الرحيم الرحمن الله الرحيم بسم الرحمن الله بسم

Neonatal thrombophiliaNeonatal thrombophiliaAlexandria University Children Alexandria University Children

HospitalHospital

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

Neonatal procoagulant Neonatal procoagulant disordersdisorders

Dr Tai Al AkawyDr Tai Al AkawyNeonatologist & PediatricianNeonatologist & Pediatrician

Alexandria University Children HospitalAlexandria University Children Hospital

ThrombophiliaThrombophilia

Is a Is a clinical tendency to thrombosis clinical tendency to thrombosis OrOr

Molecular Molecular abnomalities of hemostasis that abnomalities of hemostasis that predisposes to thromboembolic predisposes to thromboembolic disease.disease.A multicausal disease, with an interplay of A multicausal disease, with an interplay of acquiredacquired and and geneticgenetic thrombotic risk thrombotic risk factorsfactors

Hypercoagulable statesHypercoagulable states

a group of inherited or acquired a group of inherited or acquired conditions associated with a conditions associated with a predisposition to venous thrombosis, predisposition to venous thrombosis, arterial thrombosis or both.arterial thrombosis or both.

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ThrombophiliaThrombophilia

ThrombophiliaThrombophilia

iis a technical term for s a technical term for hypercoagulable hypercoagulable statestate

ThrombosisThrombosis

is produced by a shift in the balance is produced by a shift in the balance

between between procoagulant procoagulant and and

profibrynolytic profibrynolytic systemsystem

Profibrynolytic Prothrombotic

Vessel injury

(Favors fluid blood) (Favors clotting)

In neonatesIn neonates

ThrombosisThrombosis is a significant problem affecting is a significant problem affecting both term and preterm infants both term and preterm infants

Most neonates that develop thrombosis have Most neonates that develop thrombosis have predisposing disorders and triggers predisposing disorders and triggers

SepsisSepsis is a powerful promoter of prothrombotic is a powerful promoter of prothrombotic hemostatic alterations hemostatic alterations

Genetic thrombophilia Genetic thrombophilia contributes to thrombotic contributes to thrombotic tendency of newborntendency of newborn

Normal hemostasis

PhysiologyPhysiology

Role of thrombin

Abnormal hemostatic mechanisms Abnormal hemostatic mechanisms

The concept of a state ofThe concept of a state of

hypercoagulability hypercoagulability dates back to 1854dates back to 1854, , when German when German pathologist pathologist Rudolph Rudolph VirchowVirchow postulated postulated that thrombosis that thrombosis resulted from resulted from three three interrelated factorsinterrelated factors

Virchow Triad in ThrombosisVirchow Triad in Thrombosis

Hemostatic system of neonates Hemostatic system of neonates

HemorrhageHemorrhage > thrombosis > thrombosisLevels of Levels of vitamin K dependent clotting vitamin K dependent clotting factors are factors are lowlowAntithrombin, protein C, protein S Antithrombin, protein C, protein S levels are levels are lowlowDecreased fibrinolytic potentialDecreased fibrinolytic potential

Epidemiology Epidemiology ThrombosisThrombosis occurs occurs more frequently more frequently in in the neonatal period the neonatal period than at any other than at any other age in childhood.age in childhood. 2.4 per 1,000 admissions to the NICU 2.4 per 1,000 admissions to the NICU in in CanadaCanada 5.1 per 100,000 live births in 5.1 per 100,000 live births in GermanyGermany Male and female Male and female equalequal<10% is idiopathic<10% is idiopathic

Hemostatic balance

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ThrombophiliaThrombophilia

inheritedinherited

acquiredacquired

25

2626

Hereditary thrombophiliaHereditary thrombophilia

A genetically determined increased A genetically determined increased

risk of thrombosisrisk of thrombosis

DEEP VENOUS THROMBOSISDEEP VENOUS THROMBOSIS

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

mutation.

