
ThrombophiliaThrombophilia
inheritedinherited
acquiredacquired
25

26. 2626
Hereditary thrombophiliaHereditary thrombophilia
A genetically determined increasedA genetically determined increased
risk of thrombosisrisk of thrombosis

27. DEEP VENOUS THROMBOSISDEEP VENOUS THROMBOSIS

29. Results of testing for congenital hypercoagulable states projected for patients with idiopathic deep
venous thrombosis in 2003. APC-R, activated protein C resistance; PT G20210A, prothrombin G20210A

30. 3030
Inherited thrombophiliaInherited thrombophilia
(major causes)(major causes)
-- Factor V Leiden mutationFactor V Leiden mutation
(Resistance to activated protein C)(Resistance to activated protein C)
-- Prothrombin gene mutationProthrombin gene mutation
((Hyperprothrombinemia -Hyperprothrombinemia - prothrombin G20210Aprothrombin G20210A))
-- Protein S deficiencyProtein S deficiency
-- Protein C deficiencyProtein C deficiency
-- Antithrombin (AT) deficiencyAntithrombin (AT) deficiency
-- DysfibrinogenemiaDysfibrinogenemia
-- HyperhomocysteinemiaHyperhomocysteinemia

31. 3131
Factor V Leiden mutationFactor V Leiden mutation
Activated protein C resistanceActivated protein C resistance (APC(APC
resistance)resistance)
Activated protein CActivated protein C promotes enzymaticpromotes enzymatic
degradationdegradation of factorof factor VIIIaVIIIa andand VaVa
The most common cause of inheritedThe most common cause of inherited

32. Factor V Leiden mutationFactor V Leiden mutation
55 % of the population% of the population in Europein Europe areare
heterozygous forheterozygous for FVLFVL
The mutation is not present in AfricanThe mutation is not present in African
Blacks, Chinese, or Japanese populationsBlacks, Chinese, or Japanese populations

33. IIa
E C
IIa IIa
E C
P C
P C
APC
P S +
VaVa
ViVi
VIIIa
VIIIi
TM TM

34. FACTOR V LEIDEN MUTATIONFACTOR V LEIDEN MUTATION

36. CClinical manifestation of factor Vlinical manifestation of factor V
LeidenLeiden
isis deep vein thrombosisdeep vein thrombosis with or withoutwith or without
pulmonary embolismpulmonary embolism
(ie,(ie, venous thromboembolic diseasevenous thromboembolic disease))
tthe mutation is also a risk factor forhe mutation is also a risk factor for
cerebralcerebral,, mesentericmesenteric, and, and portal veinportal vein
thrombosisthrombosis 3636

37. PULMONARY EMBOLISMPULMONARY EMBOLISM
Arrow points to large
clot in pulmonary
artery
Clot dissolved after
administration of
fibrinolytic drug

38. 3838
ProthrombinProthrombin
G20210AG20210A mutationmutation
Prothrombin (factor II)Prothrombin (factor II) is the precursoris the precursor
of thrombinof thrombin
Heterozygous carriers haveHeterozygous carriers have a highera higher
plasma prothrombin levels than normalsplasma prothrombin levels than normals
Heterozygous carriers haveHeterozygous carriers have anan
increased risk of deep vein and cerebralincreased risk of deep vein and cerebral
vein thrombosisvein thrombosis

39. • Mutation in 3' untranslated (non-Mutation in 3' untranslated (non-
coding) part of prothrombin genecoding) part of prothrombin gene
• No effect on prothrombin structure orNo effect on prothrombin structure or
functionfunction
• 150-200%150-200% ↑↑ in prothrombin levelsin prothrombin levels
• AboutAbout 1-2% of population1-2% of population areare
heterozygous;heterozygous;
• 5-7% of young children5-7% of young children with DVT/PEwith DVT/PE
 autosomal dominantautosomal dominant
PROTHROMBIN G20210A GENE MUTATIONPROTHROMBIN G20210A GENE MUTATION