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Inherited thrombophiliaInherited thrombophilia)major causes()major causes(

- - Factor V Leiden mutation Factor V Leiden mutation )Resistance to activated protein C()Resistance to activated protein C(

- - Prothrombin gene mutation Prothrombin gene mutation ))Hyperprothrombinemia -Hyperprothrombinemia - prothrombin G20210Aprothrombin G20210A((

- - Protein S deficiencyProtein S deficiency

- - Protein C deficiencyProtein C deficiency

- - Antithrombin )AT( deficiencyAntithrombin )AT( deficiency

- - Dysfibrinogenemia Dysfibrinogenemia

- - HyperhomocysteinemiaHyperhomocysteinemia

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Factor V Leiden mutationFactor V Leiden mutation

Activated protein C resistance Activated protein C resistance )APC resistance()APC resistance(

Activated protein C Activated protein C promotes enzymatic promotes enzymatic

degradation degradation of factor of factor VIIIaVIIIa and and Va Va

The most common cause of inherited The most common cause of inherited

thrombophilia thrombophilia )40-50%()40-50%(

Factor V Leiden mutationFactor V Leiden mutation

5 5 % of the population % of the population in Europe in Europe are are

heterozygous for heterozygous for FVLFVL

The mutation is not present in African The mutation is not present in African

Blacks, Chinese, or Japanese populationsBlacks, Chinese, or Japanese populations

IIa

E C

IIa IIa

E C

P C

P C

APC

P S +

VaVaViVi

VIIIa

VIIIi

TM TM

FACTOR V LEIDEN MUTATIONFACTOR V LEIDEN MUTATION

CClinical manifestation of factor V linical manifestation of factor V LeidenLeiden

is is deep vein thrombosis deep vein thrombosis with or without with or without

pulmonary embolism pulmonary embolism

)ie, )ie, venous thromboembolic diseasevenous thromboembolic disease((

tthe mutation is also a risk factor for he mutation is also a risk factor for cerebralcerebral, ,

mesentericmesenteric, and , and portal vein thrombosis portal vein thrombosis

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PULMONARY EMBOLISMPULMONARY EMBOLISM

Arrow points to large clot in pulmonary

artery

Clot dissolved after administration of fibrinolytic drug

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Prothrombin Prothrombin G20210AG20210A  mutationmutation

Prothrombin )factor II( Prothrombin )factor II( is the precursor is the precursor

of thrombinof thrombin

Heterozygous carriers have Heterozygous carriers have a higher a higher

plasma prothrombin levels than normalsplasma prothrombin levels than normals

Heterozygous carriers have Heterozygous carriers have an an

increased risk of deep vein and cerebral increased risk of deep vein and cerebral

vein thrombosis vein thrombosis

• Mutation in 3' untranslated )non-coding( Mutation in 3' untranslated )non-coding( part of prothrombin genepart of prothrombin gene

• No effect on prothrombin structure or No effect on prothrombin structure or functionfunction

• 150-200% 150-200% in prothrombin levels in prothrombin levels• About About 1-2% of population 1-2% of population are are

heterozygous; heterozygous; • 5-7% of young children5-7% of young children with DVT/PE with DVT/PE autosomal dominantautosomal dominant

PROTHROMBIN G20210A GENE MUTATIONPROTHROMBIN G20210A GENE MUTATION

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Protein Protein CC deficiency deficiency

Protein C is a Protein C is a vitamin K-dependent vitamin K-dependent

protein protein synthesized in the liversynthesized in the liver

The primary effect of The primary effect of aPCaPC is to is to inactivateinactivate

coagulation factors coagulation factors VaVa and and VIIIaVIIIa

The inhibitory effect of aPC is markedly The inhibitory effect of aPC is markedly

enhanced by enhanced by protein Sprotein S

Protein C Pathway

C4BP Sinactive

Thrombin

Endothelial surface

PC

Thrombomodulin

Sactive APC

Platelet surface

Va Vi

VIIIa VIIIi

PAIa PAIi

A - Protein A - Protein CC

Activated protein C has Activated protein C has anti FVa & FVIIIa anti FVa & FVIIIa activityactivityActivated protein C has also Activated protein C has also profibrinolytic profibrinolytic acitvityacitvity

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Protein Protein CC deficiencydeficiencyProtein C deficiency is inherited in an Protein C deficiency is inherited in an

autosomal dominant autosomal dominant fashionfashion

Types:Types:

I I – decreased synthesis of normal protein– decreased synthesis of normal protein

II II – production of an abnormally functioning – production of an abnormally functioning

proteinprotein

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Protein Protein CC deficiency deficiency

clinical manifestationclinical manifestation

- - Venous thromboembolism Venous thromboembolism

- Neonatal purpura fulminans Neonatal purpura fulminans in in

hhomozygous omozygous

- Warfarin-induced skin necrosis -induced skin necrosis

in some in some heterozygousheterozygous

-

Digital gangrene in a neonate with protein C deficiency.

Digital gangrene in a neonate with protein C deficiency.

HOMOZYGOUS PROTEIN C DEFICIENCY HOMOZYGOUS PROTEIN C DEFICIENCY CAUSES NEONATAL PURPURA FULMINANSCAUSES NEONATAL PURPURA FULMINANS

HOMOZYGOUS PROTEIN C DEFICIENCY CAUSES NEONATAL PURPURA HOMOZYGOUS PROTEIN C DEFICIENCY CAUSES NEONATAL PURPURA FULMINANSFULMINANS

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Protein S )PS( deficiencyProtein S )PS( deficiency

a a vitamin K-dependent vitamin K-dependent glycoproteinglycoproteinis a is a cofactor of the protein C cofactor of the protein C systemsystemonly the only the free form free form has activated protein has activated protein C cofactor activityC cofactor activity In the presence of PSIn the presence of PS, activated , activated protein C inactivates factor protein C inactivates factor VaVa and and factor factor VIIIaVIIIa

PSPS deficiency deficiency

Autosomal dominant Autosomal dominant inheritanceinheritanceQuantitative and qualitative defectsQuantitative and qualitative defectsHomozygotesHomozygotes die because of thrombosis die because of thrombosis „„in uteroin utero” or in the ” or in the early infancyearly infancyThrombotic phenomena in Thrombotic phenomena in adolescenceadolescence Skin necrosis when warfarin therapy Skin necrosis when warfarin therapy introducedintroduced

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

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PProtein S deficiencyrotein S deficiency33 phenotypes of PS deficiency have been defined phenotypes of PS deficiency have been defined

Type IType I  — — reduced synthesis reduced synthesis ofof active protein active protein )ie, a )ie, a quantitative defect( quantitative defect(

Type IIType II  — — normal synthesis of a defective protein normal synthesis of a defective protein )ie, a )ie, a qualitative defect(qualitative defect(

Type IIIType III  — — low levels of free protein S with normal level of low levels of free protein S with normal level of bound protein S bound protein S

Clinical featureClinical feature– HomozygousHomozygous cases presents cases presents as life as life

threateningthreatening disorder in neonatal period disorder in neonatal period– Microcirculation is affected first Microcirculation is affected first ))purpura purpura

fulminansfulminans(, with features of (, with features of DICDIC– CerebralCerebral and and renalrenal vein thrombosis are vein thrombosis are

also seenalso seen– OcularOcular manifestations manifestations

–Retinal hemorrhageRetinal hemorrhage–Partial or complete blindnessPartial or complete blindness

Purpura fulminans

DiagnosisDiagnosisDIC screening is positiveDIC screening is positive

PT, APTT, TCT prolongPT, APTT, TCT prolongLow platelet and fibrinogenLow platelet and fibrinogenMAHAMAHA

Definitive diagnosis is difficultDefinitive diagnosis is difficult; levels ; levels of PC & PS are of PC & PS are lowlow at birth at birthUndetectable Proteins activity and Undetectable Proteins activity and heterozygous levels heterozygous levels in parents in parents help in help in diagnosisdiagnosis

Purpura fulminans

Neonatal Purpura Fulminans Neonatal Purpura Fulminans )Homozygous Protein C )Homozygous Protein C & S deficiency(& S deficiency(

ManagementManagementReplacement of deficient factorsReplacement of deficient factors