40. 4040
ProteinProtein CC deficiencydeficiency
Protein C is aProtein C is a vitamin K-dependentvitamin K-dependent
proteinprotein synthesized in the liversynthesized in the liver
The primary effect ofThe primary effect of aPCaPC is tois to
inactivateinactivate coagulation factorscoagulation factors VaVa andand
VIIIaVIIIa
The inhibitory effect of aPC is markedlyThe inhibitory effect of aPC is markedly
enhanced byenhanced by protein Sprotein S

41. Protein C Pathway
C4BP
S
inactive
Thrombin
Endothelial surface
PC
Thrombomodulin
S
active APC
Platelet surface
Va Vi
VIIIa VIIIi
PAIa PAIi

42. A - ProteinA - Protein CC
Activated protein C hasActivated protein C has anti FVa & FVIIIaanti FVa & FVIIIa
activityactivity
Activated protein C has alsoActivated protein C has also profibrinolyticprofibrinolytic
acitvityacitvity

43. 4343
ProteinProtein CC deficiencydeficiency
Protein C deficiency is inherited in anProtein C deficiency is inherited in an
autosomal dominantautosomal dominant fashionfashion
Types:Types:
II – decreased synthesis of normal protein– decreased synthesis of normal protein
IIII – production of an abnormally functioning– production of an abnormally functioning
proteinprotein

44. 4444
ProteinProtein CC deficiencydeficiency
clinical manifestationclinical manifestation
-- Venous thromboembolismVenous thromboembolism
- Neonatal purpura fulminansNeonatal purpura fulminans inin
hhomozygousomozygous
-- WarfarinWarfarin-induced skin necrosis-induced skin necrosis
in somein some heterozygousheterozygous
-

45. Digital gangrene in a neonate with protein C deficiency.
Digital gangrene in a neonate with protein C deficiency.

46. HOMOZYGOUS PROTEIN C DEFICIENCYHOMOZYGOUS PROTEIN C DEFICIENCY
CAUSES NEONATAL PURPURA FULMINANSCAUSES NEONATAL PURPURA FULMINANS

47. HOMOZYGOUS PROTEIN C DEFICIENCY CAUSES NEONATAL PURPURAHOMOZYGOUS PROTEIN C DEFICIENCY CAUSES NEONATAL PURPURA
FULMINANSFULMINANS

48. 4848
Protein S (PS) deficiencyProtein S (PS) deficiency
aa vitamin K-dependentvitamin K-dependent glycoproteinglycoprotein
is ais a cofactor of the protein Ccofactor of the protein C systemsystem
only theonly the free formfree form has activatedhas activated
protein C cofactor activityprotein C cofactor activity
In the presence of PSIn the presence of PS, activated, activated
protein C inactivates factorprotein C inactivates factor VaVa andand
factorfactor VIIIaVIIIa

49. PSPS deficiencydeficiency
Autosomal dominantAutosomal dominant inheritanceinheritance
Quantitative and qualitative defectsQuantitative and qualitative defects
HomozygotesHomozygotes die because of thrombosisdie because of thrombosis
„„in uteroin utero” or in the” or in the early infancyearly infancy
Thrombotic phenomena inThrombotic phenomena in adolescenceadolescence
Skin necrosis when warfarin therapySkin necrosis when warfarin therapy
introducedintroduced

50. WARFARIN-INDUCED SKIN NECROSIS IN AWARFARIN-INDUCED SKIN NECROSIS IN A
PROTEIN C-DEFICIENT PATIENTPROTEIN C-DEFICIENT PATIENT

51. 5151
PProtein S deficiencyrotein S deficiency
33 phenotypes of PS deficiency have been definedphenotypes of PS deficiency have been defined
Type IType I
—— reduced synthesisreduced synthesis ofof active proteinactive protein (ie, a(ie, a
quantitative defect)quantitative defect)
Type IIType II
—— normal synthesis of a defective proteinnormal synthesis of a defective protein (ie, a(ie, a
qualitative defect)qualitative defect)
Type IIIType III
—— low levels of free protein S with normal levellow levels of free protein S with normal level
of bound protein Sof bound protein S