– Initially FFPInitially FFP–Now specific Now specific protein C concentrates protein C concentrates are are

availableavailable–No protein S concentrate available so FFP is No protein S concentrate available so FFP is

the choicethe choiceLong term therapy Long term therapy needs to be established and needs to be established and later therapy is replaced by oral anticoagulantlater therapy is replaced by oral anticoagulant

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Antithrombin deficiencyAntithrombin deficiencyATAT, formerly called AT III, also known as , formerly called AT III, also known as heparin cofactor cofactor II

is is notnot vitamin K-dependent glycoprotein; vitamin K-dependent glycoprotein;

that is a major inhibitor of that is a major inhibitor of thrombinthrombin and and factors factors XaXa and and IXa IXa

AT AT slowlyslowly inactivates thrombin inactivates thrombin in the in the

absence of absence of heparin  

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

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Antithrombin deficiencyAntithrombin deficiency

Autosomal dominant Autosomal dominant inheritanceinheritance

Quantitative and qualitative defectsQuantitative and qualitative defects

Thrombotic phenomena in Thrombotic phenomena in adolescenceadolescence or or

even earlier in even earlier in neonatesneonates

Frequently Frequently pulmonary embolism pulmonary embolism as first as first

clinical manifestationclinical manifestation

Inherited Inherited thromboticthrombotic Disorders Disorders--EarlyEarly age of onset, age of onset, --SpontaneousSpontaneous thrombotic events thrombotic events --ExtensiveExtensive venous thrombosis venous thrombosis --IschemicIschemic skin lesions or purpura skin lesions or purpura

fulminansfulminans --A positive family A positive family H/O neonatal H/O neonatal

purpura fulminanspurpura fulminans

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ThrombophiliaThrombophilia

inheritedinherited

acquiredacquired

62

6363

Acquired deficiency of natural Acquired deficiency of natural anticoagulantanticoagulant

Acquired AT deficiencyAcquired Protein C deficiencyAcquired Protein S deficiency

- neonatal period - liver disease - DIC - Sepsis

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

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

Right sided renal vein thrombusRight sided renal vein thrombus

Approach to thromboembolismApproach to thromboembolism

In neonatesIn neonates

ThrombophiliaThrombophilia

HistoryHistory::– Family history of such disorderFamily history of such disorder– MaternalMaternal history of history of SLE and/or anti-SLE and/or anti-

phospholipid synphospholipid syn– Positive risk factorPositive risk factor– Drug historyDrug history

ThrombophiliaThrombophiliaPhysical ExaminationPhysical Examination::– Assessment of severityAssessment of severity

Area of involvementArea of involvementSkin color & compare with other Skin color & compare with other extremity- whether swollen, cyanotic, extremity- whether swollen, cyanotic, hyperemic, discolored, distended hyperemic, discolored, distended superficial veinsuperficial veinPulses of affected extremityPulses of affected extremity

– Presence of any catheterPresence of any catheter– Assessment of vital organ functionAssessment of vital organ function

TESTING FOR INHERITED THROMBOPHILIATESTING FOR INHERITED THROMBOPHILIA

• Young patientYoung patient• Family historyFamily history• Thrombosis Thrombosis in absence of known risk in 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?

Laboratory diagnosis of inherited Laboratory diagnosis of inherited thrombophiliathrombophilia

First stepSecond step

AT: Heparin cofactor synthetic substrate-based assays

PC:Synthetic substrate-based assays)venoms as a PC activators(

AT:Immunoassays, crossed immunoelectrophoresisDNA analysis PC:Immunoassays, crossed immunoelectrophoresisDNA analysis

Laboratory diagnosis of inherited Laboratory diagnosis of inherited thrombophilia thrombophilia

First stepSecond step

PS: Immunoassay of total PSImmunoassay of free PS

APC-resistance:APTT-based functional assays)using FV-deficient plasma(

PS:crossed immunoelectrophoresisDNA analysis

APC-resistance:DNA analysis )mutant factor V(

ManagementManagement

)Some limitations()Some limitations(

Fact Fact

“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 .