54. Clinical featureClinical feature
– HomozygousHomozygous cases presentscases presents as lifeas life
threateningthreatening disorder in neonatal perioddisorder in neonatal period
– Microcirculation is affected firstMicrocirculation is affected first ((purpurapurpura
fulminansfulminans), with features of), with features of DICDIC
– CerebralCerebral andand renalrenal vein thrombosis arevein thrombosis are
also seenalso seen
– OcularOcular manifestationsmanifestations
–Retinal hemorrhageRetinal hemorrhage
–Partial or complete blindnessPartial or complete blindness
Purpura fulminans

56. DiagnosisDiagnosis
DIC screening is positiveDIC screening is positive
PT, APTT, TCT prolongPT, APTT, TCT prolong
Low platelet and fibrinogenLow platelet and fibrinogen
MAHAMAHA
Definitive diagnosis is difficultDefinitive diagnosis is difficult; levels; levels
of PC & PS areof PC & PS are lowlow at birthat birth
Undetectable Proteins activity andUndetectable Proteins activity and
heterozygous levelsheterozygous levels in parentsin parents help inhelp in
diagnosisdiagnosis
Purpura fulminans

57. Neonatal Purpura FulminansNeonatal Purpura Fulminans (Homozygous Protein C(Homozygous Protein C
& S deficiency)& S deficiency)
ManagementManagement
Replacement of deficient factorsReplacement of deficient factors
–Initially FFPInitially FFP
–Now specificNow specific protein C concentratesprotein C concentrates areare
availableavailable
–No protein S concentrate available soNo protein S concentrate available so
FFP is the choiceFFP is the choice
Long term therapyLong term therapy needs to be establishedneeds to be established
and later therapy is replaced by oraland later therapy is replaced by oral
anticoagulantanticoagulant

58. 5858
Antithrombin deficiencyAntithrombin deficiency
ATAT, formerly called AT III, also known as, formerly called AT III, also known as
heparinheparin cofactorcofactor II
isis notnot vitamin K-dependent glycoprotein;vitamin K-dependent glycoprotein;
that is a major inhibitor ofthat is a major inhibitor of thrombinthrombin andand
factorsfactors XaXa andand IXaIXa
ATAT slowlyslowly inactivates thrombininactivates thrombin in thein the
absence ofabsence of heparinheparin

59. ANTITHROMBIN-ANTITHROMBIN-
HEPARINHEPARIN
INHIBITORS OF MULTIPLE STEPS IN THE CLOTTING CASCADEINHIBITORS OF MULTIPLE STEPS IN THE CLOTTING CASCADE
Xa Va
TF VII(a(
IIa
XIIa
XIa
VIIIa IXa
ANTITHROMBIN
HEPARIN
Inhibits all serine protease
clotting factors except VIIa

60. 6060
Antithrombin deficiencyAntithrombin deficiency
Autosomal dominantAutosomal dominant inheritanceinheritance
Quantitative and qualitative defectsQuantitative and qualitative defects
Thrombotic phenomena inThrombotic phenomena in adolescenceadolescence oror
even earlier ineven earlier in neonatesneonates
FrequentlyFrequently pulmonary embolismpulmonary embolism as firstas first
clinical manifestationclinical manifestation

61. InheritedInherited thromboticthrombotic DisordersDisorders
--EarlyEarly age of onset,age of onset,
--SpontaneousSpontaneous thrombotic eventsthrombotic events
--ExtensiveExtensive venous thrombosisvenous thrombosis
--IschemicIschemic skin lesions or purpuraskin lesions or purpura
fulminansfulminans
--A positive familyA positive family H/O neonatalH/O neonatal
purpura fulminanspurpura fulminans

62. 6262
ThrombophiliaThrombophilia
inheritedinherited
acquiredacquired
62

63. 6363
Acquired deficiency of naturalAcquired deficiency of natural
anticoagulantanticoagulant
Acquired AT deficiency
Acquired Protein C deficiency
Acquired Protein S deficiency
- neonatal period
- liver disease
- DIC
- Sepsis

64. Acquired thrombotic disordersAcquired thrombotic disorders
Catheter-related thrombosisCatheter-related thrombosis
Venous thrombosisVenous thrombosis
Arterial thrombosisArterial thrombosis
Non-Catheter-related thrombosisNon-Catheter-related thrombosis
Renal vein thrombosisRenal vein thrombosis
Neonatal strokeNeonatal stroke

68. An acute ischaemic
limb in a noenate
secondary to a
catheter related
thrombosis.

71. Right sided renal vein thrombusRight sided renal vein thrombus

72. Approach to thromboembolismApproach to thromboembolism
In neonatesIn neonates

73. ThrombophiliaThrombophilia
HistoryHistory::
– Family history of such disorderFamily history of such disorder
– MaternalMaternal history ofhistory of SLE and/or anti-SLE and/or anti-
phospholipid synphospholipid syn
– Positive risk factorPositive risk factor
– Drug historyDrug history

74. ThrombophiliaThrombophilia
Physical ExaminationPhysical Examination::
– Assessment of severityAssessment of severity
Area of involvementArea of involvement
Skin color & compare with otherSkin color & compare with other
extremity- whether swollen, cyanotic,extremity- whether swollen, cyanotic,
hyperemic, discolored, distendedhyperemic, discolored, distended
superficial veinsuperficial vein
Pulses of affected extremityPulses of affected extremity
– Presence of any catheterPresence of any catheter
– Assessment of vital organ functionAssessment of vital organ function

76. TESTING FOR INHERITED THROMBOPHILIATESTING FOR INHERITED THROMBOPHILIA
• Young patientYoung patient
• Family historyFamily history
• ThrombosisThrombosis in absence of known riskin absence of known risk
factorsfactors
• Warfarin-induced skin necrosis (protein C)Warfarin-induced skin necrosis (protein C)
• Neonatal purpura fulminans (protein C, S)Neonatal purpura fulminans (protein C, S)
When is it indicated?

78. Laboratory diagnosis of inheritedLaboratory diagnosis of inherited
thrombophiliathrombophilia
First step Second step
AT:
Heparin cofactor synthetic
substrate-based assays
PC:
Synthetic substrate-based
assays
(venoms as a PC activators)
AT:
Immunoassays, crossed
immunoelectrophoresis
DNA analysis
PC:
Immunoassays, crossed
immunoelectrophoresis
DNA analysis

79. Laboratory diagnosis of inheritedLaboratory diagnosis of inherited
thrombophiliathrombophilia
First step Second step
PS:
Immunoassay of total PS
Immunoassay of free PS
APC-resistance:
APTT-based functional
assays
(using FV-deficient
plasma)
PS:
crossed
immunoelectrophoresis
DNA analysis
APC-resistance:
DNA analysis (mutant
factor V)

81. ManagementManagement
(Some limitations)(Some limitations)

82. FactFact
“Recommendations for neonatal treatment are
based on extrapolation of principles of therapy
from adult guidelines, limited clinical
information from registries, individual case
studies, and knowledge of current common
clinical practice*”
*Monagle et al. Antithrombotic therapy in neonates and children: American College
of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest.
2012;141(2)(Suppl):e737s-e801s.