Practical pointsPractical points

As neonatal thromboembolism is a As neonatal thromboembolism is a multifactorial disorder look for multifactorial disorder look for

underlying diseases underlying diseases and and prothrombotic risk factorsprothrombotic risk factors

Management of Neonatal Management of Neonatal ThrombosisThrombosis

Supportive careSupportive careAnticoagulation Anticoagulation ThrombolysisThrombolysisSurgerySurgeryCounselingCounseling

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 of Treamtent of volume depletion volume depletion Electrolyte imbalanceElectrolyte imbalanceSepsisSepsisAnemiaAnemiaThrombocytopeniaThrombocytopenia

Choice of therapyChoice of therapy **Small asymptomaticSmall asymptomatic non-occlusivenon-occlusive

arterial or venous thrombi related to arterial or venous thrombi related to catheters:catheters:

Catheter removal and supportive care .Catheter removal and supportive care . **Large or occlusive Large or occlusive arterial /venous arterial /venous

thrombi thrombi :: Anticoagulation with U-heparin or LMWHAnticoagulation with U-heparin or LMWH

Choice of therapyChoice of therapy

**MassiveMassive venous thrombi or arterial venous thrombi or arterial thrombi:thrombi:

Thrombolysis Thrombolysis SurgerySurgery [[NBNB- Oral anticoagulant drugs – not - Oral anticoagulant drugs – not recommnaded for neonate]recommnaded for neonate]

AnticoagulationAnticoagulationUnfractionated heparin:Unfractionated heparin:– Heparin binds with Heparin binds with antithrombin antithrombin III )AT(, causing III )AT(, causing

conformational change that conformational change that inactivates thrombin inactivates thrombin and other proteases most notably factor and other proteases most notably factor XaXa. .

– Target Target aPTT level 60-85 secondsaPTT level 60-85 seconds– Duration 5-14 days Duration 5-14 days but can be used upto but can be used upto 3 3

monthsmonths– Reversal agent Reversal agent protaminprotamin– ComplicationsComplications : Bleeding, Heparin-induced : Bleeding, Heparin-induced

thrombocytopenia, osteoporosis thrombocytopenia, osteoporosis

Unfractionated Heparin Dosage MonitoringUnfractionated Heparin Dosage MonitoringDoseCheck APTT

loading75 U/KgAfter 4 hrsMaintenance28 U/Kg/hrDaily or 4 hrs after dose

changeAdjust APTT level as below:

APTT <50 secIncrease by 20%After 4 hrsAPTT 50-59 sec 10% 4 hrs

APTT 60-85 sec---------------------- 24 hrsAPTT 86-120 secDecrease by 10% 4 hrsAPTT >120Stop for 1 hr then

decrease by 15% 4 hrs

LMWH )Enoxaparin(LMWH )Enoxaparin(– Has Has less effect on thrombin less effect on thrombin compared to compared to

heparin, but about the same effect on heparin, but about the same effect on Factor Factor XaXa

– Duration Duration 5 days to 6 months5 days to 6 months– side effects side effects : No major bleeds in premature : No major bleeds in premature

neonates, Soreness from neonates, Soreness from injection/catheter, leakage, bruising .injection/catheter, leakage, bruising .

Before LMWH TreatmentBefore LMWH Treatment

After LMWH TreatmentAfter LMWH Treatment

Dosage Monitoring and Adjustment of LMWHDosage Monitoring and Adjustment of LMWH

LMW Heparin)ENOXAPARIN(Dose1.5 mg/kg/dose twice dailyMonitoring 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.