83. Practical pointsPractical points
As neonatal thromboembolism is aAs neonatal thromboembolism is a
multifactorial disorder look formultifactorial disorder look for
underlying diseasesunderlying diseases andand
prothrombotic risk factorsprothrombotic risk factors

84. Management of NeonatalManagement of Neonatal
ThrombosisThrombosis
Supportive careSupportive care
AnticoagulationAnticoagulation
ThrombolysisThrombolysis
SurgerySurgery
CounselingCounseling

85. Supportive care:Supportive care:
– Prompt removal of catheter if possiblePrompt removal of catheter if possible
– Emergency consultationEmergency consultation
– Local careLocal care
– Elevation of footElevation of foot
Treamtent ofTreamtent of
volume depletionvolume depletion
Electrolyte imbalanceElectrolyte imbalance
SepsisSepsis
AnemiaAnemia
ThrombocytopeniaThrombocytopenia

87. Choice of therapyChoice of therapy
**Small asymptomaticSmall asymptomatic non-occlusivenon-occlusive
arterial or venous thrombi related toarterial or venous thrombi related to
catheters:catheters:
Catheter removal and supportive care .Catheter removal and supportive care .
**Large or occlusiveLarge or occlusive arterial /venousarterial /venous
thrombithrombi ::
Anticoagulation with U-heparin or LMWHAnticoagulation with U-heparin or LMWH

88. Choice of therapyChoice of therapy
**MassiveMassive venous thrombi or arterialvenous thrombi or arterial
thrombi:thrombi:
ThrombolysisThrombolysis
SurgerySurgery
[[NBNB- Oral anticoagulant drugs – not- Oral anticoagulant drugs – not
recommnaded for neonate]recommnaded for neonate]

90. AnticoagulationAnticoagulation
Unfractionated heparin:Unfractionated heparin:
– Heparin binds withHeparin binds with antithrombinantithrombin III (AT), causingIII (AT), causing
conformational change thatconformational change that inactivates thrombininactivates thrombin
and other proteases most notably factorand other proteases most notably factor XaXa..
– TargetTarget aPTT level 60-85 secondsaPTT level 60-85 seconds
– Duration 5-14 daysDuration 5-14 days but can be used uptobut can be used upto 33
monthsmonths
– Reversal agentReversal agent protaminprotamin
– ComplicationsComplications : Bleeding, Heparin-induced: Bleeding, Heparin-induced
thrombocytopenia, osteoporosisthrombocytopenia, osteoporosis

91. Unfractionated Heparin Dosage MonitoringUnfractionated Heparin Dosage Monitoring
Dose Check APTT
loading 75 U/Kg After 4 hrs
Maintenance 28 U/Kg/hr Daily or 4 hrs after dose
change
Adjust APTT level as
below:
APTT <50 sec Increase by 20% After 4 hrs
APTT 50-59 sec 10% 4 hrs
APTT 60-85 sec ---------------------- 24 hrs
APTT 86-120 sec Decrease by 10% 4 hrs
APTT >120 Stop for 1 hr then
decrease by 15%
4 hrs

92. LMWH (Enoxaparin)LMWH (Enoxaparin)
– HasHas less effect on thrombinless effect on thrombin compared tocompared to
heparin, but about the same effect onheparin, but about the same effect on
FactorFactor XaXa
– DurationDuration 5 days to 6 months5 days to 6 months
– side effectsside effects : No major bleeds in premature: No major bleeds in premature
neonates, Soreness fromneonates, Soreness from
injection/catheter, leakage, bruising .injection/catheter, leakage, bruising .

93. Before LMWH TreatmentBefore LMWH Treatment

94. After LMWH TreatmentAfter LMWH Treatment

95. Dosage Monitoring and Adjustment of LMWHDosage Monitoring and Adjustment of LMWH
LMW
Heparin(ENOX
APARIN)
Dose 1.5 mg/kg/dose twice daily
Monitoring anti-factor Xa Level (Therapeutic level is 0.5—
1.0 U/ml)
Check 4 hrs after first dose( if in therapeutic
range check once weekly)
If dose adjusted recheck after 4 hrs.
If <0.35 units/ml , Increase by 25%
If 0.35-0.49 U/ml , increase by 10%
If 1.1 -2 U/ml, decrease by 20-30%
If >2 U/ml withhold until <0.5 & restart at
40% of original dose.

96. Comparison of UFH and LMWHComparison of UFH and LMWH
U-Heparin LMWH
1. Requires IV access
2. Short term
anticoagulation
(3 days to 3 weeks)
3. More side effects
4. needs continuous
monitroing
1. Subcutaneous
injection
2. Long term
anticoagulation
( upto 6 months)
3. Fewer side effects
4. Needs less monitoring

97. Goal-Goal-
to degrade fibrinto degrade fibrin
dissolve fibrin clotdissolve fibrin clot
IndicationIndication: Not recommended unless: Not recommended unless
major vessel occlusionmajor vessel occlusion causingcausing criticalcritical
organ or limb compromiseorgan or limb compromise
Thrombolytic TherapyThrombolytic Therapy

98. Thrombolytic TherapyThrombolytic Therapy
OutcomeOutcome: In older children vascular: In older children vascular
patencypatency 50% with anticoagulant therapy50% with anticoagulant therapy,,
followingfollowing thrombolytic therapythrombolytic therapy > 90%> 90%
If thrombolytic treatmentIf thrombolytic treatment >24 hours, there>24 hours, there
will increased risk of bleedingwill increased risk of bleeding
Treatment with heparinTreatment with heparin after thrombolyticafter thrombolytic
therapy is recommendedtherapy is recommended

99. Thrombolytic AgentsThrombolytic Agents
tPAtPA ::
No loading doseNo loading dose
0.1-0.6 mg/kg/h over 6 h0.1-0.6 mg/kg/h over 6 h
followed by heparinfollowed by heparin
StreptokinaseStreptokinase::
Loading-2,000 U/kg over 10 min thenLoading-2,000 U/kg over 10 min then
1,000-2,000 U/kg/h .Only one course1,000-2,000 U/kg/h .Only one course
should be given for 6 hshould be given for 6 h
Urokinase

100. Contraindications toContraindications to
Thrombolytic/AnticoagulationThrombolytic/Anticoagulation
TherapyTherapy
AbsoluteAbsolute
–CNS surgery or ischemiaCNS surgery or ischemia (including(including
birth asphyxia) within 10 daysbirth asphyxia) within 10 days
–Active bleedingActive bleeding
–Invasive proceduresInvasive procedures within 72 hourswithin 72 hours
–SeizuresSeizures within 48 hourswithin 48 hours

101. RelativeRelative
–Platelet count < 50000/cmmPlatelet count < 50000/cmm
(100000/cmm for ill neonates)(100000/cmm for ill neonates)
–Fibrinogen concentration <Fibrinogen concentration <
100mg/dL100mg/dL
–Severe coagulation deficiencySevere coagulation deficiency
–HypertensionHypertension

104. Surgical thrombectomySurgical thrombectomy
Not done in majority of neonatesNot done in majority of neonates
Microsurgery with thrombolytic regimen isMicrosurgery with thrombolytic regimen is
successfully used insuccessfully used in few isolated casesfew isolated cases

105. ConclusionsConclusions
Lack of randomized trialsLack of randomized trials
addressing neonatal thrombosisaddressing neonatal thrombosis
force neonatologists to baseforce neonatologists to base
decisions ondecisions on limited evidencelimited evidence
Treat effectively without causingTreat effectively without causing
harmharm