Comparison of UFH and LMWHComparison of UFH and LMWH

U-HeparinLMWH

1. Requires IV access

2. Short term anticoagulation

)3 days to 3 weeks(

3. More side effects 4. needs continuous

monitroing

1. Subcutaneous injection2. Long term anticoagulation) upto 6 months(

3. Fewer side effects4. Needs less monitoring

Goal- Goal- to degrade fibrinto degrade fibrindissolve fibrin clotdissolve fibrin clot

IndicationIndication: Not recommended unless : Not recommended unless major vessel occlusion major vessel occlusion causing causing critical critical organ or limb compromiseorgan or limb compromise

Thrombolytic TherapyThrombolytic Therapy

Thrombolytic TherapyThrombolytic Therapy

OutcomeOutcome: In older children vascular : In older children vascular patency patency 50% with anticoagulant therapy50% with anticoagulant therapy, , following following thrombolytic therapythrombolytic therapy > 90%> 90%

If thrombolytic treatment If thrombolytic treatment >24 hours, there >24 hours, there will increased risk of bleedingwill increased risk of bleeding

Treatment with heparin Treatment with heparin after thrombolytic after thrombolytic therapy is recommendedtherapy is recommended

Thrombolytic Agents Thrombolytic Agents tPA tPA :: No loading dose No 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 course should be 1,000-2,000 U/kg/h .Only one course should be

given for 6 hgiven for 6 h UrokinaseUrokinase

Contraindications to Contraindications to Thrombolytic/Anticoagulation Thrombolytic/Anticoagulation

TherapyTherapy

AbsoluteAbsolute–CNS surgery or ischemia CNS surgery or ischemia )including birth )including birth

asphyxia( within 10 daysasphyxia( within 10 days–Active bleedingActive bleeding–Invasive procedures Invasive procedures within 72 hourswithin 72 hours–SeizuresSeizures within 48 hours within 48 hours

RelativeRelative–Platelet count < 50000/cmm Platelet 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

Surgical thrombectomySurgical thrombectomy

Not done in majority of neonates Not done in majority of neonates Microsurgery with thrombolytic regimen is Microsurgery with thrombolytic regimen is successfully used in successfully used in few isolated casesfew isolated cases

ConclusionsConclusions

Lack of randomized trials Lack of randomized trials addressing neonatal thrombosis addressing neonatal thrombosis force neonatologists to base force neonatologists to base decisions on decisions on limited evidence limited evidence

Treat effectively without causing Treat effectively without causing harmharm

REFERENCESREFERENCES1. Schmidt B & Andrew M. Neonatal thrombosis: report of a prospective 1. Schmidt B & Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 95: 936–943.Canadian and international registry. Pediatrics 1995; 95: 936–943.2. Nowak-Go¨ttl U, von Kries R & Go¨bel U. Neonatal symptomatic 2. Nowak-Go¨ttl U, von Kries R & Go¨bel U. Neonatal symptomatic thromboembolism in Germany: two year survey. Archives of Disease in thromboembolism in Germany: two year survey. Archives of Disease in Childhood 1997; 76: F163–F167.Childhood 1997; 76: F163–F167.3. van Ommen H, Heijboer H, Bu¨ller HR et al. Venous 3. van Ommen H, Heijboer H, Bu¨ller HR et al. Venous thromboembolism in childhood: a prospective twoyear registry in The thromboembolism in childhood: a prospective twoyear registry in The Netherlands. Journal of Pediatrics 2001; 139: 676–681.Netherlands. Journal of Pediatrics 2001; 139: 676–681.4. Andrew M. Developmental hemostasis: relevance to thromboembolic 4. Andrew M. Developmental hemostasis: relevance to thromboembolic complications in pediatric patients.Thrombosis and Haemostasis 1995; complications in pediatric patients.Thrombosis and Haemostasis 1995; 74: 415–425.74: 415–425.5. Brenner B, Sarig G, Wiener Z et al. Thrombophilic polymorphisms 5. 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.

6. Dizon-Townson DS, Meline L, Nelson LM et al. Foetal carriers of 6. Dizon-Townson DS, Meline L, Nelson LM et al. Foetal carriers of the factor V Leiden are prone to miscarriage and placental the 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 in 7. Berg K, Roland B & Sande H. High Lp)a( lipoprotein level in maternal serum may interfere with placental circulation and cause maternal 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 fetal 8. 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 risk 9. 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

10. Kraus FT & Acheen VI. Fetal thrombotic vasculopathy in the 10. Kraus FT & Acheen VI. Fetal thrombotic vasculopathy in the placenta: cerebral thrombi and infarcts,coagulopathies, and cerebral placenta: 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 and 11. 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.