107. REFERENCESREFERENCES
1. Schmidt B & Andrew M. Neonatal thrombosis: report of a1. Schmidt B & Andrew M. Neonatal thrombosis: report of a
prospective Canadian and international registry. Pediatrics 1995; 95:prospective Canadian and international registry. Pediatrics 1995; 95:
936–943.936–943.
2. Nowak-Go¨ttl U, von Kries R & Go¨bel U. Neonatal symptomatic2. Nowak-Go¨ttl U, von Kries R & Go¨bel U. Neonatal symptomatic
thromboembolism in Germany: two year survey. Archives of Diseasethromboembolism in Germany: two year survey. Archives of Disease
in Childhood 1997; 76: F163–F167.in Childhood 1997; 76: F163–F167.
3. van Ommen H, Heijboer H, Bu¨ller HR et al. Venous3. van Ommen H, Heijboer H, Bu¨ller HR et al. Venous
thromboembolism in childhood: a prospective twoyear registry inthromboembolism in childhood: a prospective twoyear registry in
The Netherlands. Journal of Pediatrics 2001; 139: 676–681.The Netherlands. Journal of Pediatrics 2001; 139: 676–681.
4. Andrew M. Developmental hemostasis: relevance to4. Andrew M. Developmental hemostasis: relevance to
thromboembolic complications in pediatric patients.Thrombosis andthromboembolic complications in pediatric patients.Thrombosis and
Haemostasis 1995; 74: 415–425.Haemostasis 1995; 74: 415–425.
5. Brenner B, Sarig G, Wiener Z et al. Thrombophilic polymorphisms5. Brenner B, Sarig G, Wiener Z et al. Thrombophilic polymorphisms
are common in women with fetal loss without apparent cause.are common in women with fetal loss without apparent cause.
Thrombosis and Haemostasis 1999; 82: 6–9.Thrombosis and Haemostasis 1999; 82: 6–9.

108. 6. Dizon-Townson DS, Meline L, Nelson LM et al. Foetal carriers of6. Dizon-Townson DS, Meline L, Nelson LM et al. Foetal carriers of
the factor V Leiden are prone to miscarriage and placentalthe factor V Leiden are prone to miscarriage and placental
infarction. American Journal of Obstetrics and Gynecology 1997;infarction. American Journal of Obstetrics and Gynecology 1997;
177: 402–405.177: 402–405.
7. Berg K, Roland B & Sande H. High Lp(a) lipoprotein level in7. Berg K, Roland B & Sande H. High Lp(a) lipoprotein level in
maternal serum may interfere with placental circulation and causematernal serum may interfere with placental circulation and cause
fetal growth retardation. Clinical Genetics 1994; 46: 52–56.fetal growth retardation. Clinical Genetics 1994; 46: 52–56.
8. Pabinger I, Grafenhofer H, Kaider A et al. Preeclampsia and fetal8. Pabinger I, Grafenhofer H, Kaider A et al. Preeclampsia and fetal
loss in women with a history of venous thromboembolism.loss in women with a history of venous thromboembolism.
Arteriosclerosis, Thrombosis and Vascular Biology 2001; 21: 874–Arteriosclerosis, Thrombosis and Vascular Biology 2001; 21: 874–
879.879.
9. Go¨pel W, Kim D & Gortner L. Prothrombotic mutations as a risk9. Go¨pel W, Kim D & Gortner L. Prothrombotic mutations as a risk
factor for preterm birth. Lancet 1999;353: 1411–1412factor for preterm birth. Lancet 1999;353: 1411–1412

109. 10. Kraus FT & Acheen VI. Fetal thrombotic vasculopathy in the10. Kraus FT & Acheen VI. Fetal thrombotic vasculopathy in the
placenta: cerebral thrombi and infarcts,coagulopathies, and cerebralplacenta: cerebral thrombi and infarcts,coagulopathies, and cerebral
palsy. Human Pathology 1999; 30: 759–769.palsy. Human Pathology 1999; 30: 759–769.
11. Debus O, Koch HG, Kurlemann G et al. Factor V Leiden and11. Debus O, Koch HG, Kurlemann G et al. Factor V Leiden and
genetic defects of thrombophilia in childhood porencephaly.genetic defects of thrombophilia in childhood porencephaly.
Archives of Disease in Childhood 1998; 78: F121–F124.Archives of Disease in Childhood 1998; 78: F121–F124.
12. Manual of neonatal care 2012.12. Manual of neonatal care 2012.